Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV‐related disease in females and males

Summary of findings for the main comparison. Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females

Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females
Patient or population: 9‐ to 15‐year‐old females Setting: community health centres in Africa, Asia Pacific, Europe, Latin America, North America Intervention: two doses of HPV vaccine (bivalent, quadrivalent, or nonavalent) administered in months 0 and 2, 0 and 6, or 0 and 12 Comparison: three doses of HPV vaccine (bivalent, quadrivalent, or nonavalent) administered in months 0, 2, and 6, or 0, 1, and 6
Clinical and harms outcomes^*	Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with three doses of HPV vaccine	Risk with two doses of HPV vaccine
Antibody response (immunogenicity)	Two doses were non‐inferior to, or had higher GMTs than, three doses for all HPV vaccine genotypes (bivalent, quadrivalent, and nonavalent vaccines), except HPV 45 (where non‐inferiority was inconclusive), at short‐term follow‐up (4 studies, number of participants ranged from 132 to 1833 depending on HPV type and vaccine; see Appendix 5).				MODERATE/ HIGH*	Short‐term results (follow‐up 1 month after final dose)
	Two doses of bivalent vaccine had inconclusive non‐inferiority for GMTs of HPV 16 and HPV 18 compared with three doses at 60‐month follow‐up (1 study, 93 participants; see Appendix 5).				LOW*	Long‐term results (follow‐up 36 to 60 months)
	Two doses of quadrivalent vaccine resulted in non‐inferior GMTs for HPV 6, HPV 11 and HPV 16 compared with three doses, while results were inconclusive for HPV 18 at 60‐month follow‐up (1 study, 101 participants; see Appendix 5).				LOW*
	Two doses of nonavalent vaccine resulted in non‐inferior GMTs for all HPV genotypes measured except HPV 45 and HPV 52 where non‐inferiority was inconclusive, compared with three doses, at 36‐month follow‐up (1 study, 476 to 511 participants depending on HPV type; see Appendix 5).				HIGH*
High‐grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and cervical cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, and vaginal disease	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain/swelling/redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at up to 5‐year follow‐up	30 per 1000	31 per 1000 (20 to 49)	OR 1.03 (0.64 to 1.66)	2317 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^1,2	Please see Table 1 for a list of events in each RCT.
Mortality at up to 5‐year follow‐up	1 per 1000	0 per 1000 (0 to 9)	OR 0.33 (0.01 to 8.19)	1797 (3 RCTs)	⊕⊕⊝⊝ LOW ¹	One death was reported in the three‐dose group (nonavalent vaccine).
Certainty of the evidence (GRADE) for immunogenicity outcomes are presented in detail in Appendix 5. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GMT: geometric mean titre; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potential large beneficial effect and a potential large harmful effect. ²Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety.

1. Serious adverse events

Study	Group	Number of participants with serious adverse events	Details of serious adverse events*
Denny 2013	Vaccine (bivalent)	3/61	Gastroenteritis, bacterial pneumonia, migraine
Denny 2013	Control	2/59	Lobar pneumonia, skull fracture
Dobson 2013	Vaccine (quadrivalent; 2‐dose)	0/259
Dobson 2013	Vaccine (quadrivalent; 3‐dose)	0/261
Giuliano 2011	Vaccine (quadrivalent)	8/2020	8 participants with 12 events: cardiac arrest, non‐cardiac chest pain, hypersensitivity, appendicitis, cellulitis, varicella infection, cervical vertebral fracture, gunshot wound, road traffic accident, traumatic brain injury, traumatic intracranial haemorrhage, convulsion
Giuliano 2011	Control	11/2033	11 participants with 13 events: myocardial ischaemia, pericardial haemorrhage, accidental overdose, chemical poisoning, contusion, gunshot wound (3), head injury, multiple drug overdose, road traffic accident, completed suicide (2)
NCT01031069 2017	Vaccine (bivalent)	9/167	9 participants with 10 events: immune thrombocytopenic purpura, gastritis, meningitis tuberculous, pneumonia, pneumonia mycoplasmal, tonsillitis, viral infection, road traffic accident, miscarriage, renal failure
NCT01031069 2017	Vaccine (quadrivalent)	9/165	9 participants with 10 events: appendicitis (2), pneumonia bacterial, pulmonary tuberculosis, tonsillitis, urinary tract infection, monoarthritis, abortion spontaneous complete, pre‐eclampsia, suicide attempt
NCT01862874 2018	Vaccine (quadrivalent)	0/554
NCT01862874 2018	Control	1/559	Completed suicide
Hidalgo‐Tenorio 2017	Vaccine (quadrivalent)	0/66
Hidalgo‐Tenorio 2017	Control	0/63
Iversen 2016	Vaccine (nonavalent; 2‐dose, 6‐month interval in females)	6/301	6 participants with 7 events: abdominal pain (2), appendicitis, dengue fever, pharyngitis, foreign body injury, ovarian cyst
	Vaccine (nonavalent; 2‐dose, 6‐month interval in males)	9/301	9 participants with 10 events: Wolff‐Parkinson‐White syndrome, diarrhoea, animal bite, appendicitis, rotavirus gastroenteritis, Chikungunya virus infection, bacterial meningitis, pneumonia, concussion, epilepsy
	Vaccine (nonavalent; 2‐dose, 12‐month interval in males and females)	3(6)/301	1 female participant with atopic dermatitis 2 male participants with appendicitis, forearm fracture At 37 month follow‐up there were 3 additional serious adverse events: gastritis, oral herpes, radiculopathy (disaggregated data by sex were not available)
	Vaccine (nonavalent; 3‐dose in females)	6/301	6 participants with 8 events: cardiac arrest, appendicitis, subcutaneous abscess, papillary thyroid cancer, encephalitis autoimmune, status epilepticus, depression, ovarian cyst
Joura 2015	Vaccine (nonavalent)	242/7686	242 participants with 269 events: Anaemia, aortic valve incompetence, postural orthostatic tachycardia syndrome, vertigo positional, anal fistula, coeliac disease, Crohn's disease, diarrhoea, gastritis, haemorrhoids, inguinal hernia, irritable bowel syndrome, pyrexia, sudden death, cholangitis, cholecystitis, cholelithiasis, allergy to vaccine, anaphylactic reaction, hypersensitivity, sarcoidosis, jaw abscess, appendicitis (10), cholecystitis infective, chronic tonsillitis, dengue fever, infectious enteritis (2), gastroenteritis, viral gastroenteritis, haemorrhagic fever, infectious mononucleosis, influenza, pharyngitis, pyelonephritis (2), pyelonephritis acute, septic shock, tonsillitis, tonsillitis streptococcal, urinary tract infection (3), urosepsis, wound infection, bladder injury, burns second degree, craniocerebral injury, femur fracture, humerus fracture (2), ligament rupture, lower limb fracture, multiple injuries (2), pubis fracture, road traffic accident, spinal compression fracture, hyperglycaemia, myalgia, osteoarthritis, acute lymphocytic leukaemia, acute promyelocytic leukaemia, adenocarcinoma of the cervix, brain neoplasm, ependymoma, leukaemic infiltration brain, malignant melanoma (2), malignant melanoma in situ, nasal cavity cancer, ovarian neoplasm, diabetic coma, epilepsy, hypersomnia, Intracranial venous sinus thrombosis, migraine, multiple sclerosis (2), presyncope, sciatica, sensory disturbance, syncope (2), tension headache, abortion spontaneous (40), abortion spontaneous incomplete, blighted ovum, cephalo‐pelvic disproportion (4), cervix dystocia, false labour, foetal death (2), foetal distress syndrome (5), labour complication, pre‐eclampsia (2), premature labour, premature rupture of membranes (4), prolonged labour (2), uterine contractions during pregnancy, anorexia and bulimia syndrome, bipolar disorder (3), completed suicide, major depression, calculus ureteric, calculus urinary, nephrolithiasis, renal failure (2), bartholinitis, cervical dysplasia (5), cervix haemorrhage uterine, endometriosis (2), ovarian cyst, pelvic pain, asthmatic crisis, pneumonia aspiration, pneumothorax, respiratory failure, vocal cord polyp, abortion induced (79), deep vein thrombosis, hypovolaemic shock (2)
Joura 2015	Vaccine (quadrivalent)	184/7078	184 participants with 197 events: Anaemia, cleft lip and palate, Meckel's diverticulum, abdominal pain (2), abdominal pain lower, colitis ulcerative, enterocolitis, gastritis, inguinal hernia, omental infarction, cholecystitis , cholelithiasis (2), appendicitis (16), bronchitis (2), cellulitis, conjunctivitis, gastroenteritis (2), influenza, pelvic inflammatory disease, post abortion infection, pyelonephritis, pyelonephritis acute (2), urinary tract infection (2), viral pharyngitis, foreign body in eye, fracture displacement, hand fracture, head injury, joint dislocation (2), neck injury, poisoning, post procedural haemorrhage (2), spinal cord injury, spinal cord injury cervical, fibromyalgia (2), adenocarcinoma gastric, malignant palate neoplasm, pituitary tumour benign, respiratory papilloma, thyroid cancer, benign intracranial hypertension, cerebral haemorrhage, epilepsy, facial paresis, headache, hydrocephalus, hypoesthesia, multiple sclerosis, neuritis, orthostatic intolerance, spondylitic myelopathy, tension headache, abortion spontaneous (28), abortion spontaneous complete (2), blighted ovum, cephalo‐pelvic disproportion (6), cervix dystocia, ectopic pregnancy, foetal distress syndrome, foetal malposition, foetal malpresentation, gestational diabetes, oligohydramnios, pre‐eclampsia, premature labour, premature rupture of membranes (2), prolonged labour, anorexia nervosa, bipolar disorder, depression, cystitis haemorrhagic, renal failure acute, cervical dysplasia (3), dysmenorrhoea, endometriosis, fallopian tube cyst, ovarian cyst (2), dyspnoea, nasal polyps, abortion induced (53), axillary vein thrombosis
Lehtinen 2018	Vaccine (quadrivalent)	58/2436	58 participants with 62 events: Splenomegaly, vitello‐intestinal duct remnant, abdominal pain (2), colitis ulcerative, constipation, food poisoning, chest pain, pyrexia, cholesystitis, appendicitis (5), appendicitis perforated, infectious mononucleosis (4), peritonsillar abscess, pneumonia (2), pneumonia bacterial, salmonellosis, tonsillitis (4), alcohol poisoning (3), cervical vertebral fracture, concussion (4), contusion (2), forearm fracture, hand fracture (2), limb injury, lower limb fracture, muscle rupture, neck injury, radius fracture (2), upper limb fracture (2), type 1 diabetes mellitus, exostosis, juvenile idiopathic arthritis, syncope (2), anxiety, disturbance in social behaviour, emotional disorder of childhood, psychotic disorder, testicular torsion, acne, dermatitis
Lehtinen 2018	Vaccine (control, HBV)	25/1267	25 participants with 25 events: Appendicitis (3), appendicitis perforated, bronchitis, gastroenteritis bacterial, infectious mononucleosis, peritonsillar abscess, sinusitis, sinusitis bacterial, alcohol poisoning, foot fracture (2), forearm fracture, hand fracture, joint dislocation, splenic rupture, tibia fracture, traumatic renal injury, type 1 diabetes mellitus, astrocytoma low grade, depression, panic disorder, suicide attempt, dyspnoea
Leung 2015	Vaccine (bivalent; 2‐dose)	11/358	11 participants with 13 events: Abdominal pain lower, mouth cyst, appendicitis, gastroenteritis viral, lung abscess, peritonitis, viral infection, joint dislocation, teratoma, epilepsy, seizure, asthma, eczema
Leung 2015	Vaccine (bivalent; 3‐dose)	14/358	14 participants with 16 events: Lymphadenitis, vertigo positional, abdominal pain, anaphylactic shock, upper respiratory tract infection, pneumonia, influenza, vulval ulceration, ankle fracture, overdose, tendon injury, presyncope, tension headache, abortion spontaneous incomplete, completed suicide, depression, menorrhagia
Levin 2010	Vaccine (quadrivalent)	0/96
Levin 2010	Control	0/30
Lin 2014	Vaccine (quadrivalent; 10‐month interval)	0/111
Lin 2014	Vaccine (quadrivalent; 4‐month interval)	0/109
NCT00941889 2016	Vaccine (quadrivalent)	Not reported	Not reported
NCT00941889 2016	Control	Not reported	Not reported
Wilkin 2018	Vaccine (quadrivalent)	33/288	33 participants with 40 events: Pericardial effusion, abdominal mass, abdominal pain, anal fistula, colitis, chest pain (2), death, appendicitis, cellulitis, chlamydial infection, gastroenteritis viral, influenza (2), meningitis viral, peritonsillar abscess, pneumonia, pneumonia pneumococcal, pseudomembranous colitis, sepsis, lower limb fracture, multiple injuries, stab wound, anal cancer, basal cell carcinoma, Hodgkin's disease, prostate cancer, transitional cell carcinoma, cerebrovascular accident, seizure, acute psychosis, alcohol withdrawal syndrome, depression, suicide attempt, acute respiratory failure, alveolitis allergic, asthma, pleural effusion, intervertebral disc operation
Wilkin 2018	Control	46/287	46 participants with 79 events: Acute myocardial infarction (2), coronary artery disease, myocardial infarction, abdominal pain, gastrointestinal haemorrhage, large intestine perforation, pancreatitis, pancreatitis acute (2), pancreatitis chronic, small intestinal obstruction (3), chest pain (5), pyrexia, cholelithiasis, bronchitis (2), diverticulitis (2), gastroenteritis (2), gastroenteritis viral, influenza (2), orchitis, perirectal abscess, pneumonia (3), pneumonia streptococcal, primary syphilis, pyelonephritis, scrotal abscess, sepsis (3), viral infection, fall, foot fracture, overdose, radius fracture, road traffic accident, weight decreased, dehydration, osteoarthritis, anal cancer, anal squamous cell carcinoma, B‐cell lymphoma, basal cell carcinoma, follicle centre lymphoma diffuse small cell lymphoma, oesophageal adenocarcinoma, pancreatic carcinoma metastatic, prostate cancer, renal cell carcinoma, squamous cell carcinoma of head and neck, haemorrhagic stroke, syncope (2), alcohol withdrawal syndrome, completed suicide, mental status changes, psychotic disorder, substance abuse, suicide attempt, genital ulceration, chronic obstructive pulmonary disease (4), dyspnoea, pleural effusion, pulmonary hypertension, hypotension
Petaja 2009	Vaccine (bivalent)	3/181	Crohn’s disease, appendicitis, epilepsy
Petaja 2009	Control (HBV)	1/89	Osteochondrosis
Puthanakit 2016	Vaccine (bivalent; 2‐dose, 6‐month interval)	20/550	20 participants with 34 events: Lymphadenitis, autoimmune thyroiditis, strabismus, abdominal strangulated hernia, abdominal pain, anal haemorrhage, gastritis, nausea, chronic gastritis, anaphylactic reaction, cholelithiasis, infections and infestations (13), injury, poisoning and procedural complications (4), type 1 diabetes mellitus, cholesteatoma, convulsion, seizure, IgA nephropathy, respiratory disorder
	Vaccine (bivalent; 2‐dose, 12‐month interval)	24/415	24 participants with 38 events: Lymphadenitis, supraventricular tachycardia, abdominal pain lower, constipation, dyspepsia, faecaloma, drug hypersensitivity, infections and infestations (25), injury, poisoning and procedural complications, hypovolaemia, systemic lupus erythematosus, VIIth nerve paralysis, tonsillar hypertrophy, circulatory collapse
	Vaccine (bivalent; 3‐dose)	28/482	28 participants with 53 events: Infections and infestations (32), injury, poisoning and procedural complications (3), hypovolaemia (2), synovial cyst, medulloblastoma, synovial sarcoma, uterine leiomyoma, hyperemesis gravidarum, premature baby, abortion threatened, postpartum haemorrhage, stillbirth, schizoaffective disorder (3), psychotic disorder, ovarian cyst ruptured, transient tachypnoea of the newborn, ectopic pregnancy termination
Romanowski 2011	Vaccine (bivalent; 3‐dose)	15/239	15 participants with 20 events: Basedow’s disease, abdominal pain, appendix disorder, gastroenteritis, appendicitis, pharyngitis streptococcal, tonsillitis (2), urinary tract infection, ligament rupture, multiple injuries, ligament laxity, polyarthritis, migraine with aura, abortion spontaneous incomplete, abnormal behaviour, depression, renal colic, renal disorder, erythema multiforme
	Vaccine (bivalent; 2‐dose)	16/241	16 participants with 26 events: Abdominal pain, umbilical hernia (2), obstructive vomiting, gastroenteritis viral, cholecystitis acute, acute tonsillitis, appendicitis (2), endometritis decidual, vestibular neuronitis, tibia fracture, contusion, fall, fibroma, fibrosarcoma, pre‐eclampsia, premature baby, abortion missed, depression, major depression, psychotic disorder, suicide attempt, cystitis haemorrhagic, hyperventilation, circulatory collapse
	Vaccine (bivalent; 2‐dose, 6‐month interval)	19/240	19 participants with 23 events: Atrial septal defect, spina bifida, bile duct stone, appendicitis (4), tonsillitis bacterial, humerus fracture, road traffic accident, tibia fracture, upper limb fracture, malignant melanoma stage IV, basilar artery thrombosis, cerebrovascular accident, abortion spontaneous, abortion spontaneous incomplete (2), foetal distress syndrome, anorexia nervosa, bulimia nervosa, depression, circulatory collapse
	Vaccine (bivalent; 2‐dose, 2‐month interval)	14/240	14 participants with 16 events: Abdominal pain (3), hepatomegaly, pilonidal cyst, urinary tract infection, vestibular neuronitis, concussion, stab wound, coccydynia, uterine leiomyoma, benign hydatidiform mole, abortion spontaneous, ectopic pregnancy, adenomyosis, ovarian cyst
Toft 2014	Vaccine (bivalent)	0/46
Toft 2014	Vaccine (quadrivalent)	0/46
van Damme 2016	Vaccine (nonavalent)	0/249
van Damme 2016	Vaccine (quadrivalent)	6/251	Joint dislocation, ligament injury, ligament rupture, foot fracture, concussion, cytomegalovirus infection
Vesikari 2015	Vaccine (nonavalent)	1/299	One participant with two events: Anaemia and pulmonary vasculitis
Vesikari 2015	Vaccine (quadrivalent)	2/300	Complex partial seizures, Henoch‐Schonlein purpura
Abbreviations *For each event, n = 1 unless otherwise stated. HBV: hepatitis B vaccine

Summary of findings 2. Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males

Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males
Patient or population: 9‐ to 14‐year‐old females and males Setting: community health centres in Africa, Asia Pacific, Europe, Latin America, North America Intervention: two doses of bivalent or nonavalent HPV vaccine with longer interval (months 0 and 6 or 12) Comparison: two doses of bivalent or nonavalent HPV vaccine with shorter interval (months 0 and 2 or 6)
Clinical and harms outcomes^*	Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with two doses of HPV vaccine with shorter interval	Risk with two doses of HPV vaccine with longer interval
Antibody response (geometric mean titre)	Longer intervals between the first two doses of bivalent vaccine resulted in higher and non‐inferior GMTs for HPV 16 (n = 971) and HPV 18 (n = 986) compared with shorter intervals in 9‐ to 14‐year‐old females at short‐term follow‐up (2 studies; moderate‐ to high‐certainty evidence, see Appendix 6).				MODERATE/ HIGH*	Short‐term results (follow‐up one month after final dose)
	A longer interval between the first two doses of nonavalent vaccine resulted in higher and non‐inferior GMTs than a shorter interval for all HPV vaccine genotypes in girls and boys at short‐term follow‐up (1 study, number of participants ranged from 778 to 815 depending on HPV type; high‐certainty evidence, see Appendix 6).				HIGH*
	Longer intervals between the first two doses of bivalent vaccine resulted in higher and non‐inferior GMTs for HPV 16 (n=817) and HPV 18 (n=794) compared with shorter intervals in 9‐ to 14‐year‐old females at 36 months follow‐up (1 study; high‐certainty evidence, see Appendix 6).				HIGH*	Long‐term results (follow‐up 36 months)
	A longer interval between the first two doses of nonavalent vaccine resulted in higher and non‐inferior GMTs than a shorter interval for all HPV vaccine genotypes in girls and boys at seven and 36 months follow‐up (1 study, number of participants ranged from 236 to 263 depending on HPV type; high‐certainty evidence, see Appendix 6).				HIGH*
Invasive cervical, vaginal, vulval, anal, or penile cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, vaginal, penile, or anal intraepithelial neoplasia	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain/swelling/redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at up to 5‐year follow‐up	Bivalent vaccine (0 and 2 months) 58 per 1000	Bivalent vaccine (0 and 6 months) 67 per 1000 (33 to 130)	OR 1.15 (0.55 to 2.41)	481 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2	Please see Table 1 for list of events in each RCT. Data for nonavalent vaccine include males and females; fully disaggregated data were not available.
	Bivalent vaccine (0 and 6 months) 36 per 1000	Bivalent vaccine (0 and 12 months) 58 per 1000 (32 to 101)	OR 1.63 (0.89 to 2.99)	965 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2
	Nonavalent vaccine (0 and 6 months) 25 per 1000	Nonavalent vaccine (0 and 12 months) 20 per 1000 (8 to 52)	OR 0.80 (0.31 to 2.07)	903 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2
Mortality at up to 5‐year follow‐up	Bivalent vaccine (0 and 2 months) 0 per 1000	Bivalent vaccine (0 and 6 months) 0 per 1000 (0 to 0)	Not estimable	481 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
	Bivalent vaccine (0 and 6 months) 0 per 1000	Bivalent vaccine (0 and 12 months) 0 per 1000 (0 to 0)	Not estimable	965 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
	Nonavalent vaccine (0 and 6 months) 0 per 1000	Nonavalent vaccine (0 and 12 months) 0 per 1000 (0 to 0)	Not estimable	452 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
Certainty of the evidence (GRADE) for immunogenicity outcomes are presented in detail in Appendix 6. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GMT: geometric mean titre; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential small harmful effect. ²Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ³Downgraded two levels for serious imprecision: no events reported, the studies were not powered to detect a difference in mortality.

Summary of findings 3. Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males

Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males
Patient or population: 10‐ to 26‐year‐old males Setting: 18 countries in five regions (Africa, Asia‐Pacific, Europe, Latin America, North America) Intervention: quadrivalent HPV vaccine, 3 doses at months 0, 2, and 6; or bivalent HPV vaccine, 3 doses at months 0, 1, and 6 Comparison: control (vaccine adjuvant‐containing placebo), 3 doses at months 0, 2, and 6 or hepatitis B vaccine, 3 doses at months 0, 1, and 6
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk/rate with control	Risk/rate with HPV vaccine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Invasive anal or penile cancer	No studies were identified that reported on this outcome
Penile or anal intraepithelial neoplasia at up to 3‐year follow‐up	3/2824 person‐years	0/2833 person‐years	Rate ratio 0.17 (0.01 to 3.27)	2805 participants (5657 person‐years) (1 RCT)	⊕⊕⊝⊝ LOW ²
External genital lesions (any genotype) at up to 3‐year follow‐up	36/3081 person‐years	6/3173 person‐years	Rate ratio 0.16 (0.07 to 0.38)	2545 participants (6254 person‐years) (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
Anogenital warts at up to 3‐year follow‐up	28/2814 person‐years	3/2831 person‐years	Rate ratio 0.11 (0.03 to 0.38)	2805 participants (5645 person‐years) (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
Overall local/injection site adverse events at 15‐day follow‐up	537 per 1000	601 per 1000 (569 to 634)	RR 1.12 (1.06 to 1.18)	3895 (1 RCT)	⊕⊕⊕⊕ HIGH³	Data for specific local adverse events (pain, swelling, redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms at 15‐day follow‐up	248 per 1000	245 per 1000 (223 to 268)	RR 0.99 (0.90 to 1.08)	5008 (2 RCTs)	⊕⊕⊕⊝ MODERATE⁴
Serious adverse events at up to 3‐year follow‐up	Control: 11 per 1000	Bivalent vaccine: 17 per 1000 (2 to 141)	OR 1.48 (0.15 to 14.46)	270 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^2,4	In a subgroup from Lehtinen 2018, a cluster‐RCT, 58/2436 HPV vaccine recipients (2.4%) and 25/1267 control HBV vaccine recipients (2.0%) experienced serious adverse events. This was also considered very low‐certainty evidence^2,4 Please see Table 1 for list of events in each RCT.
Serious adverse events at up to 3‐year follow‐up	Control: 4 per 1000	Quadrivalent vaccine: 3 per 1000 (1 to 7)	OR 0.69 (0.29 to 1.66)	5162 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^2,4	Please see Table 1 for list of events in each RCT.
Mortality at up to 3‐year follow‐up	Control: see comment	Bivalent vaccine: see comment	OR not estimable: see comment	270 (1 RCT)	⊕⊕⊝⊝ LOW ⁵	No events were reported
Mortality at up to 3‐year follow‐up	Control: 4 per 1000	Quadrivalent vaccine: 1 per 1000 (0 to 4)	OR 0.30 (0.09 to 1.01)	5173 (2 RCTs)	⊕⊕⊝⊝ LOW ²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level for imprecision: few events. ²Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect as well as a potential large harmful effect. ³Evidence for this outcome was not downgraded: the trial was a large multi‐national trial with low risk of bias and precise estimates. ⁴Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁵Downgraded two levels for serious imprecision: no events reported.

See: Summary of findings for the main comparison Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females; Summary of findings 2 Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males; Summary of findings 3 Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males; Summary of findings 4 Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males

Summary of findings 4. Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males

Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males
Patient or population: 9‐ to 26‐year‐old females and males Setting: community health centres in Asia‐Pacific, Europe, Latin America, North America Intervention: nonavalent HPV vaccine, 3 doses administered at months 0, 2, and 6 Comparison: quadrivalent HPV vaccine, 3 doses administered at months 0, 2, and 6
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with quadrivalent HPV vaccine	Risk with nonavalent HPV vaccine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
High‐grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and cervical cancer at up to 4.5‐year follow‐up	47 per 1000	47 per 1000 (41 to 55)	OR 1.00 (0.85 to 1.16)	13,753 (1 RCT)	⊕⊕⊕⊕ HIGH¹	No studies were identified which reported on invasive anal or penile cancer in males
High‐grade cervical, vulval, and vaginal disease at up to 4.5‐year follow‐up	49 per 1000	48 per 1000 (42 to 56)	OR 0.99 (0.85 to 1.15)	14,054 (1 RCT)	⊕⊕⊕⊕ HIGH¹	No studies were identified which reported on penile or anal intraepithelial neoplasia in males
Overall local/injection site adverse events at 15‐day follow‐up	846 per 1000	905 per 1000 (888 to 914)	RR 1.07 (1.05 to 1.08)	15,863 (3 RCTs)	⊕⊕⊕⊕ HIGH	Data for specific local adverse events (pain, swelling, redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms at 15‐day follow‐up	543 per 1000	548 per 1000 (532 to 565)	RR 1.01 (0.98 to 1.04)	15,863 (3 RCTs)	⊕⊕⊕⊝ MODERATE³
Serious adverse events at up to 4.5‐year follow‐up	25 per 1000	15 per 1000 (4 to 63)	OR 0.60 (0.14 to 2.61)	15,863 (3 RCTs)	⊕⊕⊝⊝ LOW ^2,3	Please see Table 1 for list of events in each RCT. Numbers of events/number of participants (%) were: in 16‐ to 26‐year‐old females receiving nonavalent vaccine, 242/7686 (3.1%) vs quadrivalent vaccine, 184/7078 (2.6%) over a period of 4.5 years follow‐up; in 16‐ to 26‐year‐old males receiving nonavalent vaccine, 0/249 (0%) vs quadrivalent vaccine, 6/251 (2.4%) over 7 months follow‐up; in 9‐ to 15‐year‐old females receiving nonavalent vaccine, 1/299 (0.3%) vs quadrivalent vaccine, 2/300 (0.7%) over 7 months follow‐up.
Mortality at up to 4.5‐year follow‐up	1 per 1000	1 per 1000 (0 to 3)	OR 1.20 (0.37 to 3.94)	15,248 (3 RCTs)	⊕⊕⊝⊝ LOW ⁴
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Evidence from this outcome was not downgraded: the included trial was a large multi‐national trial with low risk of bias and precise estimates. ²Downgraded one level for imprecision: pooled estimate has a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential large harmful effect. ³Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁴Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential large harmful effect.

Antecedentes

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Descripción de la afección

El virus del papiloma humano (VPH) es la infección viral más común del tracto reproductivo en mujeres y hombres (OMS 2017). Aunque la mayoría de las infecciones por VPH se resuelve espontáneamente, las infecciones persistentes pueden dar lugar a lesiones precancerosas y cáncer de cuello de útero, de vagina, de vulva, de ano, de pene y de cabeza y cuello. El cáncer relacionado con el VPH representó cerca del 4,5% de todos los tipos de cáncer del mundo en 2012 (de Martel 2017). Cuando se estratifica por sexo, representa el 8,6% de los casos de cáncer en las mujeres y el 0,8% de los casos de cáncer en los hombres, y por estado de desarrollo, el 6,7% de todos los casos de cáncer en los países de ingresos bajos y medios y el 2,8% en los países de ingresos altos (de Martel 2017). En 2012, de un estimado de 636 000 casos de cáncer relacionado con el VPH en todo el mundo, 530 000 fueron casos de cáncer de cuello uterino, 35 000 de cáncer anal, 8500 de cáncer vulvar, 13 000 de cáncer de pene y 37 000 de cáncer de cabeza y cuello (de Martel 2017).

En las mujeres con resultados citológicos normales, se ha estimado que la prevalencia mundial de infección por cualquier genotipo del VPH según un metanálisis es de un 11,7%, y se observa una prevalencia más alta en África subsahariana, América Latina, el Caribe, el sudeste asiático y Europa oriental (Bruni 2010). En los hombres heterosexuales evaluados al inicio de un ensayo multicéntrico en 18 países de África, Asia‐Pacífico, Europa, América Latina y Norteamérica, la infección peniana por cualquier genotipo de VPH se encontró en un 18,7%, la infección escrotal en un 13,1%, la infección perianal en un 7,9% y la infección en cualquier sitio en un 21,0%. La mayor prevalencia se registró en África y la menor en la región de Asia‐Pacífico (Vardas 2011). La prevalencia de las infecciones por VPH en general es mayor en los hombres con infección por VIH, en los hombres que tienen relaciones sexuales con hombres (HSH), y la mayor se observa en los HSH que presentan infección por VIH (Schim van der Loeff 2014; Smith 2011).

Los principales tipos de lesiones asociadas con la infección anogenital por VPH son las verrugas anogenitales (condiloma acuminado) y la neoplasia intraepitelial del cuello uterino (neoplasia intraepitelial de cuello de útero, NIC), la vulva, la vagina, el canal anal/área perianal y el pene. La neoplasia intraepitelial es un precursor de algunos de estos tipos de cáncer, aunque puede retroceder a estadios más tempranos y no progresa a cáncer invasivo en la mayoría de las personas afectadas. Un estudio que dio seguimiento a mujeres con NIC3 tratada de manera inadecuada encontró que el 31,3% (IC del 95%: 22,7 a 42,3) desarrolló cáncer invasivo después de 30 años (McCredie 2008). El VPH también está asociado con el cáncer de células escamosas de cabeza y cuello (CCECC). De todos los tipos de cáncer de cabeza y cuello a nivel mundial en 2012 (534 000), alrededor del 7% (37 000) fueron atribuibles al VPH, incluidos 29 000 de 96 000 (31%) casos de cáncer orofaríngeo (de Martel 2017). La incidencia de cáncer de orofaríngeo ha aumentado con el tiempo, más entre los hombres que entre las mujeres (Gillison 2015). Es probable que el VPH contribuya en gran medida al aumento en el número de hombres, mientras que el tabaquismo domina el aumento en el número de mujeres (Gillison 2015).

La International Agency for Research on Cancer clasifica los genotipos del VPH según su potencial oncogénico; los genotipos 16; 18; 31; 33; 35; 39; 45; 51, 52; 56; 58 y 59 del VPH se consideran genotipos de alto riesgo (Bouvard 2009). Los genotipos 16 y 18 del VPH son los más comunes en las mujeres de todo el mundo y están asociados con la mayoría de los casos de cáncer de cuello de útero invasivo; los genotipos 16; 18; 31; 33; 45; 52 y 58 del VPH combinados causan aproximadamente el 90% de todos los carcinomas de células escamosas del cuello uterino con pruebas positivas para el VPH (Alemany 2014; Bruni 2010; de Sanjose 2010). Los genotipos 16 y 18 del VPH también son la causa del 90% de todos los casos de cáncer anal (Bosch 2002). El genotipo 16 del VPH se encuentra en cerca del 80% de los casos de cáncer de células escamosas anal relacionado con el VPH, en el 52% de los carcinomas de células escamosas penianos invasivos y en el 90% de las neoplasias intraepiteliales penianas (Krustrup 2009; Schim van der Loeff 2014). En un metanálisis, el VPH se detectó en el 22% de los casos de CCECC, y el 86,7% de los mismos se atribuyeron al genotipo 16 del VPH, aunque también se detectaron los genotipos 6 y 11 del VPH en una minoría de los casos (Syrjänen 2010). Los genotipos 6 y 11 del VPH representan hasta el 90% de las verrugas anogenitales (Greer 1995; Sturegard 2013).

Descripción de la intervención

Se dispone de tres vacunas profilácticas contra el VPH, que se administran mediante inyección intramuscular. Las tres vacunas son fabricadas por medio de tecnologías genéticas y no son infecciosas debido a que no contienen ADN viral. Están hechas de proteínas de la cápside L1 purificadas, que forman partículas parecidas a las del virus que se asemejan a la estructura de genotipos específicos del VPH. Cada vacuna está dirigida contra dos o más genotipos de alto riesgo del VPH. Las tres vacunas contienen proteínas L1 de los genotipos 16 y 18 del VPH (OMS 2017), debido a que las mismas causan cerca del 70% del cáncer de cuello uterino en todo el mundo. Las vacunas son conocidas comúnmente por el número de genotipos diferentes que contienen (es decir, la valencia, Tabla 1). La vacuna bivalente contiene proteínas L1 de dos genotipos del VPH: 16 y 18. La vacuna cuadrivalente contiene proteínas L1 de cuatro genotipos del VPH; 16 y 18; más los genotipos 6 y 11 del VPH, que causan verrugas genitales. La vacuna nonavalente es la más reciente y contiene proteínas L1 de nueve genotipos del VPH: 16; 18; 31; 33; 45; 52 y 58; más los genotipos 6 y 11 del VPH. Las tres vacunas contienen adyuvantes (Tabla 1). Además de las vacunas autorizadas, a partir de septiembre 2018, hay tres vacunas en fase de desarrollo 2 a 3; dos vacunas bivalentes fabricadas por Innovax y Walvax en China, y una vacuna cuadrivalente fabricada por el Serum Institute of India (LaMontagne 2017).

Para prevenir la infección por VPH, todas las vacunas contra el VPH deben administrarse, siempre que sea posible, antes de la primera exposición al VPH, es decir, antes del inicio de la actividad sexual. Todos los calendarios nacionales de vacunación contra el VPH incluyen a las niñas, y algunos países han extendido su calendario a los niños. Según la mayoría de los estudios de modelado, los calendarios de vacunación contra el VPH para niñas preadolescentes serán coste‐efectivos para la prevención del cáncer de cuello de útero, en particular en entornos en que la infraestructura de detección del cáncer de cuello de útero es deficiente (OMS 2017). La vacunación contra el VPH en las mujeres brinda una protección indirecta a los hombres. Estos efectos denominados de grupo significan que, a nivel de la población, los calendarios de vacunación solo para mujeres han dado como resultado una reducción de las infecciones por VPH tanto en hombres como en mujeres (Drolet 2019). Sin embargo, los efectos de grupo de la vacunación solo para mujeres no afectan a los HSH, que experimentan una carga alta de cáncer anal y verrugas anogenitales. Los estudios de modelado también indican que la vacunación contra el VPH solo para mujeres, incluso con altos niveles de cobertura, no prevendrá todos los casos de cáncer relacionado con el VPH en hombres heterosexuales (Bogaards 2015). La coste‐efectividad de la vacunación de los niños depende de la cobertura de la vacunación en las niñas, la epidemiología de la enfermedad relacionada con el VPH y los costes de la vacuna y el calendario (OMS 2017).

La aceptación de la vacunación contra el VPH varía ampliamente entre los países que la han introducido como parte de sus calendarios nacionales de inmunización. En 2017 las tasas de cobertura en 82 países oscilaban entre el 8% y el 98% (Brotherton 2018). Hasta la fecha, pocos países de África y Asia han introducido la vacuna contra el VPH. Aunque hay evidencia proveniente de algunos países de ingresos bajos y medios que ha demostrado que la vacuna contra el VPH puede introducirse de forma efectiva, también se ha informado de países con problemas. Por ejemplo, Uganda informó de una cobertura de más del 80% para la primera dosis de un calendario de vacunación de dos dosis, aunque esta cifra no se mantuvo para la segunda dosis (Brotherton 2018). En países de ingresos altos, como Inglaterra, Escocia y Australia, los programas escolares han llegado a entre el 70% y el 80% de las niñas para todas las dosis. En otros países de ingresos altos, como Francia, EE.UU., Japón y Dinamarca, la cobertura no se ha logrado o ha descendido por debajo del 50%. Las razones de la baja cobertura difieren de un país a otro, pero incluyen la organización de la implementación del calendario, la resistencia de los profesionales de atención sanitaria, la cobertura adversa de los medios de comunicación y la preocupación en cuanto a la seguridad (Gallagher 2018).

De qué manera podría funcionar la intervención

Las vacunas contra el VPH que contienen partículas similares a las del virus de la proteína L1 son profilácticas, lo que significa que previenen la infección y el desarrollo de lesiones intraepiteliales causadas por genotipos del VPH que están presentes en la vacuna (Stanley 2006). Las partículas similares al virus en las vacunas producen niveles muy altos de anticuerpos en el suero, aunque no se comprenden del todo los mecanismos exactos por los cuales las vacunas previenen la infección por VPH. No se han establecido los niveles de anticuerpos necesarios para brindar protección contra la enfermedad clínica causada por el VPH (conocido como correlación inmunológica de protección) debido a que el número de infecciones intercurrentes después de la vacunación ha sido demasiado bajo. La International Agency for Research on Cancer considera que la infección persistente por VPH de los genotipos 16 y 18 del VPH, medida con pruebas estandarizadas y validadas, es un marcador sustitutivo preciso de las lesiones precancerosas del cuello uterino y el ano (IARC 2014). Los datos posteriores a la autorización de los calendarios nacionales de inmunización muestran reducciones en las lesiones de grado alto del cuello uterino y el ano con regímenes de tres dosis de las vacunas bivalentes y cuadrivalentes (Markowitz 2018). Debido a que el precáncer se encuentra en la vía causal del cáncer invasivo, se asume que también se demostrará que la prevención de las lesiones precancerosas previene el cáncer cuando se haya acumulado suficiente tiempo de seguimiento en los estudios posteriores a la obtención de la autorización. Se conoce menos sobre el valor pronóstico de la infección persistente por VPH en el desarrollo de cáncer vaginal, vulvar y orofaríngeo (IARC 2014).

Todos los ensayos controlados aleatorizados (ECA) que establecieron la eficacia de las vacunas contra el VPH en la prevención de lesiones precancerosas de alto grado del cuello uterino utilizaron un calendario de vacunación de tres dosis (Arbyn 2018). Debido a la exposición baja al VPH y a las limitaciones éticas en la realización de investigaciones que requieren un examen genital y la recolección de muestras en poblaciones adolescentes (menores de 15 años de edad), los ensayos aleatorizados de eficacia de las vacunas se han realizado por lo general por primera vez en mujeres de 15 a 25 o 26 años de edad (Arbyn 2018). Una vez evaluada la inmunogenicidad y los efectos perjudiciales, se evalúa la no inferioridad de los resultados inmunológicos en niños de 9 a 15 años de edad en estudios puente no aleatorizados (p.ej. Block 2006; Dobson 2013). La International Agency for Research on Cancer considera que los estudios puente que demuestran la no inferioridad son una variable de evaluación suficiente para las personas menores de 16 años de edad (IARC 2014).

Los calendarios de vacunación están diseñados para producir una respuesta significativa y duradera de los anticuerpos, de modo que, cuando se enfrenten a la exposición al patógeno real, el sistema inmunológico prevenga la infección. Un calendario de vacunación de tres dosis es típico para las vacunas de proteína inactivada para neonatos; la segunda dosis se administra uno o dos meses después de la primera dosis y una tercera dosis seis meses después de la primera dosis. Las dos primeras dosis de la vacuna se denominan dosis "primarias" que generan memoria inmunitaria a través de los linfocitos B producidos en la médula ósea (Stanley 2014). La segunda dosis produce niveles más altos de anticuerpos que la primera y aumenta la afinidad de unión del anticuerpo con el antígeno, en un proceso que se prolonga durante varios meses. Como resultado de este proceso (maduración de la afinidad), las células B con niveles muy altos de afinidad, se diferencian en la médula ósea en células B de memoria que responden rápidamente para producir anticuerpos al exponerse al antígeno y células plasmáticas de larga vida que producen continuamente anticuerpos a niveles bajos. Una tercera dosis de la vacuna administrada al menos cuatro meses después de las dosis primarias «refuerza» al máximo estas respuestas para proporcionar una protección duradera (Stanley 2014).

Los calendarios simplificados de vacunación contra el VPH con menos dosis deberían permitir que más personas reciban la vacuna. Los preadolescentes y adolescentes (de 9 a 15 años de edad) producen respuestas de anticuerpos más fuertes a las vacunas contra el VPH con proteínas similares a las del virus que los adolescentes y los adultos mayores (Block 2006; Dobson 2013), incluso después de una única dosis (Sankaranarayanan 2016). Parece que no se requieren dosis múltiples repetidas de estas vacunas para la maduración de la afinidad y que las células plasmáticas de larga vida son más importantes que las células B de memoria en la respuesta inmunológica (Schiller 2018). Se cree que las características estructurales de las partículas similares a los virus permiten la producción eficiente de células plasmáticas de larga vida, que producen continuamente anticuerpos específicos para el antígeno, lo que resulta en respuestas inmunitarias fuertes y duraderas con calendarios de dosis reducidas (Schiller 2018).

La evidencia de la probable eficacia de un calendario de dos dosis de vacunas contra el VPH de partículas similares al virus en la prevención de una posible infección por VPH del tipo incluido en la vacuna proviene de estudios en que se analizaron los datos de los ECA como estudios de cohorte, según el número de dosis recibidas de la vacuna contra el VPH (Kreimer 2011; Sankaranarayanan 2016). Kreimer y colegas realizaron un análisis secundario de los datos de un ECA de la vacuna bivalente entre mujeres de 18 a 25 años de edad en Costa Rica (Kreimer 2011). En dicho ensayo, el 20% de las mujeres no recibieron las tres dosis de la vacuna. Las mujeres fueron agrupadas de acuerdo al número de dosis de la vacuna contra el VPH que recibieron. Las proporciones de mujeres con posible infección por los genotipos 16/18 del VPH que persistió durante 12 meses o más fueron similares entre las mujeres que recibieron una, dos y tres dosis (Kreimer 2011). Un análisis actualizado combinó los datos de este ensayo de la vacuna de Costa Rica y un ensayo fundamental de la vacuna bivalente, Paavonen 2007; según el número de dosis recibidas después de cuatro años de seguimiento (Kreimer 2015). En la cohorte modificada total que recibió la vacuna, la eficacia de la vacuna contra la posible infección por los genotipos 16/18 del VPH que persistió durante 12 meses o más fue del 83,7% (IC del 95%: 35,7 a 97,5%) con dos dosis, y del 92,6% (IC del 95%: 89,2 a 95,1%) con tres dosis. Sankaranarayanan y colegas analizaron un ECA de la vacuna cuadrivalente en niños de 10 a 18 años de edad en la India (que se interrumpió antes de que se completara el reclutamiento) según el número de dosis recibidas de la vacuna contra el VPH (Sankaranarayanan 2016). La incidencia del VPH 16/18 fue del 0,8% (IC del 95%: 0,2 a 1,9%; 4/526) entre los participantes que recibieron dos dosis, y del 0,4% (IC del 95%: 0,0 a 1,3%; 2/536) entre los que recibieron tres dosis (Sankaranarayanan 2016). Los datos adicionales de una revisión sistemática de los estudios posteriores a la autorización sobre los calendarios nacionales de vacunación contra el VPH muestran que la administración de dos dosis de la vacuna contra el VPH se asoció con una reducción de la incidencia de la prevalencia del VPH del tipo incluido en la vacuna, las verrugas anogenitales y las anomalías del cuello de útero en algunos estudios, pero no en todos (Markowitz 2018).

Por qué es importante realizar esta revisión

En la práctica, las tasas de vacunación contra el VPH en muchos países siguen siendo bajas.

Se ha identificado que los calendarios de inmunización contra el VPH más sencillos son una estrategia potencial para aumentar la cobertura de la vacunación (Walling 2016). La Organización Mundial de la Salud (OMS) recomendó un calendario de vacunación contra el VPH de dos dosis en 2014, sobre la base de una revisión sistemática de los estudios que incluían la inmunogenicidad como variable de evaluación (D'Addario 2017; OMS 2017). Hasta el 30 de diciembre 2017, 80 países habían introducido la vacunación contra el VPH de modo completo y cuatro países de modo parcial en sus calendarios nacionales de inmunización, y 65 países habían aplicado calendarios de dos dosis en niñas de 9 a 14 años de edad (www.who.int/immunization/monitoring_surveillance/data/en).

En 2018 una revisión Cochrane estableció la conclusión de que los calendarios autorizados de tres dosis de las vacunas bivalentes y cuadrivalentes contra el VPH producen eventos adversos limitados y son efectivos contra las lesiones precancerosas del cuello de útero en las mujeres (Arbyn 2018). Desde la recomendación de la OMS de 2014 y la revisión sistemática original de los calendarios de vacunación contra el VPH de dos dosis (D'Addario 2017; OMS 2017), se ha ampliado la base de la evidencia de los ECA sobre los calendarios de vacunación alternativos y ahora incluye más datos sobre la vacuna nonavalente contra el VPH (Iversen 2016), sobre la vacunación contra el VPH en los hombres, incluidos los HSH (Giuliano 2011), y entre las personas que viven con la infección por VIH (Toft 2014). Esta revisión fue encargada inicialmente en 2016 por la Initiative for Vaccine Research de la OMS para actualizar la evidencia en cuanto a la recomendación de dos dosis y es una actualización de D'Addario 2017. Se produjo un protocolo revisado para esta actualización (Bergman 2017).

Las revisiones Cochrane generalmente incluyen solo ECA con variables de evaluación de la enfermedad clínica debido a que los ECA proporcionan el nivel más alto de certeza acerca de los resultados críticos de las intervenciones. Sin embargo, el precáncer y el cáncer no se desarrollan hasta muchos años después de la adquisición de la infección por VPH, por lo que es difícil determinar la eficacia de las vacunas en cuanto a estos resultados. La International Agency for Research on Cancer considera que la infección persistente por VPH es suficiente como marcador sustitutivo del cáncer de cuello de útero y anal y que la no inferioridad de la inmunogenicidad es suficiente para vincular los resultados a los menores de 16 años de edad. Por lo tanto, es importante documentar todos los resultados inmunológicos y de la infección medidos en los ECA de las vacunas contra el VPH, incluso si el uso previsto de la vacuna es la prevención del cáncer.

Esta revisión tiene como objetivo ampliar la base de evidencia sobre la eficacia y los efectos perjudiciales de las vacunas contra el VPH mediante la inclusión y la evaluación de ECA de diferentes vacunas contra el VPH y diferentes calendarios de dosis en adolescentes y adultos de ambos sexos, así como en mujeres y hombres que conviven con la infección por VIH.

Aunque los ECA pueden identificar los eventos adversos que tienen lugar durante el período de estudio, se necesita vigilancia posterior a la comercialización para continuar con el control de los efectos perjudiciales asociados con las vacunas contra el VPH en la población, lo cual se incorporará en las actualizaciones futuras de esta revisión.

Objetivos

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Evaluar la eficacia, la inmunogenicidad y los efectos perjudiciales de diferentes calendarios de dosis y diferentes tipos de vacunas contra el VPH en mujeres y hombres.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Se incluyeron ECA sin restricciones de idioma. Se incluyeron estudios no publicados, estudios en prensa y resúmenes sin una publicación de texto completo, cuando cumplían con los criterios de inclusión.

Tipos de participantes

Mujeres u hombres de 9 a 26 años de edad, incluidos los HSH. Para las comparaciones entre personas que conviven con el VIH, se incluyeron todos los grupos etarios.

Tipos de intervenciones

Administración profiláctica de vacunas autorizadas bivalentes (Cervarix, GlaxoSmithKline), cuadrivalentes (Gardasil, Merck) o nonavalentes (Gardasil 9, Merck) contra el VPH. Se excluyeron los estudios que evaluaron vacunas monovalentes o de plásmidos, o que evaluaron la administración no profiláctica de las vacunas bivalentes, cuadrivalentes o nonavalentes. Además, se consideró para la inclusión cualquier ensayo que informara sobre la eficacia, la inmunogenicidad o los eventos adversos en vacunas que se encuentran actualmente en la fase 2 o 3 de desarrollo. Se excluyeron los estudios que comparaban vacunas bivalentes frente a cuadrivalentes, debido a que se incluirán en una actualización de una revisión Cochrane por separado (Arbyn 2018).

Para los hombres y las personas que conviven con el VIH, se incluyeron comparaciones de las vacunas contra el VPH frente al placebo que no contienen ningún adyuvante o solo el adyuvante de la vacuna contra el VPH, u otra vacuna contra el VPH.

En esta revisión, se utiliza el término "control" para referirse a los productos de comparación que contienen otra vacuna o solo adyuvantes de la vacuna, independientemente de la terminología utilizada en los informes de los estudios individuales. Se utiliza el término "placebo" solo para hacer referencia a los productos de comparación que no contienen ningún adyuvante o vacuna activa. En «Características de los estudios incluidos» se informaron todos los detalles del tipo de compuesto del grupo de comparación.

La revisión se centró en diferentes calendarios de dosis y comparaciones entre diferentes tipos de vacunas contra el VPH. Cuando fue posible, se estratificaron los datos según las características de los participantes en cuanto a la edad, el sexo y el estado del VIH. Específicamente, el objetivo era investigar la eficacia, la inmunogenicidad y los efectos perjudiciales de:

menos de tres dosis de la vacuna contra el VPH en mujeres y hombres;
diferentes intervalos entre las dosis en un calendario de dos dosis en mujeres y hombres;
La vacunación contra el VPH comparada con el control para los hombres (se ha publicado una revisión Cochrane para las mujeres (Arbyn 2018));
vacuna nonavalente contra el VPH comparada con las otras vacunas contra el VPH en mujeres y hombres;
vacunación contra el VPH en personas que conviven con el VIH.

Tipos de medida de resultado

Resultados primarios

A menos que se indicara lo contrario, los resultados primarios se evaluaron en el período de seguimiento más largo informado por los estudios incluidos.

Cáncer invasivo de cuello de útero, vaginal, vulvar, anal o peniano
En las mujeres, neoplasia intraepitelial de cuello de útero, vaginal, vulvar o anal de grado alto confirmada histológicamente (NIC2, NIC3 y adenocarcinoma in situ), independientemente del genotipo del VPH, o cualquier lesión asociada con los genotipos del VPH incluidos en la vacuna
En los hombres, neoplasia intraepitelial anal, peniana, perianal o perineal de cualquier grado, independientemente del genotipo del VPH, o cualquier lesión asociada con los genotipos del VPH incluidos en la vacuna
Verrugas genitales
Eventos adversos relacionados con las vacunas: eventos adversos locales (eventos adversos generales locales/en el sitio de la inyección, enrojecimiento, inflamación, dolor en el sitio de la inyección), evaluados en los seguimientos informados en los ensayos (generalmente hasta siete días); eventos sistémicos generales y síntomas generales evaluados en los seguimientos informados en los ensayos (generalmente hasta 15 días)
Eventos adversos graves y mortalidad: cualquier evento que sea mortal, potencialmente mortal o que dé lugar a hospitalización y mortalidad. Se recopiló información de cada ensayo acerca de si estos eventos se consideraron relacionados con la vacuna y los métodos de monitorización y recopilación de los datos de los eventos adversos, incluido el modo de recopilación de datos, el momento adecuado, los métodos de atribución, la intensidad de la evaluación, las reglas de monitorización e interrupción relacionadas con los efectos perjudiciales y la presentación de informes basados en la frecuencia de los eventos (es decir, el filtro basado en la frecuencia), sobre la base de la extensión de la guía CONSORT para la presentación de informes de los efectos perjudiciales (Ioannidis 2004; Lineberry 2016).

Resultados secundarios

A menos que se indicara lo contrario, los resultados secundarios se evaluaron en el seguimiento más largo informado por los estudios incluidos.

Posible infección con genotipos de la vacuna contra el VPH (genotipos 16 y 18 del VPH conjuntamente; genotipos 6; 11; 16 y 18 del VPH conjuntamente; y genotipos 31; 33; 45; 52 y 58 del VPH conjuntamente)
Infección persistente (durante al menos seis meses o al menos 12 meses) por genotipos de la vacuna contra el VPH
Resultados inmunológicos (título de la media geométrica [TMG] y seropositividad), evaluados un mes después de la última dosis y en el seguimiento a más largo plazo

Para las comparaciones de los calendarios de dosis (es decir, número de dosis e intervalo/s más largo/s o más corto/s entre las dosis) se consideraron los resultados inmunológicos como resultados primarios debido a que estos ensayos se diseñaron para mostrar la no inferioridad de la inmunogenicidad. Aunque estos ensayos no se diseñaron para evaluar la eficacia ni la seguridad de las vacunas, se incluyeron resultados clínicos cuando se informaron y las estimaciones comparativas de los efectos perjudiciales asociados con los diferentes calendarios de dosis.

Métodos de búsqueda para la identificación de los estudios

We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress).

Búsquedas electrónicas

All searches were conducted on 27 September 2018. We searched the following electronic databases:

the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 9, 2018) (published in the Cochrane Library)
Ovid MEDLINE (1946 to September week 2 2018);
Ovid Embase (1980 to 2018 week 39).

The search terms used are detailed in Appendix 1, Appendix 2, and Appendix 3. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) to identify ongoing trials using 'genital warts', 'condyloma', 'anogenital warts', 'venereal warts', 'human papilloma virus vaccine', and 'HPV vaccine' as search terms.

Búsqueda de otros recursos

We searched the reference lists of all included studies, as well as the reference lists of any relevant systematic reviews published within the search dates. We searched vaccine manufacturer web sites for relevant clinical trial reports (GlaxoSmithKline; Merck). In addition, we screened a list of HPV vaccine studies (Jørgensen 2018a), that was constructed through enquiries to HPV vaccine manufacturers and regulators, as well as searches of trial registers and journal publication databases. For each included study, where available, we identified and screened study governance documents (protocols, trial registration listings and results, manufacturers' clinical study reports) for relevant data and outcomes. We also contacted the vaccine manufacturers through the WHO Initiative for Vaccine Research for any additional, potentially relevant studies.

Obtención y análisis de los datos

Selección de los estudios

Two experienced systematic reviewers independently screened citations and abstracts of studies identified from the electronic searches for potential inclusion. A third reviewer resolved any disagreements. We obtained full‐text reports for all potentially eligible studies. Two independent reviewers determined the eligibility of studies for inclusion in the review from the full reports according to predefined criteria. A third reviewer resolved any disagreements.

Extracción y manejo de los datos

For the purpose of the review, we named studies on the basis of the first‐named study author and year of publication. Many studies have more than one document associated with them: journal publications (main study reports, reports of long‐term follow‐up, secondary outcomes and post‐hoc analyses), conference abstracts, and study governance documents (protocols, trial registration listings and results, manufacturers' clinical study reports). For each study we grouped these documents together and designated one report as the primary reference for the study; the study name is derived from the name of the first author and year of publication of this particular report.

In cases where study reports emanate from the same parent study, but are planned or reported, or both, as distinct, discrete studies, we have named and handled these separately.

Two reviewers carried out data extraction independently using pretested data extraction forms. We resolved any differences by discussion between the two reviewers and referral to the study reports.

We cross‐checked data for the efficacy outcomes and adverse events between the primary trial publications, trial registries, and clinical study reports. We used the data derived from these sources with the longest follow‐up time for the primary analysis.

Evaluación del riesgo de sesgo de los estudios incluidos

Two reviewers independently carried out 'Risk of bias' assessments using the Cochrane 'Risk of bias' tool for all included studies (Higgins 2011b). We judged the risk of bias for each domain as 'low risk', 'unclear risk' or 'high risk'. We resolved differences by discussion between the two reviewers and if necessary we referred to a third reviewer for arbitration.

Medidas del efecto del tratamiento

We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. We calculated rate ratios with 95% CIs for dichotomous clinical outcomes reported as incidence rates. For outcomes with rare events (i.e. an event rate of < 10%), serious adverse events, and deaths, we calculated Mantel‐Haenszel odds ratios (OR) for dichotomous outcomes. We assessed the robustness of the primary analysis for very rare events with alternative statistical methods (see Sensitivity analysis).

For continuous geometric mean titre (GMT) data, we calculated inverse variance (IV) ratios of GMTs with 95% CIs. Initially, we transformed the point estimates as well as the lower and upper bound of the 95% CI of GMT for each group into the logarithmic scale in order to obtain statistically correct standard deviations. Then we calculated the mean difference of the compared group and back‐transformed the results (point estimate and 95% CIs) to the original scale through exponentiation. Non‐inferiority margins for immunological outcomes were derived from the individual trials (all trials used 0.5 for the GMT ratio). For GMT ratios non‐inferiority is demonstrated if the lower 95% CI is greater than 0.5. If the lower confidence interval was below the non‐inferiority margin, but the point estimate was within the margin, we considered the result to be inconclusive (Piaggio 2012).

For adverse events and efficacy outcomes we carried out a complete‐case analysis (the number analysed) and an intention‐to‐treat analysis when data were available. For immunogenicity outcomes assessed in non‐inferiority trials, we favoured data from per‐protocol analyses, in which all participants were HPV‐seronegative at baseline. We did not pool studies with participants who were HPV‐seropositive at baseline with studies with participants who were HPV‐seronegative at baseline.

Cuestiones relativas a la unidad de análisis

If a single trial compared two or more vaccine arms (with or without a control arm), we labelled the arms separately in analyses. We grouped suitable multiple treatment arms (e.g. arms that evaluated different vaccine lots) and excluded irrelevant trial arms. We did not pool data from cluster RCTs with those from individually randomised studies.

Manejo de los datos faltantes

If data on specific outcomes or population groups were missing, we attempted to contact study authors or data owners to request this data. We did not impute missing outcome data. Where data were missing or losses to follow‐up were substantial, we downgraded the certainty of study evidence due to risk of bias according to GRADE criteria (Guyatt 2011a).

Evaluación de la heterogeneidad

We described potential sources of clinical heterogeneity, and downgraded the certainty of the evidence according to GRADE criteria due to inconsistency where appropriate (Guyatt 2011b). When pooling of studies was feasible (i.e. at least two studies included), we inspected forest plots visually for potential outlying studies and variability in the estimated effects across studies. We assessed statistical heterogeneity using the I² statistic. This statistic quantifies the percentage of inconsistency in the treatment effects across studies beyond simple chance. We regarded heterogeneity as potentially unimportant if the I² was 0% to 40%; that values of 30% to 60% might represent moderate heterogeneity; values between 50% to 90% might represent substantial heterogeneity; and that values between 75% to 100% would represent considerable heterogeneity (Higgins 2011a). Where considerable heterogeneity existed (>75%), we did not pool study data.

Evaluación de los sesgos de notificación

We had planned to use funnel plots to investigate the possible presence of small‐study effects for each outcome. However, we did not produce funnel plots, due to the limited number of studies per outcome (i.e. fewer than 10) (Guyatt 2011c).

Síntesis de los datos

When pooling was considered feasible, we employed a random‐effects meta‐analysis using the DerSimonian and Laird method (DerSimonian 1986), as it was assumed that effect size might vary across studies and settings. We used data from the last available follow‐up for clinical and adverse event outcomes, with the number of participants (rather than the number of events) used in the analysis. For immunological outcomes, we extracted data from one month after the last HPV dose and at the longest‐term follow‐up.

To assess the harms associated with the HPV vaccine comparisons in this review, we recorded the methods used in each included study to collect adverse event data, and extracted data on common events that we determined a priori as: pain, swelling, redness at the injection site and overall systemic adverse events. For all serious adverse events reported in the included studies, we extracted the number of participants, participants with events and a description of the events. We also extracted information on whether the serious adverse events were considered to be related to the vaccines. We did not conduct statistical hypothesis testing because our protocol did not prespecify hypotheses about differences in the occurrence of any specific serious adverse event.

We prepared 'Summary of findings' tables for each comparison for which data were available for the following outcomes that were assessed as critical or important according to GRADE guidelines (Guyatt 2011d):

for females: high‐grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer; high‐grade vulval and vaginal disease;
for males: invasive anal or penile cancer, external genital lesions;
for all populations: anogenital warts, overall local/injection site adverse events, overall systemic events and general symptoms, serious adverse events, deaths;
for comparisons of dose schedules (i.e. number of doses and longer or shorter interval between doses): immunological outcomes.

We assessed the certainty of evidence in the review through discussion between review authors using the GRADE approach using GRADEpro online software (GRADEpro GDT). We assessed only the primary outcomes reported in the 'Summary of findings' tables and appendices using GRADE. We considered the following factors for downgrading: limitations in the study design (risk of bias); inconsistency of results (heterogeneity); indirectness of evidence (applicability); imprecision (few events and wide confidence intervals); and publication bias (Guyatt 2011a). When evidence was downgraded, we detailed the reasons in footnotes of the 'Summary of findings' tables and summarised these in the Quality of the evidence section. Depending on whether evidence was downgraded or not, we rated the certainty of the evidence for each outcome as follows:

high‐certainty evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect (evidence was not downgraded);
moderate‐certainty evidence indicates that we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different (evidence was downgraded one step for any of the factors described above);
low‐certainty evidence indicates that our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect (evidence was downgraded two steps for any of the factors described above);
very low‐certainty evidence indicates that we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect (evidence was downgraded three steps for any of the factors described above).

We reported relative risks (ORs or RRs) in the Effects of interventions section for all relevant outcomes, but where the evidence was of very low‐certainty we reported the number of events in each group only.

Análisis de subgrupos e investigación de la heterogeneidad

We performed subgroup meta‐analyses where possible, using vaccine type, gender, and age group (9 to 15 years; 16 to 26 years) as stratifying variables.

Análisis de sensibilidad

We carried out one post‐hoc sensitivity analysis for outcomes using a Mantel‐Haenszel odds ratio where events were very rare (i.e. an event rate of < 1% across both trial arms). We compared the results of the primary analysis calculated with Mantel‐Haenzsel methods against those with Peto methods (Bradburn 2007). We also planned to conduct sensitivity analyses for the primary outcomes according to allocation concealment (high risk of bias, low risk of bias, and unclear risk of bias) for outcomes for which data could not be pooled because of considerable heterogeneity (I² > 75%).

Results

Description of studies

Overall, 20 RCTs were included for analysis in this review (Figure 1). The characteristics of individual studies and assessment of risk of bias are presented in the Characteristics of included studies section and Figure 2.

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Results of the search

The search identified a total of 3852 records; 3298 from electronic databases and 554 from other sources (systematic reviews, vaccine manufacturers, online trial registrations, WHO IVR department, HPV study index (Jørgensen 2018a)). After de‐duplication, 3291 records remained. After excluding irrelevant abstracts, we assessed 528 full texts. We excluded 438 full texts and included 20 RCTs (reported in 69 published and unpublished reports) in this review for analysis (Denny 2013; Dobson 2013; Giuliano 2011; Hidalgo‐Tenorio 2017; Iversen 2016; Joura 2015; Lehtinen 2018; Leung 2015; Levin 2010; Lin 2014; NCT00941889 2016; NCT01031069 2017; NCT01862874 2018; Petaja 2009; Puthanakit 2016; Romanowski 2011; Toft 2014; van Damme 2016; Vesikari 2015; Wilkin 2018). We identified 15 ongoing studies (reported in 16 records) and two studies (reported in five references) are awaiting classification.

Included studies

We found 20 RCTs that contained data on vaccine efficacy or harms, or both, and enrolled a total of 31,940 men, women, and children. Ten studies were multi‐national and were carried out in two to 18 countries in Africa, Asia, Asia‐Pacific, Europe, Latin America, North America, and South America. The other 10 studies were carried out in one country only (USA, including Puerto Rico (3 studies), Finland (2), Canada (1), Denmark (1), Japan (1), Spain (1), South Africa (1)). Owing to differences in the protocols of the included trials, the maximum age for inclusion was either 25 or 26 years.

Description of studies

Four RCTs evaluated the effects of reduced dose schedules (Dobson 2013; Iversen 2016; Leung 2015; Romanowski 2011). All these trials were designed as non‐inferiority trials of antibody responses. They reported on immunogenicity as the primary outcome and on adverse events. None of these trials collected data on clinical events. These four RCTs evaluated the effects of two doses of HPV vaccine versus three doses of HPV vaccine in adolescent girls (9 to 15 years). We did not identify any RCTs that evaluated the efficacy or harms of one dose of HPV vaccine.

Four RCTs compared different intervals between doses. Two RCTs compared a longer interval two‐dose schedule with a shorter schedule (0 and 6 months versus 0 and 2 months; or 0 and 12 months versus 0 and 6 months) of bivalent HPV vaccine in 9‐ to 14‐year‐old females (Puthanakit 2016; Romanowski 2011). One RCT of nonavalent HPV vaccine compared a two‐dose schedule with a longer interval (0 and 12 months) and a shorter interval (0 and 6 months) in 9‐ to 14‐year‐old females and males (Iversen 2016). One RCT compared a longer interval three‐dose schedule (administered at 0, 2 and 12 months) with a shorter schedule (administered at 0, 2 and 6 months) of quadrivalent HPV vaccine in 18‐ to 25‐year‐old males (Lin 2014).

Two RCTs compared quadrivalent HPV vaccine versus control in 5189 males aged 16 to 26 years (Giuliano 2011; NCT01862874 2018). A subgroup analysis of Giuliano 2011 also reported on the efficacy and harms of the quadrivalent HPV vaccine compared with control vaccine in MSM. Giuliano 2011 reported on clinical, adverse event, and immunogenicity outcomes, and NCT01862874 2018 reported on clinical outcomes and adverse events. One RCT compared bivalent HPV vaccine versus control hepatitis B virus (HBV) vaccine in 270 boys aged 10 to 18 years and reported on immunogenicity and harms (Petaja 2009). In addition, a cluster‐RCT investigating both direct and indirect effects of HPV vaccination of girls and boys (gender‐neutral) and girls‐only vaccination reported on adverse events in a subgroup of 3703 12‐ to 15‐year‐old males vaccinated with the bivalent vaccine or control HBV vaccine (Lehtinen 2018). We identified no studies investigating the clinical efficacy of the nonavalent vaccine in males.

Three RCTs compared three doses of nonavalent vaccine with three doses of quadrivalent vaccine: one in 9‐ to 15‐year‐old females (Vesikari 2015), one in 16‐ to 26‐year‐old females (Joura 2015), and one in males aged 16 to 26 years (van Damme 2016). Joura 2015 reported clinical outcomes for the 16‐ to 26‐year‐old population. All three studies reported on adverse event and immunogenicity outcomes.

Studies including participants living with HIV

We identified seven RCTs that examined HPV vaccines in 1723 people living with HIV (Denny 2013; Hidalgo‐Tenorio 2017; Levin 2010; NCT00941889 2016; NCT01031069 2017; Toft 2014; Wilkin 2018):

Toft 2014 compared bivalent with quadrivalent vaccine in females and males ≥ 18‐years old;
NCT01031069 2017 compared bivalent with quadrivalent vaccine in 15‐ to 25‐year‐old females;
Denny 2013 compared bivalent vaccine with control in women aged 18 to 25 years;
Hidalgo‐Tenorio 2017 compared quadrivalent vaccine with control in MSM ≥ 18‐years old;
Wilkin 2018 compared quadrivalent vaccine with control in females and males ≥ 27‐years old;
NCT00941889 2016 compared quadrivalent vaccine with control in females and males ≥ 18‐years old that had been treated for anogenital warts;
Levin 2010 compared three doses of quadrivalent vaccine with control in 126 children aged 7 to 12 years, and four versus three doses of quadrivalent vaccine in the same participants.

The studies were carried out in Brazil, Denmark, Estonia, India, South Africa, Spain, Thailand, and the USA, including Puerto Rico. Of these, only two reported on clinical outcomes (NCT00941889 2016; Wilkin 2018), as most were designed as non‐inferiority trials of antibody responses.

Adverse events

Appendix 4 lists the methods used to collect adverse event data. The mode of data collection was reported in 16 of the 20 studies and was passive in two studies (e.g. patients recording symptoms on diary cards); proactive in three (e.g. investigators observing participants after vaccine administration, or field workers visiting or calling participants in their homes); both passive and proactive in nine studies; and in two studies, the details were insufficient for us to categorise as passive or proactive. Time frame (duration of follow‐up) was reported for all but three studies; for two studies it was unclear, and one study did not report on adverse events (NCT00941889 2016). Methods to determine the relationship between vaccination and adverse events were reported by 10 studies: attribution was done by study investigators in nine studies and by a study co‐ordinator in one study. Where the attribution method was not reported, we assumed this role was performed by study investigators. Fourteen studies (74%) provided definitions for the adverse events outcomes. Withdrawals due to adverse events were reported in 14 (70%) studies, but most studies (95%) did not report on how withdrawals would be handled in the analysis. Only one study reported harms‐related monitoring and stopping rules (Hidalgo‐Tenorio 2017). Seventeen studies reported on all adverse events regardless of frequency (i.e. they did not use a frequency‐based filter); NCT01862874 2018 used a 5% threshold for other adverse events; it was unclear whether Dobson 2013 used a filter, and one study did not report on adverse events (NCT00941889 2016).

The length of follow‐up for serious adverse events in the included studies ranged from seven months to five years. Table 1 lists the serious adverse events reported in each study. In all studies, the individual serious events were listed for each study arm. In five of the 20 RCTs, 50 or more serious adverse events were reported (Joura 2015, Lehtinen 2018; Puthanakit 2016; Romanowski 2011; Wilkin 2018). Information on whether serious adverse events were considered to be related to the vaccine is reported in the section Effects of interventions.

Studies awaiting classification

We identified two studies that included both males and females randomised to HPV vaccine and control (Li 2012; Reisinger 2007). The male population in these studies would qualify for inclusion in our review, but at the time of preparing this review we were not able to access data for males only. We have requested this information from the study investigators and, should these data become available, they will be included in a future update of this review.

Li 2012 and Reisinger 2007 both compared quadrivalent HPV vaccine to vaccine adjuvant‐containing control in 9‐ to 15‐year‐old males. The studies reported on the comparison of males with females for immunogenicity outcomes and adverse events for males and females as one group. Li 2012 was carried out in China, and Reisinger 2007 was carried out in 10 countries in North America, Latin America, Europe and Asia. See Characteristics of studies awaiting classification for further details.

Ongoing studies

We identified 15 potentially relevant ongoing studies that have not been completed, but might be relevant for inclusion in future updates of this review. All studies are RCTs and studies may appear in more than one category of the list below:

eight include healthy females (NCT01735006; NCT02009800; NCT02405520; NCT02562508; NCT02733068; NCT02740777; NCT02834637; NCT03180034);
four include healthy males and females (NCT01824537; NCT02567955; NCT02710851; NCT02888418);
one includes HIV‐positive MSM (NCT02087384);
one includes males and females cured of genital warts (NCT03296397);
one includes females with genital warts (NCT02750202);
seven are evaluating new vaccines in development in China (NCT01735006; NCT02405520; NCT02562508; NCT02710851; NCT02733068; NCT02740777; NCT02888418);
four are evaluating the quadrivalent vaccine (NCT02009800; NCT02087384; NCT02750202; NCT03296397);
one is evaluating the nonavalent vaccine (NCT01824537); and
three are comparing the bivalent to the nonavalent vaccine (NCT02567955; NCT02834637; NCT03180034).

In addition to the seven studies ongoing in China, three of these studies are ongoing in Canada, and one study each in Costa Rica, France, the Netherlands, South Africa, and Tanzania. See Characteristics of ongoing studies for further details.

Excluded studies

We excluded 438 full texts. Twenty‐two of these were potentially relevant studies, and the reasons for their exclusion are included in the Characteristics of excluded studies table. We excluded six studies because they were not RCTs, and two studies because they included females over 26 years of age. Most of the excluded studies contained no comparison of relevance to the review: seven studies compared HPV‐vaccinated to HPV‐unvaccinated females, five compared different intervals in three‐dose schedules in females, one compared three‐dose schedules of the bivalent and quadrivalent vaccine in young females, and one evaluated the effect of a booster dose of HPV vaccine.

Risk of bias in included studies

The risk of bias for each included study is detailed in Characteristics of included studies and an overview is presented in Figure 2. Overall risk of bias for each comparison is discussed in each results section below.

Allocation

We assessed most studies as being at low risk of selection bias, as they reported adequate randomisation sequence generation (15/20 = 75%) and allocation concealment procedures (15/20 = 75%). Five studies did not report their methods to conceal allocation adequately (Levin 2010; Lin 2014; NCT01031069 2017; NCT00941889 2016; NCT01862874 2018), and five did not report the method of sequence generation adequately (Levin 2010; NCT01031069 2017; NCT00941889 2016; NCT01862874 2018; Wilkin 2018); we assessed them as being at unclear risk of bias.

Blinding

Blinding of participants and providers was explicitly reported by less than half of the included studies (7/20 = 35%), we assessed those studies that did as being at low risk of performance bias. We assessed eight studies as being at unclear risk of performance bias as they did not report blinding status of participants and personnel clearly (Denny 2013; Hidalgo‐Tenorio 2017; Levin 2010; NCT00941889 2016; NCT01031069 2017; NCT01862874 2018; Romanowski 2011; Wilkin 2018), and five studies as being at high risk of performance bias due to no, or partial blinding, of participants, personnel, or both (Dobson 2013; Lehtinen 2018; Puthanakit 2016; Iversen 2016; Lin 2014).

Less than half of the studies reported adequate blinding of outcome assessors (9/20 = 45%); we considered those that did to be at low risk of detection bias. Eight studies did not report details regarding blinding of outcome assessment and we assessed them as being at unclear risk of bias (Denny 2013; Hidalgo‐Tenorio 2017; Levin 2010; Lin 2014; NCT01031069 2017; NCT00941889 2016; NCT01862874 2018; Wilkin 2018), and three studies did not blind outcome assessment and were assessed as being at high risk of detection bias (Iversen 2016; Lehtinen 2018; Puthanakit 2016).

Incomplete outcome data

We assessed most included studies (18/20 = 90%) as having a low risk of attrition bias, as they reported withdrawals and provided adequate reasons for dropouts. We assessed one study as having a high risk of attrition bias because only a subgroup of included participants were analysed (Lehtinen 2018). We assessed another study as having a high risk of attrition bias because data for 62.5% (20/32) of the participants enrolled were missing due to early withdrawals from the study (NCT00941889 2016).

Selective reporting

For the majority of studies (16/20 = 80%) either a study protocol or clinical trial registry entry was available to determine that selective reporting was unlikely; we assessed these studies as having a low risk of reporting bias. We assessed four studies as having a high risk of selective reporting bias; Lehtinen 2018 because most outcomes were not reported separately for boys and girls, indeed, only adverse events were reported separately in boys, but in a selected subset; NCT00941889 2016 because predetermined outcomes, including serious adverse events, were not reported; NCT01031069 2017 because not all outcomes listed in the online trial record were reported in the trial result summary report; and NCT01862874 2018 because HPV disease was not reported as a separate outcome, but were reported as an outcome combined with persistent HPV infection.

Other potential sources of bias

All included studies provided a statement of the funding source for the trial. Thirteen studies were funded by the vaccine manufacturers (GSK, Merck or Sanofi Pasteur) and we rated them as having an unclear risk of other bias. Industry sponsored studies are associated with favourable efficacy results and conclusions (Lundh 2017) which may be mediated by factors other than those assessed by the Cochrane 'Risk of bias' tool. We also rated a further two studies as having an unclear risk of other bias because no published report was identified for either (NCT00941889 2016; NCT01031069 2017), and we extracted data from the clinical trials records, which provided insufficient information to establish whether there was a risk of other bias. We assessed the remaining five studies as being at low risk of other bias (Dobson 2013; Toft 2014; Hidalgo‐Tenorio 2017; Levin 2010; Wilkin 2018).

Effects of interventions

1. Two doses of HPV vaccine versus three doses of HPV vaccine in 9‐ to 15‐year‐old females or males

The results for this comparison are presented in summary of findings Table for the main comparison and Appendix 5. We analysed four studies in females that compared two doses (months 0 and 2, or 0 and 6, or 0 and 12) versus three doses (months 0, 1, and 6; or 0, 2, and 6) of HPV vaccine (Dobson 2013; Iversen 2016; Leung 2015; Romanowski 2011), and reported immunogenicity outcomes (seven months to five years) for all vaccine types and adverse event outcomes throughout the study period (one to five years). No studies included for this comparison collected data about clinical outcomes. No evidence was found from RCTs making this comparison in males.

Immunogenicity results comparing two doses with three doses of HPV vaccine are reported in Appendix 5. Briefly, two doses were non‐inferior to or had higher GMTs than three doses for all nine HPV genotypes measured except HPV 45 (where non‐inferiority was inconclusive) one month after the last dose (moderate‐ to high‐certainty evidence). For seroconversion one month after the last dose, there was evidence of little to no difference between groups for all nine HPV genotypes measured (high‐certainty evidence). At 60‐month follow‐up after the first dose, non‐inferiority of two doses of bivalent vaccine was inconclusive for GMTs of HPV 16 and HPV 18 (low‐certainty evidence). Two doses of quadrivalent vaccine resulted in non‐inferior GMTs for HPV 6, HPV 11 and HPV 16, while results were inconclusive for HPV 18 (low‐certainty evidence). At 36‐month follow‐up after the first dose, two doses of nonavalent vaccine resulted in non‐inferior GMTs for all HPV genotypes measured except HPV 45 and HPV 52 where non‐inferiority was inconclusive (high‐certainty evidence).

Two studies found that two doses of HPV vaccine resulted in little to no difference in pain at the injection site compared with three doses of HPV vaccine (RR 0.96, 95% CI 0.91 to 1.03; 2 studies; 1189 participants; Analysis 1.1), but reduced swelling (RR 0.76, 95% CI 0.65 to 0.89; 2 studies; 1189 participants; Analysis 1.2) and redness (RR 0.85, 95% CI 0.75 to 0.96; 2 studies; 1189 participants; Analysis 1.3) at the injection site at up to seven days follow‐up. The comparative evidence about serious adverse events was considered to be of very low‐certainty (risk with two doses 36/1158, risk with three doses 35/1159; 4 studies; 2317 participants; Analysis 1.4). We downgraded certainty for imprecision and indirectness of the composite measure of all serious adverse events, which may or may not be clinically relevant, may or may not be related to the vaccine, and may occur outside a biologically plausible time frame relative to vaccine exposure. Two of the studies reported on withdrawals from the study and reported that no participants had withdrawn because of adverse events. One death was reported in the three‐dose group (1/898) and no deaths (0/899) in the two‐dose group (OR 0.33, 95% CI 0.01 to 8.19; 3 studies; 1797 participants; low‐certainty evidence; Analysis 1.5).

2. Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females or males

The results for this comparison are presented in summary of findings Table 2 and Appendix 6. We included three studies in females that compared two doses with a longer interval between the first and second doses (months 0 and 6 or 12) with a shorter interval between the first and second doses (months 0 and 2 or 6) for immunogenicity outcomes at seven months for all vaccine types and adverse event outcomes throughout the study period (one to five years) (Iversen 2016; Puthanakit 2016; Romanowski 2011). One of these studies compared a longer interval (months 0 and 12) with a shorter interval (months 0 and 6) in males (Iversen 2016). No studies included for this comparison collected data about clinical outcomes. As each study compared different intervals, we did not pool the results in the meta‐analysis.

Immunogenicity results are reported in Appendix 6. At one month after the final dose, there was evidence of higher (and non‐inferior) GMTs for HPV 16 and HPV 18 with the longer interval schedules compared with the shorter intervals in 9‐ to 14‐year‐old females who received bivalent HPV vaccine (moderate‐ to high‐certainty evidence). There was also evidence of higher GMTs for HPV 16 and HPV 18 at 36 months with the longer interval schedules compared with the shorter intervals in 9‐ to 14‐year‐old females who received bivalent HPV vaccine (high‐certainty evidence). For seroconversion to HPV 16 and HPV 18, there was evidence of no difference between groups one month after the final dose (high‐certainty evidence). For the nonavalent vaccine in girls and boys, there was evidence that a longer interval produced higher and non‐inferior GMTs than a shorter interval for all HPV genotypes (high‐certainty evidence).

In Romanowski 2011 there was little to no difference in pain (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 477 participants; Analysis 2.1), swelling (RR 0.95, 95% CI 0.76 to 1.20; 1 study; 477 participants; Analysis 2.2), or redness at the injection site (RR 1.02, 95% CI 0.84 to 1.24; 1 study; 477 participants; Analysis 2.3) when comparing a two‐month interval between doses to a six‐month interval. In Puthanakit 2016 there was also little to no difference in pain (RR 1.02, 95% CI 0.98 to 1.06; 1 study; 963 participants; Analysis 2.1), swelling (RR 1.01, 95% CI 0.87 to 1.18; 1 study; 963 participants; Analysis 2.2), or redness at the injection site (RR 1.06, 95% CI 0.93 to 1.22; 1 study; 963 participants; Analysis 2.3) when comparing a six‐month interval between doses to a 12‐month interval.

The evidence about serious adverse events was considered to be of very low‐certainty, due to imprecision and indirectness, for comparisons of a two‐month (14/240) versus a six‐month (16/241) interval (1 study; 481 participants; Analysis 2.4) (Romanowski 2011), and of a six‐month (20/550) versus a 12‐month (24/415) interval (1 study; 965 participants; Analysis 2.4) (Puthanakit 2016). The evidence about serious adverse events was also considered to be of very low‐certainty for the comparison of an interval of six months (15/602) versus 12 months (6/301) between doses of the nonavalent vaccine (1 study; 903 participants; Analysis 2.4) (Iversen 2016). The Iversen 2016 study reported on serious adverse events in males and females, but disaggregated data were not available by sex (Table 1). One of the reported serious adverse events (one case of systemic lupus erythematosus) in the 12‐month interval group (Puthanakit 2016), was considered by the study investigators to be related to the vaccine and was the only withdrawal from the studies because of adverse events. No deaths were reported in any of the included trials (Analysis 2.5).

3. Longer interval versus shorter interval between second and third doses of quadrivalent HPV vaccine in 18‐ to 25‐year‐old males

The results for this comparison are presented in Appendix 7. We included one study that compared three doses of quadrivalent HPV vaccine with a longer interval between the second and third doses (doses administered at months 0, 2, and 12) against a shorter interval between the second and third doses (doses administered at months 0, 2, and 6) (Lin 2014). For the immunogenicity outcomes (Appendix 8), there was evidence of higher GMTs for HPV 11 with the longer interval schedule compared with the shorter schedule at one month (2 to 6 weeks test window allowed) after the last dose. For GMTs for HPV 6, 16, and 18, there was evidence of little to no difference between groups. The study did not collect data about clinical outcomes.

This study reported local, general, and serious adverse events. No usable data were available for analysis of local and general adverse events so we summarised the results in Analysis 3.1. Briefly, among all study participants 172 local and general reactions were reported. The authors reported no significant difference between groups (P = 0.26). No serious adverse events were reported (120 participants; Analysis 3.2).

4. HPV vaccines versus control in 10‐ to 26‐year‐old males

The results for this comparison are presented in summary of findings Table 3. Two studies compared quadrivalent HPV vaccine with control (vaccine adjuvant only) (three doses administered at months 0, 2, and 6) in males (Giuliano 2011, NCT01862874 2018), and two studies compared bivalent vaccine with HBV vaccine (Lehtinen 2018; Petaja 2009). Lehtinen 2018, a cluster‐randomised trial, was designed to investigate direct and indirect effects of vaccinating boys and girls (gender‐neutral) compared with girls‐only HPV vaccination. They reported that gender‐neutral vaccination was associated with herd effects and cross‐protection against a number of non‐vaccine HPV types. Clinical outcomes in girls are presented in another Cochrane Review (Arbyn 2018), which covers comparison of bivalent and quadrivalent HPV vaccine with a control HBV vaccine in females; no clinical outcomes in boys were reported.

One study reported clinical outcomes at a median of 2.9 years (Giuliano 2011). There were fewer outcomes of external genital lesions (any genotype) (rate ratio 0.16, 95% CI 0.07 to 0.38; 1 study; 2545 participants; 6254 person‐years; moderate‐certainty evidence; Analysis 4.1), external genital lesions (HPV 6, 11, 16, 18) (rate ratio 0.10, 95% CI 0.03 to 0.31; 1 study; 2805 participants; 5643 person‐years; Analysis 4.2), and anogenital warts (rate ratio 0.11, 95% CI 0.03 to 0.38; 1 study; 2805 participants; 5645 person‐years; moderate‐certainty evidence; Analysis 4.3) with the quadrivalent HPV vaccine than the control, in both intention‐to‐treat and per‐protocol analyses (per‐protocol analyses not shown). There was evidence in favour of quadrivalent HPV vaccine for the outcomes of all penile, perianal, or perineal intraepithelial neoplasia (PIN) lesions (rate ratio 0.17, 95% CI 0.01 to 3.27; 1 study; 2805 participants; 5657 person‐years; Analysis 4.4), PIN grade 1 (rate ratio 0.25, 95% CI 0.01 to 6.22; 1 study; 2805 participants; 5659 person‐years; Analysis 4.5), or PIN grade 2 or 3 (rate ratio 0.50, 95% CI 0.02 to 14.80; 1 study; 2805 participants; 5658 person‐years; Analysis 4.6), with confidence intervals that included the possibility of both fewer and more events with the quadrivalent vaccine (low‐certainty evidence for all outcomes).

In the quadrivalent vaccine group, there were more overall local/injection site adverse events than with the control (RR 1.12, 95% CI 1.06 to 1.18; 1 study; 3895 participants; high‐certainty evidence; Analysis 4.7); the events included pain at injection site (RR 1.13, 95% CI 1.07 to 1.19; 2 studies; 5162 participants; Analysis 4.8), swelling at injection site (RR 1.29, 95% CI 1.04 to 1.60; 2 studies; 5162 participants; Analysis 4.9), and redness at injection site (RR 1.12, 95% CI 0.99 to 1.27; 2 studies; 5162 participants; Analysis 4.10). There was little to no difference in overall systemic events and general symptoms (RR 0.99, 95% CI 0.90 to 1.08; 2 studies; 5008 participants; moderate‐certainty evidence; Analysis 4.11) at 15‐day follow‐up. The bivalent HPV vaccine resulted in more pain (RR 1.99, 95% CI 1.57 to 2.53; 1 study; 268 participants; Analysis 4.8), swelling (RR 2.51, 95% CI 1.17 to 5.42; 1 study; 268 participants; Analysis 4.9), and redness (RR 1.66, 95% CI 0.99 to 2.79; 1 study; 268 participants; Analysis 4.10) at the injection site than the HBV vaccine (Petaja 2009).

Evidence about serious adverse events in the Giuliano 2011 study was of very low‐certainty due to imprecision and indirectness (8/2574 participants (0.3%) in the quadrivalent vaccine group and 12/2588 participants (0.5%) in the control group; 2 studies; Analysis 4.12). None of the reported serious adverse events was considered by the study investigators to be vaccine‐related. Two participants from the quadrivalent group and seven participants from the control group discontinued participation in the studies because of adverse events. There were fewer deaths in the group that received quadrivalent vaccine (3 deaths in quadrivalent group; 11 deaths in control group), but confidence intervals for the difference were compatible with no effect (OR 0.30, 95% CI 0.09 to 1.01; 2 studies; 5173 participants; low‐certainty evidence; Analysis 4.13) at up to three years of follow‐up (Giuliano 2011). Lehtinen 2018 reported on serious adverse events for a selected subset of males (data not shown). Fifty‐eight of the 2436 subset participants (2.4%) who received the HPV vaccine and 25/1267 subset participants (2.0%) who received the control HBV vaccine experienced serious adverse events (very low‐certainty evidence). The investigators reported that four serious adverse events among the males who received the HPV vaccine (abdominal pain, ulcerative colitis, type 1 diabetes mellitus, juvenile idiopathic arthritis) could possibly be vaccine‐related and one event among the males who received the control (type 1 diabetes mellitus) could possibly be vaccine‐related. In the study on bivalent vaccine (Petaja 2009), three serious adverse events were reported in the bivalent vaccine group (3/181) and one in the control group (1/89) (Analysis 4.12; very low‐certainty evidence). The study investigators did not consider these to be related to the vaccine, and no deaths were reported in either group.

For the secondary outcome of persistent HPV infection, there was evidence that quadrivalent HPV vaccine reduced persistent infection caused by HPV 6, 11, 16 or 18 combined, or by each HPV genotype individually, in 16‐ to 26‐year‐old males compared with control (Appendix 9).

The Giuliano 2011 study also reported immunogenicity outcomes (data not shown). Briefly, there was evidence that quadrivalent vaccine increased GMTs for HPV 6, 11, 16 and 18 when compared with control at 7, 24 and 36 months. There was a trend towards GMTs levelling off after reaching a peak at month seven. Comparative data between quadrivalent vaccine and control were not available for the seropositivity outcomes (control group data not reported), but seropositivity for HPV 6, 11, 16 and 18 at seven months was above 97%. Petaja 2009 also reported immunogenicity outcomes seven months after the first dose of bivalent vaccine were higher than the HBV vaccine (Appendix 10).

5. Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males

The results of this comparison are presented in summary of findings Table 4. We included three RCTs that compared nonavalent with quadrivalent HPV vaccine (three doses administered at months 0, 2, and 6): two in females (Joura 2015; Vesikari 2015), and one in males (van Damme 2016). The Joura 2015 study collected data on clinical outcomes in females at up to 4.5 years follow‐up. All three trials reported adverse event outcomes throughout the study period and immunogenicity outcomes at seven months for all vaccine types. We did not identify any studies that collected data about clinical outcomes in males.

In females there was little to no difference between nonavalent and quadrivalent HPV vaccines in the incidence of the combined outcome of high‐grade cervical epithelial neoplasia, adenocarcinoma in situ, or cervical cancer (OR 1.00, 95% CI 0.85 to 1.16; 1 study; 13,753 participants; high‐certainty evidence; Analysis 5.1), or high‐grade cervical, vulval, or vaginal disease (OR 0.99, 95% CI 0.85 to 1.15; 1 study; 14,054 participants; high‐certainty evidence; Analysis 5.2) at up to 4.5 years follow‐up. For high grade cervical disease related to HPV 31, 33, 45, 52, or 58 (i.e. genotypes covered by the nonavalent vaccine but not the quadrivalent vaccine), the effect was in favour of the nonavalent vaccine (OR 0.03, 95% CI 0.00 to 0.21; 1 study; 11,892 participants; Analysis 5.5), but few cases were reported (1/5949 women in the nonavalent vaccine group and 35/5943 women in the quadrivalent vaccine group).

Nonavalent HPV vaccine resulted in slightly more local/injection site adverse events than the quadrivalent vaccine (RR 1.07, 95% CI 1.05 to 1.08; 3 studies; 15,863 participants; high‐certainty evidence; Analysis 5.11). There was little to no difference between the vaccines for overall systemic events and general symptoms at 15‐day follow‐up (RR 1.01, 95% CI 0.98 to 1.04; 3 studies; 15,863 participants; moderate‐certainty evidence, Analysis 5.15). For serious adverse events overall, the evidence was considered to be of low‐certainty due to imprecision and indirectness (OR 0.60, 95% CI 0.14 to 2.61; 3 studies; 15,863 participants; I² = 51%; Analysis 5.16). One study reported similar numbers of events (1/299 with the nonavalent vaccine, 2/300 with the quadrivalent vaccine) in females aged 9 to 15 years over a period of 7 months follow‐up (Vesikari 2015). In males, there were no events in 249 participants receiving the nonavalent vaccine and 6/251 with the quadrivalent vaccine over a period of 7 months follow‐up (van Damme 2016). In the largest study, in 16‐ to 26‐year‐old females, 3.1% (242/7686) of those who received the nonavalent vaccine and 2.6% (184/7078) of those who received the quadrivalent vaccine experienced any serious adverse event after up to 4.5 years of follow‐up (Joura 2015). No serious adverse events, when analysed by system organ class, were more common with the nonavalent than with the quadrivalent vaccine. The study authors examined 2269 pregnancy‐related events in 2321 women and found no differences between the nonavalent and quadrivalent vaccine arms. The study investigators considered seven serious adverse events to be related to the vaccines, four in the nonavalent group (allergic reaction; fever, body pain, and headache; hypersomnia; postural orthostatic tachycardia syndrome) and three in the quadrivalent group (headache; paraesthesia and burning sensation; orthostatic intolerance). Thirteen participants who received nonavalent vaccine and six who received quadrivalent vaccine discontinued participation because of adverse events. There was little to no difference in the number of deaths between nonavalent (6/7370) and quadrivalent (5/7378) HPV vaccine groups (OR 1.20, 95% CI 0.37 to 3.94; 2 studies; 15,248 participants; low‐certainty evidence; Analysis 5.17) at up to 4.5 years follow‐up. The study investigators considered none of the deaths reported to be related to the vaccine.

Secondary outcomes (persistent infection and immunogenicity) are presented in Appendix 11 and Appendix 12. Briefly, there was evidence of decreased rates of persistent infection with HPV 31, 33, 45, 52, and 58 at six and 12 months with nonavalent vaccine compared with quadrivalent vaccine (Joura 2015). There was little to no difference in immunogenicity between the nonavalent and quadrivalent HPV vaccines and GMTs were non‐inferior for HPV 6, 11, 16, and 18 at up to 42 months. The nonavalent HPV vaccine resulted in substantially higher GMTs for HPV 31, 33, 45, 52, and 58 than the quadrivalent HPV vaccine. For seroconversion to HPV 6, 11, 16, and 18 up to 24 months follow‐up, 100% of participants seroconverted in both the nonavalent and quadrivalent HPV vaccine groups. The data for GMTs and seroconversion to HPV 31, 33, 45, 52, and 58 were not reported in full (Joura 2015; Vesikari 2015).

6. HPV vaccination in HIV‐positive females, males and MSM

Seven RCTs reported on the effects of bivalent and quadrivalent HPV vaccines in females, males, or children living with HIV (Denny 2013; Hidalgo‐Tenorio 2017; Levin 2010; NCT00941889 2016; NCT01031069 2017; Toft 2014; Wilkin 2018). Two of the studies collected data about clinical outcomes such as anal intraepithelial neoplasia, anogenital warts or persistent infection (NCT00941889 2016; Wilkin 2018). These results are summarised in Table 3; Table 4; and Table 5.

Table 3. Summary of findings: Quadrivalent HPV vaccine compared with control in children, adults, and MSM with HIV

Quadrivalent HPV vaccine compared with control in children, adults, and MSM with HIV
Patient or population: children (7 to 12 years old) with HIV, adults (≥ 18 years old) with HIV, and MSM (≥ 18 years old) with HIV Settings: Brazil, Puerto Rico, Spain, the USA Intervention: quadrivalent HPV vaccine (3 doses at 0, 2, and 6 months) Comparison: control (3 doses at 0, 2 and 6 months; not specified whether placebo contained vaccine adjuvant)
Outcomes	Population	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Outcomes	Population	Risk with control	Risk with quadrivalent HPV vaccine	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
High‐grade anal intraepithelial neoplasia at 4‐year follow‐up	Females and males with HIV (≥ 27 years)	157 per 1000	160 per 1000 (110 to 233)	RR 1.02 (0.70 to 1.48)	574 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
Recurrence of anogenital warts at 18‐month follow‐up	Females and males with HIV treated for anogenital warts (18‐65 years)	200 per 1000	143 per 1000 (7 to 778)	RR 0.71 (0.06 to 8.90)	12 (1 study)	⊕⊝⊝⊝ VERY LOW^2,3
Abnormal anal cytology at 4‐year follow‐up	Females and males with HIV (≥ 27 years)	545 per 1000	447 per 1000 (349 to 573)	RR 0.82 (0.64 to 1.05)	262 (1 study)	⊕⊝⊝⊝ VERY LOW^1,4
Overall local/injection site adverse events at 15‐day follow‐up	Children with HIV (7‐12 years)	100 per 1000	219 per 1000 (70 to 683)	RR 2.19 (0.70 to 6.83)	126 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
Overall systemic events and general symptoms at 15‐day follow‐up	Children with HIV (7‐12 years)	33 per 1000	21 per 1000 (2 to 235)	RR 0.62 (0.05 to 7.05)	126 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2,6
Serious adverse events at 4‐year follow‐up (adults) or 7‐month follow‐up (MSM)	Females and males with HIV (≥ 27 years)	160 per 1000	115 per 1000 (74 to 174)	OR 0.68 (0.42 to 1.10)	575 (1 study)	⊕⊝⊝⊝ VERY LOW^1,4,6,7
	MSM with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	129 (1 study)	⊕⊝⊝⊝ VERY LOW^5,6,7
Mortality at 4‐year follow‐up (adults) or 7‐month follow‐up (MSM)	Females and males with HIV (≥ 27 years)	21 per 1000	10 per 1000 (3 to 41)	OR 0.49 (0.12 to 1.99)	575 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
	MSM with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	129 (1 study)	⊕⊕⊝⊝ LOW⁵
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; MSM: men who have sex with men; OR: odds ratio; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Downgraded one level for risk of bias: details about how randomisation sequence was generated or how blinding was achieved were not reported.

²Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potentially beneficial effect and a potentially harmful effect.

³Downgraded two levels for serious risk of bias: data for 62.5% (20/32) of the participants enrolled were missing due to lack of follow‐up. In addition, details about how randomisation, allocation concealment, and blinding were achieved were not reported.

⁴Downgraded two levels for imprecision: few events and wide 95% confidence interval that incorporated a potential beneficial effect and no effect.

⁵Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in serious adverse events or mortality.

⁶Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety.

⁷See Table 1 for details of each serious event.

Table 4. Summary of findings: Bivalent HPV vaccine compared with control in 18‐ to 25‐year‐old females with HIV

Bivalent HPV vaccine compared with control in 18‐ to 25‐year‐old females with HIV
Patient or population: 18‐ to 25‐year‐old females with HIV Settings: South Africa Intervention: bivalent HPV vaccine (3 doses at 0, 1, and 6 months) Comparison: control (vaccine adjuvant‐containing placebo) (3 doses at 0, 1 and 6 months)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Risk with control	Risk with bivalent HPV vaccine
High‐grade cervical epithelial neoplasia, adenocarcinoma in situ, and cervical cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, and vaginal disease	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain and swelling at injection site) are presented in the Data and analyses and Effects of interventions sections.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at 12‐month follow‐up	34 per 1000	49 per 1000 (8 to 243)	OR 1.47 (0.24 to 9.15)	120 (1 study)	⊕⊝⊝⊝ VERY LOW^1,3,4
Mortality at 12‐month follow‐up	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	120 (1 study)	⊕⊕⊝⊝ LOW²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; OR: odds ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potentially large beneficial effect and a potentially large harmful effect.

²Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in mortality.

³Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety.

⁴See Table 1 for details of each serious event.

Table 5. Summary of findings: Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults with HIV

Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults with HIV
Patient or population: adults and adolescents (combined male and female) with HIV, ≥ 15 years old Settings: Brazil, Denmark, Estonia, India, and Thailand Intervention: bivalent HPV vaccine (3 doses at 0, 1.5, and 6 months) Comparison: quadrivalent HPV vaccine (3 doses at 0, 1.5, and 6 months)
Outcomes	Population	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
		Risk with quadrivalent HPV vaccine	Risk with bivalent HPV vaccine
High‐grade neoplasia, cancer		No studies were identified that reported on this outcome.
Overall local/injection site adverse events at 4‐day follow‐up	Females and males with HIV (≥ 18 years)	696 per 1000	911 per 1000 (737 to 1000)	RR 1.31 (1.06 to 1.62)	92 (1 study)	⊕⊕⊝⊝ LOW¹
Overall systemic events and general symptoms		No studies were identified that reported on this outcome.
Serious adverse events at 6‐month follow‐up (adults) and 7‐month follow‐up (females)	Females and males with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	92 (1 study)	⊕⊝⊝⊝ VERY LOW^2,5,6
	Females with HIV (15‐25 years)	55 per 1000	54 per 1000 (21 to 128)	OR 0.99 (0.38 to 2.55)	332 (1 study)	⊕⊝⊝⊝ VERY LOW^3,4,5,6
Mortality		No studies were identified that reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; OR: odds ratio; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Downgraded two levels for serious imprecision: few events reported.

²Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in serious adverse events or mortality.

³Downgraded one level for risk of bias: details on how randomisation, allocation concealment, and blinding was achieved was not reported.

⁴Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporate a potentially large beneficial effect and a potentially large harmful effect.

⁵Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety.

⁶See Table 1 for details of each serious event.

6.1 Quadrivalent HPV vaccine compared with control

6.1.1 Quadrivalent HPV vaccine compared with control in children living with HIV

Levin 2010 included 7‐ to 12‐year‐old girls and boys with HIV. The study reported immunogenicity outcomes at seven months (Appendix 13). GMTs for HPV 6, 11, 16 and 18 were 123.8 to 935.8‐fold higher at seven months, and 29.6 to 189.4‐fold higher at 24 months, than in the control group (described as 'identical placebo', the study did not specify the contents of the placebo) (low‐certainty evidence). Seroconversion for the four HPV genotypes was over 97% at seven months (low‐certainty evidence). Injection site adverse events were more common with quadrivalent vaccine (21/96) than control (3/30) (1 study; 126 participants; very low‐certainty evidence; Analysis 6.4). Three systemic adverse events were reported, two in the quadrivalent group (2/96) and one in the control group (1/30) (1 study; 126 participants; very low‐certainty evidence; Analysis 6.5) at 14‐day follow‐up (three doses administered at months 0, 2, and 6). The study did not report on serious adverse events, but reported that 5/96 (5.2%) children in the quadrivalent vaccine group and 2/30 (6.7%) children in the control group experienced adverse events of grade 3 or 4 severity (OR 0.77, 95% CI 0.14 to 4.18, analysis not shown).

6.1.2 Quadrivalent HPV vaccine compared with control in MSM living with HIV

Hidalgo‐Tenorio 2017 included HIV‐positive MSM of 18 years of age and above, and compared quadrivalent HPV vaccine with control (saline placebo) (three doses administered at months 0, 2, and 6). This trial reported that 76% of the HPV vaccinated participants were seropositive for at least one of HPV 6, 11, 16, or 18 genotype at seven months compared with 30.2% in the control group (moderate‐certainty evidence; Appendix 13). No serious adverse events (1 study; 129 participants; Analysis 6.6) or deaths (1 study; 129 participants; Analysis 6.7) were reported in either group at seven‐month follow‐up (Table 3).

6.1.3 Quadrivalent HPV vaccine compared with control in adults living with HIV

Two studies included HIV‐positive males and females of 18 years of age and above and compared quadrivalent HPV vaccine with control (saline placebo in NCT00941889 2016 and 'placebo vaccine' in Wilkin 2018 ‐ the contents of the placebo were not specified). There was only very low‐certainty evidence on high‐grade anal intraepithelial neoplasia (46/288 in the quadrivalent group, 45/286 in the control group; 1 study; Analysis 6.1), recurrence of anogenital warts in participants treated for anogenital warts (1/7 in the quadrivalent group, 1/5 in the control group; 1 study; Analysis 6.2), or abnormal anal cytology (58/130 in the quadrivalent group, 72/132 in the control group; 1 study; Analysis 6.3). There was limited evidence for serious adverse events (quadrivalent 33/288 events; control 46/287 events; Analysis 6.6) or deaths (quadrivalent 3/288 deaths; control 6/287 deaths; Analysis 6.7) between the groups. The study investigators considered no serious adverse events to be related to vaccination, and no withdrawals from the studies due to adverse events were reported (Table 3).

6.2 Bivalent HPV vaccine compared with control in females living with HIV

Denny 2013 included HIV‐positive 18‐ to 25‐year‐old females and reported that, irrespective of baseline HPV serostatus, all participants who received the bivalent HPV vaccine were seropositive for both HPV 16 and HPV 18 after the second vaccine dose (month two), and remained seropositive at month 12 (moderate‐certainty evidence). Pain at injection site (RR 1.86, 95% CI 1.38 to 2.51; 1 study; 120 participants; Analysis 7.1) and swelling at injection site (RR 9.19, 95% CI 2.24 to 37.73; 1 study; 120 participants; Analysis 7.2) were more common in the bivalent group than in the control group (vaccine adjuvant only) at seven‐day follow‐up. The study reported 3/61 serious adverse events in the bivalent vaccine group and 2/59 events in the control group (OR 1.47, 95% CI 0.24 to 9.15; 1 study; 120 participants; low‐certainty evidence; Analysis 7.3). No deaths were reported (Analysis 7.4). The study investigators considered no serious adverse events to be related to vaccination, and no withdrawals from the study due to adverse events were reported (Table 4).

6.3 Bivalent HPV vaccine compared with quadrivalent HPV vaccine

6.3.1 Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults living with HIV

Toft 2014 included 92 HIV‐positive females and males of 18 years of age and above, and compared bivalent with quadrivalent HPV vaccine (3 doses administered at months 0, 1.5, and 6). There was evidence of no difference, and inconclusive non‐inferiority, in GMTs for HPV 16 between the bivalent and quadrivalent HPV vaccines at seven‐ and 12‐month follow‐up (moderate‐ to low‐certainty evidence; Appendix 13). There was evidence that the quadrivalent vaccine was inferior to bivalent vaccine for GMTs for HPV 18 at seven months (ratio of GMTs 0.13, 95% CI 0.04 to 0.41; moderate‐certainty evidence). Injection site reactions were more common in the bivalent group than in the quadrivalent group (RR 1.31, 95% CI 1.06 to 1.62; 1 study; 92 participants; low‐certainty evidence; Analysis 8.1) at four‐day follow‐up. No serious adverse events at six‐month follow‐up were reported (Analysis 8.2; Table 5).

6.3.2 Bivalent HPV vaccine compared with quadrivalent HPV vaccine in 15‐ to 25‐year‐old females living with HIV

One study reported on serious adverse events in 15‐ to 25‐year‐old females with HIV who were randomised to receive bivalent or quadrivalent HPV vaccine (NCT01031069 2017). Data for this study were only available through the clinical trials registry, so full details on the methods and other outcome measures were not available. There were nine serious adverse events in 167 female participants with HIV in the bivalent vaccine group and nine in 165 participants in the quadrivalent group (1 study; 332 participants; very low‐certainty evidence; Analysis 8.2; Table 5). One participant in the quadrivalent group withdrew due to an adverse event. One serious adverse event (immune thrombocytopenic purpura) was considered by study investigators to be related to the bivalent HPV vaccine.

Sensitivity analysis

We compared the results from the primary analysis with a sensitivity analysis using Peto odds ratios for outcomes with very low event rates (< 1%; Bradburn 2007). This did not change the size of effect for most of the analyses, with the exception of some clinical outcomes in the comparison of nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐old females (Appendix 14).

Changes were seen in the effect sizes and 95% CIs for the following outcomes:

high‐grade cervical disease related to HPV 31, 33, 45, 52, or 58 (Analysis 5.5) changed from OR 0.03 (0.00 to 0.21) to Peto OR 0.15 (0.08 to 0.29) (Appendix 14);
cervical intraepithelial neoplasia 2 (CIN2) related to HPV 6, 11, 16, or 18 (Analysis 5.7) changed from OR 3.00 (0.12 to 73.77) to Peto OR 7.40 (0.15 to 373.90) (Appendix 14);
CIN2 related to HPV 31, 33, 45, 52, or 58 (Analysis 5.8) changed from OR 0.03 (0.00 to 0.23) to Peto OR 0.15 (0.08 to 0.30) (Appendix 14);
CIN3, adenocarcinoma in situ, and cervical cancer related to HPV 6, 11, 16, or 18 (Analysis 5.9) changed from OR 0.33 (0.01 to 8.19) to Peto OR 0.14 (0.00 to 6.83) (Appendix 14);
CIN3, adenocarcinoma in situ, and cervical cancer related to HPV 31, 33, 45, 52, or 58 (Analysis 5.10) changed from OR 0.07 (0.00 to 1.16) to Peto OR 0.14 (0.03 to 0.59) (Appendix 14).

Discusión

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Esta revisión informa sobre la evidencia acerca de la eficacia, la inmunogenicidad y los eventos adversos del uso de calendarios de dosis reducidas o de calendarios de vacunación alternativos en mujeres y hombres, la vacunación contra el VPH en comparación con el control en hombres y los efectos de las vacunas contra el VPH en individuos con infección por VIH.

Resumen de los resultados principales

Inmunogenicidad, eficacia y eventos adversos con menos de tres dosis de la vacuna contra el VPH en mujeres

En las adolescentes (de 9 a 15 años de edad), el calendario de dos dosis no fue inferior al calendario de tres dosis de cualquier vacuna contra el VPH. Hubo cierta evidencia de que los TMG disminuyen con el tiempo después de los calendarios de dos y de tres dosis, y que un calendario de dos dosis no es inferior a un calendario de tres dosis después de cinco años. No hubo diferencias en la seroconversión entre los calendarios de dos y de tres dosis en todos los puntos temporales informados; casi todos los participantes presentaron la seroconversión en ambos grupos de intervención. No se identificaron estudios que reunieran datos sobre la eficacia en cuanto a los resultados clínicos. Hubo evidencia de certeza muy baja de poca o ninguna diferencia en los eventos adversos graves o las muertes entre los calendarios de dosis. No se identificaron ECA que evaluaran la eficacia ni los efectos perjudiciales de una dosis de la vacuna contra el VPH.

Inmunogenicidad, eficacia y eventos adversos con diferentes intervalos entre las dosis de la vacuna contra el VPH en mujeres y hombres

Tanto en las mujeres como en los hombres, para todas las vacunas contra el VPH evaluadas, un calendario con un intervalo más largo entre las dosis dio lugar a TMG más altos que un intervalo más corto. Hubo evidencia de certeza muy baja sobre el riesgo comparativo de eventos adversos graves con intervalos diferentes entre las dos dosis de la vacuna contra el VPH, debido al número muy reducido de eventos y a la falta de direccionalidad. Los resultados de los estudios individuales fueron consistentes y presentaron tasas más bajas o más altas de eventos adversos graves con los diferentes intervalos evaluados en los estudios.

Eficacia, inmunogenicidad y eventos adversos de las vacunas contra el VPH en los hombres

Tres dosis de la vacuna cuadrivalente contra el VPH redujeron la incidencia de lesiones genitales externas, verrugas anogenitales e infección persistente por los genotipos 6; 11; 16 o 18 del VPH en comparación con el control en varones de 16 a 26 años de edad durante una mediana de seguimiento de 2,9 años (evidencia de certeza moderada). La vacuna cuadrivalente produjo más eventos adversos en el sitio de la inyección, como dolor o enrojecimiento, que el control (evidencia de certeza alta). Hubo evidencia de certeza muy baja sobre el riesgo comparativo de eventos adversos graves y evidencia de certeza baja sobre el riesgo comparativo de muertes entre la vacuna cuadrivalente y el control en los varones de 10 a 26 años de edad. Se dispuso de datos limitados con respecto a la eficacia y los eventos adversos de la vacuna bivalente contra el VPH en los hombres. No se identificaron ECA que evaluaran la eficacia de la vacuna nonavalente en comparación con el control en los hombres.

Eficacia, inmunogenicidad y eventos adversos de la vacuna nonavalente contra el VPH en comparación con otras vacunas contra el VPH en mujeres y hombres

En las mujeres de 16 a 26 años de edad, tres dosis de la vacuna nonavalente o de la vacuna cuadrivalente produjeron una incidencia similar de resultados clínicos, independientemente del genotipo del VPH, en un seguimiento de hasta 4,5 años (un ECA, evidencia de certeza alta). La vacuna nonavalente dio lugar a una reducción en la incidencia de infecciones persistentes por VPH, NIC1, NIC 2/3, neoplasia intraepitelial vulvar o vaginal (grado 1) relacionadas con los genotipos del VPH únicos de la vacuna nonavalente (genotipos 31; 33; 45; 52; y 58) en comparación con la vacuna cuadrivalente. Los resultados de inmunogenicidad para las vacunas nonavalentes y cuadrivalentes contra el VPH fueron similares para hombres y mujeres. Hubo evidencia de certeza alta de que la vacuna nonavalente resultó en un número ligeramente mayor de eventos locales o en el sitio de la inyección, pero poca o ninguna diferencia en los eventos sistémicos generales. La evidencia que compara los eventos adversos graves fue de certeza baja. Hubo evidencia de certeza baja de ninguna diferencia en la mortalidad entre estas vacunas. Se informaron pocos eventos adversos graves relacionados con la vacuna (siete participantes en total) en los estudios incluidos.

Eficacia, inmunogenicidad y eventos adversos de las vacunas contra el VPH en personas que conviven con el VIH

En los niños que conviven con el VIH, la vacuna cuadrivalente contra el VPH da lugar a TMG más altos que el control a los siete meses, aunque solo hubo evidencia de certeza muy baja sobre los eventos adversos locales o sistémicos. En los adultos que conviven con el VIH, la evidencia sobre los resultados clínicos y los efectos perjudiciales de la vacuna cuadrivalente contra el VPH en comparación con el control u otras vacunas contra el VPH, fue de certeza muy baja. Un ECA en adultos que conviven con el VIH informó que la vacuna bivalente tuvo resultados de inmunogenicidad similares para el genotipo 16 del VPH a la vacuna cuadrivalente, aunque dio lugar a TMG más altos y a una mayor tasa de seroconversión al genotipo 18 del VPH.

Compleción y aplicabilidad general de las pruebas

Esta revisión recopiló evidencia acerca de la eficacia (en términos de variables de evaluación clínicas e inmunológicas) y los efectos perjudiciales de diferentes vacunas contra el VPH y diferentes calendarios de dosis en mujeres y hombres. Las fuentes de información buscadas incluyen bases de datos electrónicas, sitios web de los fabricantes de vacunas y un índice publicado de estudios sobre el VPH (Jørgensen 2018a), por lo que el nivel de completitud es alto. Sin embargo, la aplicabilidad de la evidencia para determinar la eficacia clínica y los efectos perjudiciales está limitada por la naturaleza de la enfermedad relacionada con el VPH, así como por el diseño y los resultados de los estudios. La evidencia de los ECA sobre la eficacia contra la enfermedad grave relacionada con el VPH, incluido el cáncer, se ve limitada por tres razones principales. Primero, no es ético recolectar muestras del cuello uterino de las niñas que no han tenido relaciones sexuales. En segundo lugar, durante los períodos de seguimiento del estudio se producen pocos eventos de resultados clínicos graves relacionados con la infección por VPH debido a que tardan varios años en desarrollarse después de la infección por VPH. Tercero, a los participantes del ensayo se les ofrece tratamiento cuando se les diagnostica precáncer relacionado con el VPH, por lo que se espera que la progresión hacia el cáncer de cuello uterino sea muy baja, incluso sin vacunación.

El enfoque de esta revisión se centró en los resultados clínicos y los efectos perjudiciales. La inmunogenicidad es el resultado primario para muchos ensayos de los calendarios alternativos de vacunación contra el VPH; sin embargo, como se señaló en el apartado de Antecedentes, los ensayos aleatorizados de eficacia de las vacunas contra el VPH se realizaron por primera vez en mujeres de 15 a 25 o 26 años de edad (Arbyn 2018). Una vez establecida la eficacia, la inmunogenicidad y la seguridad en este grupo etario, los estudios puente no aleatorizados evaluaron la no inferioridad de los resultados de inmunogenicidad en niñas de 9 a 15 años de edad (p.ej. Block 2006, Dobson 2013). La International Agency for Research on Cancer considera que los estudios puente que demuestran la no inferioridad son una variable de evaluación suficiente para las personas menores de 16 años de edad (IARC 2014). Los estudios puente también han demostrado la no inferioridad de los resultados de inmunogenicidad de un calendario de dos dosis en niños de 9 a 14 años de edad, en comparación con tres dosis en mujeres jóvenes de 15 a 26 años de edad (Iversen 2016). El uso de los resultados de inmunogenicidad tiene limitaciones debido a que aún no se conoce la correlación inmunológica de protección ni la duración de la protección (Donken 2015). Estos estudios proporcionan evidencia de menor certeza, debido a que las estimaciones de los resultados clínicos son imprecisas e indirectas.

La vacuna nonavalente contra el VPH se introdujo más recientemente que las vacunas bivalentes y cuadrivalentes contra el VPH. Esta revisión incluyó todos los estudios que compararon la vacuna nonavalente contra el VPH con otras vacunas contra el VPH; se identificaron dos ECA en mujeres (Joura 2015; Vesikari 2015) y uno en hombres (van Damme 2016). Una revisión Cochrane separada de los ECA completados de los calendarios de tres dosis con vacunas bivalentes y cuadrivalentes contra el VPH en mujeres de 16 a 26 años de edad muestra protección contra las lesiones de grado NIC3, pero no contra el cáncer invasivo de cuello uterino (Arbyn 2018). En una actualización de la revisión de Arbyn 2018 se incluirán más comparaciones entre las diferentes vacunas contra el VPH en las mujeres. Los estudios observacionales en países que han autorizado más de una vacuna contra el VPH también proporcionarán información importante sobre la eficacia comparativa y los efectos perjudiciales de las diferentes vacunas contra el VPH.

Con respecto a los eventos adversos graves, existe un grado alto de incertidumbre en la evidencia que compara diferentes vacunas contra el VPH y diferentes calendarios de dosis. Las tablas de "Resumen de resultados" muestran un número reducido de eventos adversos graves y muertes en la mayoría de los estudios incluidos. Incluso cuando el número total de eventos es alto (por ejemplo, Joura 2015), los eventos específicos de relevancia clínica siguen siendo muy poco frecuentes para realizar análisis comparativos significativos. En esta revisión, se utilizó un resultado compuesto, es decir, la frecuencia general de los eventos adversos graves, para cada comparación; sin embargo, los análisis basados en un resultado compuesto pueden producir resultados que son difíciles de interpretar por varias razones. Este resultado puede incluir eventos que no son clínicamente relevantes o que no están biológicamente relacionados con la vacuna (Lineberry 2016), que ocurren fuera de un marco temporal plausible en relación con la exposición a la vacuna (Huang 2011) o que no se basan en definiciones estandarizadas (Bonhoeffer 2002). Además, los ensayos miden los eventos adversos graves en diferentes puntos temporales y hay una gran variación en la duración del seguimiento, lo que podría producir estimaciones de resumen engañosas (Huang 2011). Finalmente, existe heterogeneidad entre los ensayos con respecto a la edad y el sexo de los participantes y las medidas clínicas de los eventos adversos graves (Apéndice 4). Los metanálisis de los eventos adversos graves, como los presentados en esta revisión, deben considerarse exploratorios en lugar de confirmatorios, debido a que los análisis no se planifican con antelación (es decir, cuando se diseñaron los estudios incluidos) (Huang 2011). A pesar de la incertidumbre en la evidencia sobre los efectos perjudiciales al comparar diferentes vacunas contra el VPH y diferentes calendarios de dosis, una revisión sistemática anterior informó de tasas similares de eventos adversos graves al comparar las vacunas contra el VPH con el control (Arbyn 2018).

Calidad de la evidencia

El riesgo de sesgo de los estudios incluidos en esta revisión fue generalmente bajo. Se calificaron los estudios que recibieron financiamiento del fabricante de la vacuna como "poco claros" para el dominio de "otro riesgo de sesgo". Este juicio se basó en los resultados de una revisión sistemática que mostró resultados de eficacia más favorables y en las conclusiones de estudios patrocinados por empresas fabricantes (Lundh 2017). Se ha sugerido que el patrocinio de los estudios por parte de la industria da lugar a resultados demasiado positivos a través de una variedad de opciones en el diseño y la realización de los ensayos que resultan en sesgo. Sobre la base del riesgo de sesgo bajo en otros dominios metodológicos y al informe adecuado en los ensayos, no se redujo la certeza de la evidencia con los criterios GRADE para este factor. De acuerdo con Higgins 2017, la información sobre el patrocinio de la industria y otras fuentes de financiación se refleja en las tablas de Características de los estudios incluidos.

En los estudios en que los participantes recibieron una inyección de control (específicamente para las comparaciones de las vacunas contra el VPH con el control en hombres y personas que conviven con el VIH, y diferentes calendarios de intervalos), muchos de los estudios incluidos utilizaron un adyuvante (hidróxido de aluminio u otro compuesto de aluminio) como control en lugar de un placebo "verdadero" (NCT00941889 2016 utilizó un placebo de solución salina; Levin 2010 y Wilkin 2018 no especificaron el tipo de placebo). Los adyuvantes de aluminio se han utilizado en las vacunas durante muchos años debido a que se cree que mejoran la respuesta inmunitaria (HogenEsch 2018), aunque se ha cuestionado su idoneidad como vacunas de control en los ECA (Jørgensen 2018b). Una revisión sistemática anterior no encontró evidencia de que los adyuvantes de aluminio en las vacunas contra la difteria, el tétanos y la tos ferina causaran eventos adversos graves o de larga duración (Jefferson 2004). La tasa de eventos adversos graves fue baja tanto para los grupos de vacunas como para los grupos de control en los estudios incluidos en la presente revisión. Sin embargo, los efectos beneficiosos y perjudiciales de los adyuvantes que contienen aluminio se están evaluando más a fondo en una revisión Cochrane (Djurisic 2017), y se están realizando investigaciones para determinar su idoneidad como vacunas de control para los ECA.

Para una serie de resultados presentados en las tablas de "Resumen de resultados", especialmente los eventos adversos graves y las muertes, la certeza de la evidencia se redujo debido a la imprecisión. En la mayoría de los casos, el tamaño de la muestra de los ECA incluidos fue demasiado pequeño para poder detectar un efecto entre los grupos para estos resultados, especialmente para los resultados poco frecuentes como la muerte. La anterior es otra limitación de los ECA para determinar los efectos perjudiciales asociados con las vacunas contra el VPH, y le otorga más peso al uso futuro de estudios observacionales de gran tamaño. También se redujo la evidencia sobre los eventos adversos graves por la falta de direccionalidad debido a las limitaciones en el uso de una medida de resultado compuesta de los eventos, como se describe en el apartado sobre la aplicabilidad.

Sesgos potenciales en el proceso de revisión

Se llevaron a cabo grandes esfuerzos para identificar datos relevantes publicados y no publicados, a través de una búsqueda sensible en una base de datos electrónica y de la selección de los sitios web de los fabricantes de vacunas. Mediante la vinculación de las entradas en el registro de ensayos clínicos con las búsquedas en las bases de datos publicadas y la verificación cruzada de los estudios incluidos y excluidos de la revisión con un índice publicado de estudios sobre el VPH (Jørgensen 2018a), se intentó minimizar el riesgo de que se omitieran estudios, aunque puede haber datos pertinentes sin registrar o sin publicar (Jørgensen 2018a).

Se utilizaron categorías definidas a priori de eventos adversos comunes, como dolor o inflamación en el sitio de la inyección, o resultados importantes, como eventos adversos graves y muertes, al extraer los datos de los estudios incluidos. Este método de extracción de datos pudo haber sido limitado por el informe en los estudios incluidos, ya que los resultados compuestos, como los "eventos adversos generales locales/en el sitio de la inyección", no pudieron calcularse con los informes de todos los eventos en las poblaciones del estudio. El rango de eventos adversos diferentes informados en los estudios incluidos y de métodos utilizados para evaluarlos en los estudios, hacen inviable la extracción de todos los eventos adversos con el propósito de realizar un metanálisis.

Se analizaron e informaron todos los eventos adversos graves en los estudios incluidos. Los eventos adversos graves son los que provocan hospitalización y enfermedades potencialmente mortales. Este hecho significa que se incluye cualquier lesión o enfermedad grave, incluso si es poco probable que esté relacionada con la vacuna. También se informaron los resultados y los métodos de atribución utilizados para determinar si los eventos adversos graves estaban relacionados con la vacuna. Estos resultados no se analizaron ni se informaron en las tablas de "Resumen de resultados" debido a que los métodos de atribución no eran transparentes o no eran independientes de los investigadores del estudio (Apéndice 4). Estos resultados se informan de manera narrativa en el apartado Efectos de las intervenciones.

Se restringió el análisis de sensibilidad de los eventos muy poco frecuentes a los métodos estadísticos alternativos disponibles en el software Review Manager 5. Se aplicó un análisis de sensibilidad a varios resultados en que hubo estudios con cero eventos en ambos brazos, aunque no aportaron información con el uso de ninguno de los dos métodos. Es posible que otros métodos puedan producir resultados diferentes cuando no hay ningún evento en los brazos del ensayo (Sharma 2017).

Acuerdos y desacuerdos con otros estudios o revisiones

Los resultados de esta revisión sistemática están de acuerdo con otras revisiones publicadas sobre la eficacia de menos de tres dosis de la vacuna contra el VPH (D'Addario 2017; Markowitz 2018). El objetivo de esta revisión fue proporcionar información adicional sobre los resultados clínicos y los eventos adversos. Esta revisión aporta evidencia acerca de otras comparaciones, como la vacunación de los niños y comparaciones entre tipos de vacunas contra el VPH, que no se han evaluado de forma previa.

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Analysis 1.1

Comparison 1 Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females, Outcome 1 Pain at injection site.

Analysis 1.2

Comparison 1 Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females, Outcome 2 Swelling at injection site.

Analysis 1.3

Comparison 1 Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females, Outcome 3 Redness at injection site.

Analysis 1.4

Comparison 1 Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females, Outcome 4 Serious adverse events (overall).

Analysis 1.5

Comparison 1 Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females, Outcome 5 Deaths.

Analysis 2.1

Comparison 2 Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds, Outcome 1 Pain at injection site.

Analysis 2.2

Comparison 2 Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds, Outcome 2 Swelling at injection site.

Analysis 2.3

Comparison 2 Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds, Outcome 3 Redness at injection site.

Analysis 2.4

Comparison 2 Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds, Outcome 4 Serious adverse events (overall).

Analysis 2.5

Comparison 2 Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds, Outcome 5 Deaths.

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Study

Lin 2014

Adverse events data not reported separately for each arm.

"Participants reported side effects following 646 separate vaccinations; 172 local and general reactions were reported, with no difference in proportion of side effects reported between Standard (24.4%) and Alternate (28.9%) schedule groups (P = 0.26). The majority of side effects were pain and redness at the injection site (86%; n = 148), with the remainder composed of fever (3.5%; n = 6), and miscellaneous symptoms (10.5%; n = 18). There were no reports of any serious side effects."

Analysis 3.1

Comparison 3 Three doses of HPV vaccine with longer interval versus three doses of HPV vaccine with shorter interval in 18‐ to 25‐year‐old males, Outcome 1 Adverse events.

Analysis 3.2

Comparison 3 Three doses of HPV vaccine with longer interval versus three doses of HPV vaccine with shorter interval in 18‐ to 25‐year‐old males, Outcome 2 Serious adverse events (overall).

Analysis 4.1

Comparison 4 HPV vaccine versus control in males, Outcome 1 External genital lesions (any type).

Analysis 4.2

Comparison 4 HPV vaccine versus control in males, Outcome 2 External genital lesions (HPV 6, 11, 16, or 18).

Analysis 4.3

Comparison 4 HPV vaccine versus control in males, Outcome 3 Anogenital warts.

Analysis 4.4

Comparison 4 HPV vaccine versus control in males, Outcome 4 All penile, perianal, or perineal intraepithelial neoplasia lesions.

Analysis 4.5

Comparison 4 HPV vaccine versus control in males, Outcome 5 Penile, perianal, or perineal intraepithelial neoplasia grade 1.

Analysis 4.6

Comparison 4 HPV vaccine versus control in males, Outcome 6 Penile, perianal, or perineal intraepithelial neoplasia grade 2 or 3.

Analysis 4.7

Comparison 4 HPV vaccine versus control in males, Outcome 7 Overall local/injection site adverse events.

Analysis 4.8

Comparison 4 HPV vaccine versus control in males, Outcome 8 Pain at injection site.

Analysis 4.9

Comparison 4 HPV vaccine versus control in males, Outcome 9 Swelling at injection site.

Analysis 4.10

Comparison 4 HPV vaccine versus control in males, Outcome 10 Redness at injection site.

Analysis 4.11

Comparison 4 HPV vaccine versus control in males, Outcome 11 Overall systemic events and general symptoms.

Analysis 4.12

Comparison 4 HPV vaccine versus control in males, Outcome 12 Serious adverse events (overall).

Analysis 4.13

Comparison 4 HPV vaccine versus control in males, Outcome 13 Deaths.

Analysis 5.1

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 1 High‐grade cervical epithelial neoplasia, adenocarcinoma in situ, and cervical cancer.

Analysis 5.2

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 2 High‐grade cervical, vulval, and vaginal disease.

Analysis 5.3

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 3 High‐grade cervical disease related to HPV 6, 11, 16, or 18.

Analysis 5.4

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 4 High‐grade vulval and vaginal disease related to HPV 6, 11, 16, or 18.

Analysis 5.5

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 5 High‐grade cervical disease related to HPV 31, 33, 45, 52, or 58.

Analysis 5.6

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 6 High‐grade vulval and vaginal disease related to HPV 31, 33, 45, 52, or 58.

Analysis 5.7

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 7 Cervical intraepithelial neoplasia 2 related to HPV 6, 11, 16, or 18.

Analysis 5.8

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 8 Cervical intraepithelial neoplasia 2 related to HPV 31, 33, 45, 52, or 58.

Analysis 5.9

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 9 Cervical intraepithelial neoplasia 3, adenocarcinoma in situ, and cervical cancer related to HPV 6, 11, 16, or 18.

Analysis 5.10

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 10 Cervical intraepithelial neoplasia 3, adenocarcinoma in situ, and cervical cancer related to HPV 31, 33, 45, 52, or 58.

Analysis 5.11

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 11 Overall local/injection site adverse events.

Analysis 5.12

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 12 Pain at injection site.

Analysis 5.13

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 13 Swelling at injection site.

Analysis 5.14

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 14 Redness at injection site.

Analysis 5.15

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 15 Overall systemic events and general symptoms.

Analysis 5.16

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 16 Serious adverse events (overall).

Analysis 5.17

Comparison 5 Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds, Outcome 17 Deaths.

Analysis 6.1

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 1 High‐grade anal intraepithelial neoplasia.

Analysis 6.2

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 2 Recurrence of anogenital warts.

Analysis 6.3

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 3 Abnormal anal cytology.

Analysis 6.4

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 4 Overall local/injection site adverse events.

Analysis 6.5

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 5 Overall systemic event and general symptoms.

Analysis 6.6

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 6 Serious adverse events (overall).

Analysis 6.7

Comparison 6 Quadrivalent HPV vaccine versus control in people living with HIV, Outcome 7 Deaths.

Analysis 7.1

Comparison 7 Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV, Outcome 1 Pain at injection site.

Analysis 7.2

Comparison 7 Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV, Outcome 2 Swelling at injection site.

Analysis 7.3

Comparison 7 Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV, Outcome 3 Serious adverse events (overall).

Analysis 7.4

Comparison 7 Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV, Outcome 4 Deaths.

Analysis 8.1

Comparison 8 Bivalent HPV vaccine versus quadrivalent HPV vaccine in people living with HIV, Outcome 1 Overall local/injection site adverse events.

Analysis 8.2

Comparison 8 Bivalent HPV vaccine versus quadrivalent HPV vaccine in people living with HIV, Outcome 2 Serious adverse events (overall).

Summary of findings for the main comparison. Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females

Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females
Patient or population: 9‐ to 15‐year‐old females Setting: community health centres in Africa, Asia Pacific, Europe, Latin America, North America Intervention: two doses of HPV vaccine (bivalent, quadrivalent, or nonavalent) administered in months 0 and 2, 0 and 6, or 0 and 12 Comparison: three doses of HPV vaccine (bivalent, quadrivalent, or nonavalent) administered in months 0, 2, and 6, or 0, 1, and 6
Clinical and harms outcomes^*	Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with three doses of HPV vaccine	Risk with two doses of HPV vaccine
Antibody response (immunogenicity)	Two doses were non‐inferior to, or had higher GMTs than, three doses for all HPV vaccine genotypes (bivalent, quadrivalent, and nonavalent vaccines), except HPV 45 (where non‐inferiority was inconclusive), at short‐term follow‐up (4 studies, number of participants ranged from 132 to 1833 depending on HPV type and vaccine; see Appendix 5).				MODERATE/ HIGH*	Short‐term results (follow‐up 1 month after final dose)
	Two doses of bivalent vaccine had inconclusive non‐inferiority for GMTs of HPV 16 and HPV 18 compared with three doses at 60‐month follow‐up (1 study, 93 participants; see Appendix 5).				LOW*	Long‐term results (follow‐up 36 to 60 months)
	Two doses of quadrivalent vaccine resulted in non‐inferior GMTs for HPV 6, HPV 11 and HPV 16 compared with three doses, while results were inconclusive for HPV 18 at 60‐month follow‐up (1 study, 101 participants; see Appendix 5).				LOW*
	Two doses of nonavalent vaccine resulted in non‐inferior GMTs for all HPV genotypes measured except HPV 45 and HPV 52 where non‐inferiority was inconclusive, compared with three doses, at 36‐month follow‐up (1 study, 476 to 511 participants depending on HPV type; see Appendix 5).				HIGH*
High‐grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and cervical cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, and vaginal disease	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain/swelling/redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at up to 5‐year follow‐up	30 per 1000	31 per 1000 (20 to 49)	OR 1.03 (0.64 to 1.66)	2317 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^1,2	Please see Table 1 for a list of events in each RCT.
Mortality at up to 5‐year follow‐up	1 per 1000	0 per 1000 (0 to 9)	OR 0.33 (0.01 to 8.19)	1797 (3 RCTs)	⊕⊕⊝⊝ LOW ¹	One death was reported in the three‐dose group (nonavalent vaccine).
Certainty of the evidence (GRADE) for immunogenicity outcomes are presented in detail in Appendix 5. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GMT: geometric mean titre; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potential large beneficial effect and a potential large harmful effect. ²Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety.

Summary of findings for the main comparison. Two doses of HPV vaccine compared with three doses of HPV vaccine in 9‐ to 15‐year‐old females

Table 1. Serious adverse events

Study	Group	Number of participants with serious adverse events	Details of serious adverse events*
Denny 2013	Vaccine (bivalent)	3/61	Gastroenteritis, bacterial pneumonia, migraine
Denny 2013	Control	2/59	Lobar pneumonia, skull fracture
Dobson 2013	Vaccine (quadrivalent; 2‐dose)	0/259
Dobson 2013	Vaccine (quadrivalent; 3‐dose)	0/261
Giuliano 2011	Vaccine (quadrivalent)	8/2020	8 participants with 12 events: cardiac arrest, non‐cardiac chest pain, hypersensitivity, appendicitis, cellulitis, varicella infection, cervical vertebral fracture, gunshot wound, road traffic accident, traumatic brain injury, traumatic intracranial haemorrhage, convulsion
Giuliano 2011	Control	11/2033	11 participants with 13 events: myocardial ischaemia, pericardial haemorrhage, accidental overdose, chemical poisoning, contusion, gunshot wound (3), head injury, multiple drug overdose, road traffic accident, completed suicide (2)
NCT01031069 2017	Vaccine (bivalent)	9/167	9 participants with 10 events: immune thrombocytopenic purpura, gastritis, meningitis tuberculous, pneumonia, pneumonia mycoplasmal, tonsillitis, viral infection, road traffic accident, miscarriage, renal failure
NCT01031069 2017	Vaccine (quadrivalent)	9/165	9 participants with 10 events: appendicitis (2), pneumonia bacterial, pulmonary tuberculosis, tonsillitis, urinary tract infection, monoarthritis, abortion spontaneous complete, pre‐eclampsia, suicide attempt
NCT01862874 2018	Vaccine (quadrivalent)	0/554
NCT01862874 2018	Control	1/559	Completed suicide
Hidalgo‐Tenorio 2017	Vaccine (quadrivalent)	0/66
Hidalgo‐Tenorio 2017	Control	0/63
Iversen 2016	Vaccine (nonavalent; 2‐dose, 6‐month interval in females)	6/301	6 participants with 7 events: abdominal pain (2), appendicitis, dengue fever, pharyngitis, foreign body injury, ovarian cyst
	Vaccine (nonavalent; 2‐dose, 6‐month interval in males)	9/301	9 participants with 10 events: Wolff‐Parkinson‐White syndrome, diarrhoea, animal bite, appendicitis, rotavirus gastroenteritis, Chikungunya virus infection, bacterial meningitis, pneumonia, concussion, epilepsy
	Vaccine (nonavalent; 2‐dose, 12‐month interval in males and females)	3(6)/301	1 female participant with atopic dermatitis 2 male participants with appendicitis, forearm fracture At 37 month follow‐up there were 3 additional serious adverse events: gastritis, oral herpes, radiculopathy (disaggregated data by sex were not available)
	Vaccine (nonavalent; 3‐dose in females)	6/301	6 participants with 8 events: cardiac arrest, appendicitis, subcutaneous abscess, papillary thyroid cancer, encephalitis autoimmune, status epilepticus, depression, ovarian cyst
Joura 2015	Vaccine (nonavalent)	242/7686	242 participants with 269 events: Anaemia, aortic valve incompetence, postural orthostatic tachycardia syndrome, vertigo positional, anal fistula, coeliac disease, Crohn's disease, diarrhoea, gastritis, haemorrhoids, inguinal hernia, irritable bowel syndrome, pyrexia, sudden death, cholangitis, cholecystitis, cholelithiasis, allergy to vaccine, anaphylactic reaction, hypersensitivity, sarcoidosis, jaw abscess, appendicitis (10), cholecystitis infective, chronic tonsillitis, dengue fever, infectious enteritis (2), gastroenteritis, viral gastroenteritis, haemorrhagic fever, infectious mononucleosis, influenza, pharyngitis, pyelonephritis (2), pyelonephritis acute, septic shock, tonsillitis, tonsillitis streptococcal, urinary tract infection (3), urosepsis, wound infection, bladder injury, burns second degree, craniocerebral injury, femur fracture, humerus fracture (2), ligament rupture, lower limb fracture, multiple injuries (2), pubis fracture, road traffic accident, spinal compression fracture, hyperglycaemia, myalgia, osteoarthritis, acute lymphocytic leukaemia, acute promyelocytic leukaemia, adenocarcinoma of the cervix, brain neoplasm, ependymoma, leukaemic infiltration brain, malignant melanoma (2), malignant melanoma in situ, nasal cavity cancer, ovarian neoplasm, diabetic coma, epilepsy, hypersomnia, Intracranial venous sinus thrombosis, migraine, multiple sclerosis (2), presyncope, sciatica, sensory disturbance, syncope (2), tension headache, abortion spontaneous (40), abortion spontaneous incomplete, blighted ovum, cephalo‐pelvic disproportion (4), cervix dystocia, false labour, foetal death (2), foetal distress syndrome (5), labour complication, pre‐eclampsia (2), premature labour, premature rupture of membranes (4), prolonged labour (2), uterine contractions during pregnancy, anorexia and bulimia syndrome, bipolar disorder (3), completed suicide, major depression, calculus ureteric, calculus urinary, nephrolithiasis, renal failure (2), bartholinitis, cervical dysplasia (5), cervix haemorrhage uterine, endometriosis (2), ovarian cyst, pelvic pain, asthmatic crisis, pneumonia aspiration, pneumothorax, respiratory failure, vocal cord polyp, abortion induced (79), deep vein thrombosis, hypovolaemic shock (2)
Joura 2015	Vaccine (quadrivalent)	184/7078	184 participants with 197 events: Anaemia, cleft lip and palate, Meckel's diverticulum, abdominal pain (2), abdominal pain lower, colitis ulcerative, enterocolitis, gastritis, inguinal hernia, omental infarction, cholecystitis , cholelithiasis (2), appendicitis (16), bronchitis (2), cellulitis, conjunctivitis, gastroenteritis (2), influenza, pelvic inflammatory disease, post abortion infection, pyelonephritis, pyelonephritis acute (2), urinary tract infection (2), viral pharyngitis, foreign body in eye, fracture displacement, hand fracture, head injury, joint dislocation (2), neck injury, poisoning, post procedural haemorrhage (2), spinal cord injury, spinal cord injury cervical, fibromyalgia (2), adenocarcinoma gastric, malignant palate neoplasm, pituitary tumour benign, respiratory papilloma, thyroid cancer, benign intracranial hypertension, cerebral haemorrhage, epilepsy, facial paresis, headache, hydrocephalus, hypoesthesia, multiple sclerosis, neuritis, orthostatic intolerance, spondylitic myelopathy, tension headache, abortion spontaneous (28), abortion spontaneous complete (2), blighted ovum, cephalo‐pelvic disproportion (6), cervix dystocia, ectopic pregnancy, foetal distress syndrome, foetal malposition, foetal malpresentation, gestational diabetes, oligohydramnios, pre‐eclampsia, premature labour, premature rupture of membranes (2), prolonged labour, anorexia nervosa, bipolar disorder, depression, cystitis haemorrhagic, renal failure acute, cervical dysplasia (3), dysmenorrhoea, endometriosis, fallopian tube cyst, ovarian cyst (2), dyspnoea, nasal polyps, abortion induced (53), axillary vein thrombosis
Lehtinen 2018	Vaccine (quadrivalent)	58/2436	58 participants with 62 events: Splenomegaly, vitello‐intestinal duct remnant, abdominal pain (2), colitis ulcerative, constipation, food poisoning, chest pain, pyrexia, cholesystitis, appendicitis (5), appendicitis perforated, infectious mononucleosis (4), peritonsillar abscess, pneumonia (2), pneumonia bacterial, salmonellosis, tonsillitis (4), alcohol poisoning (3), cervical vertebral fracture, concussion (4), contusion (2), forearm fracture, hand fracture (2), limb injury, lower limb fracture, muscle rupture, neck injury, radius fracture (2), upper limb fracture (2), type 1 diabetes mellitus, exostosis, juvenile idiopathic arthritis, syncope (2), anxiety, disturbance in social behaviour, emotional disorder of childhood, psychotic disorder, testicular torsion, acne, dermatitis
Lehtinen 2018	Vaccine (control, HBV)	25/1267	25 participants with 25 events: Appendicitis (3), appendicitis perforated, bronchitis, gastroenteritis bacterial, infectious mononucleosis, peritonsillar abscess, sinusitis, sinusitis bacterial, alcohol poisoning, foot fracture (2), forearm fracture, hand fracture, joint dislocation, splenic rupture, tibia fracture, traumatic renal injury, type 1 diabetes mellitus, astrocytoma low grade, depression, panic disorder, suicide attempt, dyspnoea
Leung 2015	Vaccine (bivalent; 2‐dose)	11/358	11 participants with 13 events: Abdominal pain lower, mouth cyst, appendicitis, gastroenteritis viral, lung abscess, peritonitis, viral infection, joint dislocation, teratoma, epilepsy, seizure, asthma, eczema
Leung 2015	Vaccine (bivalent; 3‐dose)	14/358	14 participants with 16 events: Lymphadenitis, vertigo positional, abdominal pain, anaphylactic shock, upper respiratory tract infection, pneumonia, influenza, vulval ulceration, ankle fracture, overdose, tendon injury, presyncope, tension headache, abortion spontaneous incomplete, completed suicide, depression, menorrhagia
Levin 2010	Vaccine (quadrivalent)	0/96
Levin 2010	Control	0/30
Lin 2014	Vaccine (quadrivalent; 10‐month interval)	0/111
Lin 2014	Vaccine (quadrivalent; 4‐month interval)	0/109
NCT00941889 2016	Vaccine (quadrivalent)	Not reported	Not reported
NCT00941889 2016	Control	Not reported	Not reported
Wilkin 2018	Vaccine (quadrivalent)	33/288	33 participants with 40 events: Pericardial effusion, abdominal mass, abdominal pain, anal fistula, colitis, chest pain (2), death, appendicitis, cellulitis, chlamydial infection, gastroenteritis viral, influenza (2), meningitis viral, peritonsillar abscess, pneumonia, pneumonia pneumococcal, pseudomembranous colitis, sepsis, lower limb fracture, multiple injuries, stab wound, anal cancer, basal cell carcinoma, Hodgkin's disease, prostate cancer, transitional cell carcinoma, cerebrovascular accident, seizure, acute psychosis, alcohol withdrawal syndrome, depression, suicide attempt, acute respiratory failure, alveolitis allergic, asthma, pleural effusion, intervertebral disc operation
Wilkin 2018	Control	46/287	46 participants with 79 events: Acute myocardial infarction (2), coronary artery disease, myocardial infarction, abdominal pain, gastrointestinal haemorrhage, large intestine perforation, pancreatitis, pancreatitis acute (2), pancreatitis chronic, small intestinal obstruction (3), chest pain (5), pyrexia, cholelithiasis, bronchitis (2), diverticulitis (2), gastroenteritis (2), gastroenteritis viral, influenza (2), orchitis, perirectal abscess, pneumonia (3), pneumonia streptococcal, primary syphilis, pyelonephritis, scrotal abscess, sepsis (3), viral infection, fall, foot fracture, overdose, radius fracture, road traffic accident, weight decreased, dehydration, osteoarthritis, anal cancer, anal squamous cell carcinoma, B‐cell lymphoma, basal cell carcinoma, follicle centre lymphoma diffuse small cell lymphoma, oesophageal adenocarcinoma, pancreatic carcinoma metastatic, prostate cancer, renal cell carcinoma, squamous cell carcinoma of head and neck, haemorrhagic stroke, syncope (2), alcohol withdrawal syndrome, completed suicide, mental status changes, psychotic disorder, substance abuse, suicide attempt, genital ulceration, chronic obstructive pulmonary disease (4), dyspnoea, pleural effusion, pulmonary hypertension, hypotension
Petaja 2009	Vaccine (bivalent)	3/181	Crohn’s disease, appendicitis, epilepsy
Petaja 2009	Control (HBV)	1/89	Osteochondrosis
Puthanakit 2016	Vaccine (bivalent; 2‐dose, 6‐month interval)	20/550	20 participants with 34 events: Lymphadenitis, autoimmune thyroiditis, strabismus, abdominal strangulated hernia, abdominal pain, anal haemorrhage, gastritis, nausea, chronic gastritis, anaphylactic reaction, cholelithiasis, infections and infestations (13), injury, poisoning and procedural complications (4), type 1 diabetes mellitus, cholesteatoma, convulsion, seizure, IgA nephropathy, respiratory disorder
	Vaccine (bivalent; 2‐dose, 12‐month interval)	24/415	24 participants with 38 events: Lymphadenitis, supraventricular tachycardia, abdominal pain lower, constipation, dyspepsia, faecaloma, drug hypersensitivity, infections and infestations (25), injury, poisoning and procedural complications, hypovolaemia, systemic lupus erythematosus, VIIth nerve paralysis, tonsillar hypertrophy, circulatory collapse
	Vaccine (bivalent; 3‐dose)	28/482	28 participants with 53 events: Infections and infestations (32), injury, poisoning and procedural complications (3), hypovolaemia (2), synovial cyst, medulloblastoma, synovial sarcoma, uterine leiomyoma, hyperemesis gravidarum, premature baby, abortion threatened, postpartum haemorrhage, stillbirth, schizoaffective disorder (3), psychotic disorder, ovarian cyst ruptured, transient tachypnoea of the newborn, ectopic pregnancy termination
Romanowski 2011	Vaccine (bivalent; 3‐dose)	15/239	15 participants with 20 events: Basedow’s disease, abdominal pain, appendix disorder, gastroenteritis, appendicitis, pharyngitis streptococcal, tonsillitis (2), urinary tract infection, ligament rupture, multiple injuries, ligament laxity, polyarthritis, migraine with aura, abortion spontaneous incomplete, abnormal behaviour, depression, renal colic, renal disorder, erythema multiforme
	Vaccine (bivalent; 2‐dose)	16/241	16 participants with 26 events: Abdominal pain, umbilical hernia (2), obstructive vomiting, gastroenteritis viral, cholecystitis acute, acute tonsillitis, appendicitis (2), endometritis decidual, vestibular neuronitis, tibia fracture, contusion, fall, fibroma, fibrosarcoma, pre‐eclampsia, premature baby, abortion missed, depression, major depression, psychotic disorder, suicide attempt, cystitis haemorrhagic, hyperventilation, circulatory collapse
	Vaccine (bivalent; 2‐dose, 6‐month interval)	19/240	19 participants with 23 events: Atrial septal defect, spina bifida, bile duct stone, appendicitis (4), tonsillitis bacterial, humerus fracture, road traffic accident, tibia fracture, upper limb fracture, malignant melanoma stage IV, basilar artery thrombosis, cerebrovascular accident, abortion spontaneous, abortion spontaneous incomplete (2), foetal distress syndrome, anorexia nervosa, bulimia nervosa, depression, circulatory collapse
	Vaccine (bivalent; 2‐dose, 2‐month interval)	14/240	14 participants with 16 events: Abdominal pain (3), hepatomegaly, pilonidal cyst, urinary tract infection, vestibular neuronitis, concussion, stab wound, coccydynia, uterine leiomyoma, benign hydatidiform mole, abortion spontaneous, ectopic pregnancy, adenomyosis, ovarian cyst
Toft 2014	Vaccine (bivalent)	0/46
Toft 2014	Vaccine (quadrivalent)	0/46
van Damme 2016	Vaccine (nonavalent)	0/249
van Damme 2016	Vaccine (quadrivalent)	6/251	Joint dislocation, ligament injury, ligament rupture, foot fracture, concussion, cytomegalovirus infection
Vesikari 2015	Vaccine (nonavalent)	1/299	One participant with two events: Anaemia and pulmonary vasculitis
Vesikari 2015	Vaccine (quadrivalent)	2/300	Complex partial seizures, Henoch‐Schonlein purpura
Abbreviations *For each event, n = 1 unless otherwise stated. HBV: hepatitis B vaccine

Table 1. Serious adverse events

Summary of findings 2. Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males

Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males
Patient or population: 9‐ to 14‐year‐old females and males Setting: community health centres in Africa, Asia Pacific, Europe, Latin America, North America Intervention: two doses of bivalent or nonavalent HPV vaccine with longer interval (months 0 and 6 or 12) Comparison: two doses of bivalent or nonavalent HPV vaccine with shorter interval (months 0 and 2 or 6)
Clinical and harms outcomes^*	Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with two doses of HPV vaccine with shorter interval	Risk with two doses of HPV vaccine with longer interval
Antibody response (geometric mean titre)	Longer intervals between the first two doses of bivalent vaccine resulted in higher and non‐inferior GMTs for HPV 16 (n = 971) and HPV 18 (n = 986) compared with shorter intervals in 9‐ to 14‐year‐old females at short‐term follow‐up (2 studies; moderate‐ to high‐certainty evidence, see Appendix 6).				MODERATE/ HIGH*	Short‐term results (follow‐up one month after final dose)
	A longer interval between the first two doses of nonavalent vaccine resulted in higher and non‐inferior GMTs than a shorter interval for all HPV vaccine genotypes in girls and boys at short‐term follow‐up (1 study, number of participants ranged from 778 to 815 depending on HPV type; high‐certainty evidence, see Appendix 6).				HIGH*
	Longer intervals between the first two doses of bivalent vaccine resulted in higher and non‐inferior GMTs for HPV 16 (n=817) and HPV 18 (n=794) compared with shorter intervals in 9‐ to 14‐year‐old females at 36 months follow‐up (1 study; high‐certainty evidence, see Appendix 6).				HIGH*	Long‐term results (follow‐up 36 months)
	A longer interval between the first two doses of nonavalent vaccine resulted in higher and non‐inferior GMTs than a shorter interval for all HPV vaccine genotypes in girls and boys at seven and 36 months follow‐up (1 study, number of participants ranged from 236 to 263 depending on HPV type; high‐certainty evidence, see Appendix 6).				HIGH*
Invasive cervical, vaginal, vulval, anal, or penile cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, vaginal, penile, or anal intraepithelial neoplasia	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain/swelling/redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at up to 5‐year follow‐up	Bivalent vaccine (0 and 2 months) 58 per 1000	Bivalent vaccine (0 and 6 months) 67 per 1000 (33 to 130)	OR 1.15 (0.55 to 2.41)	481 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2	Please see Table 1 for list of events in each RCT. Data for nonavalent vaccine include males and females; fully disaggregated data were not available.
	Bivalent vaccine (0 and 6 months) 36 per 1000	Bivalent vaccine (0 and 12 months) 58 per 1000 (32 to 101)	OR 1.63 (0.89 to 2.99)	965 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2
	Nonavalent vaccine (0 and 6 months) 25 per 1000	Nonavalent vaccine (0 and 12 months) 20 per 1000 (8 to 52)	OR 0.80 (0.31 to 2.07)	903 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2
Mortality at up to 5‐year follow‐up	Bivalent vaccine (0 and 2 months) 0 per 1000	Bivalent vaccine (0 and 6 months) 0 per 1000 (0 to 0)	Not estimable	481 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
	Bivalent vaccine (0 and 6 months) 0 per 1000	Bivalent vaccine (0 and 12 months) 0 per 1000 (0 to 0)	Not estimable	965 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
	Nonavalent vaccine (0 and 6 months) 0 per 1000	Nonavalent vaccine (0 and 12 months) 0 per 1000 (0 to 0)	Not estimable	452 (1 RCT)	⊕⊕⊝⊝ LOW ³	No deaths were reported in the trial.
Certainty of the evidence (GRADE) for immunogenicity outcomes are presented in detail in Appendix 6. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GMT: geometric mean titre; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential small harmful effect. ²Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ³Downgraded two levels for serious imprecision: no events reported, the studies were not powered to detect a difference in mortality.

Summary of findings 2. Two doses of HPV vaccine with longer interval compared with two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐old females and males

Summary of findings 3. Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males

Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males
Patient or population: 10‐ to 26‐year‐old males Setting: 18 countries in five regions (Africa, Asia‐Pacific, Europe, Latin America, North America) Intervention: quadrivalent HPV vaccine, 3 doses at months 0, 2, and 6; or bivalent HPV vaccine, 3 doses at months 0, 1, and 6 Comparison: control (vaccine adjuvant‐containing placebo), 3 doses at months 0, 2, and 6 or hepatitis B vaccine, 3 doses at months 0, 1, and 6
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk/rate with control	Risk/rate with HPV vaccine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Invasive anal or penile cancer	No studies were identified that reported on this outcome
Penile or anal intraepithelial neoplasia at up to 3‐year follow‐up	3/2824 person‐years	0/2833 person‐years	Rate ratio 0.17 (0.01 to 3.27)	2805 participants (5657 person‐years) (1 RCT)	⊕⊕⊝⊝ LOW ²
External genital lesions (any genotype) at up to 3‐year follow‐up	36/3081 person‐years	6/3173 person‐years	Rate ratio 0.16 (0.07 to 0.38)	2545 participants (6254 person‐years) (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
Anogenital warts at up to 3‐year follow‐up	28/2814 person‐years	3/2831 person‐years	Rate ratio 0.11 (0.03 to 0.38)	2805 participants (5645 person‐years) (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
Overall local/injection site adverse events at 15‐day follow‐up	537 per 1000	601 per 1000 (569 to 634)	RR 1.12 (1.06 to 1.18)	3895 (1 RCT)	⊕⊕⊕⊕ HIGH³	Data for specific local adverse events (pain, swelling, redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms at 15‐day follow‐up	248 per 1000	245 per 1000 (223 to 268)	RR 0.99 (0.90 to 1.08)	5008 (2 RCTs)	⊕⊕⊕⊝ MODERATE⁴
Serious adverse events at up to 3‐year follow‐up	Control: 11 per 1000	Bivalent vaccine: 17 per 1000 (2 to 141)	OR 1.48 (0.15 to 14.46)	270 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^2,4	In a subgroup from Lehtinen 2018, a cluster‐RCT, 58/2436 HPV vaccine recipients (2.4%) and 25/1267 control HBV vaccine recipients (2.0%) experienced serious adverse events. This was also considered very low‐certainty evidence^2,4 Please see Table 1 for list of events in each RCT.
Serious adverse events at up to 3‐year follow‐up	Control: 4 per 1000	Quadrivalent vaccine: 3 per 1000 (1 to 7)	OR 0.69 (0.29 to 1.66)	5162 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^2,4	Please see Table 1 for list of events in each RCT.
Mortality at up to 3‐year follow‐up	Control: see comment	Bivalent vaccine: see comment	OR not estimable: see comment	270 (1 RCT)	⊕⊕⊝⊝ LOW ⁵	No events were reported
Mortality at up to 3‐year follow‐up	Control: 4 per 1000	Quadrivalent vaccine: 1 per 1000 (0 to 4)	OR 0.30 (0.09 to 1.01)	5173 (2 RCTs)	⊕⊕⊝⊝ LOW ²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level for imprecision: few events. ²Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect as well as a potential large harmful effect. ³Evidence for this outcome was not downgraded: the trial was a large multi‐national trial with low risk of bias and precise estimates. ⁴Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁵Downgraded two levels for serious imprecision: no events reported.

Summary of findings 3. Three doses HPV vaccine compared with control in 10‐ to 26‐year‐old males

Summary of findings 4. Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males

Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males
Patient or population: 9‐ to 26‐year‐old females and males Setting: community health centres in Asia‐Pacific, Europe, Latin America, North America Intervention: nonavalent HPV vaccine, 3 doses administered at months 0, 2, and 6 Comparison: quadrivalent HPV vaccine, 3 doses administered at months 0, 2, and 6
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with quadrivalent HPV vaccine	Risk with nonavalent HPV vaccine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
High‐grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and cervical cancer at up to 4.5‐year follow‐up	47 per 1000	47 per 1000 (41 to 55)	OR 1.00 (0.85 to 1.16)	13,753 (1 RCT)	⊕⊕⊕⊕ HIGH¹	No studies were identified which reported on invasive anal or penile cancer in males
High‐grade cervical, vulval, and vaginal disease at up to 4.5‐year follow‐up	49 per 1000	48 per 1000 (42 to 56)	OR 0.99 (0.85 to 1.15)	14,054 (1 RCT)	⊕⊕⊕⊕ HIGH¹	No studies were identified which reported on penile or anal intraepithelial neoplasia in males
Overall local/injection site adverse events at 15‐day follow‐up	846 per 1000	905 per 1000 (888 to 914)	RR 1.07 (1.05 to 1.08)	15,863 (3 RCTs)	⊕⊕⊕⊕ HIGH	Data for specific local adverse events (pain, swelling, redness at injection site) are presented in the analysis section.
Overall systemic events and general symptoms at 15‐day follow‐up	543 per 1000	548 per 1000 (532 to 565)	RR 1.01 (0.98 to 1.04)	15,863 (3 RCTs)	⊕⊕⊕⊝ MODERATE³
Serious adverse events at up to 4.5‐year follow‐up	25 per 1000	15 per 1000 (4 to 63)	OR 0.60 (0.14 to 2.61)	15,863 (3 RCTs)	⊕⊕⊝⊝ LOW ^2,3	Please see Table 1 for list of events in each RCT. Numbers of events/number of participants (%) were: in 16‐ to 26‐year‐old females receiving nonavalent vaccine, 242/7686 (3.1%) vs quadrivalent vaccine, 184/7078 (2.6%) over a period of 4.5 years follow‐up; in 16‐ to 26‐year‐old males receiving nonavalent vaccine, 0/249 (0%) vs quadrivalent vaccine, 6/251 (2.4%) over 7 months follow‐up; in 9‐ to 15‐year‐old females receiving nonavalent vaccine, 1/299 (0.3%) vs quadrivalent vaccine, 2/300 (0.7%) over 7 months follow‐up.
Mortality at up to 4.5‐year follow‐up	1 per 1000	1 per 1000 (0 to 3)	OR 1.20 (0.37 to 3.94)	15,248 (3 RCTs)	⊕⊕⊝⊝ LOW ⁴
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HPV: human papillomavirus; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Evidence from this outcome was not downgraded: the included trial was a large multi‐national trial with low risk of bias and precise estimates. ²Downgraded one level for imprecision: pooled estimate has a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential large harmful effect. ³Downgraded one level for indirectness: this outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁴Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporates a potential large beneficial effect and a potential large harmful effect.

Summary of findings 4. Nonavalent HPV vaccine compared with quadrivalent HPV vaccine in 9‐ to 26‐year‐old females and males

Table 2. Characteristic of licensed prophylactic HPV vaccines

	Bivalent vaccine	Quadrivalent vaccine	Nonavalent vaccine
Manufacturer	GlaxoSmithKline (GSK, Rixensart, Belgium)	Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)	Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)
Antigens	L1 VLPs of HPV16 (20 μg) and HPV18 (20 μg)	L1 VLPs of HPV6 (20 μg), HPV11 (40 μg), HPV16 (40 μg) and HPV18 (20 mg)	L1 VLPs of HPV6 (30 μg), HPV11 (40 μg), HPV16 (60 μg), HPV18 (40 mg),HPV31 (20 μg), HPV33 (20 μg), HPV45 (20 μg), HPV52 (20 μg)and HPV58 (20 μg)
Vaccination schedule	3 doses: at day 1, month 1, and month 6	3 doses: at day 1, month 2, and month 6	3 doses: at day 1, month 2, and month 6
Adjuvant	AS04: 500 μg aluminium hydroxide, 50 μg 3‐deacylated monophosphoryl lipid A (MPL)	225 μg amorphous aluminium hydroxyl‐phosphate sulphate	500 μg amorphous aluminium hydroxyl‐phosphate sulphate
Trade name	Cervarix	Gardasil, Silgard	Gardasil‐9
Produced by recombinant technology using	Baculovirus in Trichoplusia in insect cells	Saccharomyces cerevisae (Baker’s yeast)	Saccharomyces cerevisae (Baker’s yeast)
Abbreviations HPV: human papillomavirus MPL: monophosphoryl lipid VLP: virus‐like particle

Table 2. Characteristic of licensed prophylactic HPV vaccines

Table 3. Summary of findings: Quadrivalent HPV vaccine compared with control in children, adults, and MSM with HIV

Quadrivalent HPV vaccine compared with control in children, adults, and MSM with HIV
Patient or population: children (7 to 12 years old) with HIV, adults (≥ 18 years old) with HIV, and MSM (≥ 18 years old) with HIV Settings: Brazil, Puerto Rico, Spain, the USA Intervention: quadrivalent HPV vaccine (3 doses at 0, 2, and 6 months) Comparison: control (3 doses at 0, 2 and 6 months; not specified whether placebo contained vaccine adjuvant)
Outcomes	Population	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Outcomes	Population	Risk with control	Risk with quadrivalent HPV vaccine	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
High‐grade anal intraepithelial neoplasia at 4‐year follow‐up	Females and males with HIV (≥ 27 years)	157 per 1000	160 per 1000 (110 to 233)	RR 1.02 (0.70 to 1.48)	574 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
Recurrence of anogenital warts at 18‐month follow‐up	Females and males with HIV treated for anogenital warts (18‐65 years)	200 per 1000	143 per 1000 (7 to 778)	RR 0.71 (0.06 to 8.90)	12 (1 study)	⊕⊝⊝⊝ VERY LOW^2,3
Abnormal anal cytology at 4‐year follow‐up	Females and males with HIV (≥ 27 years)	545 per 1000	447 per 1000 (349 to 573)	RR 0.82 (0.64 to 1.05)	262 (1 study)	⊕⊝⊝⊝ VERY LOW^1,4
Overall local/injection site adverse events at 15‐day follow‐up	Children with HIV (7‐12 years)	100 per 1000	219 per 1000 (70 to 683)	RR 2.19 (0.70 to 6.83)	126 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
Overall systemic events and general symptoms at 15‐day follow‐up	Children with HIV (7‐12 years)	33 per 1000	21 per 1000 (2 to 235)	RR 0.62 (0.05 to 7.05)	126 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2,6
Serious adverse events at 4‐year follow‐up (adults) or 7‐month follow‐up (MSM)	Females and males with HIV (≥ 27 years)	160 per 1000	115 per 1000 (74 to 174)	OR 0.68 (0.42 to 1.10)	575 (1 study)	⊕⊝⊝⊝ VERY LOW^1,4,6,7
	MSM with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	129 (1 study)	⊕⊝⊝⊝ VERY LOW^5,6,7
Mortality at 4‐year follow‐up (adults) or 7‐month follow‐up (MSM)	Females and males with HIV (≥ 27 years)	21 per 1000	10 per 1000 (3 to 41)	OR 0.49 (0.12 to 1.99)	575 (1 study)	⊕⊝⊝⊝ VERY LOW^1,2
	MSM with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	129 (1 study)	⊕⊕⊝⊝ LOW⁵
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; MSM: men who have sex with men; OR: odds ratio; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded one level for risk of bias: details about how randomisation sequence was generated or how blinding was achieved were not reported. ²Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potentially beneficial effect and a potentially harmful effect. ³Downgraded two levels for serious risk of bias: data for 62.5% (20/32) of the participants enrolled were missing due to lack of follow‐up. In addition, details about how randomisation, allocation concealment, and blinding were achieved were not reported. ⁴Downgraded two levels for imprecision: few events and wide 95% confidence interval that incorporated a potential beneficial effect and no effect. ⁵Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in serious adverse events or mortality. ⁶Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁷See Table 1 for details of each serious event.

Table 3. Summary of findings: Quadrivalent HPV vaccine compared with control in children, adults, and MSM with HIV

Table 4. Summary of findings: Bivalent HPV vaccine compared with control in 18‐ to 25‐year‐old females with HIV

Bivalent HPV vaccine compared with control in 18‐ to 25‐year‐old females with HIV
Patient or population: 18‐ to 25‐year‐old females with HIV Settings: South Africa Intervention: bivalent HPV vaccine (3 doses at 0, 1, and 6 months) Comparison: control (vaccine adjuvant‐containing placebo) (3 doses at 0, 1 and 6 months)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Risk with control	Risk with bivalent HPV vaccine
High‐grade cervical epithelial neoplasia, adenocarcinoma in situ, and cervical cancer	No studies were identified that reported on this outcome.
High‐grade cervical, vulval, and vaginal disease	No studies were identified that reported on this outcome.
Overall local/injection site adverse events	No studies were identified that reported on this outcome. Data for specific local adverse events (pain and swelling at injection site) are presented in the Data and analyses and Effects of interventions sections.
Overall systemic events and general symptoms	No studies were identified that reported on this outcome.
Serious adverse events at 12‐month follow‐up	34 per 1000	49 per 1000 (8 to 243)	OR 1.47 (0.24 to 9.15)	120 (1 study)	⊕⊝⊝⊝ VERY LOW^1,3,4
Mortality at 12‐month follow‐up	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	120 (1 study)	⊕⊕⊝⊝ LOW²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; OR: odds ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporated a potentially large beneficial effect and a potentially large harmful effect. ²Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in mortality. ³Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁴See Table 1 for details of each serious event.

Table 4. Summary of findings: Bivalent HPV vaccine compared with control in 18‐ to 25‐year‐old females with HIV

Table 5. Summary of findings: Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults with HIV

Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults with HIV
Patient or population: adults and adolescents (combined male and female) with HIV, ≥ 15 years old Settings: Brazil, Denmark, Estonia, India, and Thailand Intervention: bivalent HPV vaccine (3 doses at 0, 1.5, and 6 months) Comparison: quadrivalent HPV vaccine (3 doses at 0, 1.5, and 6 months)
Outcomes	Population	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
		Risk with quadrivalent HPV vaccine	Risk with bivalent HPV vaccine
High‐grade neoplasia, cancer		No studies were identified that reported on this outcome.
Overall local/injection site adverse events at 4‐day follow‐up	Females and males with HIV (≥ 18 years)	696 per 1000	911 per 1000 (737 to 1000)	RR 1.31 (1.06 to 1.62)	92 (1 study)	⊕⊕⊝⊝ LOW¹
Overall systemic events and general symptoms		No studies were identified that reported on this outcome.
Serious adverse events at 6‐month follow‐up (adults) and 7‐month follow‐up (females)	Females and males with HIV (≥ 18 years)	0 per 1000	0 per 1000 (0 to 0)	Not estimable, no events were reported	92 (1 study)	⊕⊝⊝⊝ VERY LOW^2,5,6
	Females with HIV (15‐25 years)	55 per 1000	54 per 1000 (21 to 128)	OR 0.99 (0.38 to 2.55)	332 (1 study)	⊕⊝⊝⊝ VERY LOW^3,4,5,6
Mortality		No studies were identified that reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HIV: human immunodeficiency virus; HPV: human papillomavirus; OR: odds ratio; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded two levels for serious imprecision: few events reported. ²Downgraded two levels for serious imprecision: no events reported, the study was not powered to detect a difference in serious adverse events or mortality. ³Downgraded one level for risk of bias: details on how randomisation, allocation concealment, and blinding was achieved was not reported. ⁴Downgraded two levels for serious imprecision: few events and a wide 95% confidence interval that incorporate a potentially large beneficial effect and a potentially large harmful effect. ⁵Downgraded one level for indirectness: This outcome is a composite measure of events which may or may not be clinically relevant, may or may not be related to the vaccine and may occur outside a biologically plausible time frame relative to vaccine exposure. This outcome is considered to provide indirect evidence about vaccine safety. ⁶See Table 1 for details of each serious event.

Table 5. Summary of findings: Bivalent HPV vaccine compared with quadrivalent HPV vaccine in adults with HIV

Comparison 1. Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain at injection site Show forest plot	2	1189	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.91, 1.03]

1.1 Bivalent vaccine	1	476	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.94, 1.03]
1.2 Quadrivalent vaccine	1	713	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 1.00]
2 Swelling at injection site Show forest plot	2	1189	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.65, 0.89]

2.1 Bivalent vaccine	1	476	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.57, 0.87]
2.2 Quadrivalent vaccine	1	713	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.66, 1.04]
3 Redness at injection site Show forest plot	2	1189	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.75, 0.96]

3.1 Bivalent vaccine	1	476	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.72, 0.99]
3.2 Quadrivalent vaccine	1	713	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.71, 1.02]
4 Serious adverse events (overall) Show forest plot	4	2317	Odds Ratio (M‐H, Random, 95% CI)	1.03 [0.64, 1.66]

4.1 Bivalent vaccine	1	479	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.64, 2.59]
4.2 Quadrivalent vaccine	2	1236	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.35, 1.74]
4.3 Nonavalent vaccine	1	602	Odds Ratio (M‐H, Random, 95% CI)	1.0 [0.32, 3.14]
5 Deaths Show forest plot	3	1797	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.19]

5.1 Bivalent vaccine	1	479	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Quadrivalent vaccine	1	716	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Nonavalent vaccine	1	602	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.19]

Comparison 1. Two versus three doses of HPV vaccines in 9‐ to 15‐year‐old females

Comparison 2. Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain at injection site Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Bivalent vaccine (0 and 2 months vs 0 and 6 months)	1	477	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.96, 1.06]
1.2 Bivalent vaccine (0 and 6 months vs 0 and 12 months)	1	963	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.98, 1.06]
2 Swelling at injection site Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Bivalent vaccine (0 and 2 months vs 0 and 6 months)	1	477	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.76, 1.20]
2.2 Bivalent vaccine (0 and 6 months vs 0 and 12 months)	1	963	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.87, 1.18]
3 Redness at injection site Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Bivalent vaccine (0 and 2 months vs 0 and 6 months)	1	477	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.84, 1.24]
3.2 Bivalent vaccine (0 and 6 months vs 0 and 12 months)	1	963	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.93, 1.22]
4 Serious adverse events (overall) Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Bivalent vaccine (0, 2 months vs 0, 6 months)	1	481	Odds Ratio (M‐H, Random, 95% CI)	1.15 [0.55, 2.41]
4.2 Bivalent vaccine (0 and 6 months vs 0 and 12 months)	1	965	Odds Ratio (M‐H, Random, 95% CI)	1.63 [0.89, 2.99]
4.3 Nonavalent vaccine (0 and 6 months vs 0 and 12 months) ‐ females and males	1	903	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.31, 2.07]
5 Deaths Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Bivalent vaccine (0 and 2 months vs 0 and 6 months)	1	481	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Bivalent vaccine (0 and 6 months vs 0 and 12 months)	1	965	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Nonavalent vaccine (0 and 6 months vs 0 and 12 months)	1	452	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Two doses of HPV vaccine with longer interval versus two doses of HPV vaccine with shorter interval in 9‐ to 14‐year‐olds

Comparison 3. Three doses of HPV vaccine with longer interval versus three doses of HPV vaccine with shorter interval in 18‐ to 25‐year‐old males

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events Show forest plot			Other data	No numeric data

2 Serious adverse events (overall) Show forest plot	1	220	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Three doses of HPV vaccine with longer interval versus three doses of HPV vaccine with shorter interval in 18‐ to 25‐year‐old males

Comparison 4. HPV vaccine versus control in males

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 External genital lesions (any type) Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

1.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.16 [0.07, 0.38]
2 External genital lesions (HPV 6, 11, 16, or 18) Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

2.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.10 [0.03, 0.31]
3 Anogenital warts Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

3.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.11 [0.03, 0.38]
4 All penile, perianal, or perineal intraepithelial neoplasia lesions Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

4.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.17 [0.01, 3.27]
5 Penile, perianal, or perineal intraepithelial neoplasia grade 1 Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

5.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.25 [0.01, 6.22]
6 Penile, perianal, or perineal intraepithelial neoplasia grade 2 or 3 Show forest plot	1		Rate Ratio (Random, 95% CI)	Subtotals only

6.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1		Rate Ratio (Random, 95% CI)	0.50 [0.02, 14.80]
7 Overall local/injection site adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Quadrivalent vaccine (16‐ to 26‐year olds)	1	3895	Risk Ratio (M‐H, Random, 95% CI)	1.12 [1.06, 1.18]
8 Pain at injection site Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Bivalent vaccine (10‐ to 18‐year‐olds)	1	268	Risk Ratio (M‐H, Random, 95% CI)	1.99 [1.57, 2.53]
8.2 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5162	Risk Ratio (M‐H, Random, 95% CI)	1.13 [1.07, 1.19]
9 Swelling at injection site Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Bivalent vaccine (10‐ to 18‐year‐olds)	1	268	Risk Ratio (M‐H, Random, 95% CI)	2.51 [1.17, 5.42]
9.2 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5162	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.04, 1.60]
10 Redness at injection site Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Bivalent vaccine (10‐ to 18‐year‐olds)	1	268	Risk Ratio (M‐H, Random, 95% CI)	1.66 [0.99, 2.79]
10.2 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5162	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.99, 1.27]
11 Overall systemic events and general symptoms Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5008	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.90, 1.08]
12 Serious adverse events (overall) Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Bivalent vaccine (10‐ to 18‐year‐olds)	1	270	Odds Ratio (M‐H, Random, 95% CI)	1.48 [0.15, 14.46]
12.2 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5162	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.29, 1.66]
13 Deaths Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

13.1 Bivalent vaccine (10‐ to 18‐year‐olds)	1	270	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
13.2 Quadrivalent vaccine (16‐ to 26‐year olds)	2	5173	Odds Ratio (M‐H, Random, 95% CI)	0.30 [0.09, 1.01]

Comparison 4. HPV vaccine versus control in males

Comparison 5. Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 High‐grade cervical epithelial neoplasia, adenocarcinoma in situ, and cervical cancer Show forest plot	1	13753	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.85, 1.16]

2 High‐grade cervical, vulval, and vaginal disease Show forest plot	1	14054	Odds Ratio (M‐H, Random, 95% CI)	0.99 [0.85, 1.15]

3 High‐grade cervical disease related to HPV 6, 11, 16, or 18 Show forest plot	1	11656	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.06, 16.01]

4 High‐grade vulval and vaginal disease related to HPV 6, 11, 16, or 18 Show forest plot	1	11769	Odds Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.77]

5 High‐grade cervical disease related to HPV 31, 33, 45, 52, or 58 Show forest plot	1	11892	Odds Ratio (M‐H, Random, 95% CI)	0.03 [0.00, 0.21]

6 High‐grade vulval and vaginal disease related to HPV 31, 33, 45, 52, or 58 Show forest plot	1	12021	Odds Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.77]

7 Cervical intraepithelial neoplasia 2 related to HPV 6, 11, 16, or 18 Show forest plot	1	11656	Odds Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 73.77]

8 Cervical intraepithelial neoplasia 2 related to HPV 31, 33, 45, 52, or 58 Show forest plot	1	11892	Odds Ratio (M‐H, Random, 95% CI)	0.03 [0.00, 0.23]

9 Cervical intraepithelial neoplasia 3, adenocarcinoma in situ, and cervical cancer related to HPV 6, 11, 16, or 18 Show forest plot	1	11656	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.19]

10 Cervical intraepithelial neoplasia 3, adenocarcinoma in situ, and cervical cancer related to HPV 31, 33, 45, 52, or 58 Show forest plot	1	11892	Odds Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.16]

11 Overall local/injection site adverse events Show forest plot	3	15863	Risk Ratio (M‐H, Random, 95% CI)	1.07 [1.05, 1.08]

11.1 9‐ to 15‐year‐old females	1	599	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.98, 1.09]
11.2 16‐ to 26‐year‐old females	1	14764	Risk Ratio (M‐H, Random, 95% CI)	1.07 [1.05, 1.08]
11.3 16‐ to 26‐year‐old males	1	500	Risk Ratio (M‐H, Random, 95% CI)	1.10 [1.00, 1.22]
12 Pain at injection site Show forest plot	3	15863	Risk Ratio (M‐H, Random, 95% CI)	1.06 [1.02, 1.11]

12.1 9‐ to 15‐year‐old females	1	599	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.96, 1.07]
12.2 16‐ to 26‐year‐old females	1	14764	Risk Ratio (M‐H, Random, 95% CI)	1.07 [1.06, 1.09]
12.3 16‐ to 26‐year‐old males	1	500	Risk Ratio (M‐H, Random, 95% CI)	1.12 [1.01, 1.24]
13 Swelling at injection site Show forest plot	3	15863	Risk Ratio (M‐H, Random, 95% CI)	1.37 [1.31, 1.44]

13.1 9‐ to 15‐year‐old females	1	599	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.10, 1.60]
13.2 16‐ to 26‐year‐old females	1	14764	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.31, 1.44]
13.3 16‐ to 26‐year‐old males	1	500	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.96, 2.58]
14 Redness at injection site Show forest plot	3	15863	Risk Ratio (M‐H, Random, 95% CI)	1.20 [1.00, 1.44]

14.1 9‐ to 15‐year‐old females	1	599	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.92, 1.47]
14.2 16‐ to 26‐year‐old females	1	14764	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.26, 1.39]
14.3 16‐ to 26‐year‐old males	1	500	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.60, 1.33]
15 Overall systemic events and general symptoms Show forest plot	3	15863	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.98, 1.04]

15.1 9‐ to 15‐year‐old females	1	599	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.07]
15.2 16‐ to 26‐year‐old females	1	14764	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.98, 1.04]
15.3 16‐ to 26‐year‐old males	1	500	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.82, 1.26]
16 Serious adverse events (overall) Show forest plot	3	15863	Odds Ratio (M‐H, Random, 95% CI)	0.60 [0.14, 2.61]

16.1 9‐ to 15‐year‐old females	1	599	Odds Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.54]
16.2 16‐ to 26‐year‐old females	1	14764	Odds Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.48]
16.3 16‐ to 26‐year‐old males	1	500	Odds Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.35]
17 Deaths Show forest plot	3	15248	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.37, 3.94]

17.1 9‐ to 15‐year old females	1	599	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
17.2 16‐ to 26‐year‐old females	1	14149	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.37, 3.94]
17.3 16‐ to 26‐year‐old males	1	500	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Nonavalent HPV vaccine versus quadrivalent HPV vaccine in 9‐ to 26‐year‐olds

Comparison 6. Quadrivalent HPV vaccine versus control in people living with HIV

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 High‐grade anal intraepithelial neoplasia Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 ≥ 27‐year‐old females and males with HIV	1	574	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.70, 1.48]
2 Recurrence of anogenital warts Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 18‐ to 65‐year‐old females and males with HIV treated for anogenital warts	1	12	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.06, 8.90]
3 Abnormal anal cytology Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 ≥ 27‐year‐old females and males with HIV	1	262	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.64, 1.05]
4 Overall local/injection site adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 7‐ to 12‐year‐old children with HIV	1	126	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.70, 6.83]
5 Overall systemic event and general symptoms Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 7‐ to 12‐year‐old children with HIV	1	126	Odds Ratio (M‐H, Random, 95% CI)	0.62 [0.05, 7.05]
6 Serious adverse events (overall) Show forest plot	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 ≥ 27 year old females and males with HIV	1	575	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.42, 1.10]
6.2 ≥ 18‐year‐old MSM with HIV	1	129	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Deaths Show forest plot	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 ≥ 27‐year‐old females and males with HIV	1	575	Odds Ratio (M‐H, Random, 95% CI)	0.49 [0.12, 1.99]
7.2 ≥ 18‐year‐old MSM with HIV	1	129	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 6. Quadrivalent HPV vaccine versus control in people living with HIV

Comparison 7. Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain at injection site Show forest plot	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.86 [1.38, 2.51]

2 Swelling at injection site Show forest plot	1	120	Risk Ratio (M‐H, Random, 95% CI)	9.19 [2.24, 37.73]

3 Serious adverse events (overall) Show forest plot	1	120	Odds Ratio (M‐H, Random, 95% CI)	1.47 [0.24, 9.15]

4 Deaths Show forest plot	1	120	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 7. Bivalent HPV vaccine versus control in 18‐ to 25‐year‐old females with HIV

Comparison 8. Bivalent HPV vaccine versus quadrivalent HPV vaccine in people living with HIV

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall local/injection site adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 ≥ 18‐year‐old females and males with HIV	1	92	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.06, 1.62]
2 Serious adverse events (overall) Show forest plot	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 ≥ 18‐year‐old females and males with HIV	1	92	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 15‐ to 25‐year‐old females with HIV	1	332	Odds Ratio (M‐H, Random, 95% CI)	0.99 [0.38, 2.55]

Comparison 8. Bivalent HPV vaccine versus quadrivalent HPV vaccine in people living with HIV