Improving vaccination uptake among adolescents

Summary of findings for the main comparison. Health education compared to usual practice

Comparison 1: health education compared to usual practice
Population: adolescents and parents Setting: Sweden and USA intervention: health education Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With health education
Uptake of HPV vaccine^a	209 per 1000	298 per 1000 (242 to 367)	RR 1.43 (1.16 to 1.76)	Health education improves uptake of HPV vaccine compared to usual practice.	1054 (3)^b	⊕⊕⊕⊕ High^c,d,e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% confidence interval) is based on the assumed likelihood of being vaccinated in the usual care group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a The lag‐time between delivery of the intervention and assessment of outcomes ranged from three months (Grandahl 2016) to 11 months (Winer 2016 ) ^bDiclemente 2015 (randomised trial); Grandahl 2016 (cluster‐randomised trial); Winer 2016 (cluster‐randomised trial). ^c Well conducted randomised trials with consistent findings (I² = 0%). ^d The findings from the one non‐randomised trial that assessed this comparison were similar to the findings of the randomised trials. ^eOne study reported that health education did not have any adverse events in relation to usual practice (Rickert 2015).

Summary of findings 2. Complex compared to simplified health education

Comparison 2: complex compared to simplified health education
Population: adolescents Setting: Australia Intervention: multi‐component health education^a Comparison: simplified health education
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With simplified education	With complex health education
Uptake of hepatitis B vaccine^b	756 per 1000	741 per 1000 (726 to 748)	RR 0.98 (0.96 to 0.99)	A complex multi‐component health education programme probably results in little or no difference in uptake of 3 doses of hepatitis B vaccine compared to simplified health education.	17,411 (1)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% confidence interval) is based on the assumed likelihood of being vaccinated in the simplified health education group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a Health education kit with 4‐lesson structured multi‐component intervention that included: a resource fact sheet and assessment, an information video and questions designed to engage an adolescent audience, small group discussion, and an activity to locate resource information on the Internet. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was not provided. ^cSkinner 2000 (randomised trial). ^d Downgraded one level due to study limitations, as the included study has an unclear risk of bias.

Summary of findings 3. Financial incentives compared to usual practice

Comparison 3: financial incentives compared to usual practice
Patient or population: adolescents Setting: UK intervention: financial incentive^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With financial incentives
Uptake of HPV vaccine^b	196 per 1000	284 per 1000 (206 to 390)	RR 1.45 (1.05 to 1.99)	Financial incentives may improve uptake of HPV vaccine compared to usual practice.	500 (1)^c	⊕⊕⊝⊝ Low^d,e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe financial incentive involved an offer of shopping vouchers worth GBP 45 upon completion of 3 HPV vaccination doses. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was one to seven months. Invitation letters promising incentives were sent in February‐March of 2010 and vaccination sessions were conducted between March and September 2010 ^cMantzari 2015 (randomised trial). ^d Downgraded one level for study limitations (unclear risk of bias in the included study). ^e Downgraded one level for imprecision of findings.

Summary of findings 4. Health education plus financial incentives compared to usual practice

Comparison 4: health education plus financial incentives compared to usual practice
Population: adolescents and parents Setting: USA Intervention: health education plus financial incentives^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With health education and incentives
Uptake of hepatitis B vaccine^b	451 per 1000	622 per 1000 (433 to 902)	RR 1.38 (0.96 to 2.00)	We are uncertain about the effects of health education plus financial incentives on the uptake of 3 doses of hepatitis B vaccine compared to usual practice.	104 (1)^c	⊕⊝⊝⊝ Very low^d,e,f
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe intervention involved (1) an educational video and PowerPoint presentation for caregivers and adolescents about hepatitis B infection and the importance of hepatitis B vaccination, (2) free vaccination, and (3) financial incentives. When the adolescents received each vaccine dose, their caregivers were given cash incentives of USD 10 for the first dose, USD 10 for the second dose, and USD 30 for the third dose. In addition, at each visit, adolescents and caregivers were given gift packages containing cosmetics for adults and sweets and toothbrushes for the children. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was three months. ^cSchwarz 2008 (randomised trial). ^d Downgraded one level for serious study limitations (unclear risk of bias in the included study). ^e Downgraded two levels for imprecision of findings with a wide confidence interval that includes both benefit and harm as well as a very small number of participants. ^f Downgraded two levels for serious indirectness, given that this finding is based on one small study from one setting.

Summary of findings 5. Mandatory vaccination versus usual practice

Comparison 5: mandatory vaccination vs usual practice
Population: adolescents Setting: USA Intervention: school entry law mandating vaccination Comparison: usual practice in other classes in the same schools
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With mandatory vaccination
Uptake of hepatitis B vaccine^a	248 per 1000	728 per 1000 (677 to 784)	RR 2.94 (2.66 to 3.25)	Mandatory vaccination probably leads to a large increase in uptake of 3 doses of the hepatitis B vaccine compared to usual practice in other classes in the same schools.	2642 (1)^b	⊕⊕⊕⊝ Moderate^d
Population: adolescents Setting: USA Intervention: school entry law mandating vaccination Comparison: usual practice in areas not affected by the mandatory vaccination law
Uptake of hepatitis B vaccine^a	186 per 1000	728 per 1000 (678 to 780)	RR 3.92 (3.65 to 4.20)	Mandatory vaccination probably leads to a large increase in uptake of 3 doses of the hepatitis B vaccine compared to usual practice in areas not affected by the mandatory vaccination law.	6462 (1)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the no‐intervention group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a The lag‐time between delivery of the intervention and assessment of outcomes was 6‐8 years. ^bWilson 2005 (non‐randomised trial) compared students in the ninth grade (affected by the hepatitis B law) and 12th grade (not affected by the law) in the state of Missouri . ^cWilson 2005 (non‐randomised trial) compared the ninth grade in the state of Missouri (affected by the hepatitis B vaccination law) to the ninth grade in the state of Kansas (not affected by the law). ^d As a non‐randomised trial, these outcomes were initially graded as low certainty evidence and then upgraded by one level for very large effect sizes.

Summary of findings 6. Provider prompts compared to usual practice

Comparison 6: provider prompts compared to usual practice
Population: healthcare workers Setting: USA Intervention: provider prompts^a Comparison: usual practice
Outcomes	Impact		№ of participants (studies)	Certainty of the evidence (GRADE)**
Outcomes	Relative effect (95% CI)	Narrative results	№ of participants (studies)	Certainty of the evidence (GRADE)**
Uptake of HPV vaccine^b	aOR 0.99 (0.55 to 1.81)^e	Provider prompts probably make little or no difference to uptake of 3 doses of HPV vaccine among adolescents compared to usual practice.	859 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of Tdap vaccine^b	aOR 1.28 (0.59 to 2.80)	Provider prompts probably make little or no difference to uptake of Tdap vaccine among adolescents compared to usual practice.	3296 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of meningococcal conjugate vaccine^b	aOR 1.09 ,(0.67 to 1.79)	Provider prompts probably make little or no difference to uptake of the meningococcal conjugate vaccine among adolescents compared to usual practice.	3219 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of seasonal influenza vaccine^b	aOR 0.91 (0.61 to 1.34)	Provider prompts probably make little or no difference to uptake of the seasonal influenza vaccine among adolescents compared to usual practice.	1439 (2)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; HPV: human papillomavirus; aOR: adjusted odds ratio; Tdap: tetanus–diphtheria–acellular–pertussis. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a When a healthcare provider opened a patient's electronic medical record, there was a screen display of the list of vaccines that were due at that visit. At the beginning of the study, a 1‐2 hour educational session was given to the providers to inform them about the electronic health record based prompts. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was 12 months. ^cSzilagyi 2015 conducted two separate randomised trials, one in a local and one in a national network, and then reported these in one paper. ^d Downgraded one level for imprecision of findings. ^e All odds ratios were adjusted based on a multilevel mixed‐effect logistic regression model with covariates for pair assignment, study time period, group assignment, and an interaction between time and group assignment.

Summary of findings 7. Provider education with performance feedback compared to usual practice

Comparison 7: provider education with performance feedback compared to usual practice
Population: paediatricians and nurse practitioners Setting: USA Intervention: education with performance feedback Comparison: usual practice
Outcomes	Impact	№ of participants (studies)	Certainty of the evidence (GRADE)*
Uptake of HPV vaccination^a	Provider education with performance feedback may increase the proportion of adolescents who are offered and accept HPV vaccination by clinicians, compared to usual practice. Compared to adolescents visiting non‐participating clinicians (in the usual practice group), the adolescents visiting clinicians in the intervention group were more likely to receive the first dose of HPV during preventive visits (5.7 percentage points increase) and during acute visits (0.7 percentage points for the first and 5.6 percentage points for the second doses of HPV).	> 200,000 children (1 CBA)^b	⊕⊕⊝⊝ Low^c
HPV: human papillomavirus; CBA: controlled before‐after study *GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a There was no lag‐time between delivery of the intervention and assessment of outcomes. The intervention period ran from 01 January to 30 November 2013. Outcomes were assessed throughout this period, starting from day 1. ^bFiks 2016 (controlled before‐after study). c This is a non‐randomised study.

Summary of findings 8. Class‐based compared to age‐based HPV vaccination in schools

Comparison 8: class‐based compared to age‐based HPV vaccination in schools
Population: adolescents Setting: Tanzania Intervention: class‐based vaccination Comparison: age‐based vaccination
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With age‐based delivery	With class‐based delivery
HPV vaccine uptake^a	721 per 1000	786 per 1000 (764 to 815)	RR 1.09 (1.06 to 1.13)	Class‐based vaccination probably leads to slightly higher HPV vaccine uptake than age‐based vaccination.	5537 (1)^b	⊕⊕⊕⊝ Moderate^c
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision
^a The lag‐time between delivery of the intervention and assessment of outcomes was 12 months. ^bWatson‐Jones 2012 (cluster‐randomised trial). ^c Downgraded one level for indirectness, given that the outcome is based on one study from one setting.

Summary of findings 9. Multi‐component provider intervention compared to usual practice

Comparison 9: multi‐component provider intervention compared to usual practice
Population: healthcare providers and their adolescent patients (boys and girls aged 11–21 years) Setting: USA Intervention: multi‐component performance improvement continuing medical education intervention^a Comparison: usual practice
Outcomes	Impact	№ of participants (studies)	Certainty of the evidence (GRADE)*
HPV vaccine uptake^b	A multi‐component provider intervention (including an education session, repeated contacts, individualised feedback, and incentives) probably improves uptake of HPV vaccine compared to usual practice. Girls in the intervention group are probably more likely to receive their next HPV vaccine dose than those in the comparison group (odds ratio 1.6, 95% CI 1.1 to 2.2). The effects are probably larger for boys (odds ratio 25.00, 95% CI 15.00 to 40.00), and this may be because publicly funded HPV vaccination for boys became available during the study.	15,849 adolescents (1)^c	⊕⊕⊕⊝ Moderate^d
HPV: human papillomavirus. *GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe intervention involved: (1) 6–8 education visits over 12 months by an HPV physician‐educator; (2) focused education sessions on HPV‐related topics designed to change the way providers viewed the importance of HPV vaccination and responded to parents' hesitation toward HPV vaccines; (3) individualised feedback where providers and practices received individual reports that showed their performance compared to other providers in their practice on HPV vaccination coverage; and (4) quality improvement incentives whereby physicians were eligible to receive maintenance‐of‐registration credits, which fulfilled requirements for maintaining board certification. ^b The lag‐time between delivery of the intervention and assessment of outcomes was six months. ^cPerkins 2015 (cluster‐randomised trial). ^d Downgraded one level because of serious indirectness, given that this finding is based on one study from one setting.

Summary of findings 10. Multi‐component provider and parent intervention compared to usual practice

Comparison 10: multi‐component provider and parent intervention compared to usual practice
Population: healthcare workers and parents Setting: USA Intervention: multi‐component provider and parent intervention^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With multi‐faced intervention
HPV vaccine uptake at 3 months	25 per 1,000	57 per 1000 (18 to 180)	RR 2.34 (0.75 to 7.32)	A multi‐component intervention involving healthcare providers and parents may improve uptake of the HPV vaccine compared to usual practice.	337 (1)^b Randomised trial	⊕⊕⊝⊝ Low^d
HPV vaccine uptake at 6 months	52 per 1,000	73 per 1000 (65 to 83)	RR 1.41 (1.25 to 1.59)		25,869 (1)^cNon‐randomised trial	⊕⊕⊝⊝ Low^e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The risk in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a In the randomised trial (Paskett 2016), healthcare providers received a one‐hour PowerPoint presentation and handouts on the HPV vaccine, focusing on current evidence‐based HPV vaccine information and strategies designed to assist physicians in discussing HPV vaccination with parents. In addition, parents were mailed a packet that included an educational brochure and DVD video about HPV infection and HPV vaccination as well as a CDC HPV vaccine information statement. Furthermore, health educators conducted an education session with parents about the HPV vaccine via telephone to reinforce the message in the educational materials regarding the need for the vaccine and addressed any vaccination barriers or questions. In the non‐randomised trial (Cates 2014), the intervention included: (1) distribution of HPV vaccination posters and brochures with the risk‐related message to health departments and healthcare providers; (2) two radio public service announcements designed to raise awareness about HPV vaccine for boys among parents of preteen boys; (3) an online continuing medical education training with video demonstrating communication among providers, parents, and preteen boys available to enrolled health providers; (4) one‐page tip sheet for providers to discuss HPV vaccination with parents and boys; and (5) a website with links to credible information sources useful for both parents and providers. ^bPaskett 2016 (randomised trial). ^cCates 2014 (non‐randomised trial). ^d Downgraded by two levels for serious imprecision and serious study limitations (unclear risk of selection bias in the included study) (Paskett 2016). ^e Downgraded by two levels for non‐randomised study design (Cates 2014).

Background

Description of the condition

The World Health Organization (WHO) defines adolescents as people aged between 10 and 19 years (WHO 2019a). Targeting adolescents with relevant vaccines offers three benefits: catch‐up on missed vaccinations, boosting of waning immunity, and primary immunisation with new vaccines (Brabin 2008; Mackroth 2010). Vaccines given during adolescence include, but are not limited to, those against human papillomavirus (HPV), diphtheria, tetanus, pertussis, measles, mumps, rubella, varicella, hepatitis B, poliomyelitis, and meningococcal disease (Gilkey 2014; Harris 2009; Lee 2005; Mavundza 2019; Piot 2019; SAHM 2013; WHO 2019b). Future vaccines against HIV and Mycobacterium tuberculosis are likely to target adolescents as the primary population (Gowda 2012; Zipursky 2010).

In many settings, adolescents usually turn to physicians only when they are ill and so there are limited opportunities to inform them that vaccines are important and should be administered (Cawley 2010; Principi 2013). In such instances, adolescents may be more interested in their current health condition than possible benefits of preventing future vaccine‐preventable diseases (VPDs) (Principi 2013). Schools have been used extensively as a delivery platform for vaccinating large numbers of school‐aged children (Barry 2013; Cawley 2010; Harris 2009; Robbins 2011; Tsu 2009). However, school‐based vaccination programmes may not be entirely successful in countries with suboptimal school attendance rates (Mackroth 2010; Warren 2004). For instance, school attendance rates in many low‐ and middle‐income countries (LMICs) are variable due to factors such as geographical location, socioeconomic status, and gender (Mackroth 2010; Warren 2004; Zipursky 2010). Strategies such as mass immunisation campaigns can be used to complement school‐based vaccination programmes in settings with poor school attendance rates (Clements 2004; Piot 2019).

Data on vaccination coverage among adolescents are limited, but coverage is generally low in this group (Brotherton 2015; Loke 2017; Newman 2018). For example, it is estimated that only 6.1% of adolescent girls worldwide completed the full series of HPV vaccination in 2014; with wide variation between LMICs and high‐income countries (Bruni 2016). HPV vaccination coverage was only 1.1% in Asia and 1.2% in Africa, compared to 35.6% in North America and 35.9% in Oceania. Overall, HPV vaccination coverage in 2014 was 33.6% in high‐income countries, compared with only 2.7% in LMICs (Bruni 2016). The most commonly reported barriers to adolescent vaccination include lack of knowledge about vaccines and VPDs; negative attitudes towards vaccination from adolescents, parents, teachers, and healthcare providers; poor vaccine infrastructure; and financial constraints (Adamu 2019; Gowda 2012; Ngcobo 2018; SAHM 2013).

Description of the intervention

Interventions to enhance the uptake of vaccines by adolescents may have multiple components, targeting adolescents and their communities, healthcare providers, the health system, or a combination of these (Wiysonge 2012).

Recipient‐oriented interventions

Interventions targeting adolescents and their communities (including their parents and teachers) may include education, reminders, incentives, and mandatory vaccination.

Educational interventions enable adolescents and their communities to understand the meaning and relevance of vaccination to their health (Willis 2013; Kaufman 2017). Such interventions may be delivered face‐to‐face or via written mail, telephone conversation, audiovisual presentation or drama, printed materials, websites, multi‐media campaigns, or community events (Willis 2013; Kaufman 2017). These types of interventions may be directed at individuals or groups, and may include information about VPDs; the risks and benefits of vaccines; where, how, and when to access vaccine services; who should be vaccinated; or a combination of these (Oyo‐Ita 2016; Williams 2011; Willis 2013; Kaufman 2017). Adolescents and communities may receive education about vaccines through prominently displayed posters in waiting rooms, brochures, e‐mails, and website resources (Stinchfield 2008).

Client reminder interventions involve reminding members of a target population that vaccinations are due or have been missed. Reminders are delivered using various methods, such as telephone calls, letters, or postcards (Jacobson Vann 2018). The contents of the reminders may include personalised information related to a specific upcoming or missed appointment (Stinchfield 2008; Willis 2013; Kaufman 2017).

Adolescent or community incentives involve providing financial or other incentives to motivate people to accept vaccinations (Briss 2000; Oyo‐Ita 2016; TFCPS 2000). Incentives can be rewards or gifts (TFCPS 2000).

Mandatory vaccination refers to a law or policy that requires students to show proof of immunisation records prior to school admission with failure to do this resulting in school admission being denied (Briss 2000; Oyo‐Ita 2016; TFCPS 2000).

Provider‐oriented interventions

Provider‐oriented interventions may include reminders, audit and feedback, and education.

Provider reminder interventions inform vaccinators that individual clients are due for vaccinations. Reminders may be delivered through client charts, computer, e‐mail, or postal mail, among many others (Briss 2000; TFCPS 2000; Ward 2012).

Audit and feedback for vaccinators involves retrospectively evaluating the performance of the vaccinators in administering vaccines and providing feedback to them (Oyo‐Ita 2016; Stinchfield 2008; Williams 2011). This information is given to providers to motivate them to improve immunisation services.

Provider education involves giving information regarding vaccinations to providers to increase their knowledge and to encourage them to adopt positive attitudes towards vaccination. Techniques by which information is delivered can include written materials, videos, lectures, continuing medical education programmes, and computerised software (TFCPS 2000; Ward 2012; Williams 2011).

Health system interventions

Outreach programmes include school‐based immunisation and mass campaigns. School‐based immunisation outreach is intended to improve delivery of vaccinations to school‐going children (TFCPS 2000). School‐based interventions usually include vaccination‐related education of students about either provision of vaccinations or referral for vaccinations (Briss 2000; Oyo‐Ita 2016; TFCPS 2000). Mass campaign programmes target adolescents both in school and out of school (Clements 2004).

Expanding access in healthcare settings is used to increase the availability of vaccines in the medical or public health settings in which vaccinations are offered. This can be achieved using several methods such as: increasing or changing the hours during which vaccination services are provided; delivering vaccinations in clinical settings in which they were previously not provided (e.g. emergency departments, inpatient units, or subspeciality clinics); or reducing administrative barriers to obtaining vaccination services within clinics (e.g. developing a 'drop‐in' clinic or an 'express lane' vaccination service) (Briss 2000; Stinchfield 2008; TFCPS 2000).

Reducing out‐of‐pocket costs can be implemented by subsiding the costs of vaccines, paying for vaccinations, providing insurance coverage, or reducing copayments for vaccinations at the point of service (Briss 2000; Oyo‐Ita 2016; TFCPS 2000).

Multi‐component interventions

Multi‐component interventions are approaches that include more than one tactic, with the aim of addressing a variety of barriers to adolescent vaccine uptake. Such interventions could enable communities to be aware of the immunisation services available to them, demonstrate the utility and relevance of these services, provide community members with the knowledge and information base to effectively take advantage of the services, or incorporate a variety of associated provider or health system strategies to improve immunisation uptake (Briss 2000; Oyo‐Ita 2016; TFCPS 2000).

How the intervention might work

We have proposed a logic model which suggests how the strategies described in the Description of the intervention section may, alone or in combination, influence adolescent vaccination uptake and other outcomes (Figure 1).

Figure 1

Logic framework on interventions for improving uptake of adolescent vaccines. KAP: knowledge, attitudes and practices; VPD: vaccine‐preventable disease.

Parents, including legal guardians or other people assuming the parental role, are routinely involved in the decision‐making process about vaccine administration to their children (Kaufman 2018). Teachers can also play a crucial role in adolescent vaccination uptake, especially where school‐based vaccination programmes are a popular platform for vaccination of adolescents (Barry 2013; Tsu 2009). In some situations, the final decision on whether an adolescent will be vaccinated or not may be entirely dependent on the parents, as adolescents may not have an independent final decision on whether to get vaccinated (Barry 2013; WHO 2019a). Hence, adequate knowledge and positive attitudes towards vaccination among parents, teachers, and adolescents may improve the uptake of vaccines among adolescents (Abdullahi 2016; Gowda 2012; Mahomed 2008). It is likely that more vaccine‐informed adolescents may be more able to positively guide and influence their parents and peers on vaccinations compared to peers who are less well informed. In addition, adolescents are future parents and investing resources in educating adolescents about vaccination may lead to improved uptake of vaccines by their children (Barry 2013). Therefore, educating adolescents about vaccination may have long‐term positive benefits on vaccine uptake in general (Principi 2013).

Healthcare providers give advice to parents and adolescents on vaccination. The ability of healthcare providers to keep up‐to‐date with knowledge on vaccines is essential, particularly when new vaccines are recommended (Gowda 2012; Principi 2013). Careful and factual advice on vaccination to adolescents and their parents by healthcare providers can result in more willingness to get vaccinated by adolescents. Health system interventions ensure that vaccines are available when adolescent girls and boys, and their communities, demand them (Kaddar 2013).

Why it is important to do this review

Adolescents represent 25% of the global population, but vaccination coverage among them is very low (Brotherton 2015; Bruni 2016; Loke 2017; Newman 2018). There is a knowledge gap around interventions to improve vaccine uptake among adolescents, especially in LMICs. Our review evaluated the evidence on strategies that can be adopted to improve vaccine uptake among adolescents. Such strategies will improve the uptake of current vaccines among adolescents, and may also increase the uptake of future vaccines. In addition, this review could be used to advocate for strengthening existing adolescent vaccination policies and to formulate new policies on the vaccination of adolescents where none currently exist. We are not aware of any previous systematic review that has assessed interventions to improve adolescent immunisation coverage across all country income categories. However, a number of reviews have assessed various strategies to improve immunisation coverage in children or the whole population (Jacobson Vann 2018; Kaufman 2018; Oyo‐Ita 2016; Saeterdal 2012; Williams 2011). These reviews considered general barriers to immunisation and assessed the effects of a variety of interventions. In our review, we used a similar approach among the adolescent population.

Objectives

To evaluate the effects of interventions to improve vaccine uptake among adolescents.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised trials, non‐randomised trials, interrupted time series studies, and controlled before‐after studies that met the quality criteria used by Cochrane Effective Practice and Organisation of Care (EPOC) (EPOC 2019a). We included both individually randomised and cluster‐randomised trials. For cluster‐randomised trials, we only included those with at least two intervention and two control clusters. Following the EPOC criteria, we included interrupted time series studies only if outcomes were measured during at least three points before and three points after the intervention. For a controlled before‐after study to be included in the review, it must have included at least two intervention groups and at least two comparable control groups, with simultaneous data collection.

We excluded simple pre–post designs; cluster‐randomised and non‐randomised trials with only one intervention or control site; and controlled before‐after studies without concurrent data collection in intervention and comparison groups in accordance with the EPOC criteria for inclusion of studies in systematic reviews of effects (EPOC 2019a).

Types of participants

Girls or boys (or both) aged 10 to 19 years eligible for WHO‐recommended vaccines and their parents or healthcare providers. In the case of studies with interventions directed at mixed populations of children and adolescents or adolescents and adults, we excluded a study if specific data for adolescents were not reported.

Types of interventions

Intervention

Recipient‐oriented interventions (i.e. interventions targeting adolescents or their communities, or both), for example:
- interventions to communicate with adolescents or their parents (or both) about adolescent immunisation;
- financial and non‐financial incentives for adolescents or their parents (or both); and
- mandatory vaccination: vaccination requirement for high school and university attendance.
Provider‐oriented interventions, for example:
- any intervention to reduce missed opportunities for vaccination (e.g. audit and feedback); and
- health education, training, and supportive supervision.
Health system interventions, for example:
- interventions to improve the quality of services, such as provision of reliable cold chain systems, provision of transport for vaccination, vaccine stock management;
- outreach programmes, for example, school‐based immunisation and mass vaccination campaign for out‐of‐school adolescents;
- expanded services, for example, extended hours for immunisation services;
- increased immunisation budget; and
- integration of immunisation services with other services.
Multi‐component interventions.

Exclusions

We excluded interventions to remind recipients or providers of immunisation services, as there is already a Cochrane Review on this topic (Jacobson Vann 2018).

Comparisons

Standard immunisation practices in the study setting.
Alternative interventions.
Similar interventions implemented with different degrees of intensity.

Types of outcome measures

Primary outcomes

Adolescent vaccination coverage, that is, the proportion of adolescents who have received the recommended dose(s) of the vaccine(s) studied.

Secondary outcomes

Proportion of adolescents completing the schedule.
Equitable uptake of immunisation (as defined by the study authors).
Knowledge, attitudes, and beliefs.
Adverse effects of the intervention.
Cost of the intervention.
Incidence of VPDs.

Search methods for identification of studies

With the assistance of the Cochrane EPOC Information Specialist, we developed search strategies, with no restrictions on language or publication date. The search strategies for the electronic databases incorporated the Cochrane EPOC search strategy for randomised trials, non‐randomised trials, interrupted time series studies, and controlled before‐after studies (EPOC 2019a), and combined selected MeSH and free‐text terms relating to adolescent vaccination uptake literature globally.

Electronic searches

We searched the following databases for primary studies:

Cochrane Central Register of Controlled Trials (CENTRAL) 2017, Issue 1; part of the Cochrane Library (www.cochranelibrary.com; searched 31 October 2018);
MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, MEDLINE Daily, and MEDLINE (1946 to 31 October 2018);
Embase Ovid (1974 to 31 October 2018);
CINAHL EBSCOhost (1981 to 31 October 2018);
Africa‐Wide Information EBSCOhost (19th century to 31 October 2018);
Global Health Ovid (1973 to 31 October 2018);
Scopus, Elsevier (searched 31 October 2018); and
Science Citation Index Expanded; Social Sciences Citation Index (1987 to October 2018), and Emerging Sources Citation Index (2015 to October 2018), Web of Science Core Collection, Thompson Reuters (searched 24 April 2017) (for papers citing any of the included studies in the review 31 April 2019).

We searched the following databases for related reviews:

Cochrane Database of Systematic Reviews (CDSR), 2017, Issue 3, part of the Cochrane Library (www.cochranelibrary.com; searched 31 October 2018);
Database of Abstracts of Reviews of Effects (DARE), 2015, Issue 2, part of the Cochrane Library (www.cochranelibrary.com; searched 31 October 2018);
Health Technology Assessment Database (HTA), 2016, Issue 4 (searched 31 October 2018);
PDQ‐Evidence (searched 31 October 2018).

In addition, in May 2019, we did a citation search using: Science Citation Index Expanded; Social Sciences Citation Index (from 1987), and Emerging Sources Citation Index (from 2015), Web of Science Core Collection, and Clarivate Analytics.

See Appendix 1 for search strategies used.

Searching other resources

Grey literature

We searched the following grey literature (31 October 2018):

WHO (www.who.int/);
Gavi, the Vaccine Alliance (www.gavi.org);
United Nations Children's Funds (UNICEF; www.unicef.org/);
PATH Vaccine Resources Library (www.path.org/);
US Centers for Disease Control and Prevention (CDC; www.cdc.gov/);
The Communication Initiative Network (www.comminit.com/);
Grey Literature Report (www.greylit.org);
OpenGrey (www.opengrey.eu/);
Eldis (www.eldis.org/);
Immunization Basics (www.immunizationbasics.jsi.com).

Trial registries

We searched the following trial registries (31 October 2018):

WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/);
ClinicalTrials.gov, US National Institutes of Health (NIH; clinicaltrials.gov/).

Reference lists

We searched the reference lists of potentially eligible studies and relevant previous reviews.

Data collection and analysis

Selection of studies

Two review authors (LA and BK) screened titles and abstracts to select potentially eligible studies. One review author (LA) then obtained the full text of potentially eligible studies and two review authors (LA and VN) independently conducted the final study selection for inclusion in the review. We resolved any disagreements regarding the inclusion of studies by discussion or by consulting a third review author (BK and CW). We used a PRISMA flow chart (Moher 2009) to summarise the search and selection of studies for the review (Figure 2).

Figure 2

Study flow diagram.

Data extraction and management

Two review authors (LA and VN) independently extracted data from selected studies using an adapted version of the Cochrane data extraction form. Disagreements on study selection and data extraction were resolved by consensus between the two review authors, failing which a third review author (BK) arbitrated. Prior to use, we piloted the data extraction form on four studies identified randomly from the list of included studies.

The data extraction form included the following items.

Setting of the study (city and country).
Type of study: randomised trials, non‐randomised trials, interrupted time series studies, and controlled before‐after studies.
Type of participants: adolescents, parents, healthcare providers.
Type of interventions: name of intervention, frequency, timing, delivery method, venue of delivery.
Type of outcomes measured: vaccine coverage, knowledge, attitudes and beliefs, cost of intervention, adverse effects of the intervention, equity.

When dichotomous outcome data were presented as percentages, we multiplied the percentages by the number of participants in the study arm to obtain the approximate number of events.

Assessment of risk of bias in included studies

We applied the Cochrane EPOC 'Risk of bias' criteria for randomised trials, non‐randomised trials, interrupted time series studies, and controlled before‐after studies, as appropriate (EPOC 2019b). For each included study, we reported our assessment of risk of bias (low, high, or unclear risk) for each domain, together with a descriptive summary of the information that influenced our judgement. Any study that was assigned a high risk of bias for allocation concealment, blinding of outcome assessment, completeness of outcome data, or a combination of these was considered to have a high risk of bias. Studies with low risk of bias for all three domains were considered to have a low risk of bias, and all other studies were considered to have an unclear risk of bias. Two review authors (LA and VN) applied the criteria independently and a third review author (CW) arbitrated any disagreements.

Measures of treatment effect

We used raw dichotomous data reported in each study to express the study's result as a risk ratio (RR) with its corresponding 95% confidence interval (CI). However, one study reported adjusted odds ratios (ORs) and we calculated the natural logarithm of the OR and its standard error for each outcome in this study. We then expressed the intervention effect for each outcome in this study as an OR with its 95% CI using inverse variance. We grouped studies with broadly similar types of participants, interventions, study designs, and outcomes to get feasible results for an overall estimate of effect. See Appendix 2 for measures of effect specified in the protocol (Abdullahi 2015), but not used in the review.

Unit of analysis issues

We did not encounter unit‐of‐analysis issues in this review. Two included studies were cluster‐randomised trials based on matched pairs of clusters (Perkins 2015; Watson‐Jones 2012). We did not reanalyse these data as matching cannot be taken into account in reanalyses in such studies unless the raw data are available. However, the studies conducted appropriate analyses of the data, and we provided the results as reported in the studies. See Appendix 2 for methods specified in the protocol (Abdullahi 2015), but not used in the review.

Dealing with missing data

For the current version of the review, we did not experience any missing data thus we did not contact the primary study authors for missing data. In Appendix 2, we indicated methods specified in the protocol (Abdullahi 2015), but not used in the review.

Assessment of heterogeneity

We reviewed heterogeneity in the type of intervention, type of setting, study design, and risk of bias of included studies in order to make an assessment of the extent to which the included studies were similar to each other. We examined the levels of heterogeneity between study results using the Chi² test of homogeneity (with significance defined at the alpha level of 10%). We quantified any statistical heterogeneity between study results using the I² statistic. We regarded heterogeneity as substantial if the I² was greater than 50% (Higgins 2019).

Assessment of reporting biases

Test for asymmetry with a funnel plot was not feasible because the number of included studies for each meta‐analysis was less that the recommended 10 studies. We have archived methods for assessing reporting biases in Appendix 2 , for use in updates of this review.

Data synthesis

We pooled data from studies of similar study designs, similar interventions, similar participants, and similar outcomes in a meta‐analysis using the random‐effects model if there was no significant statistical heterogeneity, methodological difference, or high risk of bias. For outcomes with substantial variation between studies in the reported interventions, participants, study designs, and outcome measures, we did not pool the results but summarised the findings in a narrative format. Overall, we interpreted the study findings by taking into account the methodological quality of the studies and the strength of the evidence. For each observed effect, we explicitly stated the strength of evidence and drew conclusions. See Appendix 2 for data synthesis methods specified in the protocol (Abdullahi 2015), but not used in the review.

'Summary of findings' tables

We created 'Summary of findings' tables for the main intervention comparisons and included the primary outcome: vaccination coverage. We used the GRADE approach to assess the certainty of evidence at outcome level (Guyatt 2008). Two review authors (LA and CW) independently assessed the certainty of the evidence (high, moderate, low, and very low) using the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias). We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), and the EPOC worksheets (EPOC 2019c), and used GRADEpro software. We resolved disagreements on certainty ratings by discussion and provided justification for decisions to downgrade the ratings using footnotes in the table and made comments to aid readers' understanding of the review where necessary. We used plain language statements to report these findings in the review (EPOC 2019d; Santesso 2019).

Subgroup analysis and investigation of heterogeneity

We did not have sufficient data to conduct planned subgroup analyses (Appendix 2). However, we conducted a posthoc subgroup analysis exploring the effect of variations in the intervention (Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 6.4) or comparison (Analysis 5.1) groups on vaccination coverage. We used the Chi² test for subgroup differences to test for subgroup interactions.

Sensitivity analysis

We planned to perform sensitivity analyses based on unit of analysis errors, risk of bias, and missing data (Appendix 2). However, available data were insufficient to perform these analyses.

Results

Description of studies

Results of the search

We identified 29,103 records from the electronic databases and other sources. After excluding 3476 duplicates, we screened 25,627 records, and found that 25,560 records were not relevant to our review question. We reviewed the remaining 67 potentially eligible full‐text articles for inclusion and excluded 48 of them for the reasons given in the Characteristics of excluded studies table.

Sixteen studies met the inclusion criteria and were included in the review (Table 1). Two studies are awaiting classification (Dempsey 2018; Esposito 2018; Characteristics of studies awaiting classification table), and one study is ongoing (Skinner 2015; Characteristics of ongoing studies table). The search process and selection of studies is presented in Figure 2.

Table 1. Summary of included studies

Study ID	Study design	Country	Participants	Intervention	Comparison	Duration of intervention	Vaccine target
Cates 2014	Non‐randomised trial	USA	Parents and health providers	Multi‐component providers and parents	Usual practice	3 months	HPV
Diclemente 2015	Randomised trial	USA	Adolescents	Health education	Usual practice	30 minutes	HPV
Fiks 2016	Controlled before‐after study	USA	Health provider	Provider education with performance feedback	Usual practice	1 month	HPV
Gargano 2015	Randomised trial	USA	Parents	Health education	Usual practice	2 months	Tdap, MCV, HPV, Influenza
Grandahl 2016	Cluster‐randomised trial	Sweden	Adolescents	Health education	Usual practice	30 minutes	HPV
Mantzari 2015	Randomised trial	UK	Adolescents	Financial incentives	Usual practice	6 months	HPV
Paskett 2016	Randomised trial	USA	Parents and health providers	Multi‐component providers and parents	Usual practice	—	HPV
Perkins 2015	Cluster‐randomised trial	USA	Adolescent and health providers	Multi‐component provider intervention	Usual practice	1 months	HPV
Rickert 2015	Randomised trial	USA	Parents	Health education	Usual practice	1 hour	HPV
Schwarz 2008	Randomised trial	USA	Adolescents and caregivers	Health education plus financial incentives	Usual practice	1 hour	HepB
Skinner 2000	Randomised trial	Australia	Adolescents	Complex health education	Simplified health education	1 hour	HepB
Staras 2015	Non‐randomised trial	USA	Adolescents	Health education	Usual practice	3 months	HPV
Szilagyi 2015	Randomised trial	USA	Health providers	Provider prompts	Usual practice	2 months	Tdap, MCV, HPV, Influenza
Wilson 2005	Non‐randomised trial	USA	Adolescent	Mandatory school entry vaccination	Usual practice	—	HepB, Td, and MMR
Winer 2016	Cluster‐randomised trial	USA	Parents	Health education	Usual practice	30–40 minutes	HPV
Watson‐Jones 2012	Cluster‐randomised trial	Tanzania	Adolescents	Class‐based vaccination	Age‐based vaccination	12 months	HPV

HepB: hepatitis B virus; HPV: human papillomavirus; MCV: meningococcal conjugate vaccine; MMR: measles–mumps–rubella; Td: tetanus–diphtheria; Tdap: tetanus–diphtheria–acellular–pertussis.

Included studies

Study design and setting

Sixteen studies met the inclusion criteria. Eight studies were randomised trials with individuals as the unit of randomisation (Diclemente 2015; Gargano 2015; Mantzari 2015; Paskett 2016; Rickert 2015; Schwarz 2008; Skinner 2000; Szilagyi 2015); four studies were cluster‐randomised trials that used health facilities or schools as the unit of randomisation (Grandahl 2016; Perkins 2015; Watson‐Jones 2012; Winer 2016); three studies were non‐randomised trials with at least two intervention and two control arms (Cates 2014; Staras 2015; Wilson 2005); and one study was a controlled before‐after study with two intervention and two control arms (Fiks 2016).

Twelve studies were conducted in the USA (Cates 2014; Diclemente 2015; Fiks 2016; Gargano 2015; Paskett 2016; Perkins 2015; Rickert 2015; Schwarz 2008; Staras 2015; Szilagyi 2015; Wilson 2005; Winer 2016); one study was conducted in Australia (Skinner 2000); one study was conducted in Sweden (Grandahl 2016); one study was conducted in the UK (Mantzari 2015); and one study was conducted in Tanzania (Watson‐Jones 2012).

Participants

Two studies enrolled girls only (Diclemente 2015; Watson‐Jones 2012), five studies enrolled boys and girls (Grandahl 2016; Mantzari 2015; Skinner 2000; Staras 2015; Wilson 2005), three studies enrolled parents (Gargano 2015; Rickert 2015; Winer 2016), and two studies enrolled healthcare providers (Fiks 2016; Szilagyi 2015).

Four studies enrolled mixed participants, comprising of adolescents and parents (Schwarz 2008), adolescents and healthcare providers (Perkins 2015), and parents and healthcare providers (Cates 2014; Paskett 2016). The healthcare providers included physicians, nurses, and physician assistants.

Interventions and comparisons

We present a summary of the interventions and comparisons used in the included studies in Table 1 and a detailed description in the Characteristics of included studies table.

Recipient‐oriented interventions

The recipient‐oriented intervention studies compared the following to usual care: health education (Diclemente 2015; Gargano 2015; Grandahl 2016; Rickert 2015; Staras 2015; Winer 2016), financial incentives (Mantzari 2015), health education and financial incentives (Schwarz 2008), and a school entry law mandating vaccination (Wilson 2005). The seventh health education study compared a multi‐component intervention to simplified information leaflets (Skinner 2000).

In six health education studies, participants in the intervention arm received structured 30 to 40 minute (Diclemente 2015; Grandahl 2016; Staras 2015; Winer 2016), one hour (Rickert 2015), or two to three day (Gargano 2015) interactive education on the target disease, vaccine recommendations, vaccine schedule, vaccine efficacy, and vaccine safety. Participants in the comparison 'usual care' arm received group general health education or education on the prevention of a specific non‐vaccine‐related condition. In the seventh study, participants in the education arm received a complex multi‐component intervention that included a resource fact sheet and assessment; an information video and questions designed to engage the adolescent audience; small group discussions; and an activity to locate resource information on the Internet. However, both the intervention and comparison arms received information brochures consisting of one‐page folded coloured leaflets, outlining in simple terms the risks of the target disease and the benefits and adverse effects of vaccination (Skinner 2000).

Provider‐oriented interventions

The provider‐oriented intervention studies assessed provider prompts (Szilagyi 2015), provider education with performance feedback (Fiks 2016), and a multi‐faceted intervention (Perkins 2015), compared to usual care.

Health system intervention

One study compared a class‐based vaccination strategy to an age‐based strategy (Watson‐Jones 2012).

Multi‐component interventions

Two studies assessed multi‐faceted interventions aimed at both recipients and providers of vaccination services compared to usual care (Cates 2014; Paskett 2016).

Outcomes

Fifteen studies reported data on our primary outcome, vaccination coverage. Eleven studies evaluated completion of the HPV vaccination schedule (Cates 2014; Diclemente 2015; Fiks 2016; Grandahl 2016; Mantzari 2015; Paskett 2016; Perkins 2015; Rickert 2015; Staras 2015; Watson‐Jones 2012; Winer 2016). Three studies assessed uptake of vaccines against hepatitis B virus (Schwarz 2008; Skinner 2000; Wilson 2005). One study examined uptake of tetanus–diphtheria (Td) and measles–mumps–rubella (MMR) vaccines (Wilson 2005). Finally, two studies reported data on uptake of tetanus–diphtheria–acellular–pertussis (Tdap), meningococcal conjugate, HPV, and influenza vaccines (Gargano 2015; Szilagyi 2015).

Other predefined outcome measures reported by the included studies were:

knowledge, attitudes, and beliefs (Gargano 2015; Paskett 2016; Schwarz 2008; Skinner 2000);
cost of the intervention (Fiks 2016; Watson‐Jones 2012); and
adverse effects of the intervention (Rickert 2015).

Predefined outcomes not reported by the included studies were:

incidence of VPDs; and
equitable uptake of immunisation.

The following predefined outcome was considered in a posthoc assessment as not relevant to the review: adverse events following immunisation (AEFI). An AEFI is any undesirable medical incident which follows administration of a vaccine, but is not necessarily caused by the vaccination (WHO 2019c). It is thus not a relevant outcome in this review, given that we are assessing interventions to improve vaccination uptake rather than the effects of the vaccine itself.

The studies did not report the lag‐time between delivery of interventions and assessment of outcomes.

Excluded studies

We excluded 48 studies for reasons given in the Characteristics of excluded studies table. The most common reasons for exclusion were ineligible study designs and ineligible interventions.

Risk of bias in included studies

Allocation

The risk of selection bias (random sequence generation) was low for nine studies (Diclemente 2015; Grandahl 2016; Mantzari 2015; Paskett 2016; Perkins 2015; Rickert 2015; Skinner 2000; Szilagyi 2015; Winer 2016), unclear for three studies (Gargano 2015; Schwarz 2008; Watson‐Jones 2012), and high for four studies (Cates 2014; Fiks 2016; Staras 2015; Wilson 2005).

The risk of selection bias (allocation concealment) was low for seven studies (Diclemente 2015; Grandahl 2016; Mantzari 2015; Perkins 2015; Rickert 2015; Szilagyi 2015; Watson‐Jones 2012), unclear for six studies (Cates 2014; Gargano 2015; Paskett 2016; Schwarz 2008; Skinner 2000; Winer 2016), and high for three studies (Fiks 2016; Staras 2015; Wilson 2005).

Blinding

For the types of intervention assessed in this review, blinding of participants and personnel was not possible. However, since vaccination coverage is an objective measure, we considered all studies to be at low risk of performance and detection biases.

Incomplete outcome data

The risk of attrition bias (incomplete outcome data) was low for 12 studies (Diclemente 2015; Fiks 2016; Mantzari 2015; Paskett 2016; Perkins 2015; Rickert 2015; Schwarz 2008; Skinner 2000; Szilagyi 2015; Watson‐Jones 2012; Wilson 2005; Winer 2016), unclear for one study (Cates 2014), and high for two studies (Gargano 2015; Staras 2015).

Selective reporting

Selective reporting was categorised as low risk in 12 studies (Cates 2014; Diclemente 2015; Fiks 2016; Grandahl 2016; Mantzari 2015; Paskett 2016; Perkins 2015; Schwarz 2008; Staras 2015; Szilagyi 2015; Watson‐Jones 2012; Wilson 2005), and unclear in four studies (Gargano 2015; Rickert 2015; Skinner 2000; Winer 2016).

Other potential sources of bias

None of the studies had evidence of other biases.

Summary of risk of bias assessments

We have summarised the risk of bias assessment in each of the included studies in Figure 3 and Figure 4. Overall, three studies had low risk of bias (Diclemente 2015; Grandahl 2016; Szilagyi 2015), nine studies had unclear risk of bias (Gargano 2015; Mantzari 2015; Paskett 2016; Perkins 2015; Rickert 2015; Schwarz 2008; Skinner 2000; Watson‐Jones 2012; Winer 2016), and four studies had high of bias (Cates 2014; Fiks 2016; Staras 2015; Wilson 2005).

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4

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

Effects of interventions

We present a summary of the effects of the interventions in Table 2. In this table we report the direction of the results and the certainty of the evidence for both primary and secondary outcomes.

Table 2. Intervention‐outcome matrix

Intervention	Vaccination coverage	Equity	Knowledge	Attitudes	Beliefs	Adverse effects	Cost	Vaccine‐preventable diseases
Recipient‐oriented interventions
1 Health education vs usual practice	✔㊉㊉㊉㊉¹	NR	✔㊉㊉㊀㊀²	NR	NR	NG	NR	NR
2. Complex vs simplified health education	Ø㊉㊉㊉㊀³	NR	✔㊉㊉㊀㊀³	NR	NR	NR	NR	NR
3. Financial incentives vs usual practice	✔㊉㊉㊀㊀⁴	NR	NR	NR	NR	NR	NR	NR
4. Health education plus financial incentives vs usual practice	?㊉㊀㊀㊀⁵	NR	?㊉㊀㊀㊀⁵	NR	NR	NR	NR	NR
5. Mandatory vaccination vs usual practice	✔㊉㊉㊉㊀⁶	NR	NR	NR	NR	NR	NR	NR
Provider‐oriented interventions
6. Provider prompts vs usual practice	✔㊉㊉㊉㊀⁷	NR	NR	NR	NR	NR	NR	NR
7. Provider education plus performance feedback vs usual practice	✔㊉㊉㊀㊀⁸	NR	NR	NR	NR	NR	NG	NR
Health system interventions
8. Class‐based vs age‐based HPV vaccination in schools	✔㊉㊉㊉㊀⁹	NR	NR	NR	NR	NR	NG	NR
Multi‐component interventions
9. Multi‐component provider intervention vs usual practice	✔㊉㊉㊀㊀¹⁰	NR	NR	NR	NR	NR	NR	NR
10. Multi‐component provider and parent intervention vs usual practice	✔㊉㊉㊀㊀¹¹	NR	✔㊉㊉㊀㊀¹²	NR	NR	NR	NR	NR

✔ = a desirable effect

Ø = little or no effect

? = uncertain effect

x = undesirable effect

vs = Compared to

NR = not reported

NG = outcome not graded

¹Diclemente 2015 (randomised trial), Grandahl 2016 (cluster‐randomised trial), and Winer 2016 (cluster‐randomised trial).

²Gargano 2015 (randomised trial).

³Skinner 2000 (randomised trial).

⁴Mantzari 2015 (randomised trial).

⁵Schwarz 2008 (randomised trial).

⁶Wilson 2005 (non‐randomised trial).

⁷Szilagyi 2015 (randomised trial).

⁸Fiks 2016 (controlled before‐after study).

⁹Watson‐Jones 2012 (cluster‐randomised trial).

¹⁰Perkins 2015 (cluster‐randomised trial).

¹¹Paskett 2016 (randomised trial) and Cates 2014 (non‐randomised trial).

¹²Paskett 2016 (randomised trial)

⊕⊕⊕⊕ = High‐certainty evidence

Definition: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.

Implications: this research provides a very good basis for making a decision about whether to implement the intervention. Impact evaluation and monitoring of the impact are unlikely to be needed if it is implemented.

⊕⊕⊕⊖ = Moderate‐certainty evidence

Definition: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.

Implications: this evidence provides a good basis for making a decision about whether to implement the intervention. Monitoring of the impact is likely to be needed and impact evaluation may be warranted if it is implemented.

⊕⊕⊖⊖ = Low‐certainty evidence

Definition: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.

Implications: this evidence provides some basis for making a decision about whether to implement the intervention. Impact evaluation is likely to be warranted if it is implemented.

⊕⊖⊖⊖ = Very low certainty evidence

Definition: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

Implications: this evidence does not provide a good basis for making a decision about whether to implement the intervention. Impact evaluation is very likely to be warranted if it is implemented.

Recipient‐oriented interventions

Comparison 1: health education compared to usual practice

1.1. Vaccination coverage

Three randomised trials (Diclemente 2015; Grandahl 2016; Winer 2016) and one non‐randomised trial (Staras 2015) reported vaccination coverage. A meta‐analysis of the randomised trials showed that health education improves HPV vaccination uptake compared to usual practice (RR 1.43, 95% CI 1.16 to 1.76; I² = 0%; high‐certainty evidence; 1054 participants). The non‐randomised study had similar findings, suggesting that health education may improve HPV vaccination uptake compared to usual practice (RR 1.84, 95% CI 1.34 to 2.54; low‐certainty evidence; 2822 participants)(Analysis 1.1; summary of findings Table for the main comparison).

1.2. Secondary outcomes

Knowledge, attitude, and beliefs

One randomised trial suggested that health education may improve knowledge of vaccines (HPV, meningococcal conjugate, Tdap, and Influenza) and corresponding VPDs compared to usual practice (Gargano 2015). We downgraded the certainty of the evidence to low because of serious study limitations (high risk of bias) and serious indirectness (given that this finding is based on one study from one setting).

Adverse effects of the intervention

One study reported that health education did not have any adverse events in relation to usual practice (Rickert 2015). The remaining studies did not provide any information on adverse effects.

Comparison 2: complex health education programme compared to simplified health education

2.1. Vaccination coverage

One large randomised trial (Skinner 2000) suggested that a multi‐component health education intervention probably results in little or no difference in the uptake of three doses of the hepatitis B vaccine compared to simplified information leaflets (RR 0.98, 95% CI 0.96 to 0.99; 17,411 participants; Analysis 2.1). We judged the certainty of the evidence as moderate because of serious study limitations, as the included study had an unclear risk of bias (summary of findings Table 2).

2.2. Secondary outcomes

Knowledge, attitude, and beliefs

The randomised trial showed that multi‐component health education may improve knowledge of the targeted vaccine and disease compared to simplified information leaflets (Skinner 2000). We downgraded the certainty of evidence to moderate because of serious study limitations (unclear risk of bias) and serious indirectness (given that this finding is based on one study from one setting).

Comparison 3: financial incentives compared to usual practice

3.1. Vaccination coverage

One randomised trial (Mantzari 2015) found that financial incentives may improve uptake of the first dose of the HPV vaccine compared to usual practice (RR 1.45, 95% CI 1.05 to 1.99; 500 participants; Analysis 3.1). We judged the certainty of the evidence as low, because of concerns regarding study limitations (unclear risk of bias) and imprecision of the effect (summary of findings Table 3).

3.2. Secondary outcomes

None of the included studies reported relevant secondary outcomes for this comparison.

Comparison 4: health education plus financial incentives compared to usual practice

4.1. Vaccination coverage

From the findings of one small randomised trial (Schwarz 2008), we are uncertain about the effects of combining health education and financial incentives on the completion of three doses of the hepatitis B vaccine, compared to usual practice (RR 1.38, 95% CI 0.96 to 2.00; 104 participants; Analysis 4.1). We judged the certainty of the evidence as very low because of concerns regarding risk of bias in the included study, very serious imprecision of the findings, and very serious indirectness (given that this finding is based on one small study from one setting) (summary of findings Table 4).

4.2. Secondary outcomes

Knowledge, attitude, and beliefs

One study (Schwarz 2008) assessed this outcome. We are uncertain about the effects of health education plus financial incentives on vaccine knowledge compared to usual practice because the certainty of the evidence was very low. We judged the certainty of the evidence as very low because of serious study limitations and very serious indirectness.

Comparison 5: mandatory vaccination compared to usual practice

5.1. Vaccination coverage

Wilson 2005 assessed the effects of mandating hepatitis B vaccination by law for elementary school entry in the state of Missouri in the USA. This non‐randomised trial compared students in the ninth grade (affected by the hepatitis B law) and 12th grade (not affected by the law) in the state and showed that making vaccinations mandatory probably leads to substantial improvements in vaccination uptake (RR 2.94, 95% CI 2.66 to 3.25; 2642 participants; Analysis 5.1).

In addition, the study compared the ninth grade in Missouri (affected by the mandatory hepatitis B vaccination law) to the ninth grade in the state of Kansas (not affected by the law) and confirmed that mandating vaccination probably leads to a large increase in the uptake of hepatitis B vaccine (RR 3.92, 95% CI 3.65 to 4.20; 6462 participants; Analysis 5.1). This was a well conducted non‐randomised study and, for both outcome assessments, we upgraded the certainty of the evidence to moderate because of very large intervention effects (summary of findings Table 5).

5.2. Secondary outcomes

The study reported no relevant secondary outcomes.

Provider‐oriented interventions

Comparison 6: provider prompts compared to usual practice

6.1. Vaccination coverage

Szilagyi 2015 assessed the impact of provider prompts compared to usual practice on the uptake of various recommended adolescent vaccines through two parallel randomised trials: one in a national network of paediatric clinics, covering 36 states in the USA, and one in a local network of primary care practices, based in one county in New York state in the USA.

In the national network of paediatric clinics, provider prompts probably made little or no difference to the uptake of three doses of HPV (adjusted OR 1.13 95% CI 0.68 to 1.88; 437 participants), Tdap (adjusted OR 1.16, 95% CI 0.68 to 1.99; 1746 participants), meningococcal conjugate (adjusted OR 1.08, 95% CI 0.82 to 1.41; 1752 participants), and seasonal influenza (adjusted OR 0.89, 95% CI 0.69 to 1.16; 878 participants) vaccines. These adjusted odds ratios were based on a multilevel mixed‐effect logistic regression model with covariates for pair assignment, study time period, group assignment, and an interaction between time and group assignment.

In the local network of primary care practices, provider prompts probably made little or no difference to the uptake of three doses of HPV (adjusted OR 0.93, 95% CI 0.64 to 1.34; 422 participants), Tdap (adjusted OR 1.44, 95% CI 0.82 to 2.56; 1550 participants), meningococcal conjugate (adjusted OR 1.15, 95% CI 0.64 to 2.05; 1467 participants), and seasonal influenza (adjusted OR 0.93, 95% CI 0.69 to 1.25; 561 participants) vaccines. The odds ratios were adjusted as for the national network results above.

Pooling the data from the two networks, this randomised trial shows that provider prompts probably make little or no difference to the uptake of three doses of HPV (OR 0.99, 95% CI 0.55 to 1.81; 859 participants; Analysis 6.1), Tdap (OR 1.28, 95% CI 0.59 to 2.80; 3296 participants; Analysis 6.2), meningococcal conjugate (OR 1.09, 95% CI 0.67 to 1.79; 3219 participants; Analysis 6.3), and seasonal influenza (OR 0.91, 95% CI 0.61 to 1.34; 1439 participants; Analysis 6.4) vaccines.

We judged the certainty of the evidence as moderate because of concerns regarding imprecision of findings (summary of findings Table 6).

6.2. Secondary outcomes

The study reported no relevant secondary outcomes.

Comparison 7: provider education with performance feedback compared to usual practice

7.1. Vaccination coverage

One controlled before‐after study looked at the effects of education and performance feedback on the uptake of HPV vaccination (Fiks 2016). Provider education with performance feedback may increase the proportion of adolescents who are offered and accept HPV vaccination by clinicians, compared to usual practice. Compared to adolescents visiting non‐participating clinicians (in the usual practice group), the adolescents visiting clinicians in the intervention group were more likely to receive the first dose of HPV during preventive visits (5.7 percentage points increase) and during acute visits (0.7 percentage points for the first and 5.6 percentage points for the second doses of HPV)(227 clinicians and more than 200,000 children). We judged the certainty of the evidence as low because this is a non‐randomised study (summary of findings Table 7).

7.2. Secondary outcomes

Cost

Fiks 2016 evaluated the costs required to implement the education and performance feedback programme. The authors calculated the total cost of each of the following components: creation of the performance feedback reports; time spent on creating and delivering the educational content; and time spent by participating providers on group calls, reviewing data, and planning/implementing practice change. The estimated total cost of the intervention was USD 17,887 (USD 662 per participant), of which USD 17,064 was for participant time spent on the programmes (Fiks 2016).

Health system interventions

Comparison 8: class‐based compared to age‐based HPV vaccination in schools

8.1. Vaccination coverage

Watson‐Jones 2012 assessed the effect of two HPV vaccine delivery strategies in a cluster randomised trial and showed that a class‐based delivery tactic probably leads to slightly higher HPV vaccine uptake than an age‐based delivery strategy (RR 1.09, 95% CI 1.06 to 1.13; 1 study, 5537 participants; Analysis 7.1). We judged the certainty of the evidence as moderate because of serious indirectness, given that this finding is based on one study from one setting (summary of findings Table 8).

8.2. Secondary outcomes

Cost

Watson‐Jones 2012 collected data on the costs of class‐based versus age‐based delivery of the HPV vaccine in Tanzania and found the class‐based vaccination strategy to be less expensive. In urban schools, the cost was USD 52 per girl vaccinated in a class‐based strategy compared to USD 87 for the age‐based delivery system. In rural schools, the cost was USD 67 per girl vaccinated in a class‐based strategy compared to USD 98 for the age‐based delivery system.

Multi‐component interventions

Comparison 9: multi‐component provider intervention compared to usual practice

9.1. Vaccination coverage

Perkins 2015 (cluster randomised trial) assessed the effects of a four‐component provider intervention package (education session, repeated contacts, individualised feedback, and incentives) and found that the intervention probably improves HPV vaccination coverage compared to usual practice. Girls in the intervention group are probably more likely to receive their next HPV vaccine dose than those in the control group (odds ratio 1.6, 95% CI 1.1 to 2.2; 5786 participants). The effects are probably larger for boys (odds ratio 25.00, 95% CI 15.00 to 40.00; 7332 participants), and this may be because publicly funded HPV vaccination for boys became available during the study. We judged the certainty of the evidence as moderate because of serious indirectness, given that this finding is based on one study from one setting (summary of findings Table 9).

9.2. Secondary outcomes

The study reported no relevant secondary outcomes.

Comparison 10: multi‐component provider and parent intervention compared to usual practice

10.1. Vaccination coverage

One non‐randomised trial showed that a social marketing intervention directed to parents and providers may improve HPV vaccination uptake compared to usual practice (RR 1.41, 95% CI 1.25 to 1.59; 25,869 participants; Cates 2014). The intervention included: distribution of HPV vaccination pamphlets to healthcare providers; radio messages directed at adolescents and their parents to raise awareness about HPV vaccination; an online continuing medical education training on HPV vaccination for health providers; simplified information sheet for adolescents and parents; and a website with links to credible information sources for parents and providers.

A very small randomised trial (Paskett 2016) also suggested that a multi‐component educational intervention directed to both providers and parents may improve HPV vaccination uptake (RR 2.34, 95% CI 0.75 to 7.32; 337 participants). Healthcare providers received a one‐hour presentation and handouts on HPV vaccination, and parents were mailed simplified educational material on HPV vaccination followed by a phone call to emphasise the importance of HPV vaccination.

Overall, the two studies show that using a multi‐faceted provider and parent intervention may improve HPV vaccination uptake compared to usual practice (Analysis 8.1). We judged the certainty of the evidence as low because of concerns regarding serious imprecision and serious study limitations (unclear risk of selection bias in the included study) (summary of findings Table 10).

10.2. Secondary outcomes

Knowledge, attitude, and beliefs

Paskett 2016 reported that a multi‐component educational intervention directed to both providers and parents may increase knowledge about HPV infection and HPV vaccine among providers and parents compared to usual practice. The average number of correct answers about HPV infection and HPV vaccination (out of 10) post‐intervention among parents in the intervention group was 9.4 (standard deviation 1.0), compared to 7.3 (standard deviation 1.9) among parents in the comparison group (P = 0.001). We judged the certainty of the evidence as low because of serious indirectness (given that this finding is based on one study from one setting) and serious study limitations.

Discussion

Summary of main results

We found that educating adolescents and their parents about the importance of vaccinations; passing laws stating that adolescents must be vaccinated to go to school; using a multi‐faceted package of interventions for providers of vaccination services, including education, repeated contacts, individualised feedback, and incentives; or using class‐based rather than age‐based approaches for delivering vaccines probably improve adolescent vaccination coverage. Adolescent vaccination coverage may also be improved through targeting parents and healthcare providers with a combination of vaccination education, telephone calls, and radio messages. In addition, providing adolescents and their parents with financial incentives may improve adolescent vaccination coverage. However, reminding healthcare providers to vaccinate adolescents when they open their electronic medical charts, probably makes little or no difference to adolescent vaccination coverage. From the data provided in the studies included in this review, we were uncertain about the costs of the interventions tested and their effects on knowledge and attitudes regarding adolescent vaccination. Table 2 shows a summary of the effects of the interventions, indicating the certainty of the evidence and gaps in the evidence base.

Overall completeness and applicability of evidence

Our systematic review was comprehensive as we included all known types of interventions for improving vaccination coverage (except recipient‐oriented reminders (Jacobson Vann 2018)), all vaccines recommended by WHO for boys and girls aged 10 to 19 years (WHO 2019b), and all country settings. However, we identified only 16 eligible studies, mostly conducted in high‐income countries.

There may be multiple barriers and facilitators of vaccine uptake among adolescents, from the logistics of ensuring access and the affordability of vaccination services, to the psychosocial factors that influence vaccination‐seeking behaviours and individual acceptance of vaccination. Therefore, multiple interventions may be required to achieve optimal vaccination coverage among adolescents. This review showed promising findings for a range of interventions including recipient‐oriented education, vaccine mandates, and financial incentives; provider education and a combination of interventions targeting providers alone or together with parents; and tailored school outreach programmes.

The most promising intervention was mandatory vaccination, which increased hepatitis B vaccination coverage more than four‐fold (Wilson 2005). This study was conducted in the US states of Missouri (which had a law mandating hepatitis B vaccination for school entry) and Kansas (which did not have mandatory hepatitis B vaccination at the time of the study). The study authors noted that the vaccination coverage achieved in this study (i.e. 72.8%) did not reach the high coverage levels obtained following a similar vaccination mandate in California. This was probably because, unlike in Missouri, mandatory vaccination in California was stringently enforced through measures such as expulsion of unvaccinated students and inspections to verify that vaccination coverage levels reported by schools were correct. Various countries have mandates for several vaccines (Omer 2019). However, there is considerable variation between and within countries in the implementation of mandatory vaccination; including (but not limited to) variation in what is required of people, the penalties imposed if requirements are not met, and the age groups and populations covered by vaccine mandates; (Attwell 2019; Omer 2019). Therefore, countries considering mandatory vaccination, as part of a multi‐intervention approach to reach optimal immunisation coverage among adolescents, may want to ensure that the process is consultative, involving relevant national stakeholders in its planning, implementation, and monitoring. National immunisation decision makers should bear in mind that mandatory vaccination is unlikely to be effective in settings where healthcare facility obstacles and other access issues are major drivers of sub‐optimal vaccination coverage (Adamu 2019; Nnaji 2020). In addition, the Wilson 2005 study was conducted more than 15 years ago, and it is possible that changes in health systems arrangements and other contextual changes since the time of the study may impact on the applicability of this evidence.

We also found health education to be very effective, leading to a relative increase of 43% in the completion of a three‐dose schedule of HPV vaccination (Diclemente 2015; Grandahl 2016; Staras 2015; Winer 2016). In addition, we found little or no difference in effects between a complex multi‐component health education intervention and simplified information leaflets; suggesting that interventions need to be tailored to local vaccination barriers.

This review has several limitations in relation to the applicability of this evidence. First, 15/16 included studies were conducted in high‐income countries, mainly the USA, in which vaccination services are readily available to adolescent girls and boys. The findings from these studies need to be interpreted with caution when applied to settings with different health system arrangements and access to vaccination services. Second, there was limited information from the studies on the cost‐effectiveness of the interventions tested. Only two studies reported the costs of interventions, including provider education with performance feedback (Fiks 2016) and a health system intervention (Watson‐Jones 2012). Therefore, when applying the findings of this review to any setting, local costing should be undertaken, particularly in settings differing from those of the original investigations. Third, the studies included in this review did not report information on equity. It is possible that the implementation of interventions may increase inequity if they are not adapted to populations in remote and under‐served areas in countries or if there is substantial variability in socioeconomic characteristics among populations receiving the interventions. Given these contextual issues, any adolescent vaccination programmes implemented based on our review findings should include a monitoring component to assess the performance of the intervention within the given context.

One study in our review was conducted in a country defined by the World Bank as low‐income or middle‐income (Watson‐Jones 2012). The study compared class‐based and age‐based strategies for delivering HPV vaccines among 5532 girls in 134 primary schools in northwest Tanzania (a low‐income country). There was a 9% relative increase in vaccination coverage among eligible girls in schools assigned to a class‐based approach compared to girls in schools using an age‐based strategy. This finding may be relevant to (low‐ or middle‐income) countries that do not have established healthcare programmes for adolescent boys and girls, but have introduced or are contemplating to introduce HPV (Oberlin 2018) and other vaccines for adolescents. School health programmes can have an advantage of integrating various existing health services at the same or a minimal increase in cost (Robbins 2011). In line with our findings, one previous review of school‐based programmes in 17 countries found that such programmes led to substantial increases in HPV vaccination coverage rates (Paul 2014).

Although the effect sizes reported in this review were small to moderate, even relatively small effects for interventions aimed at increasing uptake of adolescent vaccines may be important from a health service perspective, when applied across large populations. Therefore, we believe that this review is an important resource for countries and international organisations in the context of the "Immunization Agenda 2030", a global strategy which envisions a "world where everyone, everywhere, at every age, fully benefits from vaccines for good health and well‐being" (WHO 2019).

Three quarters of the studies in this review assessed the effects of various interventions on HPV vaccination coverage. Despite a global expansion of HPV vaccination programmes in recent years, HPV vaccination coverage remains sub‐optimal worldwide (Brotherton 2015; Bruni 2016; Loke 2017; Newman 2018). The current review will be supplemented by a Cochrane qualitative evidence synthesis which will explore the factors that influence acceptance of adolescent HPV vaccination (Cooper 2019). The findings may help to explain why some interventions in the current review were more effective than others, and may contribute to the development of more effective and contextualised interventions for improving HPV vaccination uptake among adolescents.

Certainty of the evidence

The certainty of the evidence on the effects of included interventions on our primary outcome (adolescent vaccination coverage) varied widely, from high to very low. Among the interventions targeting adolescents and their communities, we judged the certainty of the evidence as high for education (summary of findings Table for the main comparison), moderate for multi‐component health education (summary of findings Table 2) and legislation mandating vaccination (summary of findings Table 5), low for financial incentives (summary of findings Table 3), and very low for a combination of health education and financial incentives (summary of findings Table 4). Regarding provider‐oriented interventions, we assessed the certainty as moderate for provider prompts (summary of findings Table 6) and multi‐component performance improvement continuing medical education intervention (summary of findings Table 9) and low for provider education with performance feedback (summary of findings Table 7). For the combination of recipient and provider interventions, we assessed the certainty of evidence as moderate (summary of findings Table 10). On health system interventions, we judged the certainty of the evidence as moderate for class‐based compared to age‐based delivery of vaccines to adolescents (summary of findings Table 8). Our main concerns with the evidence related to study limitations (risk of bias; Figure 3; Figure 4), indirectness (for findings based on single studies from one setting), and imprecision.

Potential biases in the review process

We minimised potential biases in the review process by adhering to Cochrane guidelines (Higgins 2019). We conducted comprehensive searches without limiting the searches to a specific language. Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias in each included study. The eligible cluster‐randomised trials reported that they adjusted for cluster effects. However, there was some level of subjectivity in the determination of concerns that were serious enough to require rating down the evidence; and it is possible that other authors would have arrived at slightly different levels of certainty of evidence.

The searches for the main databases were done in October 2018. It is possible that some relevant studies published after the last search date have not been included in the review and the review authors acknowledge this limitation, However, we do not think that this limitation has an impact on the reliability of the main findings and conclusions of the review.

Agreements and disagreements with other studies or reviews

Few recent systematic reviews have assessed the effectiveness of interventions for improving adolescent immunisation coverage (Das 2016; Jacobson Vann 2018; Smulian 2016). Das and colleagues searched three databases for studies published up to December 2014 and included 23 studies on the effectiveness of interventions to improve vaccination coverage among adolescents. The authors reported that evidence of moderate certainty from 13 studies suggested that mandatory vaccination in schools, reminders, and national permissive recommendation increased vaccination coverage in adolescents (Das 2016). Smulian and colleagues searched five databases and included 34 intervention studies published from June 2006 to May 2015. The authors reported that many types of intervention strategies (targeting recipients, providers, and the health system) led to increases in HPV vaccination coverage in different settings (Smulian 2016). The Das 2016 and Smulian 2016 reviews had some overlap with our review in terms of included studies, but many studies included in the two reviews do not meet the EPOC criteria for inclusion of studies in systematic reviews of effects (EPOC 2019a).

Jacobson Vann and colleagues searched four databases to January 2017 for trials, controlled before‐after studies, and interrupted time series evaluating vaccination‐focused recipient reminders in children, adolescents, and adults in any setting. Based on 10 studies, the authors reported high‐certainty evidence that reminders improved adolescent vaccination coverage (Jacobson Vann 2018). There was no overlap between our review and the Jacobson Vann 2018 review since we excluded reminders of this kind.

Overall, our systematic review complements earlier relevant reviews, and is the most comprehensive systematic review to date on the effects of interventions for improving uptake of vaccines among adolescent boys and girls.

Figure 1

Logic framework on interventions for improving uptake of adolescent vaccines. KAP: knowledge, attitudes and practices; VPD: vaccine‐preventable disease.

Figure 2

Study flow diagram.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4

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

Analysis 1.1

Comparison 1 Comparison 1: health education compared to usual practice, Outcome 1 Human papillomavirus vaccine uptake.

Analysis 2.1

Comparison 2 Comparison 2: complex compared to simplified health education, Outcome 1 Hepatitis B vaccine uptake.

Analysis 3.1

Comparison 3 Comparison 3: financial incentives compared to usual practice, Outcome 1 Human papillomavirus vaccine uptake.

Analysis 4.1

Comparison 4 Comparison 4: health education plus financial incentives compared to usual practice, Outcome 1 Hepatitis B vaccine uptake.

Analysis 5.1

Comparison 5 Comparison 5: mandatory vaccination compared to usual practice, Outcome 1 Hepatitis B vaccine uptake.

Analysis 6.1

Comparison 6 Comparison 6: provider prompts compared to usual practice, Outcome 1 Human papillomavirus vaccine uptake.

Analysis 6.2

Comparison 6 Comparison 6: provider prompts compared to usual practice, Outcome 2 Tetanus–diphtheria–acellular–pertussis vaccination uptake.

Analysis 6.3

Comparison 6 Comparison 6: provider prompts compared to usual practice, Outcome 3 Meningococcal conjugate vaccination uptake.

Analysis 6.4

Comparison 6 Comparison 6: provider prompts compared to usual practice, Outcome 4 Seasonal influenza vaccination uptake.

Analysis 7.1

Comparison 7 Comparison 8: class‐based compared to age‐based HPV vaccination in schools, Outcome 1 Human papillomavirus vaccine uptake.

Analysis 8.1

Comparison 8 Comparison 10: multi‐component provider and parent intervention compared to usual practice, Outcome 1 Human papillomavirus vaccine uptake.

Summary of findings for the main comparison. Health education compared to usual practice

Comparison 1: health education compared to usual practice
Population: adolescents and parents Setting: Sweden and USA intervention: health education Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With health education
Uptake of HPV vaccine^a	209 per 1000	298 per 1000 (242 to 367)	RR 1.43 (1.16 to 1.76)	Health education improves uptake of HPV vaccine compared to usual practice.	1054 (3)^b	⊕⊕⊕⊕ High^c,d,e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% confidence interval) is based on the assumed likelihood of being vaccinated in the usual care group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a The lag‐time between delivery of the intervention and assessment of outcomes ranged from three months (Grandahl 2016) to 11 months (Winer 2016 ) ^bDiclemente 2015 (randomised trial); Grandahl 2016 (cluster‐randomised trial); Winer 2016 (cluster‐randomised trial). ^c Well conducted randomised trials with consistent findings (I² = 0%). ^d The findings from the one non‐randomised trial that assessed this comparison were similar to the findings of the randomised trials. ^eOne study reported that health education did not have any adverse events in relation to usual practice (Rickert 2015).

Summary of findings for the main comparison. Health education compared to usual practice

Summary of findings 2. Complex compared to simplified health education

Comparison 2: complex compared to simplified health education
Population: adolescents Setting: Australia Intervention: multi‐component health education^a Comparison: simplified health education
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With simplified education	With complex health education
Uptake of hepatitis B vaccine^b	756 per 1000	741 per 1000 (726 to 748)	RR 0.98 (0.96 to 0.99)	A complex multi‐component health education programme probably results in little or no difference in uptake of 3 doses of hepatitis B vaccine compared to simplified health education.	17,411 (1)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% confidence interval) is based on the assumed likelihood of being vaccinated in the simplified health education group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a Health education kit with 4‐lesson structured multi‐component intervention that included: a resource fact sheet and assessment, an information video and questions designed to engage an adolescent audience, small group discussion, and an activity to locate resource information on the Internet. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was not provided. ^cSkinner 2000 (randomised trial). ^d Downgraded one level due to study limitations, as the included study has an unclear risk of bias.

Summary of findings 2. Complex compared to simplified health education

Summary of findings 3. Financial incentives compared to usual practice

Comparison 3: financial incentives compared to usual practice
Patient or population: adolescents Setting: UK intervention: financial incentive^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With financial incentives
Uptake of HPV vaccine^b	196 per 1000	284 per 1000 (206 to 390)	RR 1.45 (1.05 to 1.99)	Financial incentives may improve uptake of HPV vaccine compared to usual practice.	500 (1)^c	⊕⊕⊝⊝ Low^d,e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effect in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe financial incentive involved an offer of shopping vouchers worth GBP 45 upon completion of 3 HPV vaccination doses. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was one to seven months. Invitation letters promising incentives were sent in February‐March of 2010 and vaccination sessions were conducted between March and September 2010 ^cMantzari 2015 (randomised trial). ^d Downgraded one level for study limitations (unclear risk of bias in the included study). ^e Downgraded one level for imprecision of findings.

Summary of findings 3. Financial incentives compared to usual practice

Summary of findings 4. Health education plus financial incentives compared to usual practice

Comparison 4: health education plus financial incentives compared to usual practice
Population: adolescents and parents Setting: USA Intervention: health education plus financial incentives^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With health education and incentives
Uptake of hepatitis B vaccine^b	451 per 1000	622 per 1000 (433 to 902)	RR 1.38 (0.96 to 2.00)	We are uncertain about the effects of health education plus financial incentives on the uptake of 3 doses of hepatitis B vaccine compared to usual practice.	104 (1)^c	⊕⊝⊝⊝ Very low^d,e,f
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe intervention involved (1) an educational video and PowerPoint presentation for caregivers and adolescents about hepatitis B infection and the importance of hepatitis B vaccination, (2) free vaccination, and (3) financial incentives. When the adolescents received each vaccine dose, their caregivers were given cash incentives of USD 10 for the first dose, USD 10 for the second dose, and USD 30 for the third dose. In addition, at each visit, adolescents and caregivers were given gift packages containing cosmetics for adults and sweets and toothbrushes for the children. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was three months. ^cSchwarz 2008 (randomised trial). ^d Downgraded one level for serious study limitations (unclear risk of bias in the included study). ^e Downgraded two levels for imprecision of findings with a wide confidence interval that includes both benefit and harm as well as a very small number of participants. ^f Downgraded two levels for serious indirectness, given that this finding is based on one small study from one setting.

Summary of findings 4. Health education plus financial incentives compared to usual practice

Summary of findings 5. Mandatory vaccination versus usual practice

Comparison 5: mandatory vaccination vs usual practice
Population: adolescents Setting: USA Intervention: school entry law mandating vaccination Comparison: usual practice in other classes in the same schools
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With mandatory vaccination
Uptake of hepatitis B vaccine^a	248 per 1000	728 per 1000 (677 to 784)	RR 2.94 (2.66 to 3.25)	Mandatory vaccination probably leads to a large increase in uptake of 3 doses of the hepatitis B vaccine compared to usual practice in other classes in the same schools.	2642 (1)^b	⊕⊕⊕⊝ Moderate^d
Population: adolescents Setting: USA Intervention: school entry law mandating vaccination Comparison: usual practice in areas not affected by the mandatory vaccination law
Uptake of hepatitis B vaccine^a	186 per 1000	728 per 1000 (678 to 780)	RR 3.92 (3.65 to 4.20)	Mandatory vaccination probably leads to a large increase in uptake of 3 doses of the hepatitis B vaccine compared to usual practice in areas not affected by the mandatory vaccination law.	6462 (1)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the no‐intervention group and the relative effect of the intervention (and its 95% CI). **GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a The lag‐time between delivery of the intervention and assessment of outcomes was 6‐8 years. ^bWilson 2005 (non‐randomised trial) compared students in the ninth grade (affected by the hepatitis B law) and 12th grade (not affected by the law) in the state of Missouri . ^cWilson 2005 (non‐randomised trial) compared the ninth grade in the state of Missouri (affected by the hepatitis B vaccination law) to the ninth grade in the state of Kansas (not affected by the law). ^d As a non‐randomised trial, these outcomes were initially graded as low certainty evidence and then upgraded by one level for very large effect sizes.

Summary of findings 5. Mandatory vaccination versus usual practice

Summary of findings 6. Provider prompts compared to usual practice

Comparison 6: provider prompts compared to usual practice
Population: healthcare workers Setting: USA Intervention: provider prompts^a Comparison: usual practice
Outcomes	Impact		№ of participants (studies)	Certainty of the evidence (GRADE)**
Outcomes	Relative effect (95% CI)	Narrative results	№ of participants (studies)	Certainty of the evidence (GRADE)**
Uptake of HPV vaccine^b	aOR 0.99 (0.55 to 1.81)^e	Provider prompts probably make little or no difference to uptake of 3 doses of HPV vaccine among adolescents compared to usual practice.	859 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of Tdap vaccine^b	aOR 1.28 (0.59 to 2.80)	Provider prompts probably make little or no difference to uptake of Tdap vaccine among adolescents compared to usual practice.	3296 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of meningococcal conjugate vaccine^b	aOR 1.09 ,(0.67 to 1.79)	Provider prompts probably make little or no difference to uptake of the meningococcal conjugate vaccine among adolescents compared to usual practice.	3219 (2)^c	⊕⊕⊕⊝ Moderate^d
Uptake of seasonal influenza vaccine^b	aOR 0.91 (0.61 to 1.34)	Provider prompts probably make little or no difference to uptake of the seasonal influenza vaccine among adolescents compared to usual practice.	1439 (2)^c	⊕⊕⊕⊝ Moderate^d
CI: confidence interval; HPV: human papillomavirus; aOR: adjusted odds ratio; Tdap: tetanus–diphtheria–acellular–pertussis. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence.: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a When a healthcare provider opened a patient's electronic medical record, there was a screen display of the list of vaccines that were due at that visit. At the beginning of the study, a 1‐2 hour educational session was given to the providers to inform them about the electronic health record based prompts. ^bThe lag‐time between delivery of the intervention and assessment of outcomes was 12 months. ^cSzilagyi 2015 conducted two separate randomised trials, one in a local and one in a national network, and then reported these in one paper. ^d Downgraded one level for imprecision of findings. ^e All odds ratios were adjusted based on a multilevel mixed‐effect logistic regression model with covariates for pair assignment, study time period, group assignment, and an interaction between time and group assignment.

Summary of findings 6. Provider prompts compared to usual practice

Summary of findings 7. Provider education with performance feedback compared to usual practice

Comparison 7: provider education with performance feedback compared to usual practice
Population: paediatricians and nurse practitioners Setting: USA Intervention: education with performance feedback Comparison: usual practice
Outcomes	Impact	№ of participants (studies)	Certainty of the evidence (GRADE)*
Uptake of HPV vaccination^a	Provider education with performance feedback may increase the proportion of adolescents who are offered and accept HPV vaccination by clinicians, compared to usual practice. Compared to adolescents visiting non‐participating clinicians (in the usual practice group), the adolescents visiting clinicians in the intervention group were more likely to receive the first dose of HPV during preventive visits (5.7 percentage points increase) and during acute visits (0.7 percentage points for the first and 5.6 percentage points for the second doses of HPV).	> 200,000 children (1 CBA)^b	⊕⊕⊝⊝ Low^c
HPV: human papillomavirus; CBA: controlled before‐after study *GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a There was no lag‐time between delivery of the intervention and assessment of outcomes. The intervention period ran from 01 January to 30 November 2013. Outcomes were assessed throughout this period, starting from day 1. ^bFiks 2016 (controlled before‐after study). c This is a non‐randomised study.

Summary of findings 7. Provider education with performance feedback compared to usual practice

Summary of findings 8. Class‐based compared to age‐based HPV vaccination in schools

Comparison 8: class‐based compared to age‐based HPV vaccination in schools
Population: adolescents Setting: Tanzania Intervention: class‐based vaccination Comparison: age‐based vaccination
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With age‐based delivery	With class‐based delivery
HPV vaccine uptake^a	721 per 1000	786 per 1000 (764 to 815)	RR 1.09 (1.06 to 1.13)	Class‐based vaccination probably leads to slightly higher HPV vaccine uptake than age‐based vaccination.	5537 (1)^b	⊕⊕⊕⊝ Moderate^c
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The anticipated absolute effects in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision
^a The lag‐time between delivery of the intervention and assessment of outcomes was 12 months. ^bWatson‐Jones 2012 (cluster‐randomised trial). ^c Downgraded one level for indirectness, given that the outcome is based on one study from one setting.

Summary of findings 8. Class‐based compared to age‐based HPV vaccination in schools

Summary of findings 9. Multi‐component provider intervention compared to usual practice

Comparison 9: multi‐component provider intervention compared to usual practice
Population: healthcare providers and their adolescent patients (boys and girls aged 11–21 years) Setting: USA Intervention: multi‐component performance improvement continuing medical education intervention^a Comparison: usual practice
Outcomes	Impact	№ of participants (studies)	Certainty of the evidence (GRADE)*
HPV vaccine uptake^b	A multi‐component provider intervention (including an education session, repeated contacts, individualised feedback, and incentives) probably improves uptake of HPV vaccine compared to usual practice. Girls in the intervention group are probably more likely to receive their next HPV vaccine dose than those in the comparison group (odds ratio 1.6, 95% CI 1.1 to 2.2). The effects are probably larger for boys (odds ratio 25.00, 95% CI 15.00 to 40.00), and this may be because publicly funded HPV vaccination for boys became available during the study.	15,849 adolescents (1)^c	⊕⊕⊕⊝ Moderate^d
HPV: human papillomavirus. *GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^aThe intervention involved: (1) 6–8 education visits over 12 months by an HPV physician‐educator; (2) focused education sessions on HPV‐related topics designed to change the way providers viewed the importance of HPV vaccination and responded to parents' hesitation toward HPV vaccines; (3) individualised feedback where providers and practices received individual reports that showed their performance compared to other providers in their practice on HPV vaccination coverage; and (4) quality improvement incentives whereby physicians were eligible to receive maintenance‐of‐registration credits, which fulfilled requirements for maintaining board certification. ^b The lag‐time between delivery of the intervention and assessment of outcomes was six months. ^cPerkins 2015 (cluster‐randomised trial). ^d Downgraded one level because of serious indirectness, given that this finding is based on one study from one setting.

Summary of findings 9. Multi‐component provider intervention compared to usual practice

Summary of findings 10. Multi‐component provider and parent intervention compared to usual practice

Comparison 10: multi‐component provider and parent intervention compared to usual practice
Population: healthcare workers and parents Setting: USA Intervention: multi‐component provider and parent intervention^a Comparison: usual practice
Outcomes	Impact				№ of participants (studies)	Certainty of the evidence (GRADE)**
	*Absolute effects (95% CI)**		Relative effect (95% CI)	Narrative results
	With usual practice	With multi‐faced intervention
HPV vaccine uptake at 3 months	25 per 1,000	57 per 1000 (18 to 180)	RR 2.34 (0.75 to 7.32)	A multi‐component intervention involving healthcare providers and parents may improve uptake of the HPV vaccine compared to usual practice.	337 (1)^b Randomised trial	⊕⊕⊝⊝ Low^d
HPV vaccine uptake at 6 months	52 per 1,000	73 per 1000 (65 to 83)	RR 1.41 (1.25 to 1.59)		25,869 (1)^cNon‐randomised trial	⊕⊕⊝⊝ Low^e
CI: confidence interval; HPV: human papillomavirus; RR: risk ratio. *The risk in the intervention group (and its 95% CI) is based on the likelihood of being vaccinated in the usual practice group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate certainty: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low certainty: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low certainty:** this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^†Substantially different = a large enough difference that it might affect a decision.
^a In the randomised trial (Paskett 2016), healthcare providers received a one‐hour PowerPoint presentation and handouts on the HPV vaccine, focusing on current evidence‐based HPV vaccine information and strategies designed to assist physicians in discussing HPV vaccination with parents. In addition, parents were mailed a packet that included an educational brochure and DVD video about HPV infection and HPV vaccination as well as a CDC HPV vaccine information statement. Furthermore, health educators conducted an education session with parents about the HPV vaccine via telephone to reinforce the message in the educational materials regarding the need for the vaccine and addressed any vaccination barriers or questions. In the non‐randomised trial (Cates 2014), the intervention included: (1) distribution of HPV vaccination posters and brochures with the risk‐related message to health departments and healthcare providers; (2) two radio public service announcements designed to raise awareness about HPV vaccine for boys among parents of preteen boys; (3) an online continuing medical education training with video demonstrating communication among providers, parents, and preteen boys available to enrolled health providers; (4) one‐page tip sheet for providers to discuss HPV vaccination with parents and boys; and (5) a website with links to credible information sources useful for both parents and providers. ^bPaskett 2016 (randomised trial). ^cCates 2014 (non‐randomised trial). ^d Downgraded by two levels for serious imprecision and serious study limitations (unclear risk of selection bias in the included study) (Paskett 2016). ^e Downgraded by two levels for non‐randomised study design (Cates 2014).

Summary of findings 10. Multi‐component provider and parent intervention compared to usual practice

Table 1. Summary of included studies

Study ID	Study design	Country	Participants	Intervention	Comparison	Duration of intervention	Vaccine target
Cates 2014	Non‐randomised trial	USA	Parents and health providers	Multi‐component providers and parents	Usual practice	3 months	HPV
Diclemente 2015	Randomised trial	USA	Adolescents	Health education	Usual practice	30 minutes	HPV
Fiks 2016	Controlled before‐after study	USA	Health provider	Provider education with performance feedback	Usual practice	1 month	HPV
Gargano 2015	Randomised trial	USA	Parents	Health education	Usual practice	2 months	Tdap, MCV, HPV, Influenza
Grandahl 2016	Cluster‐randomised trial	Sweden	Adolescents	Health education	Usual practice	30 minutes	HPV
Mantzari 2015	Randomised trial	UK	Adolescents	Financial incentives	Usual practice	6 months	HPV
Paskett 2016	Randomised trial	USA	Parents and health providers	Multi‐component providers and parents	Usual practice	—	HPV
Perkins 2015	Cluster‐randomised trial	USA	Adolescent and health providers	Multi‐component provider intervention	Usual practice	1 months	HPV
Rickert 2015	Randomised trial	USA	Parents	Health education	Usual practice	1 hour	HPV
Schwarz 2008	Randomised trial	USA	Adolescents and caregivers	Health education plus financial incentives	Usual practice	1 hour	HepB
Skinner 2000	Randomised trial	Australia	Adolescents	Complex health education	Simplified health education	1 hour	HepB
Staras 2015	Non‐randomised trial	USA	Adolescents	Health education	Usual practice	3 months	HPV
Szilagyi 2015	Randomised trial	USA	Health providers	Provider prompts	Usual practice	2 months	Tdap, MCV, HPV, Influenza
Wilson 2005	Non‐randomised trial	USA	Adolescent	Mandatory school entry vaccination	Usual practice	—	HepB, Td, and MMR
Winer 2016	Cluster‐randomised trial	USA	Parents	Health education	Usual practice	30–40 minutes	HPV
Watson‐Jones 2012	Cluster‐randomised trial	Tanzania	Adolescents	Class‐based vaccination	Age‐based vaccination	12 months	HPV
HepB: hepatitis B virus; HPV: human papillomavirus; MCV: meningococcal conjugate vaccine; MMR: measles–mumps–rubella; Td: tetanus–diphtheria; Tdap: tetanus–diphtheria–acellular–pertussis.

Table 1. Summary of included studies

Table 2. Intervention‐outcome matrix

Intervention	Vaccination coverage	Equity	Knowledge	Attitudes	Beliefs	Adverse effects	Cost	Vaccine‐preventable diseases
Recipient‐oriented interventions
1 Health education vs usual practice	✔㊉㊉㊉㊉¹	NR	✔㊉㊉㊀㊀²	NR	NR	NG	NR	NR
2. Complex vs simplified health education	Ø㊉㊉㊉㊀³	NR	✔㊉㊉㊀㊀³	NR	NR	NR	NR	NR
3. Financial incentives vs usual practice	✔㊉㊉㊀㊀⁴	NR	NR	NR	NR	NR	NR	NR
4. Health education plus financial incentives vs usual practice	?㊉㊀㊀㊀⁵	NR	?㊉㊀㊀㊀⁵	NR	NR	NR	NR	NR
5. Mandatory vaccination vs usual practice	✔㊉㊉㊉㊀⁶	NR	NR	NR	NR	NR	NR	NR
Provider‐oriented interventions
6. Provider prompts vs usual practice	✔㊉㊉㊉㊀⁷	NR	NR	NR	NR	NR	NR	NR
7. Provider education plus performance feedback vs usual practice	✔㊉㊉㊀㊀⁸	NR	NR	NR	NR	NR	NG	NR
Health system interventions
8. Class‐based vs age‐based HPV vaccination in schools	✔㊉㊉㊉㊀⁹	NR	NR	NR	NR	NR	NG	NR
Multi‐component interventions
9. Multi‐component provider intervention vs usual practice	✔㊉㊉㊀㊀¹⁰	NR	NR	NR	NR	NR	NR	NR
10. Multi‐component provider and parent intervention vs usual practice	✔㊉㊉㊀㊀¹¹	NR	✔㊉㊉㊀㊀¹²	NR	NR	NR	NR	NR
✔ = a desirable effect Ø = little or no effect ? = uncertain effect x = undesirable effect vs = Compared to NR = not reported NG = outcome not graded ¹Diclemente 2015 (randomised trial), Grandahl 2016 (cluster‐randomised trial), and Winer 2016 (cluster‐randomised trial). ²Gargano 2015 (randomised trial). ³Skinner 2000 (randomised trial). ⁴Mantzari 2015 (randomised trial). ⁵Schwarz 2008 (randomised trial). ⁶Wilson 2005 (non‐randomised trial). ⁷Szilagyi 2015 (randomised trial). ⁸Fiks 2016 (controlled before‐after study). ⁹Watson‐Jones 2012 (cluster‐randomised trial). ¹⁰Perkins 2015 (cluster‐randomised trial). ¹¹Paskett 2016 (randomised trial) and Cates 2014 (non‐randomised trial). ¹²Paskett 2016 (randomised trial) ⊕⊕⊕⊕ = High‐certainty evidence Definition: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low. Implications: this research provides a very good basis for making a decision about whether to implement the intervention. Impact evaluation and monitoring of the impact are unlikely to be needed if it is implemented. ⊕⊕⊕⊖ = Moderate‐certainty evidence Definition: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate. Implications: this evidence provides a good basis for making a decision about whether to implement the intervention. Monitoring of the impact is likely to be needed and impact evaluation may be warranted if it is implemented. ⊕⊕⊖⊖ = Low‐certainty evidence Definition: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high. Implications: this evidence provides some basis for making a decision about whether to implement the intervention. Impact evaluation is likely to be warranted if it is implemented. ⊕⊖⊖⊖ = Very low certainty evidence Definition: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high. Implications: this evidence does not provide a good basis for making a decision about whether to implement the intervention. Impact evaluation is very likely to be warranted if it is implemented.

Table 2. Intervention‐outcome matrix

Comparison 1. Comparison 1: health education compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Human papillomavirus vaccine uptake Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Non‐randomised	1	2822	Risk Ratio (M‐H, Random, 95% CI)	1.84 [1.34, 2.54]
1.2 Randomised	3	1054	Risk Ratio (M‐H, Random, 95% CI)	1.43 [1.16, 1.76]

Comparison 1. Comparison 1: health education compared to usual practice

Comparison 2. Comparison 2: complex compared to simplified health education

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hepatitis B vaccine uptake Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Comparison 2: complex compared to simplified health education

Comparison 3. Comparison 3: financial incentives compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Human papillomavirus vaccine uptake Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Comparison 3: financial incentives compared to usual practice

Comparison 4. Comparison 4: health education plus financial incentives compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hepatitis B vaccine uptake Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 4. Comparison 4: health education plus financial incentives compared to usual practice

Comparison 5. Comparison 5: mandatory vaccination compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hepatitis B vaccine uptake Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 9th graders in Missouri vs Kansas	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 9th graders in Missouri vs 12th graders in Missouri	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Comparison 5: mandatory vaccination compared to usual practice

Comparison 6. Comparison 6: provider prompts compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Human papillomavirus vaccine uptake Show forest plot	1		Odds Ratio (Fixed, 95% CI)	0.99 [0.55, 1.81]

2 Tetanus–diphtheria–acellular–pertussis vaccination uptake Show forest plot	1		Odds Ratio (Fixed, 95% CI)	1.28 [0.59, 2.80]

3 Meningococcal conjugate vaccination uptake Show forest plot	1		Odds Ratio (Fixed, 95% CI)	1.09 [0.67, 1.79]

4 Seasonal influenza vaccination uptake Show forest plot	1		Odds Ratio (Fixed, 95% CI)	0.91 [0.61, 1.34]

Comparison 6. Comparison 6: provider prompts compared to usual practice

Comparison 7. Comparison 8: class‐based compared to age‐based HPV vaccination in schools

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Human papillomavirus vaccine uptake Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 7. Comparison 8: class‐based compared to age‐based HPV vaccination in schools

Comparison 8. Comparison 10: multi‐component provider and parent intervention compared to usual practice

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Human papillomavirus vaccine uptake Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Randomised	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Non‐randomised	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 8. Comparison 10: multi‐component provider and parent intervention compared to usual practice