Elsevier

Vaccine

Volume 27, Issue 50, 23 November 2009, Pages 7021-7026
Vaccine

Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs

https://doi.org/10.1016/j.vaccine.2009.09.069Get rights and content

Abstract

Tick-borne encephalitis (TBE) virus is an important human pathogenic flavivirus that is endemic in Europe and Asia. The disease can be effectively prevented by inactivated vaccines and vaccination breakthroughs (VBTs) are rare. We investigated the characteristics of antibody responses in such VBTs in comparison to those in unvaccinated TBE patients. In contrast to the unvaccinated controls, most of the VBTs displayed a delayed IgM antibody response and had high avidity and strongly neutralizing antibodies already in the first sample taken upon hospitalization. The antibody profile of these patients therefore had the characteristics of an anamnestic immune response. In the VBTs analyzed, immunological priming and memory were apparently not sufficient or fast enough to prevent the disease.

Introduction

Vaccination is one of the most efficient means for the prevention of infectious diseases [1], [2]. The field effectiveness of licensed vaccines, however, varies strongly, ranging from 50% to 80% for inactivated influenza vaccines [3] to more than 90% for Hepatitis A vaccines [4]. No vaccine, therefore, offers 100% protection and two types of vaccination failures have been distinguished. Primary failure refers to the complete non-responsiveness to vaccination [5], [6], whereas, in secondary failures, vaccinees do not maintain adequate immunity although they had initially responded to vaccination [5], [6], [7]. The immunological explanation for vaccination failures is difficult to establish, since in the majority of cases the immune status at the time point of infection is not known and only post-infection sera are available. The characteristics of antibodies formed in the course of infection, however, allow conclusions to be drawn with respect to the type of vaccination breakthroughs (VBTs), i.e. primary or secondary failures.

Vaccines against flaviviruses – that include a number of important arthropod-borne human pathogens, such as yellow fever (YF), West Nile, Japanese encephalitis (JE), dengue, and tick-borne encephalitis (TBE) viruses – have a successful history. Licensed vaccines are available for three members of this group: inactivated vaccines for TBE and JE viruses, and live attenuated vaccines for YF virus (strain 17D) and JE virus (strain SA14-14-2; licensed in China) [8], [9]. The field effectiveness of flavivirus vaccines is high, with 76–95% for the inactivated JE vaccine [8] and even more than 95% for the YF [9] and TBE [10] vaccines.

TBE virus (TBEV) is classified as one species in the genus flavivirus of the family Flaviviridae [11] with three antigenically closely related subtypes (European, Siberian, and Far Eastern) [12]. It is endemic in parts of Europe and Asia and its main transmission vectors are the ticks, Ixodes ricinus and Ixodes persulcatus [13], [14]. In the last decade, not only an increase of TBE incidence but also the occurrence of new foci of TBE has been observed in Europe [14], [15]. Approximately 3000 hospitalized human cases per year are recorded in Europe and up to 10,000 in Russia [15]. Typically, the disease takes a biphasic course and starts with an uncharacteristic influenza-like illness about 1 week after infection. This first stage may last about a week and corresponds to the viremic phase. After an asymptomatic interval of several days, the second phase with CNS symptoms (meningitis, meningoencephalitis, meningoencephalomyelitis, or meningoencephaloradiculitis) occurs in 20–30% of infected patients, and this is generally the time point when the patients consult a physician or are hospitalized [14], [16], [17]. In Europe, the lethality of TBE is 0.5–1%, and long-lasting or permanent neurological sequelae are frequently observed [14], [16], [17]. Because of the lack of characteristic clinical symptoms, the correct diagnosis requires specific virological analyses. In most of the patients with manifest disease, TBEV-specific IgM and IgG antibodies can be detected by ELISA at the time of hospitalization – at the beginning of the second phase of the illness – and the detection of specific IgM antibodies is usually taken as proof of a recent TBEV infection [14], [17].

The TBE vaccines licensed in Europe contain highly purified formalin-inactivated European TBEV strains adsorbed to aluminium hydroxide (reviewed in [18]). The basic immunization schedules consist of two vaccinations 1–3 months apart and a third vaccination after 9–12 months. Of all European countries, Austria has the highest vaccination coverage with 88% of the total population having received at least one dose of the vaccine and 58% being within the officially recommended vaccination schedule, i.e. a fourth vaccination after 3 years and booster vaccinations every 5 years for individuals younger than 60 years and every 3 years for individuals older than 60 years. The overall effectiveness of the vaccine is about 99% in regularly, and about 95% in irregularly, vaccinated individuals [10]. Clinically manifest VBTs are thus rare and only a few individual cases have been described [19], [20], [21], [22], [23], [24].

In this study, we performed a systematic investigation of the characteristics of the antibody responses of hospitalized TBE patients with or without a history of TBE vaccination. With few exceptions, the VBTs differed from the unvaccinated group and did not display a primary but an anamnestic immune response. This was characterized by high titers of neutralizing IgG antibodies with high avidities already upon admission to the hospital in combination with low IgM antibody titers. Apparently, immunological memory in these VBT patients was not sufficient for preventing the disease.

Section snippets

Virus growth, purification and inactivation

TBEV strain Neudoerfl [25], [26] was grown in primary chicken embryo cells, harvested 48 h after infection, and purified by 2 cycles of sucrose density gradient centrifugation as described previously [27]. Virus was inactivated with formalin (final dilution 1:2000) for 24 h at 37 °C after purification.

Human serum samples

With the approval of the local ethics committee, we tested sera of TBE patients (where sufficient volume for analysis was available) that had been originally submitted to the Institute of Virology,

Serum sample selection

Serum samples from 25 hospitalized TBE patients with a vaccination history were selected for this study. One important criterion was the availability of one (preferably two) additional serum sample(s) after the first sample collected at the time of admission to the hospital. Since cases with disease despite vaccination are rare, the 25 VBTs cover a period of 7 years: only eight of the VBT patients were within the regular vaccination scheme, whereas 14 patients had not followed the recommended

Discussion

Since the effectiveness of any vaccination never reaches 100% [1], VBTs are a phenomenon accompanying even the most successful vaccines. The reasons for such vaccination failures can be different and include non-responsiveness to the antigen present in the vaccine (non-responders) [5], [6], loss of antigenicity and/or infectivity through inappropriate storage or interference with the replication of the vaccine virus in the case of live vaccines [32], [33], and insufficient or inappropriate

Acknowledgements

We thank Jutta Hutecek, Silvia Schwoediauer and Cornelia Stoeckl for their excellent technical assistance throughout the course of this work and Gabriel O’Riordain for critical reading of the manuscript. We are also grateful to Walter Holzer for help with virus production and inactivation.

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