Protection against Tick-Borne Encephalitis with a New Vaccine Formulation Free of Protein-Derived Stabilizers

Olaf Zent, MD; Angelika Banzhoff, MD; Michael Bröker, PhD; Renald Hennig, MD

Disclosures

J Travel Med. 2005;12(2):85-89. 

In This Article

Abstract and Introduction

Background: Vaccination against tick-borne encephalitis (TBE) has been successfully employed for many years in TBE-endemic countries. Post-marketing experience gained from widespread use, however, prompted the development of improved TBE vaccines, the most modern versions of which do not contain the commonly used protein-derived stabilizers (human albumin or polygeline) of former vaccines.
Method: This article summarizes both the medical need for and clinical experience with a new TBE vaccine formulation (pediatric and adult versions). To this end, data from clinical trials and post-marketing experience are presented. The clinical database comprises immunogenicity and/or safety data of approximately 7,500 subjects ages 1 to 77 years who participated in eight clinical trials. The clinical trials were conducted at 69 centers in five European countries. Post-marketing experience includes safety data from passive pharmacovigilance systems in 18 countries where these vaccines have been licensed since 2001.
Results: All subjects analyzed for immunogenicity achieved postimmunization levels of TBE antibodies that meet the definition of seroconversion or represent a fourfold increase. The pooled data of clinical trials revealed the expected rate of solicited local and systemic reactions. The majority of these transient postimmunization reactions were mild. Pharmacovigilance data confirm the high level of safety of these new TBE vaccines: only a common range of the side effects already noted for licensed TBE vaccines was reported. After the distribution of more than five million vaccine doses, no potential safety risk was noted.
Conclusion: Post-marketing experience supports results from clinical trials showing that these new TBE vaccines may safely be used for the vaccination of children, adolescents, and adults.

Tick-borne encephalitis (TBE) is an important flavivirus infection that has been known for > 70 years.[1,2] The disease is caused by the TBE virus, which is endemic in many regions of Europe and Asia, stretching in a belt from Western, Central, and Eastern Europe to Western Siberia and Japan in Asia.[3,4] Three subtypes of the TBE virus have been described, corresponding to European, Siberian, and Far Eastern subtypes.[5] Incidence and prevalence vary from region to region, being considerably higher in TBE-endemic countries that do not have a prevention policy in place. In Europe the highest incidence was recently reported from the Åland islands in Finland with > 80 cases per 100,000 in the year 2000, whereas high incidence rates of 50 to 100 cases per 100,000 have been known for many years in regions of Siberia.[3] Overall, there appears to be a trend toward increased numbers of TBE cases in endemic areas and the appearance of new foci in previously TBE-free regions in Europe.[4]

Although the common assumption is that climate change is the obvious cause of the increased incidence, one has to consider that this alone cannot yet satisfactorily explain the temporal and spatial pattern of TBE change in Europe. Only interwoven climatic, political, social, and human-driven environmental changes can plausibly account for the increase of TBE cases in many European countries.[6,7] Clinical manifestations of TBE infection range from 10 to 30% in Central and Eastern Europe, with higher rates in parts of Western and Eastern Siberia. Annually approximately 10,000 to 12,000 cases of TBE are reported worldwide.[3] Up to 30% of adults with clinical evidence of infection develop meningitis (45%), meningoencephalitis (42%), or, more rarely, meningoencephalomyelitis and meningoencephaloradiculitis (14%).[8,9] Meningitis is the predominant neurologic complication in children,[10–12] and it is accompanied by severe headache, stiff neck, a temperature of up to 40°C, nausea, and vomiting. TBE disease appears to be more severe in regions in which the Siberian and Far Eastern subtypes are present than in European TBE regions in which the European subtype predominates. Retrospective analyses revealed fatality rates of 1% in Southern Germany and of 1.5% in Russia, with much higher rates in the Far East regions of Russia (3–30%).[3,9]

No curative treatment is available yet. Thus, TBE-prevention strategies have been implemented in various European countries for many years. In Central and Western Europe, TBE vaccines are marketed by two vaccine manufacturers[13]: these vaccines are based on either the TBE virus strain Neudoerfl (isolated in Austria) or the strain K23 (isolated in Southern Germany). The first TBE vaccine was developed in the 1970s in cooperation with the Microbiological Research Establishment in Porton Down, United Kingdom, and was prepared using an Austrian TBE virus isolate (strain Neudoerfl).[14] The K23 strain was introduced for TBE vaccine development in the late 1980s and has subsequently been used by Chiron Vaccines (formerly Behringwerke) in Germany for the TBE vaccine manufacturing for more than 15 years.[15] Sequencing of the viral genome revealed a high level of homology among all the strains identified thus far.[5,16] There is evidence from in vitro studies that a vaccine formulation based on the K23 strain offers cross-protection against various European and Asian isolates of the TBE virus.[17] Cross-reacting neutralizing antibodies against Siberian and Far Eastern strains have also been documented for the vaccine based on strain Neudoerfl.[18] Initial clinical studies with a vaccine containing the K23 strain were performed in the early 1990s and revealed a dose-dependent immunogenicity and reactogenicity in man.[19] It was shown that TBE immunoglobulin G antibody titers induced in vaccinees by primary immunization were of the same order of magnitude as those found in subjects who had recovered from TBE disease.[20]

On the basis of post-marketing experience gained from the widespread use of this vaccine, major modifications of the vaccine formulation were made, and these are described in this article. The result has been an improved TBE vaccine formulation that does not contain the protein stabilizers commonly used in other viral vaccines. The present article summarizes the medical needs that led to the development of this new TBE vaccine formulation and reviews the clinical experience gained since the first clinical studies of the new formulation in 1999.

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