Immunogenicity against Far Eastern and Siberian subtypes of tick-borne encephalitis (TBE) virus elicited by the currently available vaccines based on the European subtype: systematic review and meta-analysis

Abstract

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection.

Keywords: C, capside; CEE, Central European encephalitis; CI, confidence interval; E, envelope; ELISA, enzyme-linked immunosorbent assay; European subtype; FSME, Frühsommer-Meningoenzephalitis [German] (tick-borne encephalitis); Far Eastern subtype; GMT, geometric mean titer; HI, hemagglutination inhibition; IFA, indirect immunofluorescence; IPVE, Institute of Poliomyelitis and Viral Encephalitis; IgG, Immunoglobulin G; M, membrane; NR, not reported; NS, non-structural; NT, neutralization test; RCT, randomized controlled trial; RNA, ribonucleic acid; RR, risk ratio; RSSE, Russian spring summer encephalitis virus; SCR, seroconversion rate; SD, standard deviation; SMD, standardized mean difference; SPR, seropositivity rate; Siberian subtype; TBE; TBE, tick-borne encephalitis; TBEV, tick-borne encephalitis virus; TBEV-Eu, European subtype of TBEV; TBEV-FE, Far Eastern subtype of TBEV; TBEV-Sib, Siberian subtype of TBEV; VIEU, Vienna unit; WHO, World Health Organization; cross-protection; cross-subtype immunogenicity; d, day; prM, pre-membrane; tick-borne encephalitis; vaccines; we: week; y, year; μNT, microneutralization test.

Figure 1.

Flowchart of the study selection process. Since 2 studies^41,42 used a commercial hemagglutination inhibition (HI) kit based on strain 139, 1 study¹⁷ used an enzyme-linked immunosorbent assay (ELISA) kit based on strain 205 and another study⁴⁹ used both commercial kits, 2 separate meta-analyses on the basis of serological assay were performed.

Figure 2.

Forest plot of seroconversion rates on hemagglutination inhibition assay by means of commercial kit one month after 2 doses of FSME-Immun and Russian vaccines: random effects model.