Partially Neutralizing Potency against Emerging Genotype I Virus among Children Received Formalin-Inactivated Japanese Encephalitis Virus Vaccine

Abstract

BackgroundGenotype I (GI) Japanese encephalitis virus (JEV) that replaced GIII virus has become the dominant circulating virus in Asia. Currently, all registered live and inactivated JEV vaccines are derived from genotype III viruses. In Taiwan, the compulsory JEV vaccination policy recommends that children receives four doses of formalin-inactivated Nakayama (GIII) JEV vaccine.Methodology/Principal FindingsTo evaluate the influence of genotype replacement on the post-vaccination viral neutralizing ability by GIII and GI viruses, the small panel of vaccinated-children serum specimens was assembled, and the reciprocal 50% plaque-reduction neutralizing antibody titers (PRNT50) were measured against Nakayama vaccine strain, CJN GIII human brain isolate and TC2009-1 GI mosquito isolate. The seropositivity rate (PRNT50≥1∶10) and geometric mean titers (GMT) against the TC2009-1 virus were the lowest among the three viruses. The protective threshold against the CJN and TC2009-1 viruses could only be achieved when the GMT against Nakayama virus was ≥1∶20 or ≥1∶80, respectively. Using undiluted vaccinees' sera, the enhancement of JEV infection in K562 cells was observed in some low or non-neutralizing serum specimens.Conclusions/SignificanceOur preliminary study has shown that neutralizing antibodies, elicited by the mouse brain-derived and formalin-inactivated JEV Nakayama vaccine among a limited number of vaccinees, have reduced neutralizing capacity against circulating GI virus, but more detailed studies are needed to address the potential impact on the future vaccine policy.

Review of Climate, Landscape, and Viral Genetics as Drivers of the Japanese Encephalitis Virus Ecology

“…It is now very probably the most widespread genotype in Asia, which was otherwise found to be lethal for humans [9], [29]–[33]. However, to date, vaccines are only derived from genotype III strains; whereas protective levels of cross-reactive neutralizing antibodies of these vaccines were found against the various circulating genotypes, variations between genotypes call for further studies [34], [35]. In particular, since the immune response against genotype I was less pronounced, its duration should be addressed [34].…”

Epidemiological Features of Japanese Encephalitis in Taiwan from 2000 to 2014

“…15,20,21 It has been found that antibodies elicited by JE-VAX (Nakayama strain) among Taiwanese children show reduced neutralizing potency against the genotype of the emerging GI JEV strain. 22 Taiwan has been using an inactivated mouse brain Nakayama-NIH vaccine strain since 1968, except for the brief use of an inactivated freeze-dried Beijing vaccine strain in 1988. It has been reported that the JE-VAX had several disadvantages, including vaccine-induced adverse events and the need for two or three primary doses plus boosters.…”

Japanese encephalitis vaccines: Immunogenicity, protective efficacy, effectiveness, and impact on the burden of disease

“…Nakayama vs. Beijing-1 or SA14-14-2, or any of these vs. other wild-type G-III strains) with MBDI, SA14-14-2 LAV, JE-CV as well as Vero CCDI vaccines, although the differences in SCRs or GMTs are not significant statistically. 22,24,25,27,31,65,70,71,117,120,122,136,[165][166][167] This differential neutralization as well as protection against G-III viruses has also been shown in mouse challenge studies. 168 Other studies have shown no such differences or higher GMTs with the heterologous virus strains.…”

“…In general, these studies have shown that NAb titres are highest against G-II and homologous G-III viruses, followed by G-IV and heterologous G-III viruses, whereas titres against G-I viruses are the lowest, and in some cases below protective levels. 22,[24][25][26][27][28][29] A recent study specifically evaluated the ability of a G-III virus to elicit protective responses in mice, and the ability of human post-vaccinal and acute phase sera to neutralize G-V viruses. The study found that (a) NAb titres in mice immunized with either G-III or G-V virus were higher with homologous viruses but poor against G-V, (b) the SA14-14-2 LAV or the P-3 inactivated vaccines were less protective against G-V virus challenge in mice, and (c) both GMTs and SPRs were poor against G-V virus, intermediate against G-I virus, and highest against G-III virus with both post-vaccinal and acute phase human sera.…”

“…encephalitis, 21 (b) the fact that vaccination has significantly reduced JE cases (see below), and (c) studies of in vitro neutralization of heterologous genotype viruses by sera from subjects immunized with any one of the genotype viruses. 17,[22][23][24][25][26][27][28][29] Types G-I to G-IV have been frequently detected whereas G-V is relatively rare. 30 Viruses belonging to G-I have been reported from Australia, Cambodia, China, India, Japan, Malaysia, South Korea, northern parts of Thailand, and Vietnam; G-II has been reported from Australia, Indonesia, Malaysia (especially Sarawak), Papua New Guinea, South Korea, and southern parts of Thailand; G-III has been reported from China, India, Japan, Nepal, The Philippines, South Korea, Sri Lanka, and Taiwan; G-IV has been reported from Indonesia; G-V has been reported from China, Malaysia, and South Korea 31,32 It should be noted that in most endemic countries, more than one genotype may circulate simultaneously, with possible periodic changes in dominant genotypes.…”