Immunogenicity of Hantavirus and evaluation of vaccine protective efficacy: A comparative neutralizing antibody study of vaccine strains and representative epidemic strains from selected provinces in China

Background Hemorrhagic fever with renal syndrome (HFRS) caused by Hantavirus (HV) remains a significant public health burden in the world. HFRS bivalent inactivated vaccine (HFRSbiv) with Hantaan virus (HTNV) and Seoul virus (SEOV) strains isolated 20 years ago have been used in key HFRS endemic provinces in China for HFRS prevention. After decades of effective implementation of comprehensive prevention and control measures, HFRS has entered a stage of epidemic fluctuation at low-level in China. However, the continuous transmission of the virus among rodent host animals may lead to dynamic changes in genetic diversity and immunogenicity of the virus, which may affect the pathogenic mechanism of the virus and the protective effect of vaccines. It is necessary to carry out timely monitoring and evaluation of the immunogenicity of HV. Methodology/principal findings A panel of sera was established by screening serum samples from HFRS patients at convalescent phase and individuals who had received standardized immunization with HFRSbiv. Neutralizing antibody titers against HTNV vaccine strain 84FLi, SEOV vaccine strain L99, and three representative epidemic strains from different genotypes (HTNV: SX26, SEOV: LN03 and FJ-17) were measured using an enzyme-linked immunosorbent assay-based microneutralization test (MN-ELISA). HV-neutralizing antibodies were detected from all the selected serum samples. Among HFRS patients, 47.92% (23/48) were identified as HTNV infection, 27.08% (13/48) were with SEOV infection, and 25% (12/48) were untypable. There is a significant difference in the titers of neutralizing antibodies against vaccine strains and epidemic strains detected in the serum samples. For HTNV, both patient and vaccinee sera exhibited significantly higher geometric mean titer (GMT) against vaccine strain 84FLi than against epidemic strain SX26 (1:386.08 vs. 1:223.04, 𝑃 < 0.001; 1:137.94 vs. 1:110.37, 𝑃 < 0.05, respectively). For SEOV, patient sera showed significantly lower GMT against vaccine strain L99 than against epidemic strain LN03 (1:177.02 vs. 1:297.71, 𝑃 < 0.01), and vaccinee sera showed significantly lower GMT against L99 than against epidemic strain FJ-17 (1:97.52 vs. 1:243.71, 𝑃 < 0.001). Significant immunogenicity heterogeneity was observed between SEOV epidemic strains LN03 and FJ-17. Conclusions/significance The genetic diversity and immunogenicity of HV, which causes HFRS, have certain geographical regional characteristics. The levels of cross neutralizing antibodies induced by infection of HV from different genotypes may vary significantly, but still provide sufficient cross protection. The HFRSbiv currently used in China could induce broad neutralizing antibody, the cross-protective efficacy might vary against different circulating strains and genotypes. It is of great significance to strengthen the monitoring of genetic characteristics of regional specific circulating viral strains, regularly evaluate the matching degree between vaccine protection effectiveness and epidemic strains, predict and evaluate the transmission and pathogenic risks of HV, and timely optimize HFRS prevention and control strategies and measures.