Cross-Reactive Immunity among Five Medically Important Mosquito-Borne Flaviviruses Related to Human Diseases

Abstract

Flaviviruses cause a spectrum of potentially severe diseases. Most flaviviruses are transmitted by mosquitoes or ticks and are widely distributed all over the world. Among them, several mosquito-borne flaviviruses are co-epidemic, and the similarity of their antigenicity creates abundant cross-reactive immune responses which complicate their prevention and control. At present, only effective vaccines against yellow fever and Japanese encephalitis have been used clinically, while the optimal vaccines against other flavivirus diseases are still under development. The antibody-dependent enhancement generated by cross-reactive immune responses against different serotypes of dengue virus makes the development of the dengue fever vaccine a bottleneck. It has been proposed that the cross-reactive immunity elicited by prior infection of mosquito-borne flavivirus could also affect the outcome of the subsequent infection of heterologous flavivirus. In this review, we focused on five medically important flaviviruses, and rearranged and recapitulated their cross-reactive immunity in detail from the perspectives of serological experiments in vitro, animal experiments in vivo, and human cohort studies. We look forward to providing references and new insights for the research of flavivirus vaccines and specific prevention.

Clinical Landscape and Rate of Exposure to Ilheus Virus: Insights from Systematic Review and Meta-Analysis

“…In South America, Central America, and the Caribbean, different geographic regions have multiple endemic mosquito-borne flaviviruses in co-circulation [ 75 , 76 , 77 ]. Twenty-nine (78.3%) of the 37 studies included in our meta-analysis investigated the antibody ratios against multiple arbovirus antigens.…”

“…Flavivirus species have been linked to sporadic cases of human infection, including Bussuquara (BUSV), Cacipacore (CPCV), and ILHV [ 78 , 79 ]. All these viral pathogens may cause undifferentiated febrile illness in humans, and laboratory diagnosis is difficult due to the substantial cross-reactivity of antibodies [ 75 ]. Additionally, as occurs for ILHV, BUSV, CPCV, and other native flaviviruses are neglected, with misdiagnosis of cases compared to other medical arboviruses associated with outbreaks or epidemics that attract the most public attention, such as DENV, ZIKV, and YFV.…”

“…Since the included studies used HI/NT tests to capture total antibodies in the target serum, it was not possible to determine the dominant ILHV antigen (protein) involved. There is marked variation in the amino acid identity of the polyprotein of mosquito-borne flaviviruses; for example, in the polyprotein of Japanese encephalitis, dengue, yellow fever, Zika, and West Nile viruses, the amino acid similarity ranges between 45–77% [ 75 ]. As HI and serum neutralization tests target neutralizing antibodies, virus E (envelope) protein may be a promising target.…”

The Japanese Encephalitis Antigenic Complex Viruses: From Structure to Immunity

“…Koblischke et al [ 210 ] reported peptide regions that form the immune-dominant WNV E epitopes, and one such region (E149) is unique and absent in DENV and ZIKV and lies on a structurally divergent region in WNV. Multiple research findings from mouse experiments and human studies revealed the essential role of cellular immunity and neutralizing antibodies in cross-protection between primary JEV or WNV exposure and secondary DENV and ZIKV infections [ 212 ]. The sequence of infection is known to influence disease outcomes; additionally, immune-dominant mechanisms of protection for each dyad of viral infections can be distinct and essential to elucidate if these outcomes are to inform therapeutics.…”

“…For instance, in the sequential JEV-ZIKV infection, unlike the JEV-JEV infection, JEV vaccination-induced CD8 T cell immunity was found to be essential for conferring cross-protection in mouse models compared to passive transfer of serum [ 213 , 214 ]. Alternatively, cross-protective outcomes in JEV-DENV1 infection in mouse models required the cooperative effects of humoral and T cell responses, whereas in human infections, secondary DENV following anti-JEV immunity resulted in manifestation of increased viral symptoms [ 206 , 212 , 215 ].…”