Feasibility of cross-protective vaccination against flaviviruses of the Japanese encephalitis serocomplex

Abstract

Serological cross-reactivity providing cross-protective immunity between antigenically related viruses is a cornerstone of vaccination. It was the immunological basis for the first human vaccine against smallpox introduced more than 200 years ago, and continues to underpin modern vaccine development as has recently been shown for human papillomavirus vaccines, which confer cross-protection against other oncogenic papillomavirus types not present in the vaccine. Here, we review the feasibility of cross-protective vaccination against an antigenic group of clinically important viruses belonging to the Japanese encephalitis serocomplex in the Flaviviridae family. We will discuss evidence suggesting that 'new generation' flavivirus vaccines may provide effective cross-protective immunity against heterologous Japanese encephalitis serocomplex viruses, and appraise potential risks associated with cross-reactive vaccine immunity. The review will also focus on the structural and mechanistic basis for cross-protective immunity among this group of flaviviruses, which is predominantly mediated by antibodies against a single viral surface protein.

Figure 1. Structure of the West Nile virus envelope protein

Domain I (red), DII (yellow), and DIII (blue) of the monomeric envelope protein and location of key epitopes. The fusion loop (residues 98–110, green) is located at the distal end of DII. A single carbohydrate (gray) extends from Asn154 in Domain I. The DIII-lateral ridge epitope (based on the structure of monoclonal antibody West Nile virus E16) is highlighted in magenta: the amino-terminal region (residues 302–309), the BC loop (residues 330–333), the DE loop (residues 365–368) and the FG loop (residues 389–391). The six disulfide bonds are shown in orange. DII: Domain II; DIII: Domain III.