Abstract / Summary
Nipah (NiV) and Hendra (HeV) viruses are highly lethal zoonotic Henipaviruses with pandemic potential, for which no licensed vaccines exist. The surface glycoprotein (G) is the primary target of neutralizing antibodies, yet a systematic comparison of the immunogenicity of NiV.G and HeV.G has been lacking. Here, we engineered mRNA vaccines encoding the full-length G proteins of NiV and HeV. In Syrian hamsters, while both vaccines conferred homologous protection, only HeV.G vaccination at a lower dose (5 µg) provided complete cross-protection against lethal NiV challenge. Comparative immune profiling revealed that HeV.G vaccination induced significantly higher neutralizing antibody titers, which correlated with robust germinal center B cell expansion and a stronger CD4 + T follicular helper (Tfh) cell response, despite equivalent B cell activation. Epitope mapping uncovered a structurally conserved yet immunologically divergent MHC class II-restricted peptide (YIAITKVER) in HeV.G with superior predicted binding affinity, providing a mechanistic basis for the enhanced T cell help. Our work establishes HeV.G as a superior vaccine immunogen due to its distinct epitope repertoire and underscores the critical role of CD4 + T cell help in driving cross-protective B cell immunity. We further developed a bivalent vaccine Gmix, which induced balanced antibody and cellular immune responses against both G proteins, thereby confirming the value of multivalent vaccines in broadening immune coverage. Collectively, this study defines HeV.G as the preferred antigen for pan-henipavirus vaccine development and offers a framework for rational antigen selection against future viral threats.