The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. ONE SENTENCE SUMMARY Epitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.
Panpan Zhou, Ziqi Feng, Wan-ting He et al.· bioRxiv· 0 citations
Hepatitis C virus (HCV) affects 47 million people and causes 239,000 deaths annually, yet no vaccine is on the horizon. Generating a stable native-like mimic of the envelope complex E1E2, the only target for known neutralizing antibodies, is an important aim for HCV vaccine development. Starting from a recombinant E1E2 design that utilizes a leucine zipper for proper folding, we used an iterative structure-based design approach to engineer antigens with at least 100-fold stronger binding to conformational antibodies and increased thermal stability. These new E1E2 designs facilitate production of native-like E1E2 antigens based on strains from different HCV genotypes and enable the generation of a recombinant E1E2 antigen design that lacks the immunogenic leucine zipper. A cryo-EM structure of one of the stabilized E1E2 antigens in complex with neutralizing antibody AT1211 provides atomic-level insights into an atypical epitope on the E2 subunit. Finally, immunogenicity studies in rabbits with adjuvanted E1E2 proteins show that immunogen stabilization alone does do not enhance serum neutralization breadth, but that removing the leucine zipper does increase homologous serum neutralization. The hepatitis C virus E1E2 glycoprotein is the only target of neutralizing antibodies. Here, the authors used structure-based design to generate soluble antigens that resemble the viral E1E2 heterodimer.
Joan Capella-Pujol, Fabian Mulder, F. Cannac et al.· Nature Communications· 1 citation
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