Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection

Konrath, Kylie M.; Liaw, Kevin; Wu, Yuanhan; Zhu, Xizhou; Walker, Susanne N.; Xu, Ziyang; Schultheis, Katherine; Chokkalingam, Neethu; Du, Jianqiu; Tursi, Nicholas J.; Moore, Alan; Purwar, Mansi; Reuschel, Emma L.; Frase, Drew; Sullivan, Matthew; Maricic, Igor; Andrade, Viviane M.; Iffland, Christel; Broderick, Kate E.; Humeau, Laurent M. P. F.; Smith, Trevor R.F.; Pallesen, Jesper; Weiner, David B.; Kulp, Daniel W.

Antibodies from SARS-CoV-2 vaccines may target epitopes which reduce durability or increase the potential for escape from vaccine-induced immunity. Using a novel synthetic vaccinology pipeline, we developed rationally immune focused SARS-CoV-2 Spike-based vaccines. N-linked glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and comprehensive in vitro screening, we incorporated glycans into the Spike Receptor-Binding Domain (RBD) and assessed antigenic profiles. We developed glycan coated RBD immunogens and engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicited potent neutralizing antibodies in guinea pigs, hamsters and multiple mouse models, including human ACE2 and human B cell repertoire transgenics. RBD nanoparticles encoding wild-type and the P.1 SARS-CoV-2 variant induced high levels of cross-neutralizing antibodies. Single, low dose immunization protected against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of novel, potent coronavirus vaccines.