Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

Arunachalam, Prabhu S; Walls, Alexandra C; Golden, Nadia; Atyeo, Caroline; Fischinger, Stephanie; Li, Chunfeng; Aye, Pyone; Navarro, Mary Jane; Lai, Lilin; Edara, Venkata Viswanadh; Röltgen, Katharina; Rogers, Kenneth; Shirreff, Lisa; Ferrell, Douglas E; Wrenn, Samuel; Pettie, Deleah; Kraft, John C; Miranda, Marcos C; Kepl, Elizabeth; Sydeman, Claire; Brunette, Natalie; Murphy, Michael; Fiala, Brooke; Carter, Lauren; White, Alexander G; Trisal, Meera; Hsieh, Ching-Lin; Russell-Lodrigue, Kasi; Monjure, Christopher; Dufour, Jason; Spencer, Skye; Doyle-Meyer, Lara; Bohm, Rudolph P; Maness, Nicholas J; Roy, Chad; Plante, Jessica A; Plante, Kenneth S; Zhu, Alex; Gorman, Matthew J; Shin, Sally; Shen, Xiaoying; Fontenot, Jane; Gupta, Shakti; O'Hagan, Derek T; Van Der Most, Robbert; Rappuoli, Rino; Coffman, Robert L; Novack, David; McLellan, Jason S; Subramaniam, Shankar; Montefiori, David; Boyd, Scott D; Flynn, JoAnne L; Alter, Galit; Villinger, Francois; Kleanthous, Harry; Rappaport, Jay; Suthar, Mehul S; King, Neil P; Veesler, David; Pulendran, Bali

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike receptor binding domain displayed on a protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing oil-in-water emulsion; AS37, a TLR-7 agonist adsorbed to Alum; CpG1018-Alum, a TLR-9 agonist formulated in Alum; and Alum. RBD-NP immunization with AS03, CpG1018-Alum, AS37 or Alum induced substantial nAb and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. Live-virus nAb response was maintained up to 180 days post-vaccination with RBD/AS03, and correlated with protection. RBD-NP immunization cross-neutralized the B.1.1.7 variant efficiently but showed a reduced response against the B.1.351 variant. While RBD-NP/AS03 demonstrated a 4.5-fold reduction in neutralization of B.1.351, the RBD-NP/AS37 group showed a 16-fold reduction, suggesting differences in the breadth of the nAb response induced by these adjuvants. Furthermore, RBD-NP/AS03 was as immunogenic as a prefusion stabilized Spike immunogen (Hexapro) adjuvanted with AS03. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2, and have paved the way for the clinical evaluation of this vaccine in Phase I/II clinical trials (NCT04742738 and NCT04750343).