Shankar Subramaniam, David Veesler, Lauren Carter, David Novack, Claire Sydeman, Jane Fontenot, Douglas E. Ferrell, Galit Alter, Robbert van der Most, Robert L. Coffman, Elizabeth Kepl, Mary Jane Navarro, Alexander G. White, Ching-Lin Hsieh, Kenneth S. Plante, Francois Villinger, Katharina Röltgen, Prabhu S. Arunachalam, Alexandra C. Walls, Jason S. McLellan, Lisa Shirreff, Rino Rappuoli, Sally Shin, Venkata Viswanadh Edara, Jessica A. Plante, Brooke Fiala, Stephanie Fischinger, Chunfeng Li, Caroline Atyeo, Matthew J. Gorman, Chad J. Roy, Scott D. Boyd, Bali Pulendran, Kasi E. Russell-Lodrigue, Skye Spencer, Xiaoying Shen, Shakti Gupta, Derek T. O'Hagan, Pyone P. Aye, Meera Trisal, Neil P. King, JoAnne L. Flynn, Nadia A. Golden, Marcos C. Miranda, Michael E. P. Murphy, John C. Kraft, Mehul S. Suthar, Lilin Lai, Jason Dufour, Rudolph Bohm, Deleah Pettie, Lara A. Doyle-Meyers, David C. Montefiori, Christopher Monjure, Kenneth A. Rogers, Samuel Wrenn, Harry Kleanthous, Nicholas J. Maness, Jay Rappaport, Alex Lee Zhu, and Natalie Brunette
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 protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).