We thank Adrienne Winn, Jaclyn Wear, Dalia Benetiene, Becky Chang, Danielle Nase, Heath Bradette, Natalie Jones, and Melissa Hamilton for assistance with conducting animal studies. We thank Shelby O’Connor and John James Baczenas (University of Wisconsin-Madison) for assistance with sequencing of viral stocks. We thank Sarah Ducat and Tammy Hayes for their assistance with pathology. Funding: This work was funded by a National Institutes of Health grant AI007387 (to LHT), a National Institutes of Health grant AI135098 (to AJM) Fast Grants, Emergent Ventures, Mercatus Center at George Mason University (to AJM), a National Institutes of Health grant CA260476 (to DHB), Massachusetts Consortium on Pathogen Readiness (MassCPRR) (to DHB), Ragon Institute of MGH, MIT, and Harvard (to DHB), Janssen Vaccines & Prevention BV, and Biomedical Advanced Research and Development Authority (BARDA) contract HHS0100201700018C. Author contributions: LHT, FW, RZ, and DHB designed the studies. LHT, JY, NBM, KM, CJD, TA, AC, VMG, DLH, HW, EAB, SHM performed the immunologic and virologic assays. AJM, CPM, LMW, KB performed the histopathological analyses. LP, MP, JP, AF, BS, SK, HA, MGL led the clinical care of the animals. FA and FK generated and provided variant strain proteins. FW, RZ, and HS provided the vaccine. LHT and DHB wrote the paper with input from all co-authors. Competing interests: DHB, RZ, FW and HS are co-inventors on provisional vaccine patents entitled “COMPOSITIONS AND METHODS FOR TREATING CORONAVIRUS INFECTION” (63/121,482; 63/133,969; 63/135,182). RZ, F.W., and H.S. are employees of Janssen Vaccines & Prevention BV and may hold stock in Johnson & Johnson. All other authors declare no competing interests. Data and materials availability: All data are available in the main text or the supplementary materials. Ad26.COV2.S vaccine will be made available to academic investigators by contacting H.S. ([email protected]) and completing a materials transfer agreement. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using this material.