Producing cell lines and clinical grade subunit protein typically takes more than 1 year, while manufacturing nucleic acid vaccines can be done in a matter of weeks 16, 17. Achieving an effective and rapid vaccine response to a newly emerging virus requires the precision afforded by structure-based antigen design but also a manufacturing platform to shorten time to product availability. As part of our pandemic preparedness efforts, we have studied MERS-CoV as prototype pathogen for betacoronaviruses to optimize vaccine design, to dissect the humoral immune response to vaccination, and identify mechanisms and correlates of protection. This is fundamental to the prototype pathogen approach for pandemic preparedness 12, 13.Ĭoronaviruses have long been predicted to have a high likelihood of spill over into humans and cause future pandemics 14, 15. The 2P has been widely transferrable to other beta-CoV spike proteins, suggesting a generalizable approach for designing stabilized prefusion beta-CoV S vaccine antigens. Similar to other prefusion-stabilized fusion proteins, MERS S-2P protein is more immunogenic at lower doses than wild-type S protein 11. Subsequently, we identified 2 proline substitutions (2P) at the apex of the central helix and heptad repeat 1 that effectively stabilized MERS-CoV, SARS-CoV and HCoV-HKU1 S proteins in the prefusion conformation 9– 11. We previously showed that prefusion-stabilized protein immunogens that preserve neutralization-sensitive epitopes are an effective vaccine strategy for enveloped viruses, such as RSV 4– 8. S proteins undergo dramatic structural rearrangement to fuse virus and host cell membranes, allowing delivery of the viral genome into target cells. The spike (S) protein, a class I fusion glycoprotein analogous to influenza hemagglutinin (HA), respiratory syncytial virus (RSV) fusion glycoprotein (F), and human immunodeficiency virus (HIV) gp160 (Env), is the major surface protein on the CoV virion and the primary target for neutralizing antibodies. Therefore, rapid development of vaccines against SARS-CoV-2 is critical for changing the global dynamic of this virus. If immunity remains solely dependent on infection, even at a 1% mortality rate, >40 million people could succumb to COVID-19 globally 3. It is estimated that until 60–70% population immunity is established, it is unlikely for COVID-19 to be controlled well enough to resume normal activities. In absence of a vaccine, public health measures such as quarantining newly diagnosed cases, contact tracing, and mandating face masks and physical distancing have been instated to reduce transmission 2. SARS-CoV-2 is the third novel betacoronavirus in the last 20 years to cause substantial human disease however, unlike its predecessors SARS-CoV and MERS-CoV, SARS-CoV-2 transmits efficiently from person-to-person. Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accounted for over 7 million cases of Coronavirus Disease 2019 (COVID-19) worldwide in less than 7 months 1. Baric, 3, 4 Andrea Carfi, 2, * and Barney S. Doria-Rose, 1 Guillaume Stewart-Jones, 2 Hamilton Bennett, 2 Martha C. Gully, 3 Nianshuang Wang, 8 Daniel Wrapp, 8 Nicole A. Louder, 1 Wei Shi, 1 Kwanyee Leung, 1 Eun Sung Yang, 1 Ande West, 3 Kendra L. Loomis, 1 Nedim Emil Altaras, 2 Elisabeth Narayanan, 2 Mihir Metkar, 2 Vlad Presnyak, 2 Catherine Liu, 1 Mark K. Schmidt, 1 Lingshu Wang, 1 Yi Zhang, 1 Laura J. Hutchinson, 1 Kapil Bahl, 2 Dario Garcia-Dominguez, 2 LingZhi Ma, 2 Isabella Renzi, 2 Wing-Pui Kong, 1 Stephen D. Gillespie, 1 Sunny Himansu, 2 Alexandra Schäfer, 3 Cynthia T. Abiona, 1 Seyhan Boyoglu-Barnum, 1 Rebecca A. Corbett, 1, # Darin Edwards, 2, # Sarah R.
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