We therefore evaluated mRNA formulated in lipid nanoparticles (mRNA–LNP) as a delivery vehicle for MERS-CoV S(2P), and found that transmembrane-anchored MERS-CoV S(2P) mRNA elicited more potent pseudovirus-neutralizing antibody responses than secreted MERS-CoV S(2P) (Extended Data Fig. In addition to advantages in manufacturing speed, mRNA vaccines are potently immunogenic and elicit both humoral and cellular immunity 19, 20, 21. Producing cell lines and clinical-grade subunit protein typically takes more than one year, whereas manufacturing nucleic acid vaccines can be achieved in a matter of weeks 17, 18. Achieving an effective and rapid vaccine response to a newly emerging virus requires both the precision afforded by structure-based antigen design and a manufacturing platform to shorten time to product availability.
As part of our pandemic preparedness efforts, we have studied MERS-CoV as a prototype Betacoronavirus pathogen to optimize vaccine design, dissect the humoral immune response to vaccination, and identify mechanisms and correlates of protection. Such generalizability is fundamental to the prototype pathogen approach for pandemic preparedness 13, 14.Ĭoronaviruses have long been predicted to have a high probability of causing zoonotic disease and pandemics 15, 16. The 2P mutation has similar effects on the stability of S proteins from other betacoronaviruses, suggesting a generalizable approach for designing stabilized-prefusion Betacoronavirus S protein antigens for vaccination. Similar to other prefusion-stabilized fusion proteins, MERS-CoV S(2P) protein was more immunogenic at lower doses than wild-type S protein 1. 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 human coronavirus HKU1 S proteins in the prefusion conformation 1, 11, 12. We previously showed that prefusion-stabilized protein immunogens that preserve neutralization-sensitive epitopes are an effective vaccine strategy for enveloped viruses such as RSV 6, 7, 8, 9, 10. S proteins undergo marked structural rearrangement to fuse virus and host cell membranes, enabling delivery of the viral genome into target cells. The spike (S) protein, a class I fusion glycoprotein analogous to influenza haemagglutinin, respiratory syncytial virus (RSV) fusion glycoprotein (F) and human immunodeficiency virus gp160 (Env), is the major surface protein on the coronavirus virion and the primary target for neutralizing antibodies. Therefore, rapid development of vaccines against SARS-CoV-2 will be critical for changing the global dynamics of this virus. If immunity remains solely dependent on infection, even at a case fatality rate of 1%, more than 40 million people could succumb to COVID-19 globally 5. It is estimated that until 60–70% of the population have immunity, COVID-19 is unlikely to be sufficiently well-controlled for normal human activities to resume. In the absence of a vaccine, public health measures such as quarantine of newly diagnosed cases, contact tracing, use of face masks and physical distancing have been put into place to reduce transmission 4. SARS-CoV-2 is the third novel Betacoronavirus in the past 20 years to cause substantial human disease however, unlike its predecessors SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 is transmitted efficiently from person to person. Since its emergence in December 2019, SARS-CoV-2 has accounted for more than 30 million cases of coronavirus disease 2019 (COVID-19) worldwide in 9 months 3. Nature volume 586, pages 567–571 ( 2020) Cite this article SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness
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