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bioRxiv · 10.1101/2024.07.01.601243

A stabilized MERS-CoV spike ferritin nanoparticle vaccine elicits robust and protective neutralizing antibody responses

Powell, A. E.·Caruso, H.·Park, S.·Chen, J.-L.·O'Rear, J.·Ferrer, B. J.·Walker, A.·Bruenig, A.·Hartwig, A.·Ahyong, V.·Dougherty, C. S.·Bowen, R. A.·Ledgerwood, J. E.·Kay, M. S.·Weidenbacher, P. A.- B.·Palanski, B. A.
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Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified as a human pathogen in 2012 and causes ongoing sporadic infections and outbreak clusters. Despite case fatality rates (CFRs) of over 30% and the pandemic potential associated with betacoronaviruses, a safe and efficacious vaccine has not been developed for prevention of MERS in at-risk individuals. Here we report the design, in vitro characterization, and preclinical evaluation of MERS-CoV antigens. Our lead candidate comprises a stabilized spike ectodomain displayed on a self-assembling ferritin nanoparticle that can be produced from a high-expressing, stable cell pool. This vaccine elicits robust antibody titers in BALB/c mice as measured by MERS- CoV pseudovirus and live-virus neutralization assays. Immunization of non-human primates (NHPs) with a single dose of Alhydrogel-adjuvanted vaccine elicits >103 geometric mean titer (GMT) of pseudovirus neutralizing antibodies that can be boosted with a second dose. These antibody levels are durable, with GMTs that surpass the post-prime levels for more than 5 months post-boost. Importantly, sera from these NHPs exhibit broad cross-reactivity against lentiviruses pseudotyped with spike proteins from MERS-CoV clades A, B, and C as well as a more distant pangolin merbecovirus. In transgenic mice expressing human DPP4, immunization provided dose-dependent protection against MERS-CoV lethal challenge, and in an established alpaca challenge model, immunization fully protected against MERS-CoV infection. This protein-based MERS-CoV nanoparticle vaccine is a promising candidate for advancement to clinical development to protect at-risk individuals and for future use in a potential outbreak setting.

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Powell, A. E., Caruso, H., Park, S., Chen, J.-L., O'Rear, J., Ferrer, B. J., Walker, A., Bruenig, A., Hartwig, A., Ahyong, V., Dougherty, C. S., Bowen, R. A., Ledgerwood, J. E., Kay, M. S., Weidenbacher, P. A.- B., Palanski, B. A.. 2024-07-01. A stabilized MERS-CoV spike ferritin nanoparticle vaccine elicits robust and protective neutralizing antibody responses. https://doi.org/10.1101/2024.07.01.601243

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