Broad neutralization of SARS-CoV-2 variants by circular mRNA producing VFLIP-X spike in mice

Seephetdee, C.; Bhukhai, K.; Buasri, N.; Leelukkanaveera, P.; Lerdwattanasombat, P.; Manopwisedjaroen, S.; Phueakphud, N.; Kuhaudomlarp, S.; Ollmann Saphire, E.; Thitithanyanont, A.; Hongeng, S.; Wongtrakoongate, P.

doi:10.1101/2022.03.17.484759

bioRxiv · 10.1101/2022.03.17.484759

Broad neutralization of SARS-CoV-2 variants by circular mRNA producing VFLIP-X spike in mice

Seephetdee, C.·Bhukhai, K.·Buasri, N.·Leelukkanaveera, P.·Lerdwattanasombat, P.·Manopwisedjaroen, S.·Phueakphud, N.·Kuhaudomlarp, S.·Ollmann Saphire, E.·Thitithanyanont, A.·Hongeng, S.·Wongtrakoongate, P.

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Abstract

Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized trimers (S-2P) of the wildtype spike, which have shown a reduced neutralizing activity against the variants of concern B.1.617.2 and B.1.1.529. Recently, a new version of spike trimer, termed VFLIP has been suggested to possess native-like glycosylation, and greater pre-fusion trimeric stability as opposed to S-2P. Here, we report that the spike protein VFLIP-X, containing six rationally substituted amino acids to reflect emerging variants (K417N, L452R, T478K, E484K, N501Y and D614G), offers a promising candidate for a next-generation SARS-CoV-2 vaccine. Mice immunized by a circular mRNA (circRNA) vaccine prototype producing VFLIP-X elicited neutralizing antibodies for up to 7 weeks post-boost against SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). In addition, a balance in TH1 and TH2 responses was achieved by immunization with VFLIP-X. Our results indicate that the VFLIP-X delivered by circRNA confers humoral and cellular immune responses, as well as neutralizing activity against broad SARS-CoV-2 variants.

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Seephetdee, C., Bhukhai, K., Buasri, N., Leelukkanaveera, P., Lerdwattanasombat, P., Manopwisedjaroen, S., Phueakphud, N., Kuhaudomlarp, S., Ollmann Saphire, E., Thitithanyanont, A., Hongeng, S., Wongtrakoongate, P.. 2022-03-17. Broad neutralization of SARS-CoV-2 variants by circular mRNA producing VFLIP-X spike in mice. https://doi.org/10.1101/2022.03.17.484759

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