Immunogenicity and Protective Efficacy of a SARS-CoV-2 mRNA Vaccine Encoding Secreted Non-Stabilized Spike Protein in Mice

Prompetchara, E.; Ketloy, C.; Alameh, M. G.; Tarakhet, K.; Kaewpang, P.; Yostrerat, N.; Pitakpolrat, P.; Buranapraditkun, S.; Manopwisedcharoen, S.; Thitithanyanont, A.; Jongkaewwattana, A.; Hunsawong, T.; Im-Erbsin, R.; Reed, M.; Wijagkanalan, W.; Patarakul, K.; Palaga, T.; Lam, K.; Heyes, J.; Weissman, D.; Ruxrungtham, K.

doi:10.1101/2022.09.07.506878

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bioRxiv · 10.1101/2022.09.07.506878

Immunogenicity and Protective Efficacy of a SARS-CoV-2 mRNA Vaccine Encoding Secreted Non-Stabilized Spike Protein in Mice

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Abstract

Establishment of an mRNA vaccine platform in low- and middle-income countries (LMICs) is important to enhance vaccine accessibility and ensure future pandemic preparedness. Here, we describe the preclinical studies of a SARS-CoV-2 mRNA encoding prefusion-unstabilized ectodomain spike protein encapsulated in lipid nanoparticles (LNP) "ChulaCov19". In BALB/c mice, ChulaCov19 at 0.2, 1, 10, and 30 g given 2 doses, 21 days apart, elicited robust neutralizing antibody (NAb) and T cells responses in a dose-dependent relationship. The geometric mean titer (GMT) of micro-virus neutralizing (micro-VNT) antibody against wild-type virus was 1,280, 11,762, 54,047, and 62,084, respectively. Higher doses induced better cross-neutralizing antibody against Delta and Omicron variants. This elicited specific immunogenicity was significantly higher than those induced by homologous prime-boost with inactivated (CoronaVac) or viral vector (AZD1222) vaccine. In heterologous prime-boost study, mice primed with either CoronaVac or AZD1222 vaccine and boosted with 5 g ChulaCov19 generated NAb 7-fold higher against wild-type virus (WT) and was also significantly higher against Omicron (BA.1 and BA.4/5) than homologous CoronaVac or AZD1222 vaccination. AZD1222-prime/mRNA-boost had mean spike-specific IFN{gamma} positive T cells of 3,725 SFC/106 splenocytes, which was significantly higher than all groups except homologous ChulaCov19. Challenge study in human-ACE-2-expressing transgenic mice showed that ChulaCov19 at 1 g or 10 g protected mice from COVID-19 symptoms, prevented SARS-CoV-2 viremia, significantly reduced tissue viral load in nasal turbinate, brain, and lung tissues 99.9-100%, and without anamnestic of Ab response which indicated its protective efficacy. ChulaCov19 is therefore a promising mRNA vaccine candidate either as a primary or a boost vaccination and has entered clinical development.

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Prompetchara, E., Ketloy, C., Alameh, M. G., Tarakhet, K., Kaewpang, P., Yostrerat, N., Pitakpolrat, P., Buranapraditkun, S., Manopwisedcharoen, S., Thitithanyanont, A., Jongkaewwattana, A., Hunsawong, T., Im-Erbsin, R., Reed, M., Wijagkanalan, W., Patarakul, K., Palaga, T., Lam, K., Heyes, J., Weissman, D., Ruxrungtham, K.. 2022-09-07. Immunogenicity and Protective Efficacy of a SARS-CoV-2 mRNA Vaccine Encoding Secreted Non-Stabilized Spike Protein in Mice. https://doi.org/10.1101/2022.09.07.506878

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