Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models

Hajnik, Renee L; Plante, Jessica A.; Liang, Yuejin; Alameh, Mohamad-Gabriel; Tang, Jialei; Bonam, Srinivasa Reddy; Zhong, Chaojie; Adam, Awadalkareem; Scharton, Dionna; Rafael, Grace; Liu, Yang; Hazell, Nicholas; Sun, Jiaren; Soong, Lynn; Shi, Pei–Yong; Wang, Tian; Walker, David H.; Sun, Jie; Weissman, Drew; Weaver, Scott C.; Plante, Kenneth S.; Hu, Haitao

doi:10.1126/scitranslmed.abq1945

Cited by 87 publications

(125 citation statements)

References 67 publications

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“…Our murine model provided additional insights into specific features of T cell immunity within various anatomical sites. In addition to humoral responses, cellular immunity contributes to protection against COVID-19 and recent evidence suggests that viral-vector and mRNA vaccines elicit long-lasting S-specific or nucleoprotein-specific CD4 + and CD8 + T cell responses, with broad cross-reactivity against VOCs 29 , 30 . While T RM cells are induced by high concentration mRNA vaccines 31 ; we report that lower concentrations of unmodified mono- or bivalent mRNA vaccines induced lung parenchymal tissue resident T cells.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models

et al. 2023

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Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve control of the COVID-19 pandemic. We compare monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein in a transgenic mouse and a Wistar rat model. The blended low-dose bivalent mRNA vaccine contains half the mRNA of each respective monovalent vaccine, but induces comparable neutralizing antibody titres, enrichment of lung-resident memory CD8+ T cells, antigen-specific CD4+ and CD8+ responses, and protects transgenic female mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduces viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized female Wistar rats also contain neutralizing antibodies against the B.1.1.529 (Omicron BA.1 and BA.5) variants. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins are feasible approaches for extending the coverage of vaccines for emerging and co-circulating SARS-CoV-2 variants.

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Section: Discussionmentioning

confidence: 99%

Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models

et al. 2023

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“…Emerging pre-clinical data suggest a potential role for vaccine-elicited nucleocapsid responses in controlling virus replication in the lung 29 . Though the limited sequence evolution in nucleocapsid compared to spike could make nucleocapsid an attractive target, the shorter durability of circulating antibodies against nucleocapsid compared to spike following infection necessitates the study of the comparative durability of vaccine-elicited nucleocapsid versus spike antibodies.…”

Section: Discussionmentioning

confidence: 99%

Interim results from comparison of immune responses elicited by an inactivated and a vectored SARS-CoV-2 vaccine in seronegative and seropositive participants in India

Asokan

Joan

Babji

et al. 2023

Preprint

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Background There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the 18 to 45-year age-group began in April 2021 when seropositivity rates in the general population were rising due to the Delta wave in April-May 2021. Methods Between 30 June 2021 and 28 January 2022, we enrolled 691 participants in the 18-45 age group across 4 clinical sites in India. In this non-randomized and laboratory blinded study, participants received either two doses of Covaxin® 4 weeks apart or two doses of Covishield™ 12 weeks apart per the national vaccination policy. The primary outcome was the seroconversion rate and the geometric mean titer (GMT) of antibodies against the SARS-CoV-2 spike and nucleocapsid proteins. The secondary outcome was the frequency of cellular immune responses pre- and post-vaccination. Findings When compared to pre-vaccination baseline, both vaccines elicited statistically significant seroconversion and binding antibody levels in both seronegative and seropositive individuals. In the per-protocol cohort, Covishield™ elicited higher antibody responses than Covaxin® as measured by seroconversion rate (98.3% vs 74.4%, p<0.0001 in seronegative individuals; 91.7% vs 66.9%, p<0.0001 in seropositive individuals) as well as by anti-spike antibody levels against the ancestral strain (GMT 1272.1 vs 75.4 BAU/ml, p<0.0001 in seronegative individuals; 2089.07 vs 585.7 BAU/ml, p<0.0001 in seropositive individuals). Not all sites recruited at the same time, therefore site-specific immunogenicity was impacted by the timing of vaccination relative to the Delta and Omicron waves. Surrogate neutralizing antibody responses against variants-of-concern were higher in Covishield™ recipients than in Covaxin® recipients and in seropositive than in seronegative individuals after both vaccination and asymptomatic Omicron infection. T cell responses are reported from only one of the four site cohorts where the vaccination schedule preceded the Omicron wave. In seronegative individuals, Covishield™ elicited both CD4+ and CD8+ spike-specific cytokine-producing T cells whereas Covaxin® elicited mainly CD4+ spike-specific T cells. Neither vaccine showed significant post-vaccination expansion of spike-specific T cells in seropositive individuals. Interpretation Covishield™ elicited immune responses of higher magnitude and breadth than Covaxin® in both seronegative individuals and seropositive individuals, across cohorts representing the pre-vaccination immune history of the majority of the vaccinated Indian population.

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“…However, on-going analyses of licensed SARS-CoV-2 vaccine efficacy has shown that vaccine-induced immunity wanes over time, resulting in breakthrough infections 20–22 . In addition, intranasal administration of mRNA vaccines to mice did not confer protection against SARS-CoV-2 challenge 23 . As a result, there is a growing need to develop a second generation of SARS-CoV-2 vaccines that can be administered through intranasal routes to induce protective mucosal immunity 24,25 .…”

Section: Introductionmentioning

confidence: 94%

Intranasal SARS-CoV-2 RBD decorated nanoparticle vaccine enhances viral clearance in the Syrian hamster model

Patel

Minns

Sim

et al. 2022

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic and multiple vaccines have been developed and authorized for human use. While these vaccines reduce disease severity, they do not prevent infection allowing SARS-CoV-2 to continue to spread and evolve. To confer protection against infection and limit transmission, vaccines must be developed that induce mucosal immunity in the respiratory tract. Therefore, we performed proof-of-principle pre-clinical vaccine and challenge studies with a virus-particle mimicking intranasal vaccine against SARS-CoV-2. The vaccine candidate consisted of the self-assembling 60-subunit I3-01 protein scaffold covalently decorated with the SARS-CoV-2 receptor binding domain (RBD) using the SpyCatcher-SpyTag system. We verified the intended antigen display features by reconstructing the I3-01 scaffold to 3.4A using cryo-EM, and established RBD decoration through both SDS-PAGE and negative stain TEM. Using this RBD grafted SpyCage scaffold (RBD+SpyCage), we performed two vaccination studies in Syrian hamsters using an intranasal prime and boost vaccine regiment followed by SARS-CoV-2 challenge. The initial study focused on assessing the immunogenicity of RBD+SpyCage, which indicated that vaccination of hamsters induced a non-neutralizing antibody response that enhanced viral clearance but did not prevent infection. In an expanded study, we demonstrated that covalent bonding of RBD to the scaffold was required to induce an antibody response. Consistent with the initial study, animals vaccinated with RBD+SpyCage more rapidly cleared SARS-CoV-2 from both the upper and lower respiratory tract, whereas admixtures of SpyCage and RBD, or either component alone did not. These findings demonstrate the intranasal SpyCage vaccine platform can induce protection against SARS-CoV-2 and, with additional modifications to improve immunogenicity, is a versatile and adaptable system for the development of intranasal vaccines targeting respiratory pathogens.

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Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models

Cited by 87 publications

References 67 publications

Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models

Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models

Interim results from comparison of immune responses elicited by an inactivated and a vectored SARS-CoV-2 vaccine in seronegative and seropositive participants in India

Intranasal SARS-CoV-2 RBD decorated nanoparticle vaccine enhances viral clearance in the Syrian hamster model

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