Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models
Open accessAbstract
Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8 + T cell depletion suggested a potential role for CD8 + T cells in protection conferred by mRNA-S+N vaccination. Antigen-specific immune analyses indicated that N-specific immunity, as well as augmented S-specific immunity, was associated with enhanced protection elicited by the combination mRNA vaccination. Our findings suggest that combined mRNA-S+N vaccination is an effective approach for promoting broad protection against SARS-CoV-2 variants.
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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.
“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 VOCs29,30.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [30]
The Results report that combined mRNA-S+N vaccination elicited S- and N-specific CD4+ and CD8+ T-cell responses in mice at week 5. The Discussion reports cross-recognition of Omicron by S-specific T cells after infection or vaccination, but does not establish broad cross-reactivity of the vaccine-induced responses; it explicitly says their durability remains to be assessed. The paper also does not demonstrate long-lasting T-cell responses from viral-vector vaccines. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCellular immunity contributes to protection against COVID-19.
“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 VOCs29,30.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [30]
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References 61 · Cited by 122
Research works printed but not linked: 1
- [41]Cele S, Jackson L, Khoury DS, Khan K, Moyo-Gwete T, Tegally H, San JE, Cromer D, Scheepers C, Amoako DG, Karim F, Bernstein M, Lustig G, Archary D, Smith M, Ganga Y, Jule Z, Reedoy K, Hwa SH, Giandhari J, Blackburn JM, Gosnell BI, Karim SSA, Hanekom W; NGS-SA; COMMIT-KZN Team, von Gottberg A, Bhiman JN, Lessells RJ, Moosa MS, Davenport MP, de Oliveira T, Moore PL, Sigal A, Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature 602, 654– 656 (2022). 35016196 PMC8866126
- Authors
- Hajnik, R. L., Plante, J. A., Liang, Y., Alameh, M.-G., Tang, J., Bonam, S. R., Zhong, C., Adam, A., Scharton, D., Rafael, G. H., Liu, Y., Hazell, N. C., Sun, J., Soong, L., Shi, P.-Y., Wang, T., Walker, D. H., Sun, J., Weissman, D., Weaver, S. C., Plante, K. S., & Hu, H.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- University of Pennsylvania (US)
- Mayo Clinic (US)
- Corresponding author
- Hajnik, Renee L.
- Plante, Jessica A.
- Liang, Yuejin
- Plante, Kenneth S.
- Hu, Haitao
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2022-09-14
- Volume
- 14
- Issue
- 662
- Pages
- eabq1945-eabq1945
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC9926941
- OpenAlex
- W4295709321
- Cited by
- 122
- References
- 61
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 42 · 2023: 35 · 2022: 5
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- National Institutes of Health (UL1TR001439)
- National Institute of Allergy and Infectious Diseases (R43AI145617, R24AI120942, R01AI154598, R01AI134907, R01AI112844, R21AI147903, HHSN 272201600013C, R21AI140569, U01AI056536, R01AI127744, P01AI158571, R01AI132674, R01AI147394, R01AI157852)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, Omicron variant, Delta variant, mRNA vaccines, nucleocapsid protein, spike protein, nucleoside-modified mRNA, variants of concern, CD8+ T cells, hamster model, COVID-19 vaccines
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Animals, Cricetinae, Humans, RNA, Messenger, Vaccination, Vaccines, Synthetic, Viral Proteins, Viral Vaccines, CD8-Positive T-Lymphocytes, Nucleocapsid
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