In a recent study published in the journal Science Translational Medicine, researchers in the United States designed a vaccine against bivalent coronavirus disease 2019 (COVID-19) on the messenger ribonucleic acid (mRNA) platform.
This mRNA lipid nanoparticle (LNP) vaccine encoded a full-length nucleocapsid (N) protein of the ancestral Wuhan-Hu1 strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They evaluated their immunogenicity and efficacy in mouse and hamster models against all SARS-CoV-2 (COV) variants of concern alone and in combination with current clinically used mRNA-based vaccines based on spike protein (S) .
Study: Double-spiked and nucleocapsid mRNA vaccination confers protection against Omicron and Delta variants of SARS-CoV-2 in preclinical models. Image credit: Orpheus FX / Shutterstock
background
All COVID-19 vaccines that fight SARS-CoV-2 infections target the SARS-CoV-2 S protein or its receptor binding domain (RBD) to elicit a potent antibody response neutralizing agents (nAb). Thus, the researchers hypothesized that a vaccine targeting a more conserved SARS-CoV-2 protein or multivalent vaccines would provide broader protection against new, highly mutated SARS-CoV-2 variants. The SARS-CoV-2 N protein is a highly conserved and potent immunogen that has been shown to elicit a strong T-cell response, making it an ideal candidate for incorporation into next-generation vaccines .
About the study
In the present study, the investigators evaluated the immunogenicity of the mRNA-N vaccine formulation in BALB/c mice. They created two groups, with seven mice each, and vaccinated them with phosphate-buffered saline (PBS) (sham) or 1 μg of m-RNA N vaccine intramuscularly (IM) at week zero (first) and week 3 (reinforcement). After primary vaccination, the team collected serum samples for antibody analysis. After booster vaccination, mice were sacrificed for further immunological analyses.
The team examined T-cell responses to splenocytes using flow cytometry. They also measured the N-specific T-cell response by intracellular cytokine staining (ICS) of splenocytes. In addition, they performed an enzyme-linked immunosorbent spot (ELISPOT) assay with gamma interferon (IFN-γ) to assess T-cell responses induced by the mRNA-N vaccine.
In addition, the researchers used an enzyme-linked immunosorbent assay (ELISA) to determine N-specific immunoglobulin G (IgG)-binding antibody titers. The team conducted similar vaccine evaluations against SARS-CoV-2 Delta VOC in Syrian hamsters.
Results of the study
The N-mRNA was highly immunogenic but only moderately controlled SARS-CoV-2 infection. However, combined mRNA-S + N vaccination more robustly controlled SARS-CoV-2 Delta and Omicron VOCs in the lungs of infected mice than mRNA-S alone and provided additional protection against both variants, resulting in a reduced viral load in their upper respiratory tract. tract (URT).
Double-spiked and nucleocapsid mRNA vaccination confers protection against Omicron and Delta variants of SARS-CoV-2 in preclinical models
The study provided considerable evidence suggesting the involvement of T cells in mRNA-S+N vaccine-induced protection against SARS-CoV-2 variants. For example, mRNA-N induced only modest protection against SARS-CoV-2 and Delta strains in the absence of neutralizing antibodies. Likewise, the results of the in vivo cell depletion analysis suggested the possible involvement of a group of differentiation 8 (CD8+) T cells in the immune protection induced by the mRNA-S+ vaccine N. The authors performed an antigen-specific immune analysis and observed that induction of N-specific immunity with enhanced S-specific immunity helped the bivalent mRNA vaccine to mount a more vigorous immune response.
Interestingly, the S-mRNA-based vaccine and the combination vaccine (mRNA-S+N) had similar doses of mRNA-S, but increased S-specific immunity. One hypothesis is that priming effects occurred cross between N and S antigens after vaccination by mRNA-S+N vaccine. It is also likely that mRNA-N co-immunization induced an immune environment that favored the development of S-specific immunity. However, future studies should investigate all events following mRNA-S combined vaccination +N, including antigen presentation and stimulation of innate and inflammatory responses.
Conclusions
The study highlighted that since the mRNA-LNP platform has been tested and shown a favorable safety profile in multiple human clinical studies, this approach could quickly become clinically viable against SARS-CoV-2 VOCs that they haven’t emerged yet. Previous studies have demonstrated challenges in designing COVID-19 vaccines with specific VOC sequences. The vaccine tested in the current study had amino acid sequences of mRNA-N and mRNA-S of Wuhan-Hu-1. However, it did get solid protection against Delta and Omicron VOCs, which was exemplary. Additional testing of the combination vaccine approach in non-human primates (NHPs) will provide further opportunities to assess its safety and efficacy.
In hamsters challenged with SARS-CoV-2 VOCs, the combination mRNA-S+N vaccine induced robust viral control in the lungs. However, its additive antiviral effect seemed to decrease in URT. Therefore, future studies should investigate heterologous vaccination approaches involving different vaccine platforms and routes of immunization. For example, vaccination strategies using IM, intranasal, and oral routes of delivery to enhance protection against VOCs in the URT.
Journal reference:
- Nucleocapsid and double-spiked mRNA vaccination confers protection against Omicron and Delta variants of SARS-CoV-2 in preclinical models, Renee L. Hajnik, Jessica A. Plante, Yuejin Liang, Mohamad-Gabriel Alameh, Jinyi Tang, Srinivasa Reddy Bonam, Chaojie Zhong, Awadalkareem Adam, Dionna Scharton, Grace H. Rafael, Yang Liu, Nicholas C. Hazell, Jiaren Sun, Lynn Soong, Pei-Yong Shi, Tian Wang, David H. Walker, Jie Sun, Drew Weissman, Scott C. Weaver, Kenneth S. Plante, Haitao Hu, Science Translational Medicine 2022, DOI: 10.1126/scitranslmed.abq1945,