Omicron-specific mRNA vaccine generates immune responses in mice, hamsters and Macaques

As of March 7, 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 446 million worldwide and caused more than six million deaths. In November 2021, the B.1.1.529 (Omicron) SARS-CoV-2 variant was first identified and subsequently classified as a variant of concern (VOC) by the World Health Organization (WHO).

The Omicron variant is highly transmissible and capable of infecting humans more quickly as compared to the previous SARS-CoV-2 variants. As a result, the Omicron variant quickly became the dominant strain in most countries, representing about 99% of new infections.

Study: Omicron-specific mRNA vaccine elicits potent immune responses in mice, hamsters, and nonhuman primates. Image Credit: angellodeco / Shutterstock.com

Background

The Omicron variant consists of approximately 30 mutations that help it escape from the majority of existing SARS-CoV-2 neutralizing antibodies (nAbs), which has prevented most spike (S) protein monoclonal antibodies from neutralizing Omicron. Additionally, convalescent individuals who have previously been infected with other variants were found to have little nAbs against Omicron, thereby increasing their vulnerability to reinfection.

Several studies have reported that Omicron either weakened or completely evaded the protection conferred by two coronavirus disease 2019 (COVID-19) vaccine doses. Even after a third booster shot, nAb titers were found to be 20-fold less potent in neutralizing Omicron as compared to the other variants.

However, the third dose of major COVID-19 vaccines has remained sufficient in reducing deaths, hospitalizations, and severe infections caused by Omicron. Nevertheless, the Omicron variant remains a threat for elderly individuals, those with pre-existing conditions, and those who have been vaccinated with less potent vaccines. Therefore, an Omicron-specific vaccine is urgently required.

A new study published on the preprint server bioRxiv* aimed to develop an Omicron variant sequence-based messenger ribonucleic acid (mRNA) vaccine that will be more potent in generating nAbs in multiple animal models against the Omicron variant as compared to other available vaccines.

About the study

The current study involved the design and synthesis of mRNA of the original SARS-CoV-2 strain and the Omicron variant, which were referred to as SWT-2P and SOmicron-6P respectively. Thereafter, the mRNAs were encapsulated in lipid nanoparticles (LNPs) for vaccine production.

HEK293T cells were transfected with Omicron-specific spike mRNA and incubated with SARS-CoV-2 S neutralizing antibodies that could recognize Omicron S protein. The detection of vaccine antigens was achieved through immunofluorescence.

Female BALB/c mice between the ages of eight and 12 weeks old, female Syrian hamsters between six and ten weeks of age, as well as Male macaques between the ages of three and five years were divided into groups and immunized. Enzyme-linked immunosorbent assay (ELISA) was carried out, followed by pseudovirus neutralization assay, plaque reduction neutralization assay, flow cytometry, and ELISPOT assay. Finally, the analysis of the viral load was carried out by reverse transcriptase qualitative polymerase chain reaction (RT-qPCR) and plaque assays.

Study findings

An increase in total B-cells and plasma B-cells in the spleens of immunized mice. Both SOmicron-6P and SWT-2P were found to elicit immunoglobulin G (IgG) antibodies in a dose-dependent manner.

SOmicron-6P was reported to induce higher IgG antibodies as compared to SWT-2P at 5 and 10 µg dose levels. SOmicron-6P vaccinated mice were also found to elicit between 14.4- to 27.8-fold higher neutralizing activity as compared to SWT-2P. Additionally, 28.3- to 50.3-fold higher neutralizing titers were observed in a plaque reduction neutralization test for mice immunized with SOmicron-6P.

Significant increases in activated CD4+ and CD8+ T-cells were reported in mice that received two doses of SOmicron-6P. An increase in cytotoxic CD8+ T-cells was also observed post-vaccination.

An expansion of effector memory CD4+ and CD8+ T-cells was observed in the spleen of SOmicron-6P immunized mice. Furthermore, high levels of interferon (IFN)-148 γ and interleukin-2 (IL-2) secreting Th1 cells were observed in SOmicron-6P immunized mice.

In the case of Syrian hamsters, a significant amount of IgG was observed on days 14 and 21 after the first dose of the vaccine. However, no dose-dependency was observed.

High neutralizing antibody titers were reported to be elicited by even a 1 µg dose of SOmicron-6P. Small amounts of viral RNA were detected in the lung tissue of vaccinated animals that were challenged with the Omicron virus. The results of plaque assay determined no detectable virus in both lungs and nasal turbinates of vaccinated hamsters after viral challenge.

In the case of Macaques, significant levels of IgG and almost no nAbs were generated after the first dose of the vaccine. After the second dose, higher amounts of nAbs were elicited; however, the nAbs elicited by SOmicron-6P could not provide much protection against the Delta, Beta, and wild-type SARS-CoV-2.

Conclusions

The current study demonstrates that the Omicron-specific vaccine was capable of providing more protection to naïve animals as compared to previous mRNA vaccines with boosters.  In fact, Omicron-specific vaccines were capable of eliciting significant IgG antibodies along with nAbs; therefore, the Omicron-specific vaccines should be administered to individuals with weaker immune systems instead of boosters.

However, this vaccine did not show promising cross-protection against the Delta, Beta, and wild-type SARS-CoV-2. Therefore, the development of a multivalent vaccine that can help fight against the evolution of SARS-CoV-2 remains urgently needed.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Suchandrima Bhowmik

Written by

Suchandrima Bhowmik

Suchandrima has a Bachelor of Science (B.Sc.) degree in Microbiology and a Master of Science (M.Sc.) degree in Microbiology from the University of Calcutta, India. The study of health and diseases was always very important to her. In addition to Microbiology, she also gained extensive knowledge in Biochemistry, Immunology, Medical Microbiology, Metabolism, and Biotechnology as part of her master's degree.

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