Thermostable next-generation vaccine candidate against SARS-CoV-2 variants of concern studied in mice

In a recent study posted to the bioRxiv* preprint server, researchers developed a highly thermo-tolerant vaccine candidate that elicited high neutralizing antibody (nAb) titers in mice against several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs).

Study: Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies Against Delta and Omicron in Mice. Image Credit: Design_Cells/Shutterstock
Study: Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies Against Delta and Omicron in Mice. Image Credit: Design_Cells/Shutterstock

Background

Although vaccines remain the key defense against SARS-CoV-2, they have been unable to completely contain community transmission of coronavirus disease 2019 (COVID-19). The cold chain storage requirements of several currently approved COVID-19 vaccines have resulted in poor coverage and inequitable access, one of the four factors listed by the World Health Organization (WHO) driving the impact of SARS-CoV-2.

As cold storage requirements are of varying degrees, they inexplicably impact low-income countries (LICs) and lower-middle-income countries (LMICs) where the average temperatures are higher. The continuing inequitable access has been most striking for LICs that have administered 13-fold fewer vaccines compared to both upper-middle-income countries (UMICs) and high-income countries (HICs).

Therefore, the world urgently needs next-generation COVID-19 vaccines that are not only highly effective against all existing and emerging SARS-CoV-2 variants but are also thermostable and do not have cold chain transport and storage requirements.

About the study

In the current study, researchers tested six vaccine formulations of a vaccine candidate developed by Mynvax Private Limited that is entering the phase I human clinical trials. Of this receptor-binding domain (RBD)-derived vaccine, 1-3 and 4-6 were monomers- and trimer protein subunit-based vaccine formulations, respectively.

Three SARS-CoV-2 isolates, viz., VIC31-D614G, Delta, and Omicron BA.1.1 were provided by the Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne, Australia. The researchers propagated and titrated these virus stocks in Vero E6 cells.

To be used for a live virus neutralization assay, they collected sera from mice on Day 57. These mice received their respective adjuvanted antigen doses 1, 2, and 3 on days 0, 21, and 42, respectively. Seroneutralization (SN50) titers, expressed as reciprocal of the viral neutralizing titer (VNT), were calculated using the Spearman-Kärber formula.

They determined statistically significant differences between vaccines, antigens, and adjuvants between different vaccine groups using one-way and two-way variance analysis(ANOVA) tests.           

Study findings

The study showed that for three monomeric formulations, the fold reduction in neutralization was 2.5 and 14.4, and for three trimeric formulations was 3 and 16.5, to Delta and Omicron, respectively, compared to VIC31- D614G.

The authors observed an average 2.7-fold reduction in neutralizing titers to Delta compared with VIC31-D614G, whereas they observed an average 15.4-fold reduction in titers for Omicron across all six vaccine formulations.

Compared to Delta, the fold-reduction in neutralizing titers for Omicron was 5.7- and 6.0-fold for monomeric and trimeric formulations, respectively. Likewise, the fold-reduction for Delta compared to VIC31-D614G ranged from 2.1- to 4.2-fold for all six vaccine formulations, although this reduction was only statistically significant for vaccine formulation 5.

The reduction in the neutralization of Omicron was more pronounced, ranging from a 10.1- to 22.0-fold decrease for the six vaccine formulations, when compared to VIC31-D614G, and was statistically significant (p<0.1).

Vaccine 3 showed the highest fold-reduction in neutralizing titers against Omicron (10-fold lower), compared to VIC31, whereas the other five formulations yielded an average fold decrease of 16.5. Compared to Delta, the fold-reduction for Omicron was statistically significant for all vaccine formulations except Vaccine 3.

The average VNT titers showed a statistically significant increase against Delta and Omicron. However, for VIC31-D614G, immunization with the vaccine formulations 1-3 showed a statistically non-significant increase compared to the trimers vaccine formulation 4-6.

From the perspective of adjuvants used in vaccine formulations, they noted no significant differences in VNT titers for all three variants.

Conclusions

The vaccine candidate evaluated in the present study elicited high nAb titers in mice pre-immunized with the wildtype (WT) SARS-CoV-2 strain; additionally, these nAbs neutralized SARS-CoV-2 variant VIC31 (with spike mutation D614G), plus Delta and Omicron (BA.1.1) VOCs. Furthermore, it was highly thermo-tolerant, capable of withstanding 100°C for 90 minutes and 37° C for four weeks, and hence did not need a cold chain for transportation.

The study also demonstrated that the steric hindrance of epitopes required to elicit effective B-cell immune responses and irrelevant antibodies likely contributed to mice’s immune response to the trimeric antigen vaccine formulations. These findings, however, need to be confirmed by studies examining a wider range of hosts and SARS-CoV-2 variants.

At the dosages used in the study, monomeric vaccine formulations appeared relatively more effective at generating nAb responses against VOCs and hence are favored for phased clinical trials of this vaccine in humans. The average 14.4-fold reduction in neutralization against Omicron compared favorably with other COVID-19 vaccines; this vaccine matching should help guide ways to improve the nAb titers against emerging SARS-CoV-2 variants.

Finally, and more importantly, the vaccine’s thermostability and ability to withstand transient heat shocks appear promising to address vaccine inequity that has severely affected most LICs and LMICs.

*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:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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