Bivalent mRNA vaccine induces powerful antibody response to SARS-CoV-2 Omicron subvariants

Scientists are continuously working on developing strategies to contain the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by a highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

To date, several COVID-19 vaccines have received emergency use authorization (EUA) from various global regulatory bodies. However, the COVID-19 pandemic persists due to the accumulation of various genomic mutations in SARS-CoV-2 that have reduced the efficacy of current vaccines, as well as waning antibody levels in both vaccinated individuals and those who have recovered from COVID-19.

Study: Bivalent mRNA vaccine booster induces robust antibody immunity against Omicron subvariants BA.2, BA.2.12.1 and BA.5. Image Credit: OSORIOartist / Shutterstock.com

Study: Bivalent mRNA vaccine booster induces robust antibody immunity against Omicron subvariants BA.2, BA.2.12.1 and BA.5. Image Credit: OSORIOartist / Shutterstock.com

Background

To combat waning antibody levels in individuals who have received two doses of primary COVID-19 vaccination, the administration of a booster vaccine has been approved in many nations throughout the world. However, previous studies have revealed that immune protection conferred by the first booster vaccine declines over time.

Additionally, the Omicron variant, which is the dominant circulating SARS-CoV-2 strain in most countries, is capable of evading the immune response elicited by COVID-19 vaccination and previous infection. Hence, there is a need for variant-adapted vaccine boosters that are effective against newly emerging SARS-CoV-2 variants.

On June 28, 2022, the United States Food and Drug Administration (FDA) voted in favor of incorporating an Omicron component into COVID-19 vaccine booster doses. During this time, the Omicron subvariant BA.1 was the dominant circulating strain in the U.S.

However, this strain was quickly replaced by other subvariants, the first of which was BA.2, followed by BA.2.12.1, and, more recently, BA.4 and BA.5. The continual evolution of SARS-CoV-2 variants poses difficulties for updating the vaccine. 

Previous studies have reported that all three Omicron subvariants of BA.1, BA.2, and BA.2.12.1 cause a quick surge and decrease in infection rates within three months or even shorter. Furthermore, reinfection and breakthrough infection in vaccinated and COVID-19 convalescent individuals by a new dominant strain has been shown to further complicate the process of updating or redesigning COVID-19 booster vaccines, especially within the short window of each Omicron wave.

About the study

It is imperative to determine effective variant-based antigen(s) to develop next-generation COVID-19 boosters that can be effective against current and emerging SARS-CoV-2 variants. A new study posted on the bioRxiv* preprint server discusses the development and efficacy of a bivalent (Delta+ BA.2) messenger ribonucleic acid (mRNA) vaccine against emerging variants such as BA.2.12.1, BA.4 or BA.5.

During the time of the study, BA.2 was the dominant strain and was gradually replaced by BA.2.12.1, BA.4, and BA.5. As compared to the BA.2 spike protein, that of BA.2.12.1 contains additional L452Q and S704L mutations. Both BA.4 and BA.5 display similar mutations in their spike proteins, including L452R, Del69-70, R493Q, and F486V. 

Recently, researchers have proposed bivalent vaccine candidates that target two variants to induce broader immunity that can effectively inhibit many SARS-CoV-2 variants. At present, the bivalent vaccine candidate developed by Moderna is being evaluated in clinical trials. This bivalent vaccine is composed of an equivalent mixture of two spike-encoding mRNAs, which includes 25 μg targeting the ancestral SARS-CoV-2 strain and 25 μg targeting the original Omicron B.1.1.529 variant.

Study findings

Bivalent COVID-19 booster vaccines that combine dominant and former dominant variants have the potential to significantly reduce the time required to develop a booster vaccine. This is because the development of booster vaccines by predicting and targeting new variants is a time-consuming approach. Additionally, the rapid displacement of circulating variants enhances the possibility of a mismatch between the strain used to update the booster and the actual dominant strain.

In the current study, the researchers compared the antibody response triggered by wild-type (WT), Delta, and BA.2 spike-based monovalent vaccine boosters with a Delta and BA. 2-based bivalent mRNA booster against Omicron subvariants in a mouse model. The level of neutralization was assessed using an enzyme-linked immunosorbent assay (ELISA) and pseudovirus neutralization assay. All mice were pre-immunized with two doses of WT lipid nanoparticle mRNA (LNP-mRNA). 

All three monovalent and one bivalent booster enhanced binding of the Omicron spike protein with neutralizing antibody titers to a varying degree. Furthermore, Delta and BA.2 bivalent LNP-mRNA booster vaccines exhibited better performance in the production of antibodies as compared to monovalent vaccines.

The antibodies generated from the bivalent vaccine could also inhibit the ancestral SARS-CoV-2 strain, as well as all studied Omicron subvariants. Notably, the monovalent vaccines were also effective against the tested variants to a varying degree.

Conclusions

WT or variant monovalent and bivalent boosters can improve the antibody response against Omicron subvariants. The current study emphasizes the importance of SARS-CoV-2 booster vaccine doses and proposes that variant boosters with closer antigenic distance to dominantly circulating strains exhibit universally better performance as compared to WT boosters.

Importantly, as compared to monovalent boosters, bivalent booster vaccines exhibited robust immune responses against diverse SARS-CoV-2 variants. Taken together, the current study provides pre-clinical evidence supporting the development of a bivalent or multivalent COVID booster vaccine.

*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:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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