Inactivated virion-based vaccine confers robust cell-mediated immunity against major SARS-CoV-2 variants

The Indian vaccine BBV152 is a whole-virion inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine based on Asp614Gly variant and has been formulated with the toll-like receptor (TLR) 7/8 agonist molecule imidazoquinoline adsorbed to alum. Notably, the BBV152 vaccine is also the first alum-imidazoquinoline adjuvanted vaccine approved for use in a large population.

BBV152 is administered as two intramuscular doses of 6 micrograms (µg) of the inactivated virus at four weeks apart. Previous studies have shown that almost every individual vaccinated with BBV152 seroconverted after four weeks of complete vaccination.

Recently, Phase III data have indicated the efficacy of up to 78% against symptomatic infection, 93.4% from severe disease, and 63.6% from asymptomatic disease. However, little is known on the mechanism and breadth of cell-mediated and humoral responses elicited by this vaccine.

Study: Inactivated virus vaccine BBV152/Covaxin elicits robust cellular immune memory to SARS-CoV-2 and variants of concern. Image Credit: Numstocker / Shutterstock.com

Background

It is crucial to understand the immune responses elicited by vaccines to understand the nature and duration of protection they offer against the virus. Previous studies have highlighted that CD4+ T-cells might be the major contributors in combating SARS-CoV-2 by limiting viral replication and dissemination, as well as ensuring adequate B-cell synthesis in germinal centers to elicit immunological memory.

In fact, CD4+ T-and B-cells are detected for extended periods of time, even as the levels of neutralizing antibodies have waned. This highlights the role of cellular responses in conferring the long-term protective efficacy to a vaccine.

Studies largely carried out with messenger ribonucleic acid (mRNA) vaccines highlight that other immune effector mechanisms including T-cells and non-neutralizing antibodies might be crucial to protect against SARS-CoV-2, apart from the neutralizing antibodies. Breakthrough infections after patients have received both doses of these vaccines further highlight the protective contribution of cellular responses.

Considering that BBV152 exposes the whole SARS-CoV-2 virion formulated with a first-in-human adjuvant to the human immune system, there is growing interest to understand the traits of immune memory established by this vaccine and its effectiveness against the SARS-CoV-2 variants. Indian researchers have recently published a report on the preprint server medRxiv* determining the magnitude, quality, and persistence of cellular and humoral memory responses after vaccination with BBV152/Covaxin.

About the study

The current study included 73 convalescent individuals who had previously recovered from mild coronavirus disease 2019 (COVID-19). Their samples were collected between November 2020 to January 2021, which was prior to the Delta variant surge in India. Their cellular and humoral immunity levels were compared against 71 individuals who were fully vaccinated with BB152/Covaxin.

All vaccinated and recovered individuals had detectable anti-spike immunoglobulin G (IgG) levels with a geometric mean end-point titer of 2 x 103, and 3 x 103, respectively. The anti-spike IgG titers were not significantly different between vaccinated and convalescent individuals.

As the inactivated virus vaccine exposes multiple proteins of the virus to the immune system, it is likely that proteins other than virus-spike will also be targeted during the vaccine-induced antibody responses. Like anti-spike IgG, the researchers found that this vaccine was capable of inducing anti-nucleoprotein IgG with no significant difference than those following natural infection.

The vaccine-induced antibodies showed a neutralization potential of about 92% (22/24) of the tested samples from the vaccine group as compared to convalescent individuals. The virus neutralizing ability of antibodies was not different between the vaccinated and the convalescent groups.

Moreover, a significant correlation between spike and nucleoprotein antibodies was found in vaccinated individuals, thus suggesting that the vaccine-induced coordinated immune response is against different virus proteins, as observed in case of infection.

BBV152 can also induce antibodies against other proteins that may be helpful in reducing cell-to-cell virus spread through the effector mechanism. Like a natural infection, the anti-spike and anti-nucleoprotein IgG levels were detectable for at least six months after the complete vaccination. Receptor-binding domain (RBD) specific antibodies directly correlated with the levels of virus-neutralizing antibodies.

There was a three to 10-fold reduction in RBD-specific antibodies against the SARS-CoV-2 variants in a decreasing order starting with the Alpha (B.1.1.7) variant, followed by the Delta (B.1.617.2), and Beta (B.1.351) variant, with no observed impact against the Gamma (P.1) and Kappa (B.1.617.1) variants. BBV152-induced memory B-cells, similar to natural infection, were impacted by variants in the same order as antibodies.

The vaccine further induced antigen-specific functionally potent multi-cytokine expressing CD4+ T cells in about 85% of the subjects, targeting spike and nucleoprotein of SARS-CoV-2. A marginal 1.3 fold-reduction was observed in vaccine-induced CD4+ T-cells against the Beta variant, with no significant impact against the Alpha and Delta variants. The antigen-specific CD4+ T-cells were populated in the central memory compartment and persisted for up to six months post-vaccination.

Most importantly, the vaccine generated follicular helper T (Tfh) cells, which are a special subset of CD4+ T-cells that are endowed with the potential to boost immune memory, at levels that were similar to those produced in convalescents. Altogether, these findings established that the inactivated virus vaccine BBV152 induced robust immune memory to SARS-CoV-2 and variants of concern, which persisted for at least six months after complete vaccination.

Implications

The BBV152 vaccine has the dual advantage of including the whole virus, as well as the utilization of a new adjuvant, alum-adsorbed imidazoquinoline. Understanding the traits of immune memory established by this vaccine will provide relevant knowledge on future vaccine development and the application of TLR7/8 agonist molecules as an adjuvant.

With the encouraging results on cell-mediated immune-memory conferred by this inactivated virion-based vaccine, it is worth investigating whether a booster immunization via the intranasal route can mediate localized immune memory in the common infection sites, especially the upper respiratory tract.

*Important notice

medRxiv 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:
Sreetama Dutt

Written by

Sreetama Dutt

Sreetama Dutt has completed her B.Tech. in Biotechnology from SRM University in Chennai, India and holds an M.Sc. in Medical Microbiology from the University of Manchester, UK. Initially decided upon building her career in laboratory-based research, medical writing and communications happened to catch her when she least expected it. Of course, nothing is a coincidence.

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