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B cells create antibodies to protect against viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But SARS-CoV-2 is evolving with more mutations that make it harder for antibodies to identify — making the role of memory B cells that produce broader reactivity even more valuable.

Study: Two doses of mRNA vaccine elicit cross-neutralizing memory B-cells against SARS-CoV-2 Omicron variant. Image Credit: Viacheslav Lopatin/Shutterstock

New research recently published in the bioRxiv* preprint server suggests memory B cells play an essential role in the increased protection against variants of concern after vaccination. The study found increases in resting memory B cell subsets showed strong cross-reactivity against several variants, including Omicron.

The study

The research team enrolled 51 healthcare workers who were fully vaccinated with the two-dose Pfizer-BioNTech mRNA vaccine and were willing to donate blood samples. Blood samples were taken 31 days and 146.5 days after receiving the second dose to study antibody levels and the number of circulating memory B cells.

A separate cohort of 40 volunteers who previously recovered from coronavirus disease 2019 (COVID-19) infection and had naturally acquired immunity also donated their blood samples for research.

Neutralizing antibody protection against several SARS-CoV-2 variants of concern

In this study, the researchers studied the capabilities of vaccine-induced neutralizing antibodies over time. Their focus was neutralizing antibodies identifying and binding to the receptor-binding domain as it contains many epitopes. Receptor binding domain proteins were created using several SARS-CoV-2 strains including the original one discovered in Wuhan, Beta, and Delta.

Against the Wuhan strain, two doses of the mRNA vaccine produced robust IgG antibody titers with over a 2000-fold increase one month after vaccination. Additionally, 2 testosterone cream dosage IgA titers rose 44-folds following vaccination. Given the greater boost in IgG antibody levels, the researchers suggest IgG antibodies play a significant role in neutralization.

There was a reduction in vaccine-induced IgG titers against Beta and Delta. The vaccines produced a 2.4-2.7 fold for Beta and 1.1-fold for Delta. Neutralizing antibodies had a challenging time against variants with mutations that allow them to escape detection. Nevertheless, IgG antibodies were modestly successful in binding to the variants’ receptor binding domain.

As time passed, vaccine-induced neutralizing antibodies targeting Wuhan and the Delta variant decreased. But with Beta, other neutralizing antibodies beyond IgG increased over time resulting in a gradual increase in neutralizing potency.

There was a 1.1-fold increase in IgG levels against the Beta variant months after vaccination. Overall, the range of neutralizing antibodies increased two-fold against the Beta variant but decreased by 1.1-fold against Delta.

B memory cells against the variants

While IgG antibodies decreased over time following vaccination, the researchers found the opposite effect in receptor binding domain-binding IgG+ memory B cells. These memory B cells showed a 1.8-fold increase as time passed.

Four subsets of IgG+ memory B cells were studied. One month after vaccination produced the four subsets but after 4.9 months, the number of B memory cell subsets differed.

Resting memory B cell subsets increased by 3.5-fold, but atypical memory B cell subset decreased. This led to an expansion in resting memory B cells to compensate for the loss of the atypical subset.

The memory B cells showed strong cross-reactivity when exposed to the receptor-binding domains of Beta and Delta. Cross-reactivity against Beta ranged from 73.3% to 79% while there was 71.4% to 79.3% cross-reactivity against Delta.

Resting memory B cell subset showed increased cross-reactivity against both variants over time, suggesting increased variant-reactivity and cellularity.

Omicron drastically reduced the number of IgG antibodies that could bind to its receptor-binding domain. The decline in neutralization against Omicron persisted over time, suggesting the mutations on Omicron outweighed maturing neutralizing responses.

But to the researcher’s surprise, resting memory B cells produced similar neutralizing activities to the Beta and Omicron variants. About 59% produced antibodies with cross-neutralization against Beta and 27% produced cross-neutralization against Omicron.

Study limitations

Because booster shots have only recently been made available, the researchers could not study the third dose’s effect on memory B-cells over time. For this reason, it is difficult to measure the number of cross-neutralizing memory B-cells and how it’s linked to cross-neutralizing antibody responses after a third dose. Additionally, the current study focuses on neutralizing antibodies, but animal models have shown protection is also garnered from non-neutralizing antibodies.

*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.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.