Third dose of mRNA-based COVID-19 vaccine efficiently recalls Omicron-reactive B cell memory

By Neha MathurFeb 24 2022Reviewed by Aimee Molineux

In a recent study posted to the bioRxiv* pre-print server, researchers examined how the quantity and quality of antibody and memory B cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) change temporally and with the number of exposures to antigens.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

The scientific data showing the quality and durability of antibody and memory B cell responses induced by the messenger ribonucleic acid (mRNA)-based vaccine, specifically by the third dose of a vaccine, remains sparse. Moreover, studies providing insights into the dynamics of the immune recall responses to booster doses or post-vaccination reinfections are urgently needed.

About the study

In the present longitudinal cohort study, researchers screened 61 individuals who had received Pfizer BNT162b2 or Moderna mRNA-1273 vaccines to examine antibody and memory B cell responses to SARS-CoV-2.

While 45 individuals were infection naïve, 16 had recovered from a prior SARS-CoV-2-infection. The researchers collected their paired serum and peripheral blood mononuclear cell (PBMC) samples at 10 different time points ranging from pre-vaccine baseline and approximately three months after receiving the third booster dose.

The researchers quantified antigen-specific memory B cell responses from bulk PBMCs by flow cytometry using fluorescently labeled SARS-CoV-2 spike (S) and receptor-binding domain (RBD) probes. They quantified neutralizing capacity of vaccine-induced antibody responses against variants of concern (VOCs) using pseudotyped viruses encoding the Delta and Omicron S proteins.

Of all the study participants, post-vaccination, seven had a confirmed breakthrough infection (BTI) during the study period.

Findings

There are several important findings of the study. The quality of antibody responses was measured using an antibody potency index; it increased significantly after the second vaccine dose. While antibody concentrations began to stabilize in the infection naïve group, potency continually surged from six to nine months post-vaccination.

One of the key findings was that the third booster dose increased antibody response close to 10-100-fold, including against the new SARS-CoV-2 Omicron VOC. The observed antibody levels were similar to those observed in hybrid immunity, i.e., after two doses of mRNA vaccine in SARS-CoV-2-recovered individuals.

Interestingly, BTIs induced similar antibody boosting as induced by two doses of an mRNA vaccine; moreover, these antibodies were present up to three months post the third dose.

B cell responses remained highly stable without evidence of decay for up to nine months from primary vaccination. Two doses of the vaccine induced a robust memory B cell response against the Omicron variant, with ~40-50% of the receptor-binding domain (RBD)-binding memory B cells able to cross-bind Alpha, Beta, Delta, and Omicron.

The booster dose efficiently recalled over 50% of memory B cells with cross-reactivity to multiple VOCs. Thus, revealing that the memory B cell-secreted antibodies targeted more conserved epitopes of SARS-CoV-2 RBD or are of higher quality, hence overcoming epitope changes associated with mutations in VOCs.

Conclusions

To summarize, the study findings suggested that mRNA vaccines effectively generated and boosted memory B cell responses and associated antibodies with the capacity to recognize all current SARS-CoV-2 VOCs and may provide lasting protection against future variants.

The study predicted the absolute and relative benefits of booster vaccine doses while highlighting the immunological constraints that call for setting up a limit on maximum antibody levels achieved by repeated short interval boosting.

Nevertheless, the infected-then-vaccinated individuals reached slightly higher neutralizing titers against D614G and Omicron than SARS-CoV-2 naïve individuals who received three doses of vaccine. This finding suggested that additional vaccination or infection following a three-dose vaccine regimen has a quantitative benefit to antibody responses.

More importantly, the relative value of additional vaccine doses (a fourth vaccine dose or a new episode of infection) will likely be greatest for individuals with lower pre-boost antibodies, including immunocompromised or older populations. Therefore, the third exposure to SARS-CoV-2 spike antigen increased antibody levels 10- to 100-fold, whereas the fourth exposure in individuals with higher pre-boost antibodies resulted in a lesser five- to 10-fold boosting. This happened because pre-existing high titers of antibodies possibly compete with memory B cells for antigens and limit the extent of antibody-boosting.

Future studies should define a threshold of antibody titers necessary for protection against infection and severe coronavirus disease 2019 (COVID-19). It could help with serological testing to maximize the benefit and equity of additional vaccine doses. Furthermore, studies should examine VOC-specific vaccines and how boosting with a modified antigen may augment B cell recall responses compared with the mRNA vaccines containing the original Wuhan strain as an antigen.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources