In a recent study published on the medRxiv* preprint server, researchers examine neutralizing antibody responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals aged 70 or above who had received two primary doses of the AZD1222 (ChAdOx1 nCov-19) vaccine, followed by one booster dose of either the BNT162b2 or mRNA-1273 messenger ribonucleic acid (mRNA) vaccine.
Study: Atypical B cells and impaired SARS-CoV-2 neutralisation following booster vaccination in the elderly. Image Credit: Prostock-studio / Shutterstock.com
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
In the United Kingdom, the adenoviral vector vaccine AZD1222 and the mRNA BNT162b2 and mRNA-1273 vaccines have been used for widespread vaccination against the coronavirus disease 2019 (COVID-19).
Emerging SARS-CoV-2 variants are associated with improved immune evasion, courtesy of mutations primarily in the spike protein's receptor binding domain (RBD). However, in addition to newly emerging variants, waning immunity has reinforced the need for booster doses.
A third booster dose has been shown to induce stable spike-protein-specific B-cells that elicit a neutralizing response against SARS-CoV-2 variants with RBD mutations. However, the longevity of B-cell immunity is determined mainly by age.
Previous studies have shown that neutralizing responses to the two primary mRNA vaccine doses have been suboptimal in the elderly population. However, the neutralizing antibody responses in the elderly to a booster vaccination dose have not yet been investigated.
About the study
The present study comprised 60 individuals who had received two doses of the AZD1222 vaccine and one dose of either of the two mRNA booster vaccines. The participants were divided into two groups based on age, in which one group consisted of individuals younger than 70, and the other consisted of individuals 70 years old or above.
Blood samples were collected one month after the second dose, six months after the second dose, and one month after the booster dose.
Vaccination-elicited antibody neutralization activity in the serum was measured based on the serum dilution required for 50% infection inhibition (ID50). The cutoff for insufficient neutralization was an ID50 value of 20 or less.
Multiplex particle-based flow cytometry was employed to assess the antibody binding to the SARS-CoV-2 spike protein. In addition, FLUOROSPOT assays for interferon-gamma (IFNγ) and interleukin-2 (IL-2) were performed to measure T-cell responses.
Mean fluorescence intensity measured total spike immunoglobulin G (IgG) levels. Spike-pseudotyped lentiviruses for the SARS-CoV-2 D614G wild-type, Delta, and Omicron spike proteins were used to assess neutralizing antibodies.
Additionally, the researchers performed single-cell ribonucleic acid sequencing (scRNAseq) to measure gene expression. Sequencing of the B- and T-cell receptors were also carried out on peripheral blood mononuclear cells (PBMC).
Study findings
The neutralizing antibodies and both B- and T-cell responses showed no difference across the two age groups after primary vaccination. Moreover, neutralizing antibodies diminished significantly in the six months following the second primary vaccination dose.
The first mRNA vaccine booster dose resulted in a significant increase in antibody titers. However, individuals in the 70 or above age group showed lower neutralization responses compared to individuals younger than 70.
Serum IgG levels against the SARS-CoV-2 spike protein and spike-specific B-cells were the same across the two age groups. However, the older age group exhibited impaired T-cell responses for IFNγ and IL-2 secretions.
T-cell receptor sequencing indicated that the expression of the signaling pathway genes for T-cell receptors was lower for individuals aged 70 or older. In contrast, scRNAseq data suggested that the expression of B-cell receptor signaling pathway genes was enhanced.
The older age group also exhibited increased atypical memory B-cell levels, which the authors believe is elicited by the secretion of IFNγ and IL-21 that is a consequence of increased inflammation in the elderly.
Earlier studies with mice have reported that the AZD1222 vaccine elicits a lower germinal center response in older mice. This suggests that the atypical B-cell proliferation in older individuals could be due to the involvement of the extra-follicular pathway in memory B-cell production.
Conclusions
The study findings indicate that a booster dose of an mRNA vaccine resulted in lower neutralizing antibody responses in the older age group and spike-specific B-cell and IgG responses that were similar for both age groups.
Individuals aged 70 and older showed an accumulation of atypical memory B-cells and reduced T-cell receptor responses and signaling pathway gene expression, which the authors believe explains the lower neutralizing antibody levels. The impaired vaccine responses could cumulatively result in increased susceptibility of the elderly to COVID-19.
*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.
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