Booster vaccinations in older people lead to impaired neutralization of SARS-CoV-2 and atypical B cells

In a recently published study on the medRxiv* Preprint servers are investigating neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in people 70 years and older who had received two base doses of vaccine AZD1222 (ChAdOx1 nCov-19) followed by a booster dose of either BNT162b2 or the mRNA-1273 messenger ribonucleic acid (mRNA) vaccine.

To learn: Atypical B cells and impaired SARS-CoV-2 neutralization after booster vaccination in the elderly. Photo credit: Prostock Studio / Shutterstock.com

background

In the UK, adenoviral vector vaccine AZD1222 and mRNA vaccines BNT162b2 and mRNA-1273 have been used for widespread vaccination against Coronavirus disease 2019 (COVID-19).

Emerging SARS-CoV-2 variants are associated with enhanced immune evasion, mainly due to mutations in the receptor-binding domain (RBD) of the spike protein. However, in addition to emerging variants, declining immunity has increased 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 primarily determined by age.

Previous studies have shown that the neutralizing responses to the two primary mRNA vaccine doses were suboptimal in the elderly population. However, the neutralizing antibody responses in elderly patients to a booster dose have not been studied.

About the study

The present study included 60 subjects who received two doses of the AZD1222 vaccine and one dose of either mRNA booster vaccine. The participants were divided into two groups by age, one group consisting of people under the age of 70 and the other group consisting of people over the age of 70.

Blood samples were taken one month after the second dose, six months after the second dose and one month after the booster dose.

Vaccination-evoked serum antibody neutralizing activity was measured based on the serum dilution required for 50% inhibition of infection (ID50). The cut-off for insufficient neutralization was an ID50 value of 20 or less.

Multiplex particle-based flow cytometry was used to assess 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.

In addition, researchers performed single-cell ribonucleic acid sequencing (scRNAseq) to measure gene expression. The sequencing of the B and T cell receptors was also performed on peripheral blood mononuclear cells (PBMC).

study results

The neutralizing antibodies and both the B and T cell responses showed no difference between the two age groups after the primary vaccination. In addition, the neutralizing antibodies decreased significantly in the six months after the second primary immunization dose.

The first booster dose of mRNA vaccine resulted in a significant increase in antibody titers. However, people in the age group of 70 years and older showed lower neutralization reactions compared to people under 70 years of age.

Serum IgG levels against the SARS-CoV-2 spike protein and spike-specific B cells were the same in both age groups. However, the older age group showed an impaired T cell response for IFNγ and IL-2 secretions.

T-cell receptor sequencing showed that expression of T-cell receptor signaling genes was lower in people aged 70 and older. In contrast, scRNAseq data indicated that expression of B-cell receptor signaling pathway genes was enhanced.

The older age group also showed increased levels of atypical memory B cells, which the authors believe are triggered by the secretion of IFNγ and IL-21, which is a consequence of increased inflammation in the elderly.

Previous studies in mice have reported that the AZD1222 vaccine elicited a lower germinal center response in older mice. This suggests that the atypical B cell proliferation in older individuals may be due to the involvement of the extrafollicular pathway in memory B cell production.

Conclusions

The study results indicate that a booster dose of mRNA vaccine in the older age group resulted in lower neutralizing antibody responses and in spike-specific B-cell and IgG responses that were similar for both age groups.

Individuals 70 years and older showed an accumulation of atypical memory B cells and reduced T cell receptor responses and pathway gene expression, which the authors believe explains the lower neutralizing antibody levels. The impaired vaccination responses could cumulatively lead to an increased susceptibility of older people to COVID-19.

*Important NOTE

medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health behavior or treated as established information.