The effect of CMV serostatus on humoral and cellular measures of vaccine responses after 2 and 3 doses of SARS-CoV-2 mRNA vaccines in older adults

In a recent study posted to the medRxiv* preprint server, researchers evaluated the impact of cytomegalovirus (CMV) seropositivity on humoral and cellular immune responses generated after double and/or triple messenger ribonucleic acid (mRNA) vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among the elderly.

Study: CMV seropositivity in older adults changes T cell functionality, but does not prevent antibody or cellular SARS-CoV-2 vaccine responses. Image Credit: Rido/Shutterstock
Study: CMV seropositivity in older adults changes T cell functionality, but does not prevent antibody or cellular SARS-CoV-2 vaccine responses. Image Credit: Rido/Shutterstock

CMV seropositivity has been associated with decreased humoral immune responses to Ebola vaccines and influenza vaccines. On the contrary, cellular or humoral immune responses induced by ChAdOx1 nCoV-19 vaccination among young adults have been reported to be unaffected by CMV serostatus. Therefore, data on the impact of CMV seropositivity on host antiviral immune responses has conflicting results. Moreover, the impact of CMV serostatus on SARS-CoV-2 mRNA vaccine-induced immunity is yet unknown.

About the study

In the present study, researchers evaluated the effects of CMV serostatus on humoral and cellular immune responses after two and three doses of SARS-CoV-2 mRNA vaccines (mRNA-1273 or BNT162b2) among elder individuals residing in assisted living facilities.

The study was conducted between March and December 2021 on 188 individuals aged ≥65 years who resided in congregate living facilities (14 nursing homes and three retirement homes) in Ontario, Canada. Blood samples were collected from all participants a minimum of one week after either the second dose or after the third dose of mRNA vaccines. For 47 participants, blood samples were obtained after double and triple mRNA vaccination.

CMV seropositivity was assessed by evaluating the anti-CMV immunoglobulin G (IgG) titers using enzyme-linked immunosorbent assays (ELISA). The impact of CMV seropositivity on humoral immune responses after SARS-CoV-2 vaccination was determined based on the effect of CMV seropositivity on the anti-SARS-CoV-2 spike (S) antibody titers and anti-SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin G (IgG), IgA, and IgM titers. In addition, the neutralization capacity of antibodies against SARS-CoV-2 wildtype and Beta strains was assessed using cell culture assays with Vero E6 cells.

Immunophenotyping assays and flow cytometry analysis were performed to identify five subsets of T lymphocytes as follows: naïve (N), terminally differentiated (TD), central memory (CM), effector memory (EM), effector memory re-expressing CD45RA (EMRA) lymphocytes. Subsets of the cluster of differentiation 4 positive (CD4+) T lymphocytes such as T helper 1 (Th1), Th2, and Th17 were identified based on their C-C chemokine receptor type 4 (CCR4), CCR6, and chemokine receptor 3 (CXCR3) expression. In addition, the absolute T lymphocyte counts were determined.  

Further, T lymphocyte activation assays were performed to identify activation-induced marker (AIM)-positive and antigen-specific T lymphocytes based on the CD25 and CD134 co-expression on CD4+ T lymphocytes and CD69 and CD137 co-expression on CD8+ T lymphocytes. In addition, recall (memory) responses of AIM+ cells were assessed using the SARS-CoV-2 S peptide pool.

The impact of CMV seropositivity on COVID-19 incidence and the effect of prior SARS-CoV-2 infections on the antibody-mediated humoral immune responses and T lymphocyte-mediated cellular immune responses were assessed. Prior SARS-CoV-2 infection was identified based on positive polymerase chain reaction (PCR) reports or seropositivity for IgA or IgG nucleocapsid antibodies.

Results

Of 188 participants, 131 (69.7%) participants demonstrated CMV seropositivity. Five to seven months after double mRNA vaccination, anti-S IgG and anti-RBD IgG titers were detected in 89% and 64% of participants, respectively, which increased to 97% and 95% three months after triple mRNA vaccination, respectively. CMV seropositive and seronegative participants demonstrated similar neutralization capacity against the wildtype and Beta strains. Moderate correlations were observed between the anti-S, anti-RBD IgG, and anti-RBD IgA titers and the neutralization capacity, irrespective of CMV serostatus. This indicated that CMV seropositivity did not affect mRNA vaccine-induced anti-SARS-CoV-2 humoral immunity.

In the flow cytometry analysis, CMV serostatus did not significantly alter the counts of total CD4+ T lymphocytes, or CD4N, CD4EM, CD8N, or CD8EM T lymphocytes. However, increased total CD8+ T lymphocytes and CD4EMRA, CD4TD, CD8EMRA, and CD8TD T lymphocyte counts and decreased CD4CM and CD8CM T lymphocyte counts were observed among CMV seropositive participants.

T lymphocyte activation assays showed that CMV seropositivity reduced CD28 expression on CD8CM and CD8EM lymphocytes; however, CMV serostatus did not affect CD57 or CD28 expression on CD4N T lymphocytes. CMV serostatus was associated with elevated CD8+ T lymphocyte expression. Still, it did not enhance CD4+ T lymphocyte recall responses against SARS-CoV-2 S. CMV serostatus significantly impacted Th1 S-CD4+ T lymphocyte frequency but not Th17 S- and Th2 S-CD4+ T lymphocyte frequencies. In addition, CMV serostatus did not affect the number of individuals with SARS-CoV-2 S-activated CD4+ T lymphocytes or CD8+ T lymphocytes after double or triple mRNA vaccinations.

Further, CMV seropositivity elevated AIM+ CD8+ T lymphocyte counts but not AIM+CD4+ T lymphocyte frequency. CMV serostatus altered memory T lymphocyte functional composition, with SARS-CoV-2 S-targeted effects; however, there was no change in the capacity to generate CD4+ or CD8+ T lymphocyte memory COVID-19 incidence after mRNA vaccination was observed among CMV seropositive elders.

Overall, the study findings showed that CMV seropositivity may alter T lymphocyte composition but does not impede cellular or humoral immune responses after mRNA vaccinations in the elderly.

*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:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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