Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study

Abstract

Background: Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65-80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses.

Methods: 4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries.

Findings: Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04).

Interpretation: Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing.

Funding: Norwegian Institute of Public Health, Norwegian Ministry of Health, Research Council of Norway, and Coalition for Epidemic Preparedness Innovations.

Figure 1

Humoral and cellular responses after two and three doses of mRNA vaccine (A) Individual anti-spike antibody concentrations before vaccination (n=211) and after two (n=299) and three doses (n=210; grey lines). Median time since vaccination was shorter for the subset with cell sampling (n=90; red lines); time between sampling and vaccination for each subset varied slightly between second (B) and third (C) vaccinations. CD4 (D) and CD8 (E) T cell responses to SARS-CoV-2 spike peptides before vaccination (n=69) and after two (n=90) and three vaccine doses (n=71), and to cytomegalovirus pp65 peptides (n=69). Unstimulated background was subtracted from all conditions. (F) Correlation of post-vaccination receptor binding domain levels and spike-specific CD4 T cell responses after third dose (n=71) by non-linear regression analysis. Points indicate individual responses for all plots. Box-and-whisker plots (D–E) show the median, IQR, and range; all statistics calculated by paired Wilcoxon tests.

Figure 2

Vaccine induced CD4 and CD8 T cells also respond to delta and omicron SARS-CoV-2 variants T cell responses to SARS-CoV-2 spike-specific peptides (n=71) after three vaccine doses. CD4 (A–C) and CD8 (D–F) T cell responses to mutated regions from SARS-CoV-2 variants of concern were upregulated compared with unstimulated cells. CD4 and CD8 T cell responses to the mutated regions correlated with their reference sequences for delta (B and E) and omicron (C and F), respectively. r and p values are shown on each plot. Box-and-whisker plots indicate the median, IQR, and 5th and 95th percentiles. NS=not significant.