Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

Vaccines remain the cornerstone for containing the SARS-CoV-2 pandemic. mRNA vaccines provide protection in clinical trials using a two-dose approach, separated by a three-week gap. Here we assessed real world immune responses following vaccination with mRNA-based vaccine BNT162b2. Following the first and second doses of the BNT162b2 vaccine, we measured IFNgamma; T cell responses, both total IgG Spike, IgG Spike RBD and neutralising antibody responses to Spike in sera using a lentiviral pseudotyping system. Median age was 82 amongst 26 participants. Three weeks after the first dose a lower proportion of participants over 80 years old achieved adequate neutralisation titre of >1:4 for 50% neutralisation as compared to those under 80 (8/15 versus 11/11, p<0.05). Mean neutralisation titres in this age group after the first dose were lower than in younger individuals (p<0.05). Following the second dose, neutralising antibody response 50% titres were above 1:4 in all individuals and there was no longer a difference by age grouping. A significant proportion of individuals over 80 appear to require a second dose of vaccine, given in this study at three weeks, to achieve virus neutralisation.

While CD8+ T cells specific for human cytomegalovirus (HCMV) have been extensively studied in both healthy HCMV seropositive carriers and patients undergoing immunosuppression, studies on the CD4+ T cell response to HCMV had lagged behind. However, over the last few years there has been a significant advance in our understanding of the importance and contribution that CMV-specific CD4+ T cells make, not only to anti-viral immunity but also in the potential maintenance of latently infected cells. During primary infection with HCMV in adults, CD4+ T cells are important for the resolution of symptomatic disease, while persistent shedding of HCMV into urine and saliva is associated with a lack of HCMV specific CD4+ T cell response in young children. In immunosuppressed solid organ transplant recipients, a delayed appearance of HCMV-specific CD4+ T cells is associated with prolonged viremia and more severe clinical disease, while in haematopoietic stem cell transplant recipients, it has been suggested that HCMV-specific CD4+ T cells are required for HCMV-specific CD8+ T cells to exert their anti-viral effects. In addition, adoptive T-cell immunotherapy in transplant patients has shown that the presence of HCMV-specific CD4+ T cells is required for the maintenance of HCMV-specific CD8+ T cells. HCMV is a paradigm for immune evasion. The presence of viral genes that down-regulate MHC class II molecules and the expression of viral IL-10 both limit antigen presentation to CD4+ T cells, underlining the important role that this T cell subset has in antiviral immunity. This review will discuss the antigen specificity, effector function, phenotype and direct anti-viral properties of HCMV specific CD4+ T cells, as well as reviewing our understanding of the importance of this T cell subset in primary infection and long-term carriage in healthy individuals. In addition, their role and importance in congenital HCMV infection and during immunosuppression in both solid organ and haemopoietic stem cell transplantation is considered.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes severe disease following congenital infection and in immunocompromised individuals. No vaccines are licensed, and there are limited treatment options. We now show that the addition of anti-HCMV antibodies (Abs) can activate NK cells prior to the production of new virions, through Ab-dependent cellular cytotoxicity (ADCC), overcoming viral immune evasins. Quantitative proteomics defined the most abundant HCMV proteins on the cell surface, and we screened these targets to identify the viral antigens responsible for activating ADCC. Surprisingly, these were not structural glycoproteins; instead, the immune evasins US28, RL11, UL5, UL141, and UL16 each individually primed ADCC. We isolated human monoclonal Abs (mAbs) specific for UL16 or UL141 from a seropositive donor and optimized them for ADCC. Cloned Abs targeting a single antigen (UL141) were sufficient to mediate ADCC against HCMV-infected cells, even at low concentrations. Collectively, these findings validated an unbiased methodological approach to the identification of immunodominant viral antigens, providing a pathway toward an immunotherapeutic strategy against HCMV and potentially other pathogens.