Understanding the immunogenicity and efficacy of vaccinations is essential to guide global vaccination strategies and when to deploy non-pharmacological countermeasures to protect the immunologically vulnerable [19, 20]. Herein, we report the immunogenicity of the AstraZenca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b vaccinations in patients with antibody deficiency, a cohort who have historically responded poorly to vaccinations [24–26].
Overall seropositivity following vaccination was 54.8%, significantly lower than healthy controls; comparable seropositivity was observed in the two largest subgroups of patients, common variable immunodeficiency (52.1%) and secondary immunodeficiency arising from haematological cause (55.8%). However, less than 10% of individuals with primary or secondary antibody deficiency made a neutralising antibody response equivalent to that of healthy controls following two doses of a SARS-CoV-2 vaccine. Furthermore, almost 40% of vaccine responders did not demonstrate binding to the SARS-CoV-2 delta variant and are likely to have limited neutralising capacity against it [27]. These data suggest that vaccine-induced antibody responses are inadequate in the majority of individuals with antibody deficiency and additional strategies such as the use of prophylactic monoclonal antibodies to provide passive protection and antivirals are likely to be necessary to prevent severe disease.
T cell responses to vaccination displayed significant heterogeneity in this cohort, as has been found in similar studies using identical laboratory methods [28]. The interferon-gamma release assay was originally validated to study T cell responses following natural infection, where it displays 98% sensitivity [29]. 46.2% of participants in COVAD mounted a detectable T cell response following vaccination using this assay, compared to 54% of healthy individuals [30]. T cell responses in patients with evidence of previous SARS-CoV-2 infection were significantly greater than those detected following vaccination in infection-naive participants. The discordance between the detection of vaccine- and infection-induced T cell responses potentially arises from differences in MHC restriction to the constituents of the peptide pool and the antigen-specific T cell repertoire in each circumstance.
Our study found strong T cell responses in XLA patients, as has been shown previously [5]. The clinical correlates of infection- or vaccine-induced T cell responses in patients with antibody deficiency, in particular, in the absence of humoral immunity remain uncertain. The absence of humoral immunity is a characteristic feature of individuals with prolonged SARS-CoV-2 infection [7]; however, robust T cell responses can limit the severity of disease in some individuals in the absence of humoral immunity as has been shown previously in patients with haematological malignancy [31]. Further studies are necessary to characterise the quality and breadth of T cell responses and its relationship to the development of effective humoral immunity following infection and vaccination in more detail.
With respect to vaccination strategies, we have shown that the Pfizer BioNTech 162b vaccine demonstrated significantly greater humoral immunogenicity in patients with antibody deficiency than the AstraZeneca ChAdOx1 nCoV-19 vaccination, a finding consistent with larger studies in healthy individuals [13, 32] and renal transplant recipients [28]. Furthermore, over 90% of vaccine breakthrough infections occurred in recipients of the AstraZeneca vaccine, 60.0% of whom made no serological response to the initial 2-dose vaccine schedule. Studies in the general population have suggested adenoviral-vectored vaccines demonstrate reduced vaccine-efficacy against severe disease when directly compared to mRNA vaccines (https://www.cdc.gov/mmwr/volumes/70/wr/mm7038e1.htm). These observations support the use of mRNA vaccines in patients with antibody deficiency.
It could be argued that the deployment of a 3rd dose of vaccination in individuals that have not responded to a first dose is futile. However, we have found that serological and cellular responses to the SARS-CoV-2 spike protein were positively incremented by the second vaccine dose, in keeping with previous studies in patients with inborn errors of immunity [16] suggesting potential benefit from further doses. Further studies will be necessary to explore whether different vaccination combinations (homologous/heterologous) or dosing schedules may improve responses and efficacy in patients with primary and secondary humoral immunodeficiencies.
Existing studies have reported wide variation in the serological response to vaccination in patients with immunodeficiency: post-vaccine seroprevalence have ranged from 20.0–80.0% [14–18]. The COVAD study is the largest reported study of patients with antibody deficiency and finds a seropositivity rate of 54.8% overall. At a cohort level, total B cell numbers were the principal determinate of serological response to vaccination, also in keeping with other SARS-CoV-2 vaccine studies [17]. Additional correlates of vaccine responsiveness remain to be elucidated: Salinas et al demonstrated patients with CVID have a relative paucity of receptor-binding domain-specific, CD19+ CD24+ CD27+ B cells compared to healthy controls [18] and Hagin et al were unable to demonstrate a common T-cell immunophenotype in vaccine non-responders beyond an inverted CD4/CD8 ratio [17]. Future work in COV-AD will employ detailed phenotypic and functional profiling to investigate potential correlates of vaccine immunogenicity and efficacy within this heterogeneous cohort.
This is a large study in a rare disease cohort and, although heterogeneous, we have had the opportunity to compare the immunogenicity of an mRNA and adenoviral-vectored vaccine in an immunodeficient cohort. To some extent, the generalisability of our study to the wider world is confounded by the extended UK vaccine schedule, which has not yet been widely adopted elsewhere. On the one hand, extension of the interval between first and second doses has been associated with greater neutralising antibody responses and enrichment of virus specific CD4+ T cells in healthy individuals [33], but shorter dosing intervals were associated with better humoral responses in a smaller study of patients vaccinated following treatment with B cell depleting agents (Shields AM, in press). There is an urgent need for further studies that explore how to maximise vaccine immunogenicity and efficacy in larger and heterogeneous cohorts of immune deficient patients.
In conclusion, we demonstrate profound impairment of serological responses following SARS-CoV-2 vaccination in patients with antibody deficiency and evidence of the superior immunogenicity of the Pfizer BioNTech 162b vaccine. These data highlight the ongoing risk of SARS-CoV-2 infection in antibody deficiency patients and should inform public health policy on vaccination strategies and other treatments to prevent morbidity and mortality.