Antibody and cellular immune responses following dual COVID-19 vaccination within infection-naive residents of long-term care facilities: an observational cohort study

Abstract

Background: Older age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for individuals with these factors, but there is concern that immune responses might be impaired due to age-related immune dysregulation and comorbidity. We aimed to study humoral and cellular responses to COVID-19 vaccines in residents of long-term care facilities (LTCFs).

Methods: In this observational cohort study, we assessed antibody and cellular immune responses following COVID-19 vaccination in members of staff and residents at 74 LTCFs across the UK. Staff and residents were eligible for inclusion if it was possible to link them to a pseudo-identifier in the COVID-19 datastore, if they had received two vaccine doses, and if they had given a blood sample 6 days after vaccination at the earliest. There were no comorbidity exclusion criteria. Participants were stratified by age (<65 years or ≥65 years) and infection status (previous SARS-CoV-2 infection [infection-primed group] or SARS-CoV-2 naive [infection-naive group]). Anticoagulated edetic acid (EDTA) blood samples were assessed and humoral and cellular responses were quantified.

Findings: Between Dec 11, 2020, and June 27, 2021, blood samples were taken from 220 people younger than 65 years (median age 51 years [IQR 39-61]; 103 [47%] had previously had a SARS-CoV-2 infection) and 268 people aged 65 years or older of LTCFs (median age 87 years [80-92]; 144 [43%] had a previous SARS-CoV-2 infection). Samples were taken a median of 82 days (IQR 72-100) after the second vaccination. Antibody responses following dual vaccination were strong and equivalent between participants younger then 65 years and those aged 65 years and older in the infection-primed group (median 125 285 Au/mL [1128 BAU/mL] for <65 year olds vs 157 979 Au/mL [1423 BAU/mL] for ≥65 year olds; p=0·47). The antibody response was reduced by 2·4-times (467 BAU/mL; p≤0·0001) in infection-naive people younger than 65 years and 8·1-times (174 BAU/mL; p≤0·0001) in infection-naive residents compared with their infection-primed counterparts. Antibody response was 2·6-times lower in infection-naive residents than in infection-naive people younger than 65 years (p=0·0006). Impaired neutralisation of delta (1.617.2) variant spike binding was also apparent in infection-naive people younger than 65 years and in those aged 65 years and older. Spike-specific T-cell responses were also significantly enhanced in the infection-primed group. Infection-naive people aged 65 years and older (203 SFU per million [IQR 89-374]) had a 52% lower T-cell response compared with infection-naive people younger than 65 years (85 SFU per million [30-206]; p≤0·0001). Post-vaccine spike-specific CD4 T-cell responses displayed single or dual production of IFN-γ and IL-2 were similar across infection status groups, whereas the infection-primed group had an extended functional profile with TNFα and CXCL10 production.

Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naive residents of LTCFs, and they suggest the need for optimisation of immune protection through the use of booster vaccination.

Funding: UK Government Department of Health and Social Care.

Figure 1

Spike-specific antibody titre before vaccination, after one dose, and after two doses of COVID-19 vaccination (A) Spike-specific antibody titre after two doses of COVID-19 vaccine. Black solid line indicates median. Dotted line indicates assay cutoff. (B) Spike-specific antibody response of the infection-primed group before vaccination, after the first dose of vaccine, and after the second dose of vaccine (n=39). (C) Spike-specific antibody response of the infection-naive group before vaccination, after the first dose of vaccine and after the second dose of vaccine (n=37). One individual in the infection-promed group had no available baseline data.

Figure 2

Neutralisation of the original Wuhan (B.1.1.7) and delta (1.617.2) variant spike-ACE2 binding after completed vaccine schedule for residents and staff by previous infection status Relative inhibition of spike-ACE2 binding sera after completion of the vaccine schedule. Data are from 488 individuals. Black solid line indicates median.

Figure 3

Spike-specific T-cell responses following vaccination IFN-γ ELISpot following spike-specific PBMC. Data are from 488 individuals. Black solid line indicates median. Dotted line indicates assay cut-off. PBMC=peripheral blood mononuclear cell. SFU=spot forming units.

Figure 4

Spike-specific cytokine response profile following vaccination Data are from 175 individuals. Black solid line indicates median. Control indicates cells were incubated with dimethyl sulfoxide only.

Figure 5

Spike-specific antibody and cellular responses after completion of BNT162b2 (BioNTech–Pfizer) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccine schedules Spike-specific antibody (A) and cellular (B) responses in long-term care facility staff and residents after dual vaccination with either ChAdOx1 nCoV-19 or BNT162b2. Data are from 488 individuals. Black solid line indicates median. Dotted line indicates assay cut-off. PBMC=peripheral blood mononuclear cell. SFU=spot forming units.

Figure 6

Relative expression of IFN-γ and IL-2 within spike-specific CD4 T cells following dual vaccination (A) Detection of virus-specific CD4+ T cells, represented as a proportion of the total CD4+ repertoire, by single or dual expression of IFN-γ or IL-2 following stimulation with spike or N, M, or E peptides. Data are from 35 individuals from the infection-primed group and 27 individuals from the infection-naive group. Dimethyl sulfoxide is negative control. Black solid line indicates median. (B) Distribution of single or dual IFN-γ and IL-2 positive virus-specific CD4 T cells. (C) Memory phenotype distribution of IFN-γ and IL-2 positive CD4 virus-specific cells. E=envelope. M=membrane. N=nucleocapsid.