S-antibody levels over time
Of the 44,204 individuals enrolled in Virus Watch, a total of 9320 individuals, who submitted samples between 24 February 2021 and 13 October 2021, were eligible for inclusion in the descriptive analysis of antibody levels over time following Dose 1 (Table 1, Supplementary Table S1, Fig. S1a). For the corresponding Dose 2 analysis, 8471 individuals who submitted samples between 1 July 2021 and 17 December 2021 were included (Table 1, Supplementary Fig. S1b). For these descriptive analyses, individuals contributed a median of 5 (IQR 2, 9) samples each. Amongst included ChAdOx1-S recipients the proportions of individuals aged 45–64 years and ≥65 years were roughly equal, while BNT162b2 recipients were predominantly ≥65 years. The proportions of males and females, and White British and Minority Ethnic groups, and the prevalence of most clinical risk factors of interest were roughly equal across the two vaccine types for both Dose 1 and 2 cohorts.
Table 1 Demographic and clinical characteristics of individuals who were sampled following Dose 1 and Dose 2 of either ChAdOx1-S or BNT162b2 vaccines
On plotting Dose 1 samples by time since vaccination, it was evident that S-antibody levels for BNT162b2 recipients rose more quickly than ChAdOx1-S recipients, however both groups achieved similar levels by eight weeks after vaccination (Fig. 1). At 12 weeks after vaccination, there is a suggestion of slight waning in levels for BNT162b2 recipients, whilst levels in ChAdOx1-S recipients continue to rise very slightly.
Fig. 1: S-antibody levels over time following the first dose (left) and the second dose (right) of COVID-19 vaccination.
Geometric means and 95% confidence intervals of Spike-antibody (U/ml) for each week since receiving first and second doses of vaccination, stratified by vaccine type (blue = ChAdOx1-S; pink = BNT162b2).
Following Dose 2, S-antibody levels once again rose more sharply for BNT162b2 recipients, this time achieving substantially higher peak levels than ChAdOx1 recipients. For both groups, antibody levels peaked around 2–4 weeks after vaccination, and then appeared to decline at a similar log-linear rate between 4 and 16 weeks after vaccination. Peak antibody levels following Dose 2 were remarkably higher than peak levels after Dose 1, and remained so even at 16 weeks after Dose 2.
A total of 8514 individuals submitted a serum sample that was taken ≥28 days following Dose 1 and prior to Dose 2. Taking the earliest valid sample within this timeframe from each participant, 166/5364 of ChAdOx1 recipients and 86/2898 of BNT162b2 recipients remained seronegative at ≥28 days following Dose 1, with n = 57 (34% [27, 42]) and n = 42 (49% [38, 60]) of these individuals classified as Clinically Extremely Vulnerable, respectively (Table 2). For both ChAdOx1-S and BNT162b2 recipients respectively, use of long steroid courses (n = 16, 9.6% [5.8, 15]; n = 7, 8.1% [3.6, 17]), DMARDs (n = 23, 14% [9.2, 20]; n = 15, 17% [10, 27]), MABs (n = 13, 7.8% [4.4, 13]; n = 5, 5.8% [2.2, 14]), and diagnosis of haematological malignancy (n = 15, 9.0% [5.3, 15]; n = 7, 8.1% [3.6, 17]) appeared highly over-represented in the seronegative category, compared to the wider cohort and the seropositive category. Obesity and diagnoses of ischaemic heart disease, solid organ cancer, Type 1 and 2 diabetes mellitus, heart failure, and neurological, liver, and inflammatory conditions also appeared to be slightly over-represented in the seronegative groups, for both ChAdOx1-S and BNT162b2 respectively.
Table 2 Demographic and clinical characteristics of individuals who were seronegative and individuals who were seropositive (as per the ≥0.8 U/ml cut-off for Spike-antibody level) at ≥28 days after receiving Dose 1, with percentage estimates and 95% confidence intervals for seropositivity and seronegativity rates
Notably, less than 10 individuals remained seronegative after Dose 2, with >95% of those who were seronegative at ≥28 days after Dose 1 becoming seropositive at ≥28 days after Dose 2 (data not presented in the tables due to small numbers).
S-antibody levels by clinical risk factor
8356 individuals, including 5568 (67%) ChAdOx1 recipients and 2788 (33%) BNT162b2 recipients were included in the multivariable analyses of S-antibody levels at ≥28 days after Dose 2, by different clinical risk factors (Table 3). Of these 4821 (58%) were female, 4031 (48%) were ≥65 years old, and 7720 (92%) were of White British ethnicity. The median time since Dose 2 was 81 (62, 99) days, and the median Dose 1–2 interval was 77 (71, 78) days.
Table 3 Beta coefficients, 95% confidence intervals, and associated unadjusted p values (from two-tailed t-tests) derived from a single multivariable linear regression model of demographic and vaccination factors associated with log(n) Spike-antibody levels at ≥28 days after Dose 2. These covariates were subsequently included in the adjusted linear regression models examining the association between each clinical risk factor and log(n) Spike-antibody levels at ≥28 days after receiving Dose 2
All analyses adjusted for the following covariates: days since Dose 2, which appeared to be inversely associated with log(n) S-antibody levels (−0.01 [−0.01, −0.01]; p < 0.001); dose interval in days, which was positively associated (0.01 [0.01, 0.01]; p < 0.001); minority ethnicity, which was not associated (0.02 [−0.06, 0.11]; p = 0.6); for female sex, which was positively associated (0.08 [0.04, 0.13]; p < 0.001); age, where the youngest two age group (18–24 years: 0.32 [0.06, 0.59], p = 0.017; 25–44 years: 0.10 [0.01, 0.18], p = 0.034) had higher log(n) S-antibody levels than the reference group of 45–64 years, with no significant difference seen for the oldest group though the estimates were suggestive of an age-based gradient; and for BNT162b2 vaccine type, which was strongly positively associated compared to ChAdOx1-S (1.7 [1.7, 1.8]; p < 0.001) (Table 3).
Results from the main multivariable models demonstrated that several of the examined clinical risk factors were inversely associated with antibody levels, and none were positively associated (Fig. 2, Supplementary Table S3). MAB therapies (−1.42 [−1.67, −1.17]), DMARDs (−0.72 [−0.87, −0.58]), haematological cancer (−0.66 [−0.89, −0.43]), and long courses of steroids (−0.55 [−0.74, −0.36]), were most strongly inversely associated with log(n) S-antibody levels.
Fig. 2: Dose 2 S-antibody levels linear regression forest plot.
Beta coefficients and 95% confidence intervals, which are displayed as point estimates and associated error bars, derived from adjusted linear regression models for the effect of each clinical risk factor (investigated using a separate model) on log(n) S-antibody levels (U/ml) at ≥28 days after Dose 2. Each model controls for age, sex, ethnicity, vaccine type, dose interval and time since vaccination. Numbers included in each clinical group are as follows: Type 2 Diabetes n = 411, Type 1 Diabetes n = 46, Stroke n = 131, Severe respiratory n = 436, Neurological n = 168, Mental ill-health n = 119, Liver condition n = 144, Ischaemic heart disease n = 374, Inflammatory conditions n = 608, Immunosuppression Steroid long course n = 114, Immunosuppression MAB n = 67, Immunosuppression DMARD n = 194, Hypertension n = 2208, Heart failure n = 40, Haematological (non-malignancy) n = 52, COPD = 244, Clinically vulnerable n = 2319, Clinically extremely vulnerable n = 1144, Chronic viral (HBV, HCV, HIV) n = 45, Chronic kidney disease n = 101, Cancer Non-Haematological n = 666, Cancer Haematological n = 80, BMI underweight n = 82, BMI overweight n = 2619, BMI obese n = 1464, Asthma n = 1375.
A number of more common conditions also appeared to be inversely associated with S-antibody response in the main analysis (Fig. 2, Supplementary Table S3), which were confirmed through the sensitivity analysis (Supplementary Fig. S2, Table S4): ischaemic heart disease (−0.15 [−0.26, −0.04]), obesity when compared to normal BMI (−0.12 [−0.19, −0.06]), Type 1 Diabetes (−0.32 [−0.62, −0.02]), Type 2 Diabetes (−0.15 [−0.25, −0.05]), heart failure (−0.55 [−0.87, −0.24]), CKD (−0.43 [−0.64, −0.23]), hypertension (−0.06 [−0.11, −0.01]). While inflammatory conditions were initially inversely associated with S-antibody levels (−0.22 [−0.31, −0.13]) in the main model, this association was no longer seen in the sensitivity analysis (−0.02 [−0.11, 0.07]).
Notably, JCVI definitions of clinical vulnerability to COVID-19 were strongly inversely associated with S-antibody levels in both models, with a much stronger association seen for the Clinically Extremely Vulnerable group (−0.32 [−0.38, −0.25]) than the Clinically Vulnerable group (−0.11 [−0.16, −0.05]) in the main model, however estimates became more similar in the sensitivity analysis (−0.15 [−0.22, −0.07] vs −0.10 [−0.15, −0.05]), after adjustment for immunosuppressive therapies and conditions, which form part of the criteria for extreme clinical vulnerability.