This open-label controlled intervention study was conducted at the Sheba Medical Centre (SMC), the largest tertiary hospital in Israel. Eligible participants were HCW that had previously received three doses of the BNT162b2 vaccine, had no known history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and had recorded baseline IgG levels < 700 BAU (full eligibility criteria are described in the Methods section). Participants (n = 700) were enrolled to either receive the BNT162b2 vaccine, the mRNA1273 vaccine, or to serve as controls for one or both of the two arms. Participants were followed up for immune response and clinical outcomes.
Of a total of 6,597 HCW enrolled to the Sheba HCW COVID Cohort (4, 9, 25–26), 1050 were eligible to participate. Of these, 154 were enrolled to the BNT162b2 arm on December 27–28, 2021. One week later, on January 5–6, 2022, 120 participants were enrolled to the mRNA1273 arm. From the remaining eligible 776 participants, a total of 426 controls were age-matched in a 2:1 ratio to participants in each arm. See Fig. 1 for the complete study population flow chart.
Baseline characteristics of the study population are described in Table 1. Baseline characteristics of the population used in the analysis of the clinical outcomes (which excludes those infected during the first 7 days of follow-up) are described in Table S1.
Table 1
Baseline characteristics of the study population.
| | BNT162b2 | Control (BNT162b2) | mRNA1273 | Control (mRNA1273) |
Participants enrolled | N | 154 | 308 | 120 | 239 |
Female sex | N (%) | 91 (59) | 218 (71) | 81 (67) | 178 (74) |
Male sex | N (%) | 63 (41) | 90 (29) | 39 (33) | 61 (26) |
Age | Median (range) | 60.85 (30.44–85.31) | 61.33 (30.27–89.61) | 55.97 (29.26–86.94) | 56.85 (29.21–89.61) |
BMI (kg/m2) Missing data | Median (IQR) | 26.03 (23.11–28.4) | 25.48 (23.15–28.12) | 24.77 (22.4-28.23) | 25.48 (22.96–28.76) |
% | 16 | 14 |
Comorbidities |
0 | N (%) | 92 (60) | 195 (63) | 80 (67) | 150 (63) |
1 | N (%) | 41 (27) | 51 (17) | 28 (23) | 41 (17) |
≥ 2 | N (%) | 21 (13) | 62 (20) | 12 (10) | 48 (20) |
Hypertension | N (%) | 42 (27) | * | 23 (19) | * |
Diabetes | N (%) | 14 (9) | * | 13 (11) | * |
Lung disease | N (%) | 7 (5) | * | 7 (6) | * |
Heart disease | N (%) | 11 (7) | * | 7 (6) | * |
Liver disease | N (%) | 1 (0.6) | * | 1 (1) | * |
Chronic kidney disease | N (%) | 1 (0.6) | * | 3 (3) | * |
Autoimmune disease | N (%) | 12 (8) | * | 4 (3) | * |
Immunosuppression Missing data | N (%) | 3 (2) | 4 (2) | 2 (2) | 1 (0.5) |
% | 9 | 10 |
Profession |
Physician | N (%) | 41 (27) | * | 35 (29) | * |
Nurse | N (%) | 34 (22) | * | 21 (18) | * |
Paramedical personnel | N (%) | 34 (22) | * | 35 (29) | * |
Administrative personnel | N (%) | 43 (28) | * | 26 (22) | * |
Other personnel | N (%) | 2 (1) | * | 3 (2) | * |
BMI – body mass index. *Data was not available in this group.
Immunogenicity
Crude values of the serological markers are presented in Table S2 and Fig. 2. The different immunological markers show a similar trend of reaching a maximum level 2–3 weeks following vaccination and then slowly declining. During the first month after vaccination, a 9-10-fold increase was demonstrated in anti-RBD immunoglobulin G (IgG) titer in both vaccine recipient groups. Waning of this response was observed over time, with IgG geometric mean titer (GMT) of 1442 binding antibody units (BAU) (95% CI, 1194–1741) in the mRNA1273 group and 854 BAU (95% CI, 738–989) in the BNT162b2 group observed after 90 days. In neutralizing antibodies, the increase to peak levels was of 16.5-fold in the mRNA1273 group and 9-fold in the BNT162b2 group. After 90 days, the GMT of neutralizing antibodies in the mRNA1273 group was 1046 (95% CI, 772–1417), while the BNT162b2 group had a neutralizing antibody titer of 347 (95% CI, 238–507), close to their pre-fourth dose titers. Fourteen days following the fourth dose, a 4.5-fold increase in the mRNA1273 group and a 3-fold increase in the BNT162b2 group was observed in anti-RBD immunoglobulin A (IgA), reaching GMT of 4.63 sample-to-cutoff ratio (s/co) (95% CI, 3.88–5.53) and 3 s/co (95% CI, 2.57–3.53), respectively. After three months, IgA levels declined to 1.82 (95% CI, 1.48–2.25) and 1.39 (95% CI, 1.16–1.65), respectively. The number of activated T cells elevated in the mRNA1273 group from 6 per 106 peripheral blood mononuclear cells (PBMC) (95% CI, 2–14) to 52 per 106 PBMC (95% CI, 20–134) and declined to 11 per 106 PBMC (95% CI, 3–48) after three months, while smaller changes were observed in the BNT162b2 group.
Using an adjusted model for each vaccine, we estimated in the mRNA1273 vaccine arm a 11% (ß=0.89, 95% CI, 0.88–0.9) multiplicative decay per week in IgG, 21% (ß=0.79, 95% CI, 0.76–0.82) in neutralizing antibody titers, and 10% (ß=0.9, 95% CI, 0.88–0.92) in IgA. In the BNT162b2 vaccine arm, we estimated a multiplicative decay per week of 14% (ß=0.86, 95% CI, 0.86–0.87), 26% (ß=0.74, 95% CI, 0.72–0.76), and 8% (ß=0.92, 95% CI, 0.9–0.93), respectively. No significant decay was shown in the number of activated T cells in both groups [10% (ß=0.9, 95% CI, 0.77–1.05) and 10% (ß=0.9, 95% CI, 0.74–1.09), respectively] (Table S3).
Using an adjusted model comparing the two mRNA vaccines, we demonstrated a significant difference in the decline of IgG and neutralizing antibody titers between the two vaccines, with a further multiplicative decay of 2% per week (ß=0.98, 95% CI, 0.96–0.99) and 7% (ß=0.93, 95% CI, 0.89–0.98), respectively, in the BNT162b2 group. Furthermore, we showed a 29% (ß=0.71, 95% CI, 0.57–0.89) lower IgA peak in the BNT162b2 group (Table S4).
Higher direct neutralization titers were observed for the wild-type strain and the Delta VOC than for the Omicron VOC. All direct neutralization titers demonstrated waning between days 14 and 90 post-vaccination. Additionally, direct neutralization results for the Omicron BA.2 VOC were comparable and perhaps higher than for Omicron BA.1 (Fig. 3).
Vaccine efficacy
Cumulative incidence was estimated in both arms for two clinical outcomes: (i) infection, defined by positive SARS-CoV-2 test, with or without symptoms, as determined by active surveillance, and (ii) substantial disease, as defined by two or more days in which the participant was mostly in bed due to feeling unwell (Table S5 and Fig. 4). Within 102 days of follow-up, 40–50% of the study population were infected, with only little difference between the intervention arms and their controls. In contrast, the cumulative incidence of substantial symptomatic disease was higher in the control groups: 2o% (incidence = 0.2, 95% CI, 0.11–0.27) in the controls compared with 3% (incidence = 0.03, 95% CI, 0-0.06) in the mRNA1273 vaccine arm, and 23% (incidence = 0.23, 95% CI, 0.15–0.3) and 9% (incidence = 0.09, 95% CI, 0.03–0.13) in the controls and vaccine recipients in the BNT162b2 arm, respectively.
A multivariable model, adjusted for age and sex, estimated a VE against SARS-CoV-2 infection of 25% (IRR 0.75, 95% CI, 0.51–1.11) for mRNA1273 and 3% (IRR 0.97, 95% CI, 0.69–1.38) for BNT162b2. The VE against substantial disease was 89% (IRR 0.11, 95% CI, 0.02–0.37) in the mRNA1273 group and 71% (IRR 0.29, 95% CI, 0.13–0.57) in the BNT162b2 group (Table 2, Table S6, and Fig. 4E).
Table 2
COVID-19 Vaccine efficacy for infection and substantial disease
A. COVID-19 VE for infection |
Variable | Person-days | Positive cases | Incidence rate per 1000 person-days | Crude VE | Adjusted VE |
mRNA1273 controls (N = 129) | 7,577 | 61 | 8.05 | -ref- | -ref- |
mRNA1273 (N = 115) | 8,029 | 45 | 5.6 | 30.4% | 24.6% (-10.8-49.1%) |
BNT162b2 controls (N = 297) | 9,669 | 69 | 7.14 | -ref- | -ref- |
BNT162b2 (N = 150) | 10,697 | 66 | 6.17 | 13.6% | 2.8% (-37.7-31.5%) |
B. COVID-19 VE for substantial disease |
mRNA1273 controls (N = 126) | 7,377 | 20 | 2.71 | -ref- | -ref- |
mRNA1273 (N = 115) | 8,029 | 2 | 0.25 | 90.8% | 89.3% (63.2–98.3%) |
BNT162b2 controls (N = 291) | 9,395 | 35 | 3.73 | -ref- | -ref- |
BNT162b2 (N = 147) | 10,541 | 10 | 0.95 | 74.5% | 71% (42.63-86-63%) |
Vaccine efficacy is calculated as 1-IRR.