Effects of BNT162b2 mRNA vaccine on COVID-19 infection and hospitalisation amongst older people: matched case control study for England

Several vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) have been demonstrated to be safe and highly effective in phase 3 randomised clinical trials, with efficacy estimates for prevention of symptomatic disease ranging from 62 to 95% [1‐4]. However, it is also important to examine their effectiveness when deployed in mass vaccination campaigns across diverse populations, where trial exclusion criteria do not apply and where deviations from dosing and handling protocols may occur.

Early evidence from a matched case-control study of mass vaccination using the BNT162b2 mRNA COVID-19 vaccine in Israel estimated real-world effectiveness consistent with reported trial efficacy [3, 5]. This indirectly provided evidence that vaccine effectiveness was maintained against the more transmissible B.1.1.7. (Alpha) variant [5, 6], which was widespread in the population during the study period. Vaccine effectiveness estimates were consistent across age groups, though they were slightly lower amongst people with multiple coexisting health conditions [5]. Similarly, estimates from Scotland [7] and England [8, 9] provide further early evidence of effectiveness. However, such non-randomised matching studies may be biased by systematic differences between intervention and control groups and between those receiving the intervention at different points in time. The remarkable speed of COVID-19 vaccination rollouts [5, 7‐9] and specific prioritisation of vulnerable groups [10] heighten the risk of these biases, as acknowledged in existing studies [5, 7‐9].

We exploit age-based eligibility phasing in the early stages of the nationwide National Health Service (NHS) population vaccination programme in England to estimate the real-world effectiveness of the BNT162b2 mRNA vaccine. We match vaccinated persons aged 80 to 83 years to slightly younger persons who did not become eligible for the vaccine until three weeks later and compare their rates of COVID-19 infection and hospitalisation over the 45 days following the date of their first dose. It is particularly important to assess real-world vaccine effectiveness in this older population group, because severe COVID-19 is strongly age-associated [11] and adaptive immune responses decline with age [12].

We considered 171,931 individuals aged 80 to 83 years in England who received a first dose of BNT162b2 mRNA COVID-19 vaccine as part of the nationwide NHS vaccination campaign in England. We compared their rates of SARS-CoV-2 positive tests and COVID-19 hospitalisations in the subsequent 45 days to those for slightly younger individuals with the same characteristics who became eligible for vaccination later. Emergency admission was 50.1% (19.9 to 69.5%) less likely 21 to 27 days after vaccination and 75.6% (52.8 to 87.6%) less likely 35 to 41 days after first vaccination and 7 days after 80% had received their second dose. COVID-19 infection was 55.2% (40.8 to 66.8%) less likely 21 to 27 days after vaccination and 70.1% (55.1 to 80.1%) less likely 35 to 41 days after first vaccination and 7 days after 80% had received their second dose. Collectively, these results are consistent with one dose of the BNT162b2 mRNA vaccine reducing events from 14 days after vaccination, with more effectiveness in reducing the severity of symptoms than preventing infection.

Our results are broadly consistent with existing estimates of BNT162b vaccine effectiveness, despite variations in study design, participant demographics, and outcome definitions [21]. We estimate effectiveness against documented infection of approximately 55% 21–27 days after one dose, rising to 70% after the majority received a second dose. These estimates are relatively consistent with results from a similar studies in England (55% after one dose, 80% 7 days after all received a second dose) [8] and Scotland (78% 21–27 days after one dose) [7] and from the older age group in a similar study in Israel (50% after one dose, 95% 7 days after all received a second dose) [5]. These estimates are also comparable to estimates of vaccine effectiveness against documented infection in working-age adults in England (70% after one dose, 85% 7 days after second dose) [9] and to all-age results from a randomised controlled trial (52% rising to 95%) [3]. Our point estimate of effectiveness against hospitalisation with COVID-19 (76% 7 days after most received a second dose) is somewhat lower than, though statistically compatible with, other estimates (80–87%) [5, 8].

Several factors likely contribute to these differences. First, our estimates are specifically for an older population where vaccine-induced immune responses may be sub-optimal [12]. In addition, our population included 20% of vaccinated individuals for whom the second dose was extended beyond the study period. This may explain the greater agreement with existing estimates for effectiveness 21–27 days after vaccination than for longer follow-up when second dose coverage varied between studies. However, a study based in Scotland where the majority received only single dose BNT162b estimated 87% (70 to 94) effectiveness against hospitalisation in those aged 80 and over at an equivalent time point (35–41 days post vaccination) [7], suggesting that differences in second dose coverage may not explain the differences between estimated effectiveness.

Finally, an important consideration in observational studies is bias in selection into the intervention group. While all existing studies used statistical methods to adjust for biases [5, 7, 8, 21], we exploited the precise age thresholds that determined temporal eligibility for vaccination, thereby reducing the risk of unmeasured confounding between cases and controls. Such biases are exacerbated with longer follow-up periods as those remaining unvaccinated become increasingly different from those vaccinated earlier. The divergence between our effectiveness estimates and those in other studies with longer follow-up may reflect less bias in our study design and adjustment methodology.

We focused on older people at high risk of serious COVID-19 outcomes. We considered a period and country experiencing widespread transmission and large numbers of hospitalisations. This provided statistical precision in the effectiveness estimates within a short period. We exploited a precise age cut-off that determined access to the vaccine, which reduced bias from selection into treatment.

Nonetheless, there is a risk of bias from unmeasured confounding with any observational study. We matched cases and controls on combinations of 12 personal, household and area variables. We also compared four measures of hospital use in the previous 18 months and history of negative SARS-CoV-2 tests (see Appendix 5). Vaccinated individuals did not have lower event rates and had higher use of hospital services and more community-based COVID-19 tests prior to vaccination when compared to the control group. This likely reflects the age difference which may bias our estimates towards lower than true effectiveness.

The rich set of matching variables meant some cases were excluded because there was no control available. These exclusions were more likely for some populations, including minority ethnic groups and residents of London, but the included individuals had similar outcomes to the excluded individuals and the effectiveness results were similar when we matched on fewer variables (Appendix 4).

The speed of the rollout of the NHS vaccination programme in England into younger populations reduced the pool of similar people who had not been vaccinated. We adjusted for the selection bias this generated and assessed the robustness of this adjustment by comparing to a younger age group where the selection bias occurred later in the monitoring period.

Finally, we considered COVID-19 related hospitalisations as well as positive COVID-19 tests. Hospitalisations are less likely to be influenced by changes in attitudes after receiving a vaccine that may affect whether individuals seek COVID-19 tests, such as misperceptions of immunity or misinterpretations of symptoms as side effects.

We provide evidence of high real-world effectiveness of the original dosing schedule of the BNT162b2 mRNA COVID-19 vaccine in preventing infections and hospitalisations despite the widespread transmission of the B.1.1.7 variant shortly after the study population was vaccinated. There have been concerns about reduced vaccine effectiveness, though our data is consistent with mass vaccination data [5, 7, 8] and only slightly reduced neutralisation of B.1.1.7 pseudovirus relative to the Wuhan reference strain [22].

Our study provides rigorous evidence to support effectiveness of vaccination in the real-world amongst older people. Future research priorities include the optimal dosing regimen, the longevity of this protection and applicability to other variants, effectiveness amongst younger people and specific population subgroups, and effects on onward transmission and asymptomatic infection.