Summary
Background
Following the emergency use authorisation of the Pfizer–BioNTech mRNA COVID-19 vaccine BNT162b2 (international non-proprietary name tozinameran) in Israel, the Ministry of Health (MoH) launched a campaign to immunise the 6·5 million residents of Israel aged 16 years and older. We estimated the real-world effectiveness of two doses of BNT162b2 against a range of SARS-CoV-2 outcomes and to evaluate the nationwide public-health impact following the widespread introduction of the vaccine.
Methods
We used national surveillance data from the first 4 months of the nationwide vaccination campaign to ascertain incident cases of laboratory-confirmed SARS-CoV-2 infections and outcomes, as well as vaccine uptake in residents of Israel aged 16 years and older. Vaccine effectiveness against SARS-CoV-2 outcomes (asymptomatic infection, symptomatic infection, and COVID-19-related hospitalisation, severe or critical hospitalisation, and death) was calculated on the basis of incidence rates in fully vaccinated individuals (defined as those for whom 7 days had passed since receiving the second dose of vaccine) compared with rates in unvaccinated individuals (who had not received any doses of the vaccine), with use of a negative binomial regression model adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85 years), sex, and calendar week. The proportion of spike gene target failures on PCR test among a nationwide convenience-sample of SARS-CoV-2-positive specimens was used to estimate the prevelance of the B.1.1.7 variant.
Findings
During the analysis period (Jan 24 to April 3, 2021), there were 232 268 SARS-CoV-2 infections, 7694 COVID-19 hospitalisations, 4481 severe or critical COVID-19 hospitalisations, and 1113 COVID-19 deaths in people aged 16 years or older. By April 3, 2021, 4 714 932 (72·1%) of 6 538 911 people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Adjusted estimates of vaccine effectiveness at 7 days or longer after the second dose were 95·3% (95% CI 94·9–95·7; incidence rate 91·5 per 100 000 person-days in unvaccinated vs 3·1 per 100 000 person-days in fully vaccinated individuals) against SARS-CoV-2 infection, 91·5% (90·7–92·2; 40·9 vs 1·8 per 100 000 person-days) against asymptomatic SARS-CoV-2 infection, 97·0% (96·7–97·2; 32·5 vs 0·8 per 100 000 person-days) against symptomatic COVID-19, 97·2% (96·8–97·5; 4·6 vs 0·3 per 100 000 person-days) against COVID-19-related hospitalisation, 97·5% (97·1–97·8; 2·7 vs 0·2 per 100 000 person-days) against severe or critical COVID-19-related hospitalisation, and 96·7% (96·0–97·3; 0·6 vs 0·1 per 100 000 person-days) against COVID-19-related death. In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 outcomes declined. 8006 of 8472 samples tested showed a spike gene target failure, giving an estimated prevalence of the B.1.1.7 variant of 94·5% among SARS-CoV-2 infections.
Interpretation
Two doses of BNT162b2 are highly effective across all age groups (≥16 years, including older adults aged ≥85 years) in preventing symptomatic and asymptomatic SARS-CoV-2 infections and COVID-19-related hospitalisations, severe disease, and death, including those caused by the B.1.1.7 SARS-CoV-2 variant. There were marked and sustained declines in SARS-CoV-2 incidence corresponding to increasing vaccine coverage. These findings suggest that COVID-19 vaccination can help to control the pandemic.
Funding
None.
Introduction
including 821 748 cases and 6236 deaths in Israel
(population 9·1 million). Among the SARS-CoV-2 strains characterised globally in 2020, the D614G variant was dominant.
More recently, the SARS-CoV-2 variant B.1.1.7, first identified in the UK and associated with increased transmissibility, has emerged in several countries.
B.1.1.7 was first reported in Israel on Dec 23, 2020.
Evidence before this study
The Pfizer–BioNTech mRNA COVID-19 vaccine BNT162b2, administered as two doses 21 days apart, was authorised for emergency use in Israel in December, 2020, after it was shown to have high efficacy against symptomatic laboratory-confirmed COVID-19 in a randomised controlled trial of individuals aged 16 years and older. Since the initiation of vaccine rollout, we have been closely monitoring the scientific literature (including preprint servers) and press coverage to identify reports of BNT162b2 vaccine effectiveness. Although observational studies have estimated the effectiveness of BNT162b2, precise nationwide effectiveness estimates of two doses of BNT162b2 against SARS-CoV-2 outcomes are lacking. More data are particularly needed regarding the vaccine’s effectiveness against severe disease and deaths, and effectiveness in older adults. Finally, no country has yet described the nationwide public health impact of a national COVID-19 vaccination campaign.
Added value of this study
This analysis of nationwide surveillance data, done in a period when SARS-CoV-2 variant B.1.1.7 was the dominant strain, provides precise real-world estimates of the high effectiveness of two doses of BNT162b2 against a range of SARS-CoV-2 outcomes, including symptomatic and asymptomatic infection and hospitalisation or death due to COVID-19. The median follow-up time of 7 weeks after the second dose for vaccinated individuals was longer than that in previous reports. Marked and sustained declines in the incidence of SARS-CoV-2 infections were observed in all age groups as the percentage of individuals vaccinated with two BNT162b2 doses began to rise, thereby showing, at a national level, the beneficial public health impact of a nationwide vaccination campaign.
Implications of all the available evidence
Vaccination with two doses of BNT162b2 has high efficacy and effectiveness against a range of SARS-CoV-2 outcomes, including among older adults (aged ≥85 years), offering hope that COVID-19 vaccination will eventually control the pandemic. These findings are of international importance as vaccination programmes ramp up across the rest of the world, suggesting that other countries can similarly achieve marked and sustained declines in SARS-CoV-2 incidence if they can achieve high vaccine uptake.
After emergency use authorisation of BNT162b2 in Israel on Dec 6, 2020, the Ministry of Health (MoH) launched a nationwide vaccination campaign to administer two doses of BNT162b2 to the 6·5 million people aged 16 years and older (71% of the population). On April 3, 2021, 61% of the population of Israel had received at least one dose of a COVID-19 vaccine, a proportion higher than that of any other country in the world.
Israel,
,
the UK,
,
and the USA,
and estimates for two doses of BNT162b2 have been described for a subset of the Israeli population enrolled in a health maintenance organisation.
However, no estimates of the effectiveness of two doses of BNT162b2 against a range of SARS-CoV-2 outcomes, including among older adults, have been reported. Furthermore, population-level estimates of the impact of a COVID-19 vaccine on the incidence of SARS-CoV-2 infections have not been reported.
In this study, we provide nationwide estimates of the effectiveness of two doses of BNT162b2 against a range of SARS-CoV-2 outcomes and to evaluate the nationwide public-health impact following the widespread introduction of the vaccine.
Methods
Study design and population
In this observational study, we analysed nationwide surveillance data from Jan 24 to April 3, 2021, to assess the effectiveness of the BNT162b2 vaccine against various SARS-CoV-2 outcomes. The study population consisted of residents of Israel (ie, the census population) aged 16 years and older. The start of the study period corresponded to 14 days after the first individuals received their second BNT162b2 dose.
Clalit (in which 54% of the population are enrolled), Maccabi (26%), Meuhedet (12%), and Leumit (8%).
All Israeli residents are assigned a unique identification number that enables data linkage in the national medical records database.
The Israel MoH planned, organised, and continues to lead the nationwide vaccination campaign, which began on Dec 20, 2020, and was initially targeted at people aged 65 years and older, health-care workers, and residents of long-term care facilities. Vaccine availability was subsequently expanded, approximately weekly, to younger age cohorts in 5-year intervals. Until Feb 28, 2021, because of an insufficient vaccine supply, individuals with a previous diagnosis of laboratory-confirmed SARS-CoV-2 infection were instructed to not seek vaccination, unless they were a resident of a long-term care facility. However, an unknown number of previously diagnosed people received vaccine. Immunisations were given at around 400 vaccination sites. At these sites, information about the administered vaccine was entered into the patient’s electronic health record and reported to the national database.
Surveillance of COVID-19 and vaccine uptake are part of the national pandemic response and are collected under Public Health Ordinance number 40. Only aggregate data, with no personal identifiers, were used in this analysis.
Testing for SARS-CoV-2, including variant B.1.1.7
,
Public health surveillance
,
Outcomes
Vaccine effectiveness estimates were assessed against six SARS-CoV-2 outcomes, comprising asymptomatic infections and five other hierarchical laboratory-confirmed outcomes: all SARS-CoV-2 infections (symptomatic and asymptomatic), symptomatic COVID-19 cases, and COVID-19-related hospitalisations, severe or critical hospitalisations (including those who died), and deaths. Asymptomatic infection was defined as a person with laboratory-confirmed SARS-CoV-2 infection who reported no fever and no respiratory symptoms during the symptom interview portion of the epidemiological investigation, and who was not subsequently hospitalised for or did not die from COVID-19.
Statistical analysis
was used to derive incidence rate ratios (IRRs) with 95% CIs for each outcome adjusted for age group, sex, and calendar week. The exposure command was used to account for varying patient-days across strata.
Vaccine effectiveness estimates were calculated as (1 – IRR) × 100. In sensitivity analyses, vaccine effectiveness estimates were also calculated with the same method for people who had received two BNT162b2 doses and for whom at least 14 days had passed after the second dose, as well as for those who had received one dose and for whom 14–21 days had passed after the first dose.
Role of the funding source
The Israel MoH and Pfizer separately provided in-kind support to this study. No funding was exchanged between the Israel MoH and Pfizer. MoH and Pfizer were involved in the study design and writing of the report, and approved the decision to submit for publication.
Results
Figure 1Daily laboratory-confirmed SARS-CoV-2 infections in Israel (Nov 1, 2020, to April 3, 2021)
From Jan 24 to April 3, 2021 (the study period), there were 232 268 SARS-CoV-2 infections. 213 919 (92·1%) of infected individuals were interviewed and 186 109 (87·1%) answered the questions about the presence or absence of symptoms. People aged 16 years or older accounted for 154 648 (66·6%) infections, among which 31 548 (20·4%) were in the Arab sector, 24 280 (15·7%) in the ultra-Orthodox sector, and 98 220 (63·9%) in the general Jewish (non-ultra-Orthodox) sector. During the study period, 7694 COVID-19 hospitalisations, 4481 severe or critical COVID-19 hospitalisations, and 1113 COVID-19 deaths occurred in people aged 16 years or older. 8472 (60%) of Leumit PCR tests used TaqPath during the study period, of which 8006 had an SGTF, giving an estimated prevalence of 94·5% for the B.1.1.7 variant.
Table 1Numbers and proportions of people fully vaccinated with BNT162b2 in the Israel population aged 16 years and older (Jan 24 to April 3, 2021)
Among 154 648 SARS-CoV-2 infections in those aged 16 years and older, 109 876 (71·0%) were unvaccinated and 6266 (4·1%) were fully vaccinated (with ≥7 days after the second dose). Among 54 677 people aged 16 years and older who had symptomatic COVID-19, 39 065 (71·4%) were unvaccinated and 1692 (3·1%) received two doses (with ≥7 days after the second dose). Among 7694 people aged 16 years and older who were hospitalised with COVID-19, 5526 (71·8%) were unvaccinated and 596 (7·7%) received two doses with ≥7 days after the second dose. 4481 COVID-19-related severe or critical hospitalisations occurred in people aged 16 years and older, among which 3201 (71·4%) people were unvaccinated and 364 (8·1%) were fully vaccinated. Of the 1113 people aged 16 years and older who died from COVID-19, 715 (64·2%) were unvaccinated and 138 (12·4%) were fully vaccinated.
Table 2Estimated effectiveness of two doses of BNT162b2 (≥7 days after the second dose) against laboratory-confirmed SARS-CoV-2 outcomes by age group (Jan 24 to April 3, 2021)
Numbers and incidence rates of outcomes are shown for unvaccinated and fully vaccinated individuals. Vaccine effectiveness estimates are % (95% CI).
Table 3Estimated effectiveness of two doses of BNT162b2 (≥7 days after the second dose) against laboratory-confirmed SARS-CoV-2 outcomes in the oldest age groups (Jan 24 to April 3, 2021)
Estimates are % (95% CI).
Table 4Estimated effectiveness of two doses of BNT162b2 (≥14 days after the second dose) against laboratory-confirmed SARS-CoV-2 outcomes by age group (Jan 24 to April 3, 2021)
Numbers and incidence rates of outcomes are shown for unvaccinated and fully vaccinated individuals. Vaccine effectiveness estimates are % (95% CI).
Figure 2Incident cases of SARS-CoV-2 infection and prevalence of BNT162b2 vaccination by age group in Israel (Dec 1, 2020, to March 6, 2021)
Graphs show the 7-day daily moving average of laboratory-confirmed SARS-CoV-2 infections and the percentage of the population who had received one and two doses of the vaccine at each time point in people aged 65 years and older (A), 45–64 years (B), 25–44 years (C), and 16–24 years (D). Note that y-axis scales showing infection incidence differ between age groups.
Discussion
This nationwide observational study, with a median follow-up period of almost 7 weeks after receipt of the second vaccine dose, showed high effectiveness of two doses of BNT162b2, including among older adults, against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, severe disease, and deaths. Corroborating the high effectiveness observed, marked declines in incident cases of SARS-CoV-2 infection were observed as vaccine coverage increased. Although population-level vaccine effectiveness data are ecological, and teasing apart the impact of a vaccination programme from the impact of non-pharmaceutical interventions (including a nationwide lockdown) is complex, it is noteworthy that declines in incident cases of SARS-CoV-2 for each age group corresponded with achieving high vaccine coverage in that age group rather than initiation of the nationwide lockdown. These findings suggest that the primary driver of reductions in the incidence of SARS-CoV-2 infections was high vaccine coverage, not implementation of the lockdown. Furthermore, even after reopenings occurred, SARS-CoV-2 incidence remained low, suggesting that high vaccine coverage might provide a sustainable path towards resuming normal activity. These data provide nationwide evidence of the beneficial public health impact of a COVID-19 vaccination campaign.
Notably, another clinically important variant, B.1.351, which was initially identified in South Africa, has recently been identified in Israel.
Vaccine effectiveness against B.1.351, however, could not be estimated in our study because of the small number of B.1.351 infections identified in Israel during the study period.
This study also suggests that two doses of BNT162b2 are effective against asymptomatic SARS-CoV-2 infections (with vaccine effectiveness estimates of 92% at ≥7 days after the second dose and 94% at ≥14 after the second dose). Estimates of effectiveness against asymptomatic infections were slightly lower than those against COVID-19, which could suggest a higher threshold of protection for asymptomatic infection compared with symptomatic illness. We conservatively defined asymptomatic infections as SARS-CoV-2 infections in interviewees who reported no fever and no respiratory symptoms at the time of the interview. Additionally, it is possible that some SARS-CoV-2-infected individuals who reported being asymptomatic at the time of interview might have instead been presymptomatic (ie, developed symptoms later). Although we made efforts to avoid this type of misclassification by excluding the small number of people who were initially reported to be asymptomatic but were later hospitalised for or died from COVID-19, some presymptomatic individuals who later developed symptoms without being hospitalised or dying might still have been included. This type of misclassification, however, was probably uncommon and would be unlikely to substantially influence the vaccine effectiveness estimate against asymptomatic infection.
Notably, Israel’s SARS-CoV-2 testing policy was different for unvaccinated and vaccinated individuals during the study period. At 7 days after the second dose, vaccinated individuals were exempt from the SARS-CoV-2 testing required of individuals who either had contact with a laboratory-confirmed case or returned from travel abroad. This testing policy might have resulted in a differential bias that would cause overestimation of vaccine effectiveness against asymptomatic infection (ie, asymptomatic people who received two doses were less likely to be tested than unvaccinated asymptomatic people). However, 19% of the 4·4 million PCR tests conducted during the study period were done on exempted individuals (MoH, unpublished data). Additionally, symptomatic individuals might have been reluctant to report symptoms for fear of being blamed for infecting other individuals, in which case asymptomatic vaccine effectiveness would also be overestimated. Conversely, individuals who were hesitant to receive a COVID-19 vaccine might also have been reluctant to seek SARS-CoV-2 testing, which would lead to underestimation of vaccine effectiveness against asymptomatic infection. Further studies are needed to confirm the magnitude of BNT162b2 protection against asymptomatic infection that we observed. Specifically, studies are needed to evaluate testing behaviour of vaccinated and unvaccinated people and to determine the extent to which prevention of asymptomatic infection leads to interruption of transmission.
Our study adds important new data about the effectiveness of BNT162b2 derived from outside of the RCT setting. We found high vaccine effectiveness against a wider range of SARS-CoV-2 outcomes (including severe COVID-19 and deaths) than were evaluated in the RCT, as well as high effectiveness in older adults with a level of precision not available in the RCT. In addition, although pregnant women and immunocompromised individuals were excluded from the RCT, these groups were recommended to receive BNT162b2 in Israel and an unknown number would, therefore, have been vaccinated. Finally, unlike the clinical trial, our study provides evidence that achieving high population-level coverage with BNT162b2 can lead to marked declines in the incidence of SARS-CoV-2 infections and COVID-19 outcomes.
,
early in the vaccine campaign and in the UK.
,
Estimated effectiveness against all outcomes at 14–21 days after the first dose was lower than that of two doses at 7 days or longer or at 14 days or longer after the second dose, demonstrating the importance of fully vaccinating adults. Furthermore, despite indications of at least partial effectiveness after one dose of BNT162b2, relying on protection against COVID-19 from a single dose might not be prudent; BNT162b2 was developed and evaluated in the RCT as a two-dose schedule,
and substantially lower levels of neutralising antibodies were observed after one dose compared with after two doses.
Additionally, little is known about the duration of protection of one dose and how it compares with the durability after two doses. It is possible that one dose will provide a shorter duration of protection than two doses, particularly in an environment where new SARS-CoV-2 variants continue to emerge.
Although we adjusted our estimates for age, sex, and calendar week, the effect of additional covariates such as location, comorbidities, race or ethnicity, socioeconomic status, and likelihood of seeking SARS-CoV-2 testing should be evaluated in future studies. Preliminary findings from a study in Israel, for example, indicate that neighbourhood might be an important confounder.
Misclassification of exposures and outcomes in our study are potentially more common than in the RCT, although misclassification was probably limited by Israel’s readily available SARS-CoV-2 testing and comprehensive surveillance system. Misclassification of vaccine history in our study was also unlikely because of comprehensive recording of vaccine administration in Israel. With nearly 7 weeks of follow-up after the second dose, our study has the longest follow-up reported so far, although longer-term data on effectiveness are needed. Another limitation is that the time from symptom onset to hospitalisation and death might have prevented identification of all hospitalisations and deaths during the study period. Such unidentified hospitalisations and deaths are unlikely, however, to be differential between the vaccinated and unvaccinated groups. Finally, given differences between countries in how vaccines are rolled out and in how the pandemic evolves, caution should be used in extrapolating our findings to other populations. Further real-world effectiveness studies of BNT162b2, and other COVID-19 vaccines, in other populations and settings are needed.
which has been estimated to be at least 60%,
although the emergence of more transmissible SARS-CoV-2 variants could result in higher herd immunity thresholds. Achieving the SARS-CoV-2 herd immunity threshold might not be reached, however, without vaccinating some individuals younger than 16 years. In addition, the duration of immunity to SARS-CoV-2, either from infection or immunisation, is not known, and progress towards herd immunity in Israel could be disrupted by the emergence of new SARS-CoV-2 variants if those variants are less susceptible to the current vaccine-induced immune response and if they were to become broadly disseminated. Further studies are needed to monitor the population level of immunity, identify disruption of viral transmission, and detect and evaluate the effects of emerging SARS-CoV-2 variants.
This study showed that two doses of BNT162b2 were highly effective, including in older adults, against laboratory-confirmed SARS-CoV-2 infections and COVID-19 hospitalisations, severe disease, and deaths in a nationwide observational study where variant B.1.1.7 was the dominant strain. Marked nationwide declines in the incidence of SARS-CoV-2 infections and COVID-19 outcomes corresponded with increasing vaccine coverage, and these declines were sustained even after societal reopening. Finally, the high effectiveness against all SARS-CoV-2 infections and apparent effectiveness against infections that were asymptomatic at the time of epidemiological investigation suggest that BNT162b2 might reduce SARS-CoV-2 transmission. Taken together, these findings suggest that high vaccine uptake can meaningfully stem the pandemic and offers hope for eventual control of the SARS-CoV-2 outbreak as vaccination programmes ramp up across the rest of the world.
EJH and SA-P conceived the study, conducted the analysis, and edited the final manuscript. EJH, FJA, JMM, and DLS wrote the first draft of the protocol. EJH, JMM, FK, and KP cleaned and analysed the data. All authors contributed to study design, drafting the protocol, and revising the manuscript for important intellectual content, were responsible for the decision to submit for publication, and approved the final submitted version of the manuscript. All authors had full access to the deidentified and aggregated data in the study. EJH, JMM, and FK accessed and verified the data underlying the study and take responsiblity for the data.
Acknowledgments
We thank Natalia Bilenko, Tal Brosh, Dani Cohen, Ron Dagan, Aharona Glatman-Freedman, Michael Gdalevich, Manfred Green, Yoram Hamu, Amit Huppert, Udi Kaliner, Boaz Lev, Ella Mendelson, Ami Mizrachi, Walid Salliba, Avigdor Shafferman, Chen Stein-Zamir, Michal Stein, Dana Wolf, and Gidon Zuriely of the Israel Advisory Council for COVID-19 Vaccine Effectiveness for their guidance and feedback on data management and analysis. We also thank Rona Kaiser, Hanna Levi, Gilad Saar, Osnath Dreyfuss, and Natalia Pertsovsky from the Israel MoH for data management and programming assistance; Yotam Shenhar from Leumit Health Services and Ron Milo and Yinon Bar On from the Weizmann Institute of Science for assistance with data on SARS-CoV-2 variant B.1.1.7 in Israel; and Marc Lipsitch and Miguel Hernan from Harvard University for epidemiological guidance. We acknowledge Ugur Sahin and Özlem Türeci from BioNTech, the holder of the emergency use authorisation for BNT162b2 in Israel; BNT162b2 is produced using BioNTech proprietary mRNA technology and was developed by BioNTech and Pfizer.
