Medical Health Cluster

24 abril, 2022

Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting



With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.


To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19–related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.


The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction–confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19–related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19–related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19–related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.


A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19–related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)

The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in November 2021, has generated the largest waves of infection in the coronavirus disease 2019 (Covid-19) pandemic thus far, even in countries with successful mass-vaccination campaigns.1,2 Although early data from South Africa3 and subsequently from the United Kingdom4 suggested that the omicron variant was less virulent than the B.1.617.2 (delta) variant, with lower rates of hospitalization and severe disease, the large number of infections observed over a short period of time led to concerns that health care resources might be overwhelmed.

Initial evidence indicated that two doses of vaccine (BNT162b2 [Pfizer–BioNTech], mRNA-1273 [Moderna], or ChAdOx1 nCoV-19 [AstraZeneca]) offered limited protection against the omicron variant and that a recently administered third (booster) dose was effective in preventing symptomatic and severe disease.5,6 Laboratory and real-world studies have since shown evidence of waning immunity as early as 10 weeks after the third dose.5-7 In countries with early booster-dose campaigns such as Israel, the United Kingdom, and the United States, the onset of the omicron wave occurred at a time when many persons — especially those who were more vulnerable to severe Covid-19 — had received their booster dose several months earlier. Therefore, policymakers considered offering a fourth vaccine dose to the most vulnerable persons as possible protection against the omicron variant.

On January 3, 2022, the Israeli Ministry of Health launched a national fourth-dose vaccination campaign for high-risk persons (i.e., those who were ≥60 years of age or who had an immune deficiency) at least 4 months after their third vaccine dose. To date, more than 700,000 people in Israel have received a fourth BNT162b2 mRNA vaccine dose.8,9 In the United States, in response to the omicron wave, the Centers for Disease Control and Prevention (CDC) reduced the period between the third and fourth vaccine doses for immunocompromised persons from 6 months to 5 months.10 Other countries, including the United Kingdom, have also started rolling out targeted fourth-dose vaccination campaigns.11

Real-world evidence of the effectiveness of the fourth dose of BNT162b2 was published in a recent study,12 which showed that a fourth dose is more effective in preventing SARS-CoV-2 infection and severe Covid-19 than three doses. However, evidence regarding the effectiveness of a fourth dose in preventing additional outcomes, such as Covid-19–related hospitalization and Covid-19–related death, was not included in the study, and some potentially important confounders, such as coexisting conditions, were unable to be addressed.

We used the data repositories of the largest health care organization in Israel to estimate the relative effectiveness of a fourth dose of the BNT162b2 vaccine, as compared with three doses, in preventing a range of Covid-19–related outcomes among persons 60 years of age or older, while taking into account potential confounders.



We used data collected between January 3 and February 18, 2022, when the omicron variant was predominant in Israel,13 to emulate a target trial evaluating the effectiveness of a fourth vaccine dose as compared with three vaccine doses. We analyzed data from Clalit Health Services (CHS), the largest integrated payer–provider health care organization in Israel. With more than 4.7 million members, CHS covers more than half of the population of Israel. The CHS population is largely representative of the general Israeli population.14,15 CHS health records have been fully digitized since 2000, and its data repositories include demographic, diagnostic, pharmacologic, laboratory, procedure, imaging, and hospitalization data. Data related to SARS-CoV-2 infections (polymerase-chain-reaction [PCR] and antigen tests) and Covid-19 outcomes (including hospitalization, severe illness, and death) are stored centrally by the Israeli Ministry of Health and delivered daily to the four national health organizations.

This study was approved by the institutional review board of CHS. An exemption from the requirement for informed consent was granted. The authors vouch for the accuracy and completeness of the data in this report.


We included persons who, at baseline (defined below), were 60 years of age or older, had been members of CHS for at least 1 year, and were eligible to receive the fourth vaccine dose at any time during the study period (i.e., had been vaccinated with a third dose of BNT162b2 at least 4 months earlier16) and had no previous PCR-confirmed SARS-CoV-2 infection. As in previous studies,17-19 we also excluded health care workers, persons in long-term care facilities, persons confined to the home, and persons who had interacted with the health care system (e.g., saw a doctor or had blood tests performed) during the previous 3 days. This last exclusion criterion reduces the probability that persons who opted to delay receipt of a fourth vaccine dose because they were feeling unwell (possibly with symptoms of Covid-19) would be included in the control group. Given the rarity of missing data in the CHS data set (<1%), we also excluded persons with missing data on body-mass index (BMI), population sector, or residency area. A detailed description of all the study variables is provided in Table S1 in the Supplementary Appendix, available with the full text of this article at


We examined five outcomes: PCR-confirmed SARS-CoV-2 infection, symptomatic Covid-19, Covid-19–related hospitalization, severe Covid-19 (defined according to National Institutes of Health criteria), and Covid-19–related death. All outcomes were assessed over two follow-up periods of interest: days 7 to 30 after the fourth dose and days 14 to 30 after the fourth dose. In addition, to estimate the gradual build-up of immunity and evaluate the similarity of the study groups during the initial days after vaccination (the negative control period20), PCR-confirmed infection was also assessed separately during each day of follow-up.


The study design of the primary analysis was similar to that used in our previous vaccine-effectiveness studies,17,19 which examined the same population in a similar setting. On each day of the study period, eligible persons who received the fourth dose of the BNT162b2 mRNA vaccine on that day (four-dose group) were exactly matched to eligible persons who had not yet received a fourth dose as of that day (control group) according to a set of potential confounders: age (categorized into 1-year bins), sex, residency area, population sector (three categories: Arab, General Jewish, and Ultra-Orthodox Jewish), calendar month in which each person received the third vaccine dose, number of preexisting chronic conditions defined by the CDC (on December 20, 202021) as risk factors for severe Covid-19 (categorized into four bins: 0, 1, 2, and ≥3), and number of hospital admissions in the previous 3 years (categorized into 5 bins: 0, 1, 2, 3 or 4, and ≥5). The latter two variables, together, were designed to capture the load and stability of chronic conditions.

Each matched pair was followed from the matching date until the earliest of the following events: the outcome of interest; death; 30 days of follow-up; February 18, 2022 (the final day of data collection); or fourth-dose vaccination of the control member of the matched pair (at which point data for both members of the matched pair were censored). Controls who received a fourth vaccine dose after they had been matched as controls became eligible to be rerecruited to the four-dose group and matched to a new control.


Cumulative incidence curves were constructed with the use of the Kaplan–Meier estimator. For each follow-up period, only matched pairs in which data for both members had not been censored as of the beginning of the follow-up period were included. Risk was defined as the probability of a given outcome developing during the follow-up period. The estimated risks in each group were compared both as risk ratios and as risk differences. Vaccine effectiveness was estimated as 1 minus the risk ratio. We calculated 95% confidence intervals using the nonparametric bootstrap method with 500 repetitions. The widths of the confidence intervals have not been adjusted for multiplicity and should not be used to infer statistical significance.

We performed two sensitivity analyses to explore the robustness of our estimates. First, our estimates of the observational analogue of the per-protocol effect, in which data from matched pairs were censored when the control received a fourth dose, would have been biased if the probability of vaccination changed around the time of infection (i.e., nonrandom censoring). We therefore performed an analysis identical to the primary analysis except that when the control received a fourth vaccine dose, the censoring of data from the matched pair was delayed by 7 days,17 a period during which the additional dose was not yet expected to have taken effect. In this sensitivity analysis, controls did not subsequently undergo rerecruitment to the four-dose group.

Second, as an alternative to our nonparametric Kaplan–Meier approach, we also fit three parametric Poisson regression models with a log-link function22 on all eligible persons, with each model incorporating a different definition of time-varying exposure: no fourth vaccine dose, days 1 to 4 after the fourth vaccine dose, days 5 and 6, and day 7 and onward; no fourth vaccine dose, days 1 to 4, days 5 and 6, days 7 to 13, and day 14 and onward; and no fourth vaccine dose and each day of follow-up treated as a separate category. Persons were able to contribute follow-up data to each of these four-dose groups (i.e., the groups based on time since receipt of the fourth dose) and to the control group dynamically and regardless of interactions with the health care system. The outcome of interest was PCR-confirmed documented SARS-CoV-2 infection. All models included, as covariates, the calendar date of each day of follow-up and the matching factors described above, with residency area (a covariate with hundreds of categories) replaced by a measure of local Covid-19 burden (the proportion of positive PCR tests in the residency area on the previous day) (Methods section S1). In this analysis, vaccine effectiveness was defined as 1 minus the incidence rate ratio estimated from the model.

Analyses were performed with the use of R software, version 4.1.0, and the additional freely available R software packages “tidyverse,” version 1.3.1, and “survminer,” version 0.4.9.

Créditos: Comité científico Covid

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