Exploring protection via a 4th dose of BNT162b2 against SARS-CoV-2 Omicron variant in Israel

In a recent study posted to the medRxiv* preprint server, researchers from Israel assessed the effectiveness of a fourth dose of BNT162b2 vaccine (Pfizer-BioNTech) against confirmed infection and severe illness due to coronavirus disease 2019 (COVID-19).

Study: Protection by 4th dose of BNT162b2 against Omicron in Israel. Image Credit: Yuri Dondish/Shutterstock

Study: Protection by 4th dose of BNT162b2 against Omicron in Israel. Image Credit: Yuri Dondish/Shutterstock


COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has globally caused over 5.6 million deaths. Despite robust COVID-19 vaccines developed within a short span and administered across many countries, variants of concern (VOCs) have emerged in the ongoing pandemic. Of the VOCs, the latest is the Omicron variant, which was first identified in  South Africa in November 2021.

Omicron has increased transmissibility and virulence. It has immune evasive properties, reducing the effectiveness of public health and social measures, as well as the available diagnostics and vaccines.

In Israel, as of late December 2021, the Omicron variant was fast spreading and causing increased infections and severe illness. The third vaccine dose was administered more than four months ago, and the effects of immune protection were waning off.

In an effort to address these challenges due to the Omicron variant and to reduce the load on the healthcare system, the Israeli authorities on January 3, 2022, began administering a fourth dose of the BNT162b2 vaccine firstly to people aged over 60 years and high-risk populations as well as healthcare workers, who had received a third dose of vaccine at least 4 months earlier.

Using data from the Israeli Ministry of Health national database, the researchers in the present study assessed the real-world effectiveness of the fourth dose in reducing the confirmed COVID-19 cases and severe illness.

About the study

To determine the effectiveness of the fourth COVID-19 vaccine dose, the researchers compared it with the observed efficacy  of the third vaccine dose. Specifically, they compared the rate of the confirmed COVID-19 cases and severe illness between 1) those individuals who had received a fourth dose at least 12 days earlier, 2) those who had received only three doses, and 3) those individuals, 3 to 7 days after receiving the fourth dose.

The control group included individuals who were eligible for the fourth dose but had not yet received it. To account for unmeasured confounding variables, the researchers included a second control group of individuals for whom 3-7 days had passed since receiving the fourth dose.

This control group included the same individuals who were assessed 12 days later (the treatment group) – only at an earlier time period when the fourth dose was not expected to be effective. Because the vaccine is expected to take effect only after 3-7 days following the vaccination, a longitudinal comparison with the effect after 12 days of vaccination was also observed here.

The researchers calculated the total number of person-days at risk, and the incidence rate of the SARS-CoV-2 infection and severe illness due to COVID-19 in the control groups and the treatment group. The infection was confirmed either by state-regulated rapid antigen tests or by polymerase chain reaction tests (PCR). The severe illness due to COVID-19 was defined using the National Institutes of Health (NIH) definition, which included a resting respiratory rate of more than 30 breaths per minute, oxygen saturation of less than 94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 300.

The study period was from January 15 to January 27, 2022, extracting data regarding the SARS-CoV-2 infection and severe illness due to COVID-19. It is to be noted that during this period, the infections were overwhelmingly caused by the Omicron variant. This study started 12 days after the start of the vaccination campaign (January 3, 2022).

Based on a set of exclusion criteria, such as those who died before this study, individuals who were abroad, and those who received a vaccine dose other than Pfizer-BioNTech, etc. the study included a total of 1,138,681 participants. These participants were 60 years of age or older and had received three doses of BNT162b2 at least 4 months before the start of the study period.

While the Israeli Ministry of Health and Pfizer have a data-sharing agreement, the researchers pointed out that only the final results of this study were shared.

Analysis of the study population

The researchers presented the demographic and clinical characteristics of the different cohorts in this study. Because this study involved dynamic cohorts (people could move between the cohorts), the proportion of person-days at risk for confirmed infection was calculated instead of the number of individuals.

Compared to those who did not receive the fourth dose, the person-days were found to include those over the age of 80 and enriched with the general Jewish population. Individuals without the fourth dose had twice the risk days compared to the fourth-dose vaccinated ones and also had many confirmed infections and severe illness cases.

Protection conferred by the fourth COVID-19 vaccine dose

The incidence rate for confirmed infection in the group of people who did not receive the fourth dose was twice the people who received the fourth dose before 12 days or longer. Similarly, the rate of severe disease was reduced by a factor of four in the people who received the fourth dose compared to those who did not receive it.

Within the group of people who received the fourth dose, the results for incidence of infections and severe illness were similarly reduced in the group of people who received the fourth dose before 12 or more days compared to those who received a dose just 3-7 days before.

Thus, the study demonstrated that the fourth BNT162b2 vaccine dose is still able to provide protection against confirmed infection and severe illness with Omicron compared to three vaccine doses that were given at least four months previously.

The protection conferred by the fourth dose is observed to increase up to 2-3 weeks, beyond which further evaluation studies are required.

In an additional analysis, the researchers observed similar results for protection against confirmed infections in selected groups of people who were 20-59 years old.


While the fast-spreading Omicron may evade the immune response induced by three doses of COVID-19 vaccines, the fourth dose of the BNT162b2 vaccine is effective against SARS-CoV-2 infections and severe illness due to COVID-19, as observed in this study in Israel.

Therefore, the Omicron variant, though genetically divergent from the ancestral SARS-CoV-2 strain against which the BNT162b2 vaccine was developed, appears susceptible to a fourth vaccine dose.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Journal reference:

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