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Fourth COVID jab gives 76% added protection against death – Israeli study

Compared with a third vaccine dose, a fourth Pfizer/BioNTech COVID-19 shot lowered the risk of infection, symptomatic infection, hospitalisation, severe illness, and death from 52% to 76%, depending on the measure, amid the Omicron surge among older adults, an Israeli study found.

CIDRAP reports that protection against infection waned, however, after five weeks, but not protection against severe COVID-19.

The findings were published in the New England Journal of Medicine last Wednesday (13 April). Clalit Research Institute investigators in Tel Aviv led the study, which compared the effectiveness of a fourth vaccine dose eight days earlier – after a third dose at least four months before – relative to a third dose only (control group) and a fourth dose three to seven days earlier (internal control group), among 1,252,331 participants 60 and older from 3 January to 18 February 2022.

Greater, more durable protection against severe outcomes

Seven to 30 days after the fourth COVID-19 dose, vaccine effectiveness (VE) relative to the third dose was estimated at 45% against infection (95% confidence interval [CI], 44% to 47%), 55% against symptomatic illness (95% CI, 53% to 58%), 68% against COVID-19 hospitalisation (95% CI, 59% to 74%), 62% against severe disease (95% CI, 50% to 74%), and 74% against death (95% CI, 50% to 90%).

Fourteen to 30 days after the fourth dose, VE was 52% (95% CI, 49% to
54%) against infection, 61% (95% CI, 58% to 64%) against symptomatic illness, 72% (95% CI, 63% to 79%) against hospitalisation, 64% (95% CI, 48% to 77%) against severe disease, and 76% (95% CI, 48% to 91%) against death.

In the fourth week after the fourth dose, the adjusted infection rate was lower by a factor of 2.0 (95% CI, 1.9 to 2.1) than that in the three-dose group and lower by a factor of 1.8 (95% CI, 1.7 to 1.9) than that among controls.

The difference in absolute risk for COVID-19 hospitalisation seven to 30 days after a fourth vaccine dose, relative to a third, was 180.1 per 100,000 people (95% CI, 142.8 to 211.9), while it was 68.8 cases per 100,000 (95% CI, 48.5 to 91.9) for severe disease. A sensitivity analysis of VE against infection had similar results as those in the primary analysis.

Starting in the fifth week after the fourth dose, the rate ratio (RR) for infection began to fall. The adjusted rate of infection in the eighth week after the fourth dose was comparable to that of internal controls. The RR for the three-dose group relative to the four-dose group was 1.1, while the rate ratio for the internal control group, compared with the four-dose groups, was 1.0.

The RRs comparing controls with fourth-dose recipients were larger and lasted longer for severe disease. In the fourth week after the fourth dose, the adjusted rate of severe disease was lower by a factor of 3.5 than in three-dose recipients and a factor of 2.3 than in internal controls.

The adjusted rate of severe illness in the fourth week after the fourth dose was 1.6 cases per 100,000 person-days, compared with 5.5 cases per 100,000 in three-dose recipients and 3.6 cases per 100,000 in internal controls. The adjusted rate differences were 3.9 fewer cases per 100,000 person-days and 2.1 fewer cases per 100,000 than the three-dose group and internal controls, respectively.

Severe illness continued to occur at lower rates among fourth-dose recipients than in controls in later weeks after the fourth dose, with no signs of waning by the sixth week.

“Rates of confirmed SARS-CoV-2 infection and severe COVID-19 were lower after a fourth dose of BNT162b2 [Pfizer] vaccine than after only three doses,” the researchers wrote. “Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.”

The authors noted that previous studies had suggested waning immunity to the Delta variant as soon as 10 weeks after a third dose. A study by a different Israeli group published earlier this month found that protection against Omicron infection began to wane four weeks after a fourth dose, while it was still strong against severe illness at six weeks.

Public confused about intent of vaccines

In a related commentary, Dr Paul Offit of Children’s Hospital of Philadelphia said that many people are confused about the definition of “fully vaccinated”.

“Arguably, the most disappointing error surrounding the use of COVID-19 vaccines was the labelling of mild illnesses or asymptomatic infections after vaccination as ‘breakthroughs’,” he wrote. For all mucosal vaccines, Offit said, the goal is to protect against hospitalisation, intensive care unit admission, and death.

“The term ‘breakthrough’, which implies failure, created unrealistic expectations and led to the adoption of a zero-tolerance strategy for this virus,” he wrote. “If we are to move from pandemic to endemic, at some point we are going to have to accept that vaccination or natural infection or a combination of the two will not offer long-term protection against mild illness.”

Because additional COVID-19 doses aren’t risk-free – and all age-groups are susceptible to developing a decreased ability to respond to a new invading substance (eg, variants) because the immune system has “locked” on to the original one – Offit urged clarification of which groups benefit the most.

“It is now incumbent on the CDC [US Centers for Disease Control and Prevention] to determine who most benefits from booster dosing and to educate the public about the limits of mucosal vaccines,” he concluded. “Otherwise, a zero-tolerance strategy for mild or asymptomatic infection, which can be implemented only with frequent booster doses, will continue to mislead the public about what COVID-19 vaccines can and cannot do.”

Study details

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

Ori Magen, Jacob Waxman, Maya Makov-Assif, Roni Vered, Dror Dicker, Miguel Hernán, Marc Lipsitch, Ben Reis, Ran Balicer, and Noa Dagan.

Published in New England Journal of Medicine on 13 April 2022


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 analysed data recorded by the largest healthcare organisation 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 hospitalisation, 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 hospitalisation 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.


Cidrap article – Fourth COVID vaccine dose gives 76% added protection against death (Open access)


NEJM article – Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting (Open access)


NEJM accompanying article – Covid-19 Boosters — Where from Here? (Open access)


See more from MedicalBrief archives:


Warning from WHO and EU regulator against repeat COVID boosters


UK vaccination committee says 4th booster not necessary


Booster mRNA vaccines wane in effectiveness at 4 months – CDC


Boosters significantly strengthen immunity — Cov-Boost trial




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