Fourth COVID vaccine dose gives 76% added protection against death

Needle inserted into Pfizer COVID vaccine vial
Needle inserted into Pfizer COVID vaccine vial

Diverse Stock Photos / Flickr cc

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

Protection against infection waned, however, after 5 weeks, but not protection against severe COVID-19. The findings were published yesterday in the New England Journal of Medicine.

Clalit Research Institute investigators in Tel Aviv led the study, which compared the effectiveness of a fourth vaccine dose 8 days earlier—after a third dose at least 4 months before—relative to a third dose only (control group) and a fourth dose 3 to 7 days earlier (internal control group), among 1,252,331 participants 60 and older from Jan 3 to Feb 18, 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 hospitalization (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 hospitalization, 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 hospitalization 7 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 analyses 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 4 weeks after a fourth dose, while it was still strong against severe illness at 6 weeks.

Public confused about intent of vaccines

In a related commentary, Paul Offit, MD, 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 labeling of mild illnesses or asymptomatic infections after vaccination as 'breakthroughs,'" he wrote. For all mucosal vaccines, Offit said, the goal is to protect against hospitalization, 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" onto the original one—Offit urged clarification of which groups benefit the most.

"It is now incumbent on the CDC [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."

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