Fourth Pfizer Dose Averts Most Severe COVID Outcomes in Older Adults

A fourth dose of the Pfizer COVID-19 vaccine provided modest protection against infection in older adults, as well as greater protection against more severe outcomes, real-world data from Israel showed.

In a cohort of 182,122 matched pairs of adults ages 60 and up, relative vaccine effectiveness ranged from 52% against asymptomatic infection to 76% against COVID-related death 14 to 30 days after the fourth dose, reported Noa Dagan, MD, of Clalit Health Services in Tel Aviv, and colleagues in the New England Journal of Medicine.

This study filled in some gaps about the effectiveness of a fourth dose that were not covered by other recent real-world studies from Israel, mainly regarding protection against more severe outcomes, such as COVID-related death.

Dagan’s group examined data from January 3 to February 18 on adults ages 60 and up who were eligible to receive a fourth dose of Pfizer vaccine and had no prior PCR-confirmed SARS-CoV-2 infection using the largest healthcare database in Israel. Healthcare workers, long-term care facility residents, and people who “interacted with the health system” during the previous 3 days were excluded.

Those who received a fourth dose (cases) were matched with those yet to receive a fourth dose (controls). Among both groups, median age was 72 years, 53% were women, and 37% had three or more CDC-defined risk factors for severe COVID.

Not surprisingly, protection against all clinical outcomes increased as days after vaccination increased, with the highest protection at days 14 to 30 after the fourth dose:

• Asymptomatic infection: 52% (95% CI 49-54)
• Symptomatic COVID: 61% (95% CI 58-64)
• COVID-related hospitalization: 72% (95% CI 63-79)
• Severe COVID: 64% (95% CI 48-77)
• COVID-related death: 76% (95% CI 48-91)

An accompanying editorial from Paul Offit, MD, of the Children’s Hospital of Philadelphia, noted that the findings of this study “were considered by the FDA and CDC in their decision-making process” for a second booster of mRNA vaccine for adults ages 50 and up.

Offit is also a member of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), which recently met to discuss considerations around subsequent booster doses for a larger swath of the U.S. population. In his editorial, Offit made his views clear about the confusion surrounding boosters.

One mistake that he pointed out was labeling mild illnesses or asymptomatic infections as “breakthrough” infections.

“The term ‘breakthrough,’ which implies failure, created unrealistic expectations and led to the adoption of a zero-tolerance strategy for this virus,” Offit 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.”

Boosters are “not risk-free,” as “all age groups are at risk for the theoretical problem of an ‘original antigenic sin’ — a decreased ability to respond to a new immunogen because the immune system has locked onto the original immunogen,” he added.

Dagan’s group acknowledged that they were unable to assess the longer-term effects of boosters, as well as the potential for unmeasured confounders, and “interpretation of the results should be made with respect to the population analyzed.”

It is important that the CDC educate the public “about the limits of mucosal vaccines,” Offit emphasized. “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.”