Paxlovid does not significantly reduce COVID-19 hospitalization and mortality among vaccinated older adults, according to new UCLA-led research.
The study questions the assumption that Paxlovid’s effectiveness in reducing COVID-19 hospitalizations and deaths in unvaccinated adults also applies to vaccinated adults. Pfizer’s 2022 clinical trial found reduced COVID-19 hospitalization in unvaccinated middle-aged adults; while a subsequent 2024 clinical trial found no significant reduction in vaccinated middle-aged adults. Since most older Americans have already received two or more COVID-19 vaccines, Paxlovid’s effectiveness on vaccinated older adults has remained an important unanswered question.
“Since the strongest predictor of severe COVID-19 is advanced age, it has been crucial to obtain evidence on whether the results of the Pfizer trials generalized to older and vaccinated populations,” said Dr. John Mafi, an associate professor-in-residence of medicine in the division of general internal medicine and health services research at the David Geffen School of Medicine at UCLA and the study’s lead author.
Weaker effect
“Our study effectively rules out the notion that Paxlovid causes large reductions in COVID-19 hospitalization in vaccinated older adults,” Mafi said. “While we cannot rule out a small reduction in COVID-19 hospitalization, our results indicate that at best, Paxlovid’s potential effect on COVID-19 hospitalization among vaccinated older adults is four times weaker than the effect originally reported in Pfizer’s 2022 clinical trial.”
The findings, to be published in the peer-reviewed JAMA, “are important because Pfizer’s 2022 clinical trial continues to serve as the foundation of evidence supporting Paxlovid’s perceived effectiveness, list price of about $1,650 per treatment course, and widespread global use,” Mafi said.
“Since the study found no significant effect on COVID-19 hospitalizations and deaths among vaccinated older adults, our findings underscore the urgent need for further randomized-clinical trials investigating Paxlovid’s effects in higher-risk populations, such as older subgroups who are frail or immunosuppressed,” said Dr. Katherine Kahn, distinguished professor of medicine in the general internal medicine division and the study’s senior author.
Natural experiment
To determine the association between Paxlovid and COVID-19-related hospitalizations, all-cause hospitalizations and all-cause mortality outcomes, the researchers exploited a natural experiment in Ontario, Canada. Between April 1 and November 30, 2022, Ontario implemented an age-restrictive policy on access to Paxlovid—reserving it for symptomatic, COVID-19-positive adults aged 70 years and older, unless they were immunocompromised or had other risk factors. The researchers used data from several Ontario health databases linked by ICES, the major steward of Ontario health data.
They compared outcomes of patients who were just below vs just above 70-years-old who were plausibly similar except for their exposure to Paxlovid. The researchers found that among 1.6 million highly vaccinated older Ontarians, the policy to restrict Paxlovid to those aged 70, increased the rate of Paxlovid prescriptions by 118% at age 70. This doubling in the prescription rate did not, however, translate into improved COVID-19-related hospitalization, all-cause hospitalization, or all-cause mortality outcomes.
By restricting Paxlovid access by age, the policy created a rare natural experiment that the study analyzed to evaluate Paxlovid’s impact on key health outcomes, effectively avoiding the common observational research pitfall known as unobserved confounding. “Unobserved confounding is a problem because the decision to use Paxlovid is not random, and the factors that influence its use are able to influence the risk of hospitalization or mortality,” said study co-author Sitaram Vangala, biostatistician in the Department of Medicine Statistics Core.
Randomized access
“Because access to Paxlovid in this study was in effect randomized for those close to the age 70 cutoff, our results are unlikely to reflect unobserved confounding,” Vangala said. “This may explain why our results align with the recent negative 2024 clinical trial among vaccinated middle-aged adults, but not with observational studies showing that Paxlovid is associated with large reductions in hospitalization and mortality in vaccinated older adults.”
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The study is limited by a lack of individual patient-level data regarding symptoms, timing of previous COVID-19 vaccinations, receipt of Paxlovid, and medication adherence.
Additional co-authors Manying Cui and Artem Romanov of UCLA, and Dr. Moira Kapral and Dr. Peter Wu of the University of Toronto. Dr. Wu is affiliated with ICES.
The study was funded by the Commonwealth Fund and a National Institute on Aging Beeson Emerging Leaders in Aging Research Career Development Award (K76AG064392-01A1). This study was also supported by ICES, which is supported by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC).
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