VA Study Called for New Vaccines to Be Developed
Click to Enlarge: Cumulative incidence of documented SARS-CoV-2 infections, SARS-CoV-2–associated hospitalizations*, and SARS-CoV-2–associated deaths† in vaccinated vs. matched unvaccinated participants of a target trial emulation study extending from 2 October 2023 to 10 May 2024.
Enrollment was from 2 October 2023 to 3 January 2024, and follow-up extended to 10 May 2024, resulting in a mean follow-up of 176 days. The analysis is limited to 585,920 matched pairs, both of whom remained uninfected and alive as of day 10 after the index date.
* Any hospitalization occurring the day prior through 10 d after the eligible positive SARS-CoV-2 test result.
† Any death occurring the day of through 30 d after the eligible positive SARS-CoV-2 test result. Source: Annals of Internal Medicine
SEATTLE — Serious concerns were raised in a new VA study about the effectiveness of COVID-19 vaccines targeting the XBB.1.5 Omicron variant, which were introduced in September 2023.
“COVID-19 vaccines targeting the XBB.1.5 variant of Omicron were not effective in preventing infection and had relatively low VE against hospitalization and death, which declined rapidly over time,” wrote researchers from the VA Puget Sound Healthcare System and the University of Washington, both in Seattle, and colleagues.
In an article published in Annals of Internal Medicine, the researchers noted, “In the absence of randomized controlled trials demonstrating their efficacy, information on real-world vaccine effectiveness (VE) is needed.”1
In response, the study team sought to determine XBB.1.5 COVID-19 VE and the extent to which it declines over time, using target trial emulation at the VHA. The researchers matched 1:1 eligible XBB.1.5 veteran vaccine recipients to unvaccinated people in 7 sequential biweekly trials with enrollment from Oct. 2, 2023, through Jan. 3, 2024.
The outcomes were ascertained through May 10, 2024, and included any positive result on a SARS-CoV-2 test from Day 10 after the matched index date, subsequent hospitalization within 1 day before or 10 days after the positive result or death within 30 days after the positive result. Vaccine effectiveness was estimated as 100 × (1 − risk ratio).
The participants were 91.3% male and had a mean age of 69.9 years and were included in 587,137 pairs of vaccinated and matched unvaccinated persons.
Results over a mean follow-up of 176 days (range, 118 to 211 days), indicated that VE was −3.26% (95% CI, −6.78% to −0.22%) against documented SARS-CoV-2 infection, 16.64% (CI, 6.47% to 25.77%) against SARS-CoV-2–associated hospitalization and 26.61% (CI, 5.53% to 42.32%) against SARS-CoV-2–associated death.
“When estimated at 60, 90, and 120 days, respectively, VE against documented infection (14.21%, 7.29%, and 3.15%), hospitalization (37.57%, 30.84%, and 25.25%), or death (54.24%, 44.33%, and 30.25%) showed substantial waning,” the authors pointed out.
A limitation of the study, they said, was the potential for residual confounding and incomplete capture of COVID-19 vaccination and SARS-CoV-2–related outcomes.
Updated monovalent COVID-19 vaccines from Pfizer–BioNTech and Moderna targeting the XBB.1.5 variant of omicron were approved by the U.S. Food and Drug Administration in September 2023. During the 2023-to-2024 respiratory disease season, the national Centers for Disease Control and Prevention (CDC) recommended that all persons age 6 months or older be vaccinated with the XBB.1.5 COVID-19 vaccine.
“Despite this recommendation, fewer than one-quarter of adults in the United States received the XBB.1.5 COVID-19 vaccines,” according to study authors.
They advised that real-world studies are needed to estimate the VE of each new COVID-19 vaccine for each respiratory disease season, such as the XBB.1.5 vaccine for the 2023-to-2024 season, and the extent to which VE declines over time. “Such studies will provide a measure of the success of the current strategy of targeting a new, annual COVID-19 vaccine based on the most recent predominant variants at the beginning of each season,” the researchers noted. “New COVID-19 vaccines targeting the KP.2 variant were introduced in September 2024 for the 2024-to-2025 season; they have also not been tested in RCTs.”
The VHA was chosen for the study because it is the largest integrated healthcare system in the United States, providing care to more than 9 million veterans, most of whom are older and have a high burden of underlying medical conditions. “The VHA’s comprehensive electronic health record (EHR) system has provided an opportunity for target trial emulation studies of the original COVID-19 vaccines,” the authors explained.
The study team advised that no clinical trials of XBB.1.5 COVID-19 vaccine efficacy were done before approval by the FDA because it would have been impossible to conduct such trials and still make the vaccine available before the surge in cases of SARS-CoV-2 infection anticipated during the respiratory virus season.
Additional Dose
Because the recent study showed a substantial decline in VE against both hospitalization and death between 60 and 120 days and which continued to decline at 176 days, the study’s mean follow-up time, the authors suggested that a single vaccine dose was unlikely to provide adequate protection for an entire season. They say they support the CDC recommendation made in February 2024 for a second XBB.1.5 vaccine 4 months after the first in persons aged 65 years or older.
What This Means for the VA’s Vaccine Program
The authors, led by George Ioannou, MD, MSC, professor of medicine at the University of Washington and director of hepatology at the VA Puget Sound Health Care System, responded, “Although updated vaccines targeting the KP.2 variant recommended for the current 2024-to-2025 respiratory season should be emphasized, particularly among vulnerable persons at high risk for COVID-19-related hospitalization or death, our findings call for accelerated efforts to develop new vaccination strategies that could provide higher and more sustained protection in the current era of COVID-19.”
They added that, because of the lack of VE against infection and the relatively low and rapidly waning VE against hospitalization and death for the XBB.1.5-targeted vaccines during the 2023-to-2024 season in an elderly population with multiple comorbid conditions, “the VE of the KP.2-targeted vaccines that were introduced in September 2024 should be closely monitored as the 2024-to-2025 season unfolds to determine if it is similarly low. Furthermore, ongoing efforts to develop alternative vaccine strategies should be prioritized and accelerated. Mucosal vaccines may be able to prevent infection and transmission, whereas needle-free, inhalational administration may improve uptake.”
They also noted that vaccines effective against all variants, including those presumed to develop in the future and as the virus continues to mutate, are needed.
- Ioannou GN, Berry K, Rajeevan N, Li Y, et. Al. Effectiveness of the 2023-to-2024 XBB.1.5 COVID-19 Vaccines Over Long-Term Follow-up : A Target Trial Emulation. Ann Intern Med. 2025 Feb 4. doi: 10.7326/ANNALS-24-01015. Epub ahead of print. PMID: 39903865.
