2 0 2 6 C O M P E N D I U M O F F E D E R A L M E D I C I N E 9 7 researchers said their findings were intended to inform prioritization of targeted vaccination outreach and implementation efforts by identifying patient groups in whom the burden of severe disease is greatest “Our data highlight that individuals with multiple ‘stacked’ risk factors, who are at the highest risk for severe COVID-19 outcomes and have long been eligible for vaccination under CDC recommendations, remain undervaccinated. This highlights the need for targeted, system-level outreach strategies that use existing clinical and administrative data to identify high-risk, underva- ccinated patients and proactively engage them through vaccination reminders and discussions during routine care, including chronic disease management visits,” they wrote. In addition, they recommended that, as opposed to using risk scores that often show limited transport- ability across populations and over time, their com- bination-based approach focuses on CDC-recognized high-risk conditions and identifies specific multi- morbidity patterns associated with the highest risk of severe COVID-19. “Our large national cohort study demonstrated that the risk for severe COVID-19 increased with the number of risk factors present,” the authors concluded. “Patient populations 50 years and older, with heart conditions, hypertension, smokers, and not being up-to-date on COVID-19 vaccination were at the highest risk for severe COVID-19. Not being up-to-date on vaccination appeared in 72.4% of significant combinations, under- scoring its critical role in mitigating severe COVID-19 outcomes. Heart conditions, smoking, and hypertension emerged as key contributors to adverse outcomes, both individually and in combination with other chronic con- ditions. The overlap of metabolic conditions such as dia- betes, hypertension, and obesity with heart conditions suggests the need for integrated approaches to address these interrelated risks.” Pointing out the problem of persistent undervaccina- tion—even among a population at high risk for severe COVID-19—“these findings support focused vaccina- tion messaging, outreach, and proactive reminders for patients with the highest-risk multimorbidity profiles, particularly during routine and chronic disease manage- ment visits. As recommendations have shifted toward risk-based clinical decision-making, identifying patients with particularly high-risk combinations of conditions is increasingly important to support targeted vaccination and timely antiviral treatment,” they said. In a recent article in the Morbidity & Mortality Weekly Report, the CDC noted that the 2025-2026 LP.8.1- adapted mRNA COVID-19 vaccine demonstrates pro- tection against currently predominant JN.1 strains but had the lowest antibody neutralization against BA.3.2 in a laboratory study of seven variants, potentially affect- ing vaccine-conferred protection, although observa- tional data are also needed. That is significant, because the SARS-CoV-2 BA.3.2 lineage has been detected in Africa, Asia, Europe, North America and Oceania since November 2024.3 “Numbers of reported detections have increased since September 2025; however, because many countries have limited genomic detection and surveillance capacities, these detections likely underrepresent the actual geo- graphic extent of spread. Phylo-genetic analyses have identified the emergence of two BA.3.2 sublineages (BA.3.2.1 and BA.3.2.2), indicating ongoing viral evo- lution,” the CDC said, cautioning that “the observed increases in BA.3.2 detections, particularly in certain northern European countries, might be driven by sub- stantial antibody evasion enabling infection of previ- ously immune persons among populations in which pre- vious variants circulated.” Public health officials offered some reassurance, however, adding that “in contrast to previous strain replacement events, BA.3.2 has not rapidly overtaken other variants; rather, in several European countries, BA.3.2 has cocirculated with various JN.1 de-scendant lineages with prevalences of approximately 10%-40%. Two laboratory studies found that BA.3.2.1 and BA.3.2.2 had substantially reduced angiotensin-converting enzyme 2 (ACE2) binding and lung cell entry compared with XFG and NB.1.8.1, potentially constraining its ability to rapidly become a dominant variant (9,10). Seasonal increases in COVID-19 transmission or fur- ther evolution of BA.3.2, potentially via com-pensatory mutations restoring ACE2 binding or infectivity, could enable broader circulation, although this has not yet been observed.” 1Appaneal HJ, Lopes VV, Puzniak L, Allen KE, Zasowski EJ, Caffrey AR. Impact of Risk Factor Combinations on Severe COVID-19 Outcomes Among Outpa-tients. Infect Dis Ther. 2026 Mar 25. doi: 10.1007/s40121- 026-01328-1. Epub ahead of print. PMID: 41882459. 2Kompaniyets L, Pennington AF, Goodman AB, et al. Underlying medical condi-tions and severe illness among 540,667 adults hospitalized with CO- VID-19, March 2020-March 2021. Prev Chronic Dis. 2021;18:E66. https:// doi.org/10.5888/pcd18.210123. 3Shakya M, Ma KC, Hughes LJ, et al. Early Detection and Surveillance of the SARS-CoV-2 Variant BA.3.2 — Worldwide, November 2024–Febru- ary 2026. MMWR Morb Mortal Wkly Rep 2026;75:130–137. DOI: http:// dx.doi.org/10.15585/mmwr.mm7510a1.
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