Highlights
- 2024-2025 updated COVID-19 vaccines provide moderate protection against medically attended COVID-19 outcomes including emergency/urgent care visits, hospitalizations, and critical illness in adults.
- Vaccine effectiveness (VE) ranges from approximately 26% against mild outcomes to over 40% against critical illness within 7 to 299 days after vaccination, with notable waning over time.
- Effectiveness is observed across immunocompetent and immunocompromised populations, with slightly lower protection in the latter group.
- Variant-specific VE estimates demonstrate differential effectiveness, underscoring the importance of continued vaccine composition monitoring and updated vaccination strategies.
Background
The COVID-19 pandemic has evolved with the emergence of multiple SARS-CoV-2 variants, notably sublineages of Omicron, that challenge prior immunity and vaccine effectiveness. The introduction of 2024-2025 vaccine formulations, including updated mRNA vaccines and variant-adapted platforms, aims to mitigate the disease burden in the adult population. Given evolving viral genetics and immune escape features, real-world effectiveness data are imperative to guide immunization policies, especially among high-risk groups such as older adults and immunocompromised individuals.
Key Content
Methodological Approaches and Data Sources
The cornerstone study by Wiegand et al. (2026) employed a large-scale, multisite test-negative case-control design using the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION) encompassing over 300,000 emergency department/urgent care (ED/UC) encounters and nearly 100,000 hospitalizations across six US states from September 2024 to September 2025. Patients with COVID-19-like illness undergoing molecular or antigen SARS-CoV-2 testing were selected, providing robust real-world assessment of vaccine effectiveness (VE) against medically attended COVID-19.
Effectiveness Against Medically Attended COVID-19
The adjusted VE of 2024-2025 COVID-19 vaccination 7 to 299 days post-immunization was estimated at 26% (95% CI: 23%-29%) against COVID-19-associated ED/UC encounters and 35% (95% CI: 30%-40%) against hospitalization in immunocompetent adults aged ≥18 years. Protection against critical illness (hospitalization requiring intensive care or culminating in death) was higher, at 41% (95% CI: 28%-51%). Among adults aged ≥65 years, VE estimates were similar, reflecting consistent moderate vaccine protection in this older population.
Effectiveness in Immunocompromised Populations
In a subset analysis, among over 32,000 hospitalizations in immunocompromised adults, VE against COVID-19-associated hospitalization was slightly reduced at 24% (95% CI: 13%-34%). These findings reaffirm that although COVID-19 vaccines confer benefit in vulnerable groups, additional protective measures remain critical.
VE Dynamics and Waning Immunity
Multiple studies corroborate waning immunity over time. Wiegand et al. demonstrated decreasing VE beyond 299 days post-vaccination. Complementary data from Gao et al., examining BNT162b2 XBB.1.5-adapted vaccine in Europe, show durable protection against JN.1-related hospitalization up to 30 weeks, with significant waning beyond this period. Similarly, Quebec regional data on KP.2 vaccines indicate meaningful protection that declines to negligible levels by 32 weeks post-vaccination.
Variant-Specific Effectiveness
Effectiveness varies by circulating variants. For instance, VE against hospitalization was higher for KP.3.1.1 (~49%) compared to XEC (34%) and LP.8.1 (24%) variants, with the latter showing immune evasion characteristics affecting vaccine impact (Wiegand et al., 2026). Japanese studies demonstrate high efficacy of JN.1-adapted vaccines, particularly self-amplifying mRNA formulations, against symptomatic infection and hospitalization in older adults, with VE up to 74.5% shortly after vaccination.
Comparative International Evidence
International data from Japan, Canada, South Korea, and Africa provide context on VE under diverse epidemiological and healthcare settings. Notably, hybrid immunity (vaccine plus prior infection) in Japan confers enhanced neutralizing responses and innate immunity via IL-8 mediated pathways, suggesting biological synergy in protective mechanisms. African cohort studies reveal moderate protection against symptomatic infection persisting for up to 12 months post-dose, emphasizing vaccination’s role despite less defined seasonality patterns.
Impact of Vaccination Correlations and Co-infections
Bias analyses highlight the importance of adjusting VE estimates for correlated vaccination behaviors (influenza, RSV) and co-infections to avoid under- or overestimation of COVID-19 vaccine efficacy. Studies suggest that multiplex respiratory virus testing enhances the precision of VE estimates by differentiating primary infections and co-infections.
Expert Commentary
The accumulated evidence presents a nuanced picture of COVID-19 vaccine effectiveness in the 2024-2025 period, revealing moderate but clinically meaningful protection against diverse COVID-19 outcomes. The modest VE against mild to moderate disease, juxtaposed with stronger protection against severe and critical illness, aligns with evolving host immunity, viral evolution, and vaccine adaptation strategies.
Methodologically, the test-negative design remains the standard for VE estimation, minimizing healthcare seeking and testing biases. However, waning immunity and variant immune escape necessitate ongoing surveillance and flexible vaccine policy, especially for at-risk groups including immunocompromised individuals, the elderly, and those with comorbidities.
Biologically, variant-adapted vaccines and emerging platforms, such as self-amplifying mRNA vaccines, enhance immunogenicity and may counter immune evasion. Hybrid immunity mechanisms underscore the integration of humoral and innate responses as pivotal to sustained protection.
Controversies persist around optimal vaccination timing, dosing intervals, and strategies for boosting to maintain durable protection. Moreover, global disparities in vaccine uptake and variant circulation patterns complicate universal application of findings.
Conclusion
The 2024-2025 COVID-19 vaccines confer moderate to substantial protection against medically attended COVID-19 outcomes and critical illness in adults, with demonstrated benefit across age groups and immunological statuses. While VE wanes over months and varies by viral variant, vaccination remains a cornerstone of pandemic control. Future research should prioritize longitudinal VE monitoring, variant-specific immunogenicity assessments, and integration of emergent vaccine technologies to optimize protection.
References
- Wiegand RE et al. Estimated Effectiveness of 2024-2025 COVID-19 Vaccines in Adults. JAMA Intern Med. 2026;186(8):976-986. PMID: 42295789.
- Gao Y et al. Durability of the BNT162b2 XBB:1.5-adapted vaccine against JN.1 hospitalisation. PLoS One. 2026;21(2):e0342382. PMID: 41671248.
- Mak J et al. Effectiveness of JN.1-adapted COVID-19 vaccine in Japan. Vaccine. 2026;80:128544. PMID: 41932291.
- Payne AB et al. Interim Estimated Effectiveness of 2025-2026 COVID-19 Vaccines in Adults. JAMA Netw Open. 2026;9(6):e2625152. PMID: 42334917.
- Kang G et al. Effectiveness of the 2023-2024 monovalent XBB.1.5 vaccine in South Korea. Int J Infect Dis. 2026;163:108238. PMID: 41271028.
- Kim SJ et al. Vaccine effectiveness against severe COVID-19 in patients with lung cancer. BMC Infect Dis. 2026;26(1):692. PMID: 41652347.
- Leung MW et al. Hybrid immunity enhances protection against Omicron XBB.1.16. Front Immunol. 2026;17:1807238. PMID: 42465771.
- Johnston S et al. Influence of correlated vaccination behaviors on COVID-19 VE estimates. Vaccine. 2026;89:128891. PMID: 42391690.
- Bouchard R et al. 2024/25 KP.2 vaccine effectiveness against COVID-19 hospitalization in older adults. Vaccine. 2026;88:128786. PMID: 42241837.
