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[Preprint]. 2025 Sep 3:2025.08.29.25334612.
doi: 10.1101/2025.08.29.25334612.

Effectiveness of 2024-2025 COVID-19 Vaccination Against COVID-19 Hospitalization and Severe In-Hospital Outcomes - IVY Network, 26 Hospitals, September 1, 2024-April 30, 2025

Kevin C Ma  1 , Alexander Webber  1 , Adam S Lauring  2 , Emily Bendall  2 , Leigh K Papalambros  2 , Basmah Safdar  3 , Adit A Ginde  4 , Ithan D Peltan  5 , Samuel M Brown  5 , Manjusha Gaglani  6 , Shekhar Ghamande  7 , Cristie Columbus  8 , Nicholas M Mohr  9 , Kevin W Gibbs  10 , David N Hager  11 , Matthew E Prekker  12 , Michelle N Gong  13 , Amira Mohamed  13 , Nicholas J Johnson  14 , Akram Khan  15 , Catherine L Hough  15 , Abhijit Duggal  16 , Jennifer G Wilson  17 , Nida Qadir  18 , Steven Y Chang  18 , Christopher Mallow  19 , Laurence W Busse  20 , Jennie H Kwon  21 , Matthew C Exline  22 , Ivana A Vaughn  23 , Mayur Ramesh  24 , Jarrod M Mosier  25 , Aleda M Leis  26 , Estelle S Harris  27 , Adrienne Baughman  28 , Sydney A Cornelison  29 , Paul W Blair  30 , Cassandra A Johnson  29 , Nathaniel M Lewis  31 , Sascha Ellington  31 , Todd W Rice  32 , Carlos G Grijalva  33 , H Keipp Talbot  32 , Jonathan D Casey  32 , Natasha Halasa  34 , James D Chappell  34 , Yuwei Zhu  29 , Wesley H Self  35 , Fatimah S Dawood  1 , Diya Surie  1
Affiliations

Effectiveness of 2024-2025 COVID-19 Vaccination Against COVID-19 Hospitalization and Severe In-Hospital Outcomes - IVY Network, 26 Hospitals, September 1, 2024-April 30, 2025

Kevin C Ma et al. medRxiv. .

Abstract

Importance: As SARS-CoV-2 JN.1 lineage descendants continue to evolve, evaluating COVID-19 vaccine effectiveness (VE) against severe COVID-19 is necessary to inform vaccine composition updates.

Objective: To estimate effectiveness of 2024-2025 COVID-19 vaccines against COVID-19-associated hospitalizations and severe in-hospital outcomes overall and by time since dose (7-89, 90-179, and ≥180 days), JN.1 descendant lineage (KP.3.1.1, XEC, LP.8.1), and spike mutations potentially associated with immune evasion.

Design setting and participants: This test-negative, case-control analysis included adult patients hospitalized during September 1, 2024-April 30, 2025 at 26 hospitals in 20 U.S. states. Cases presented with COVID-19-like illness and a positive SARS-CoV-2 nucleic acid or antigen test; controls had COVID-19-like illness but tested negative.

Exposure: Receipt of 2024-2025 COVID-19 vaccine ≥7 days before illness onset.

Main outcomes and measures: Main outcomes were COVID-19-associated hospitalization and severe in-hospital outcomes (supplemental oxygen therapy, acute respiratory failure, intensive care unit admission, invasive mechanical ventilation [IMV] or death). Logistic regression was used to estimate the odds of vaccination in cases and controls adjusting for demographics, clinical characteristics, and enrollment region. VE was estimated as (1 - adjusted odds ratio) x 100%.

Results: 1,888 COVID-19 cases (including 348 with KP.3.1.1, 218 with XEC, and 134 with LP.8.1 infections) and 6,605 controls were enrolled (median [IQR] age, 66 [54-76] years; 4,338 [51%] female). VE against COVID-19-associated hospitalization was 40% (95% CI, 27%-51%) and protection was sustained through 90-179 days after vaccination. VE was higher against the most severe outcome of IMV or death at 79% (95% CI, 55%-92%). VE was 49% (95% CI, 25%-67%) against hospitalization with KP.3.1.1, 34% (95% CI, 4%-56%) against XEC, and 24% (95% CI, -19% to 53%) against LP.8.1, with increasing median time since dose receipt due to sequential circulation patterns (60, 89, and 141 days, respectively). VE was similar against lineages with spike protein S31 deletion (41% [95% CI, 22%-56%]) and T22N and F59S substitutions (37% [95% CI, 9%-57%]).

Conclusion and relevance: 2024-2025 COVID-19 vaccines provided additional protection against severe disease as multiple JN.1 descendant lineages circulated.

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Conflict of interest statement

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonathan D. Casey reports receiving personal fees from Reprieve Cardiovascular, Inc., outside the submitted work. James D. Chappell received support from Merck for studies of RSV epidemiology among hospitalized children in Jordan and from QuidelOrtho for diagnostic detection of RSV among hospitalized children in Jordan, outside the submitted work. Michelle Ng Gong reports grant funding from NIH and CDC for research, receives fees for serving on the DSMB for clinical trials from NIH, Regeneron, Emory, fees for serving as scientific advisor or consultant for Philips Healthcare, Novartis, Radiometer, receives travel expenses and payment as President Elect of American Thoracic Society, payment as Section Editor for UpToDate from Wolters Kluwer, and travel expenses and honorarium as faculty for ISICEM international conference, outside the submitted work. Carlos G. Grijalva has received consultant fees from GSK and Merck, and has received research support from CDC, NIH, FDA, AHRQ and SyneosHealth, outside the submitted work. Natasha Halasa reports a grant from Merck that ended December 31, 2025, outside the submitted work. Akram Khan reports that his institution has received grant funding from Dompe Pharmaceuticals, 4D Medical, Direct Biologics, BARDA and NIH for patient enrollment in clinical trials, outside the submitted work. Adam S. Lauring reports research support from Roche related to Baloxavir and influenza, outside the submitted work. Christopher Mallow reports ROMTech Investments, outside the submitted work. Ithan D. Peltan receives funding from NIGMS (R35GM151147), funding from NHLBI, and payments to his institution from Regeneron, Novartis, and Bluejay Diagnostics, outside the submitted work. H. Keipp Talbot reports grant funding from CDC outside the submitted work.

Figures

Figure 1.
Figure 1.. Effectiveness of 2024–2025 COVID-19 vaccine against COVID-19–associated hospitalization among immunocompetent adults by time since dose receipt and age group – IVY Network, 26 hospitals, September 1, 2024–April 30, 2025.
Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; IQR, interquartile range; IVY, Investigating Respiratory Viruses in the Acutely Ill; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. a Time since vaccination with a 2024–2025 COVID-19 vaccine. b Vaccine effectiveness was calculated by comparing the odds of 2024–2025 COVID-19 vaccination in cases and controls using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios were estimated by multivariable logistic regression adjusted for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region), calendar time (biweekly intervals), and Charlson comorbidity index. c Estimates are imprecise due to limited numbers of enrolled patients with dose receipt ≥180 days earlier than hospitalization.
Figure 2.
Figure 2.. Effectiveness of 2024–2025 COVID-19 vaccine against COVID-19–associated severe in-hospital outcomes among immunocompetent adults by age group and outcome – IVY Network, 26 hospitals, September 1, 2024–April 30, 2025.
Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; IMV, invasive mechanical ventilation; ICU, intensive care unit; IQR, interquartile range; IVY, Investigating Respiratory Viruses in the Acutely Ill; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. a Time since vaccination with a 2024–2025 COVID-19 vaccine. b Vaccine effectiveness was calculated by comparing the odds of 2024–2025 COVID-19 vaccination in cases and controls using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios were estimated by multivariable logistic regression adjusted for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region), calendar time (biweekly intervals), and Charlson comorbidity index. c Supplemental oxygen therapy was defined as supplemental oxygen at any flow rate and by any device for those not on chronic oxygen therapy, or with escalation of oxygen therapy for patients receiving chronic oxygen therapy, between hospital admission to the first of hospital discharge, patient death, or hospital day 28. d Acute respiratory failure was defined as new receipt of high-flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation, between hospital admission to the first of hospital discharge, patient death, or hospital day 28. e Patients on home IMV prior to the acute illness were not eligible for this outcome (n = 31). f Patients on home IMV prior to the acute illness were not eligible for this outcome (n = 9).
Figure 3.
Figure 3.. Number of COVID-19 cases by hospital admission week and SARS-CoV-2 lineage – IVY Network, 26 hospitals, September 1, 2024–April 30, 2025.
Abbreviations: COVID-19, coronavirus disease 2019; IVY, Investigating Respiratory Viruses in the Acutely Ill; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Dates are for the start of the admission week. SARS-CoV-2 lineage was identified using Nextstrain after conducting viral whole-genome sequencing.
Figure 4.
Figure 4.. Effectiveness of 2024–2025 COVID-19 vaccine against hospitalization among adults aged ≥18 years by SARS-CoV-2 lineage and N-terminal domain substitutions or deletions – IVY Network, 26 hospitals, September 1, 2024–April 30, 2025.
Abbreviations: COVID-19, coronavirus disease 2019; IVY, Investigating Respiratory Viruses in the Acutely Ill; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NTD, N-terminal domain; IQR, interquartile range; CI, confidence interval. a Time since vaccination with a 2024–2025 COVID-19 vaccine. b Vaccine effectiveness was calculated by comparing the odds of 2024–2025 COVID-19 vaccination in cases and controls using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios were estimated by multivariable logistic regression adjusted for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region), calendar time (biweekly intervals), and Charlson comorbidity index. These results include both immunocompetent and immunocompromised persons. Some estimates are imprecise, which might be due to a relatively small number of persons in each level of vaccination or case status. This imprecision indicates that the actual vaccine effectiveness could be substantially different from the point estimate shown, and estimates should therefore be interpreted with caution. c SARS-CoV-2 lineage was identified using Nextstrain after conducting viral whole-genome sequencing. KP.3.1.1 was defined as Nextstrain clade 24E, XEC was defined as Nextstrain clade 24F, and LP.8.1 was defined as Nextstrain clade 25A.
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