COVID-19 Severity and Risk of SARS-CoV-2-associated Asthma Exacerbation by Time Since Booster Vaccination: a Longitudinal Analysis of Data from the COVIDENCE UK Study

Background In several countries, COVID-19 booster vaccinations are offered annually to priority groups, but many people have not been vaccinated in over a year. We aimed to assess the association between time since booster vaccination and characteristics of breakthrough infection. We also assessed whether incident COVID-19 continued to associate with asthma exacerbations in boosted individuals, and whether risk of COVID-19-associated exacerbation was affected by time since vaccination. Methods COVIDENCE UK is a prospective, longitudinal, population-based study of COVID-19. We included adult participants who had received ≥1 booster vaccination. Time since vaccination was binarised at 6 months or 12 months according to vaccine eligibility subgroup. We used logistic, Cox, and linear regression to obtain adjusted estimates for the association between time since vaccination and breakthrough infection severity, symptom duration, and acute changes to health-related quality of life (measured by the EQ-5D-3L Index). We then assessed the association of incident COVID-19 with asthma exacerbations using multilevel mixed models, by time since vaccination. Results 7391 boosted participants reported a breakthrough infection. Across all eligibility subgroups, greater time since vaccination associated with increased odds of infection requiring bedrest (vs milder symptoms), with the highest odds for adults aged 65–75 years (1.83 [95% CI 1.51–2.23] when vaccinated >6 months vs ≤6 months prior). However, we observed little evidence of association between time since vaccination and symptom duration. Vaccination >12 months prior (vs ≤12 months) was associated with a small decrease in EQ-5D-3L Index among participants younger than 65 years (-0.03 points [-0.04 to -0.01]). Among 2100 participants with asthma, incident COVID-19 associated with increased risk of asthma exacerbation, both ≤12 months after vaccination (OR 5.31 [4.36–6.48]) and later (6.06 [3.23–11.38]), with a greater difference in point estimates when specifically considering severe asthma exacerbations (6.82 [4.88–9.54] for ≤12 months vs 10.06 [3.90–25.92] for >12 months). Conclusion Longer time since booster vaccination consistently associates with more severe breakthrough infections, and may potentially increase risk of severe asthma exacerbations. These findings highlight the importance of ensuring those currently eligible receive their booster vaccinations, and the need for research on further vaccinations in people with asthma no longer eligible for boosters. ### Competing Interest Statement PEP declares grants paid to their institution from the National Institute for Health and Care Research, UK Research and Innovation, GlaxoSmithKline, and AstraZeneca,; honoraria for lectures from AstraZeneca, GlaxoSmithKline, and Chiesi; support for attending meetings from AstraZeneca, GlaxoSmithKline, and Sanofi; advisory board participation for AstraZeneca, GlaxoSmithKline, and Sanofi; and payments to their institution for clinical trial participation by AstraZeneca, GlaxoSmithKline, Sanofi, Novartis, and Regeneron, all outside of the submitted work. The remaining authors declare no competing interests. ### Funding Statement COVIDENCE UK has received support from Barts Charity (MGU0459, MGU0466), Pharma Nord, the Fischer Family Foundation, DSM Nutritional Products, the Exilarch's Foundation, the Karl R Pfleger Foundation, the AIM Foundation, Synergy Biologics, Cytoplan, the UK NIHR Clinical Research Network (52255; 52257), the Health Data Research UK BREATHE Hub, the UKRI Industrial Strategy Challenge Fund (MC\_PC\_19004), Thornton & Ross, Warburtons, Matthew Isaacs (personal donation), Barbara Boucher (personal donation), and Hyphens Pharma. MT was supported by Barts Charity (MGU0570). The views expressed are those of the authors and not necessarily those of the funders. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is registered with ClinicalTrials.gov, [NCT04330599][1]. COVIDENCE UK was approved by Leicester South Research Ethics Committee (ref 20/EM/0117). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified participant data will be made available upon reasonable request to the corresponding author. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04330599&atom=%2Fmedrxiv%2Fearly%2F2024%2F06%2F30%2F2024.06.28.24309666.atom