Association between COVID-19 mRNA vaccination and COVID-19 illness and severity during Omicron BA.4 and BA.5 sublineage periods
Open accessAbstract
Importance: Recent sublineages of the SARS-CoV-2 Omicron variant, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 following vaccination. Objective: To evaluate the association between COVID-19 mRNA vaccination with 2, 3, or 4 doses among immunocompetent adults and the risk of medically attended COVID-19 illness during a period of BA.4/BA.5 predominant circulation; to evaluate the relative severity of COVID-19 in hospitalized cases across Omicron BA.1, BA.2/BA.2.12.1, and BA.4/BA.5 sublineage periods. Setting, Design and Participants: Test-negative study of adults with COVID-19-like illness (CLI) and molecular testing for SARS-CoV-2 conducted in 10 states from December 16, 2021, to August 20, 2022. Exposure: mRNA COVID-19 vaccination. Main Outcomes and Measures: Emergency department/urgent care encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. The adjusted odds ratio (OR) for the association between prior vaccination and medically attended COVID-19 was used to estimate VE, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as reference group). Among hospitalized case-patients, demographic and clinical characteristics and in-hospital outcomes including ICU admission and death were compared across sublineage periods. Results: Between June 19 – August 20, 2022, 82,229 ED/UC and 21,007 hospital encounters were included for the BA.4/BA.5 vaccine effectiveness analysis. Among adults hospitalized with CLI, the adjusted odds ratio (OR) was 0.75 (95% CI: 0.68-0.83) for receipt of 2 vaccine doses at ≥150 days after receipt, 0.32 (95% CI: 0.20-0.50) for a third dose 7-119 days after receipt, and 0.64 (95% CI: 0.58-0.71) for a third dose ≥120 days (median 235 days) after receipt for cases vs controls. For COVID-19-associated hospitalization, among patients ages ≥65 years 7-59 and ≥60 days (median 88 days) after a fourth dose, ORs were 0.34 (95% CI: 0.25-0.47) and 0.43 (95% CI: 0.34-0.56), respectively. Among hospitalized cases, ICU admission and/or in-hospital death occurred in 21.4% during the BA.1 vs 14.7% during the BA.4/BA.5 period (standardized mean difference: 0.17). Conclusion: VE against medically attended COVID-19 illness decreased over time since last dose; receipt of one or two booster doses increased effectiveness over a primary series alone. KEY POINTS: Question: What is the association between receipt of first-generation COVID-19 mRNA vaccines and medically attended COVID-19 during Omicron BA.4/BA.5 sublineage predominance? Findings: This test-negative analysis included 82,229 emergency department or urgent care encounters and 21,007 hospitalizations for COVID-19-like illness. Among hospitalized patients, the likelihood of recent vaccination (7-119 days) with 3 mRNA vaccine doses (vs unvaccinated) was significantly lower (odds ratio, 0.32) in cases than SARS-CoV-2-negative controls, but with lower associated protection ≥120 days post-vaccination (odds ratio, 0.64). Meaning: First-generation COVID-19 vaccines were associated with protection against COVID-19 during the Omicron BA.4/BA.5 sublineage-predominant periods but this declined over time.
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Of two studies reporting primary series VE against hospitalization/severe disease against BA.1, BA.2, and BA.4/5, one reported lower VE against BA.2 and BA.4/5 than BA.1, while the other showed no statistically significant differences.
“Of two studies reporting primary series VE against hospitalization/severe disease against BA.1, BA.2, and BA.4/5, one reported lower VE against BA.2 and BA.4/5 than BA.1, while the other showed no statistically significant differences [25,26,31,32].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
The Discussion (page unavailable) says VE during BA.4/BA.5 predominance was lower than during BA.1 across outcomes, and the Results report two-dose VE against hospitalization during BA.4/BA.5. The Limitations call BA.2 VE estimates similar to those in this analysis, but the paper does not establish the claimed three-period comparison specifically for primary-series VE against hospitalization or severe disease, or report whether those differences were statistically significant. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the US VISION network, for hospitalization, lower vaccine effectiveness and faster waning of vaccine effectiveness were observed for BA.2 and BA.4/5 compared to BA.1, although with wider confidence intervals than for emergency department or urgent care visits.
“For hospitalization, similar results were observed, with lower VE and faster waning of VE for BA.2 and BA.4/5 compared to BA.1, although with wider confidence intervals than for ED/UC visits.”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn the US VISION network, differences in vaccine effectiveness by subvariant were larger when more time had elapsed since the last dose, suggestive of faster waning of vaccine effectiveness against BA.2 and BA.4/5.
“the differences in VE by subvariant were larger when more time had elapsed since the last dose suggestive of faster waning of VE against BA.2 and BA.4/5 [25,26].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
The Discussion (page unavailable) says protection declined within several months of the last dose during BA.4/BA.5 predominance. It also says hospitalization VE was similar to that reported during BA.2/BA.2.12.1 predominance, but does not establish that differences between subvariants grew with time since vaccination or that waning was faster against BA.2 and BA.4/BA.5. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the US VISION network, among immunocompetent adults aged 18 years or older, absolute vaccine effectiveness for either BNT162b2 or mRNA-1273 was lower for emergency department or urgent care visits for BA.2 and BA.4/5 compared to BA.1 after the primary series and the first booster dose.
“Among immunocompetent adults 18 years old, the absolute VE for either BNT162b2 or mRNA-1273 was lower for ED/UC visits for BA.2 and BA.4/5 compared to BA.1 after the primary series and the first booster dose;”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn the US VISION network, median follow-up time within each post-vaccination period was longer during the BA.2 and BA.4/5 periods compared to the BA.1 period; for the hospitalization outcome in the 120+ days period, median follow-up times since the booster dose for BA.1, BA.2 and BA.4/5 were 135, 168, and 235 days, respectively.
“the median follow-up time within each period was longer during the BA.2 and BA.4/5 periods, compared to the BA.1 period; for example, for the hospitalization outcome in the period post-vaccination indicated as ''120 + days', the median follow-up times since the booster dose for BA.1, BA.2 and BA.4/5 were 135, 168, and 235 days, respectively.”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Of three studies assessing VE against infection/symptomatic disease during both BA.2 and BA.4/BA.5 periods, all showed similar VE estimates or estimates with overlapping 95 % confidence intervals against both subvariants.
“Of three studies assessing VE against infection/symptomatic disease during both BA.2 and BA.4/BA.5 periods, all showed similar VE estimates or estimates with overlapping 95 % confidence intervals against both subvariants [25,26,31-33].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
The Limitations section says VE estimates during BA.2/BA.2.12.1 predominance were similar to those in this BA.4/BA.5 analysis. However, the paper estimates VE during BA.4/BA.5, not both periods; its explicit comparison in the Discussion concerns hospitalization, rather than infection or symptomatic disease. It therefore does not fully support counting this paper as one of the studies assessing that outcome in both periods. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEight studies assessed VE of primary series or first booster dose vaccination separately for at least two different Omicron subvariants (six assessed VE of both primary series and booster dose vaccination and two assessed VE of a booster dose only).
“Eight studies assessed VE of primary series or first booster dose vaccination separately for at least two different Omicron subvariants (six assessed VE of both primary series and booster dose vaccination and two assessed VE of a booster dose only, Tables 1 and 2) [21,24-26,28-33].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
The Statistical Analysis and results report VE estimates for two doses (a primary series) and three doses (a first booster). But the Introduction says VE was estimated during the combined BA.4/BA.5 period; earlier Omicron periods were used to compare hospitalized cases, not to produce separate VE estimates for two subvariants. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAmong three studies comparing VE against BA.1 and BA.4/5, two showed a lower VE against BA.4/5.
“Among three studies comparing VE against BA.1 and BA.4/5, two showed a lower VE against BA.4/5 [24-26,31,32].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
For several studies that evaluated median time since last dose, time since last dose was longer for BA.4/5 compared to BA.1.
“For several studies that evaluated the median time since last dose, indeed the time since last dose was longer for BA.4/5 compared to BA.1 [25,26,30].”
From Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization (2023) · cites this paper as [25]
The ‘Participants included in VE analysis’ section reports median times since selected vaccine doses during BA.4/BA.5, and ‘Differences in epidemiology and outcomes of hospitalized COVID-19 cases by sublineage period’ compares vaccination prevalence with BA.1. Neither passage gives a BA.1 median time since last dose, so the claimed comparison cannot be checked in our copy (searched for median time since last dose and BA.1). Page numbers were not available. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Cites
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“1, while the other showed no statistically significant differences [25,26,31,32].”
BackgroundResultInfluentialSelf-citation
- Authors
- Link-Gelles, R., Levy, M. E., Natarajan, K., Reese, S. E., Naleway, A. L., Grannis, S. J., Klein, N. P., DeSilva, M. B., Ong, T. C., Gaglani, M., Hartmann, E., Dickerson, M., Stenehjem, E., Kharbanda, A. B., Han, J., Spark, T. L., Irving, S. A., Dixon, B. E., Zerbo, O., McEvoy, C. E., Rao, S., Raiyani, C., Sloan-Aagard, C., Patel, P., Dascomb, K., Uhlemann, A.-C., Dunne, M. M., Fadel, W. F., Lewis, N., Barron, M. A., Murthy, K., Nanez, J., Griggs, E. P., Grisel, N., Annavajhala, M. K., Akinseye, A., Valvi, N. R., Goddard, K., Mamawala, M., Arndorfer, J., Yang, D.-H., Embí, P. J., Fireman, B., Ball, S. W., & Tenforde, M. W.
- Affiliations
- Westat (United States) (US)
- NewYork–Presbyterian Hospital (US)
- Kaiser Permanente (US)
- Regenstrief Institute (US)
- HealthPartners (US)
- University of Colorado Anschutz (US)
- Baylor Scott & White Medical Center - Temple (US)
- Centers for Disease Control and Prevention (US)
- Intermountain Healthcare (US)
- Children's Minnesota (US)
- Columbia University Irving Medical Center (US)
- Brigham Young University (US)
- ORCID
- Levy, Matthew E.
- Natarajan, Karthik
- Reese, Sarah E.
- Naleway, Allison L.
- Grannis, Shaun J.
- Klein, Nicola P.
- DeSilva, Malini B.
- Ong, Toan C.
- Gaglani, Manjusha
- Dickerson, Monica
- Stenehjem, Edward
- Kharbanda, Anupam B.
- Spark, Talia L.
- Irving, Stephanie A.
- Dixon, Brian E.
- Zerbo, Ousseny
- McEvoy, Charlene E.
- Rao, Suchitra
- Raiyani, Chandni
- Sloan-Aagard, Chantel
- Patel, Palak
- Dascomb, Kristin
- Uhlemann, Anne-Catrin
- Dunne, Margaret M.
- Fadel, William F.
- Lewis, Ned
- Barron, Michelle A.
- Murthy, Kempapura
- Griggs, Eric P.
- Annavajhala, Medini K.
- Valvi, Nimish R.
- Goddard, Kristin
- Mamawala, Mufaddal
- Yang, Duck-Hye
- Embí, Peter J.
- Fireman, Bruce
- Ball, Sarah W.
- Tenforde, Mark W.
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2022-10-05
- OpenAlex
- W4302283217
- Cited by
- 10
- References
- 2
- Citations by year
- 2026: 1 · 2023: 4 · 2022: 5
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- medRxiv (acceptedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
- Keywords
- COVID-19 mRNA vaccination, vaccine effectiveness, SARS-CoV-2, COVID-19 hospitalization, COVID-19 severity, booster vaccination, emergency department visits, intensive care unit admission, in-hospital mortality, immune evasion, immunocompetent adult
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