key: cord-0335011-83caose4
authors: Simons, M. J. P.
title: Vaccines provide disproportional protection to the increased hospitalisation risk posed by the Delta variant of SARS-CoV2: a meta-analysis
date: 2021-12-17
journal: nan
DOI: 10.1101/2021.12.15.21267799
sha: efecfd455d782b3a9b8aed32388b4c08dedff437
doc_id: 335011
cord_uid: 83caose4

Variants of SARS-CoV2 that achieved global dominance (Alpha and Delta) have been associated with increased hospitalisation risk. A quantification of this risk across studies is currently lacking for Delta. Furthermore, how risk for severe disease changes in both vaccinated and unvaccinated individuals is important as the underlying risks determine public health impact. The surplus risk of Delta versus Alpha on hospitalisation was determined using random-effects meta-analysis. Infection with the Delta compared to the Alpha variant increased hospitalisation risk (unvaccinated: log HR 0.62, CI: 0.41 -- 0.84, P < 0.0001; linear HR 1.87). This finding should inform our response to future variants of concern, currently Omicron. SARS-CoV2 variants that achieve dominance, have achieved this through a higher rate of infection and this evolutionary trajectory has also come with a correlated higher risk of severe disease. The surplus risk posed by Delta was significantly lower however in the vaccinated (model estimate -0.40, CI: -0.73 -- -0.07, P = 0.017). Vaccination thus provided a disproportionate level of protection to hospitalisation with the Delta variant and provides further rationale for vaccination for SARS-CoV2 as a durable public health measure.

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The copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

During the SARS-CoV2 pandemic a key question was do vaccines work? After the 28 emergence of variants focus shifted to whether vaccines still provide protection. Both these 29 questions have been answered with a resounding yes thus far 1 . However, a largely overlooked 30 and understudied question has been if vaccines protect against the increased severe disease 31 risk that has now been suggested for the two variants that achieved global dominance, Alpha 32 (B.1.1.7) 2-4 and Delta (B 1.617) 5 . A quantification of this risk and its interplay with the 33 protection offered by vaccination across studies is currently lacking for Delta. Vaccines could 34 provide proportional protection, i.e. lower the increased hazard of hospitalisation posed by a 35 variant by a similar proportional amount, could be escaped or provide disproportional 36 protection. Note, such an analysis is different to studying vaccine effectiveness, as this is a 37 ratio of risks resulting from infection with the same variant. The consideration of how risk 38 changes with a new variant is of utmost concern. Even when vaccine effectiveness is 39 unaffected, the underlying risks for both categories, vaccinated and unvaccinated can still be 40 higher (or lower), changing the impact on public health of a variant. The recent emergence of 41

Omicron has again highlighted this importance. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint Infection with the Delta compared to the Alpha variant increased hospitalisation risk ( Figure  59 1; Table S1 ; unvaccinated: log HR 0.62, CI: 0.41 -0.84, P < 0.0001; linear HR 1.87). This 60 risk was significantly lower in the vaccinated individuals (Table S1, model estimate of  61 vaccination: log HR -0.40, CI: -0.73 --0.07, P = 0.017). When data was split for first and 62 second doses, second doses showed the strongest response (Table S2 , but note only two 63 studies included estimates for single dosage). Estimates of these vaccination status specific 64 risks remained similar and statistically significant when the three studies that only estimated 65 risk in the unvaccinated were excluded (Table S3- variants of concern, currently Omicron. SARS-CoV2 variants that achieve dominance, have 73 achieved this through a higher rate of infection and this evolutionary trajectory has also come 74 with a correlated higher risk of severe disease. These consequences were now seen twice 75 during the pandemic, with both Alpha and Delta. Fortunately, vaccination reduces 76 hospitalisation risk. For Delta there is even a disproportionate rescue of surplus 77 hospitalisation risk compared to Alpha (Figure 1) , and limited data available for Alpha also 78 support this notion compared to the wildtype variant (two studies 7,13 , Table S5 ). Such a 79 response could be due to several currently unknown reasons. For example, specific aspects of 80 immunity 14 primed by vaccination or a disproportionate rescue by vaccination of the gained 81 virulence of variants of concern. 82 83

The data summarised here through meta-analysis provide unique insight into how variants of 84 concern have impacted the SARS-CoV2 pandemic. The disproportionate rescue from 85 hospitalisation risk through vaccination identified provides additional support for vaccination 86 as a durable public health intervention. The gain in virulence in both Alpha and Delta in the 87 unvaccinated does pose a warning for future variants when vaccination coverage is low or 88 spread of the variant is wide. In practice, estimating the impact of novel variants of concern 89 on risk to develop severe disease can only be conducted on a very small timescale and easily is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 17, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint

Effectiveness and safety of SARS-CoV-2 vaccine in 158 real-world studies: a systematic review and meta-analysis

The Disease Severity and Clinical Outcomes of the 161

SARS-CoV-2 Variants of

Severity of SARS-CoV-2 alpha variant (B.1.1.7) in England

SARS-CoV-2 variants and considerations of inferring 165 causality on disease severity

Hospital admission and emergency care attendance risk for 167

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Hospitalisation associated with SARS-CoV-2 delta variant in Denmark

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Scotland: demographics, risk of hospital admission, and vaccine effectiveness

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COVID-19 vaccines: modes of immune activation and 193 future challenges

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Conducting Meta-Analyses in R with the metafor Package

Veneti, L. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted December 17, 2021. Records excluded** (n = 205) As these did not appear to include relevant epidemiological data from the title/abstract, e.g. reviews or other topic.Reports sought for retrieval (n = 21)Reports not retrieved (n = 0)Reports assessed for eligibility (n = 21) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.15.21267799 doi: medRxiv preprint