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Review 3: "Influence of Vitamin D Supplementation on SARS-CoV-2 Vaccine Efficacy and Immunogenicity"

Reviewers were mixed on the reliability of the pre-print. The large sample size was highlighted, but there were concerns about the exclusion criteria and cut-off criteria, among other concerns.

Published onAug 15, 2022
Review 3: "Influence of Vitamin D Supplementation on SARS-CoV-2 Vaccine Efficacy and Immunogenicity"
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key-enterThis Pub is a Review of
Influence of vitamin D supplementation on SARS-CoV-2 vaccine efficacy and immunogenicity

SUMMARYBackground & AimsVitamin D deficiency has been reported to associate with impaired development of antigen-specific responses following vaccination. We aimed to determine whether vitamin D supplements might boost immunogenicity and efficacy of SARS-CoV-2 vaccination.MethodsWe conducted three sub-studies nested within the CORONAVIT randomised controlled trial, which investigated effects of offering vitamin D supplements at a dose of 800 IU/day or 3200 IU/day vs. no offer on risk of acute respiratory infections, including COVID-19, in UK adults with circulating 25-hydroxyvitamin D concentrations <75 nmol/L. Sub-study 1 (n=2808) investigated effects of vitamin D supplementation on risk of breakthrough SARS-CoV-2 infection following two doses of SARS-CoV-2 vaccine. Sub-study 2 (n=1853) investigated effects of vitamin D supplementation on titres of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies in eluates of dried blood spots collected after SARS-CoV-2 vaccination. Sub-study 3 (n=100) investigated effects of vitamin D supplementation on neutralising antibody and cellular responses in venous blood samples collected after SARS-CoV-2 vaccination.Results1945/2808 (69.3%) sub-study 1 participants received two doses of ChAdOx1 nCoV-19 (Oxford–AstraZeneca); the remainder received two doses of BNT162b2 (Pfizer). Vitamin D supplementation did not influence risk of breakthrough SARS-CoV-2 infection (800 IU/day vs. no offer: adjusted hazard ratio 1.28, 95% CI 0.89 to 1.84; 3200 IU/day vs. no offer: 1.17, 0.81 to 1.70). Neither did it influence IgGAM anti-Spike titres, neutralising antibody titres or IFN-γ concentrations in supernatants of S peptide-stimulated whole blood.ConclusionsAmong adults with sub-optimal baseline vitamin D status, vitamin D replacement at a dose of 800 or 3200 IU/day did not influence protective efficacy or immunogenicity of SARS-CoV-2 vaccination.Clinical Trial RegistrationClinicalTrials.govNCT04579640.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



Authors report the results of three sub-studies nested within the CORONAVIT randomized controlled trial. The study evaluated the effects of vitamin D supplementation (with two different doses of oral vitamin D) as compared with no supplementation on vaccine efficacy (sub-study 1), on immunogenicity as measured by post-vaccination anti-Spike titers (sub-study 2), and on neutralising antibodies and cellular response to the vaccine (sub-study 3). Overall, the study is interesting and the hypothesis is very relevant. A minor limitation is that the sample size calculation lacks of the expected event rate.

The study was open-label, and participants that reported taking less than 50% of the time during the study (in the intervention group) or taking any supplemental vitamin D (control group) were excluded from the analyses (per-protocol population). The main limitation is the large number of participants excluded after randomization and the fact that the exclusion was approximately double in the control group as compared with intervention groups. The association between group assignment and the probability of being excluded from analyses could result in selection bias and affect the observed results (this phenomenon occurred in the three sub-studies). The manuscript would benefit from the presentation of the intention to treat analysis. There are no mentions of the large numbers of exclusions and of the differential exclusions among study groups in the discussion.


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