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Review 2: "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 2: "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.



Vitamin D (25OHD) status is widely used or tested as supplementation to improve or boost medication to various health outcomes such as hypocalcaemia, cancer, HIV and various respiratory viruses including SARS-CoV-2. The manuscript presents sub-studies of a randomised RCT investigating the role of vitamin D supplementation on SARS-CoV-2 immunization efficacy and immunogenicity.

A large dataset was available, participants who received 2 vaccine doses were allocated to one of 3 arms with (800 IU/day or 3200 IU/day) or without vitamin D supplementation. Two sources of supplementation were available depending on the diet preference of the participant. Outcomes were time to breakthrough infection >2 weeks after the second dose, anti-spike G, A, M and anti-neutralising antibody titres and in-vitro assessment of markers of inflammation and immunogenicity.

The study shows no beneficial effect of supplementing with vitamin D for the efficacy of vaccination against SARS-CoV-2. In vitro, PBMCs from participants in each arm show no differential response to stimulation with SARS-CoV-2 S protein. Participants were chosen to have 25OHD < 75nmol/L, cut-off the authors considered to be sub-optimal based on publication predating 2008. New threshold for vitamin D status have since been re-evaluated and shown to differ depending on the health outcome and the population. The large population should offer the opportunity to calculate a cut-off of circulating 25OHD above which no supplementation is required and 25OHD concentrations are high enough to enable an efficient immune response, if at all. The manuscript may benefit from such analysis. The cut-off of 75nmol/L may be too high to see any benefit of Vitamin D supplementation.

Measuring baseline 25OHD for the “no supplement” arm would be of interest and would indicate whether an increase from baseline was also shown for this group in relation to non-disclosed self-supplementation and/or seasonal variation of 25OHD. From Review manuscript reference 21 (CORONAVIT manuscript), the “no offer” group vitamin D median at 6 months appears to be higher than the baseline vitamin D from the 2 other arms.

In regard to the neutralising antibodies and IFN-γ measurements, no information is given as to the 25OHD concentration of the participants contributing to these sub-studies, many participants within the 3 groups have similar 25OHD concentrations, effect of supplementation may be hidden if all participants at the time of analysis have similar 25OHD, this should be highlighted in the manuscript.

The statistical analysis is a pairwise comparison between each arm which may increase the type I error, comparing the 3 arms altogether with Bonferroni or similar correction may be interesting to consider. The quality of figures is low.

This is a rather comprehensive study on the effect of vitamin D supplementation on SARS-CoV-2 vaccination efficiency using relatively large data sets and take into consideration many confounding factors and should provide very useful information for the usefulness of vitamin D supplementation in the protection against COVID-19.

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