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.
RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
The authors nested three sub-studies conducted within the CORONAVIT randomized controlled trial. Sub-study 1 performed vaccine efficacy analysis to assess the influence of vitamin D supplementation on the risk of breakthrough COVID-19 infection among immunocompetent participants vaccinated with two SARS-CoV-2 vaccine doses. Sub-study 2 performed a dried blood spot analysis that assessed the impact of supplementing vitamin D on combined immunoglobulin G (IgG), IgA, and IgM (IgGAM) antibody responses to the SARS-CoV-2 spike (S) protein. In addition, sub-study 3 investigated the effects of vitamin D supplementation on neutralizing antibodies and cell responses.
All participants had 25(OH)D concentrations below 75 nmol/L at baseline, and supplementation of both 800 IU and 3200 IU of vitamin D per day was effective in increasing end-study 25(OH)D concentrations in the intervention groups. However, improvements in vitamin D status have not been associated with inter-arm differences in the risk of breakthrough SARS-CoV-2 infection, post-vaccination titres of anti-S or neutralising antibodies or any cellular immune response investigated.
The study design was concise and could effectively address the question of whether vitamin D supplements can contribute to the effectiveness of the SARS-CoV-2 vaccine in clinical scenarios.
The study has limitations. Randomization could not be stratified according to sub-study participation. The study population was limited to immune-competent individuals and participants residing in the United Kingdom. Besides evaluating the efficacy of the vaccine in the prevention of breakthrough infection, the authors may also consider assessing the vaccine's effectiveness in preventing an exposed person from developing serious diseases that require hospitalization and lead to death.
The demands of the main study are in general justified by its methods and data. The authors report that daily administration of 800 IU or 3200 IU vitamin D3 was effective in elevating circulating 25(OH)D concentrations, but that neither dose influenced SARS-CoV-2 vaccine efficacy or immunogenicity. Although these findings do not support the use of vitamin D supplements as an adjunct to SARSCoV-2 vaccination, how optimal vitamin D level should be suggested to be achieved in the general population and how long-term vitamin D supplement should be given to enhancing the vaccine’s efficacy warrants further investigation.