Abstract: BRIEF RESEARCH REPORT published: 17 September 2021 doi: 10.3389/fimmu.2021.699389 Nutritional Immunity, Zinc Sufficiency, and COVID-19 Mortality in Socially Similar European Populations Samer Singh 1*, Amita Diwaker 2, Brijesh P. Singh 3 and Rakesh K. Singh 4 1 Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India, Department of Obstetrics and Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India, 3 Department of Statistics, Institute of Science, Banaras Hindu University, Varanasi, India, 4 Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India 2 Edited by: Julio Villena, Centro de Referencia para Lactobacilos (CERELA) (CONICET), Argentina Reviewed by: Ivan Milos Stankovic, University of Belgrade, Serbia Leonardo Albarracin, Centro de Referencia para Lactobacilos (CERELA) (CONICET), Argentina *Correspondence: Samer Singh samer.singh10@bhu.ac.in orcid.org/0000-0002-0921-1686 Specialty section: This article was submitted to Nutritional Immunology, a section of the journal Frontiers in Immunology Received: 16 May 2021 Accepted: 18 August 2021 Published: 17 September 2021 Citation: Singh S, Diwaker A, Singh BP and Singh RK (2021) Nutritional Immunity, Zinc Sufficiency, and COVID-19 Mortality in Socially Similar European Populations. Front. Immunol. 12:699389. doi: 10.3389/fimmu.2021.699389 The impact of zinc (Zn) sufficiency/supplementation on COVID-19-associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of “nutritional immunity” to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8,000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150-fold difference in death rates) and at the matching stage of the pandemic (March 12 to June 26, 2020; first wave of COVID19 incidence and mortality). Our results suggest a positive correlation between populations’ Zn-sufficiency status and COVID-19 mortality [r (23): 0.7893–0.6849, pvalue < 0.0003] as well as incidence [r (23):0.8084–0.5658; p-value < 0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients’ data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19. Keywords: COVID-19, nutritional immunity, zinc supplementation, infection, oxidative stress, redox, SARSCoV-2, mortality Frontiers in Immunology | www.frontiersin.org 1 September 2021 | Volume 12 | Article 699389 Singh et..