Abstract: Received: 16 October 2020 DOI: 10.1002/rmv.2204 REVIEW - Revised: 30 November 2020 Accepted: 1 December 2020 Mega doses of retinol: A possible immunomodulation in Covid‐19 illness in resource‐limited settings Ish K. Midha1 1 | Nilesh Kumar2 | Amit Kumar3 | Taruna Madan4 Pentamed Hospital, New Delhi, India 2 Saint Vincent Hospital, Worcester, Massachusetts, USA 3 Dwight D. Eisenhower VA Medical Center, Leavenworth, Kansas, USA 4 Department of Innate Immunity, ICMR‐ National Institute for Research in Reproductive Health, Mumbai, India Correspondence Ish K. Midha, Pentamed Hospital, New Delhi, India. Email: midhaik@gmail.com Summary Of all the nutrients, vitamin A has been the most extensively evaluated for its impact on immunity. There are three main forms of vitamin A, retinol, retinal and retinoic acid (RA) with the latter being most biologically active and all‐trans‐RA (ATRA) its main derivative. Vitamin A is a key regulator of the functions of various innate and adaptive immune cells and promotes immune‐homeostasis. Importantly, it augments the interferon‐based innate immune response to RNA viruses decreasing RNA virus replication. Several clinical trials report decreased mortality in measles and Ebola with vitamin A supplementation. During the Covid‐19 pandemic interventions such as convalescent plasma, antivirals, monoclonal antibodies and immunomodulator drugs have been tried but most of them are difficult to implement in resource‐limited settings. The current review explores the possibility of mega dose vitamin A as an affordable adjunct therapy for Covid‐19 illness with minimal reversible side effects. Insight is provided into the effect of vitamin A on ACE‐2 expression in the respiratory tract and its association with the prognosis of Covid‐19 patients. Vitamin A supplementation may aid the generation of protective immune response to Covid‐19 vaccines. An overview of the dosage and safety profile of vitamin A is presented along with recommended doses for prophylactic/therapeutic use in randomised controlled trials in Covid‐19 patients. Abbreviations: 9‐cisRA, 9‐cis retinoic acid; ACE‐2, angiotensin converting enzyme 2; ACE‐I, angiotensin converting enzyme inhibitor; AID, activation‐induced cytidine deaminase; ALDH1A, aldehyde dehydrogenase 1A; APCs, antigen presenting cells; ARB, angiotensin‐receptor blockers; ARDS, acute respiratory distress syndrome; ATRA, all‐trans‐retinoic acid; Blimp‐1, B lymphocyte‐induced maturation protein‐1; BMP, Bone morphogenic protein; BRSV, bovine respiratory syncytial virus; Covid‐19, coronavirus disease 2019; COX‐2, cyclooxygenase‐2; CSIF, human cytokine synthesis inhibitory factor; CXCL10, C‐X‐C motif chemokine ligand 10; CXCL9, C‐X‐C motif chemokine ligand 9; EBF1, early B cell factor 1; FDA, U.S. Food and Drug Administration; FDCs, follicular dendritic cells; GATA3, G‐A‐T‐A binding protein 3; GCs, germinal centers; GM‐CSF, granulocyte macrophage colony stimulating factor; IFNγ, interferon gamma; IL‐1, interleukin‐1; IL‐10, interleukin 10; IL‐12, interleukin 12; IL‐13, interleukin 13; IL‐1β, interleukin 1 beta (leukocytic pyrogen); IL‐23, Interleukin 23; IL‐4, Interleukin 4; IL‐6, interleukin 6; IL‐6R, interleukin 6 receptor; IL‐8, interleukin 8 (or chemokine [C‐X‐C motif] ligand 8, CXCL8); ILC, innate lymphoid cells; IP‐10, interferon gamma inducible protein 10 kD (or CXCL10); IRF‐4, interferon regulatory factor 4; LPS, lipopolysaccharide; LTBP, latent TGF‐β binding proteins;..