key: cord-0684565-8e7p2oao authors: Boretti, Alberto; Banik, Bimal K title: Zinc role in Covid-19 disease and prevention date: 2021-09-07 journal: Vacunas DOI: 10.1016/j.vacun.2021.08.003 sha: 9ccb27ce8a5e4167638a0bcefd599fa31fa5d2b9 doc_id: 684565 cord_uid: 8e7p2oao Treatments for Covid-19 do not replace vaccines and other measures such as restrictions. However, every practical, effective, and safe means to reduce Covid-19 mortality, morbidity, and collateral damage should be used. Vaccines are not 100% effective for all current and future variants and have associated adverse events. Zinc (Zn) has positive effects against Covid-19 infection. Zn is also an anti-inflammatory and detox compound. As such, it may reduce Covid-19 vaccines’ adverse events while also preventing more serious consequences from Covid-19 infection. Despite no data suggest yet Zn may mitigate damages induced by Covid-19 vaccines, no data similarly suggest Zn may limit or boost the efficacy of the vaccines. Thus, logical arguments support monitoring of Zinc levels to satisfy sufficiency irrespective of the administration of vaccines during the Covid-19 emergency, as it is well established Zn is effective as a preventive treatment. Zinc (Zn) is a very valuable metal because of its many functions [1] , [2] . It maintains the neurological, immune, reproductive, and skin systems [3] . Zn involves in enzyme catalysis, protein-protein functions, and protein oligonucleotide maintenance [4] . The intracellular Zn is connected to metallothionein (MT). This J o u r n a l P r e -p r o o f controls the Zn levels through an intracellular process [5] . Zn modulation of MT mRNA expression is known [6] , [7] . Zn modulates mRNA levels of cytokines. It down-regulates microRNA expression and key enzymes and proteins necessary for microRNA maturation and stability [8] , [9] , [10] . Zn concentration in cells is controlled by homeostasis which helps the organism to accumulate diverse dietary Zn. Zn enables the body to make proteins and DNA. It promotes wound healing. It is important in childhood growth and development. It also has antioxidant properties. Zn is also important in cell-mediated immune function. Zn may reduce the duration of cold symptoms, support blood sugar control, improve severe and inflammatory acne, decrease heart disease risk, and slow the progression of macular degeneration [11] . Zn has also been shown to regulate gene transcription in cancer cells. Zn is an anti-inflammatory and detox compound that also helps as detailed later with Covid-19 infection in prophylaxis and treatment. It may thus also improve the efficacy, as well as reduce inflammation and toxic effects of Covid-19 vaccines. This work advocates for ensuring zinc sufficiency before and after vaccination. The Australian Therapeutic Goods Administration in their weekly report of Covid-19 vaccine safety [12] , received 22,031 communications of adverse events from the administration of 3,613,053 doses of AZ, which is a DNA vaccine, and Comirnaty (Pfizer) which is an mRNA vaccine. In between them, there have been 210 reports of deaths following immunization. Thus, the fatality rate from receiving one dose of a two-shot vaccine is 0.01%. Because two doses are needed, and that protection from vaccines lasts less than one year [13] , we may estimate the fatality rate from universal vaccination of the population at 0.02% per year. This number has to be put in the context of the fatalities that could have been experienced in Australia by using more relaxed border control, less harsh lockdowns, but also better therapeutic approaches as done in countries of a similar level of health system. Australia had a singular approach to Covid-19, targeting risk avoidance rather than risk management, and keeping the borders mostly closed. This has translated into a small percentage of infected over 14 months, 0.11% [14] . Similarly remarkable is the therapeutic approach to only use Dexamethasone, and conditionally in very specific cases Tocilizumab [15] , i.e. adjuvants therapies, while practically preventing the use of antivirals, as Remdesivir is only used conditionally in very specific cases and Anakinra, Favipiravir, Hydroxychloroquine, Interferon Beta-1a, and Lopinavir/Ritonavir are specifically declared not to be used for the treatment of COVID-19 [15] . Not a surprise if the national average case fatality rate from contracting Covid-19 is 3.03% [14] , with the state of Victoria 3.99%. We may consider as an example of more sustainable restrictions but also a much better therapeutic approach the case of the United Arab Emirates. The percentage of cases over 14 months has been 5.67% [14] . Then, treatment in the United Arab Emirates has been much more sophisticated, Page 3 of 9 J o u r n a l P r e -p r o o f with many combinatory therapies inclusive of antivirals offered to hospitalized patients, and therapies also offered to asymptomatic off-patients in risk categories [16] . Up to their case-specific discretion, physicians have the opportunity to use individual and combinatory therapies based on Chloroquine Phosphate, Hydroxychloroquine, Favipiravir, Lopinavir-Ritonavir, Camostat, Remdesivir, nebulized Interferon Alpha or Interferon Beta, Ribavirin, and adjunctive Anticoagulation, Steroids or Tocilizumab as well [16] . As a result, the case fatality rate is 0.30% (10 times smaller than in Australia and 13 times smaller than in the state of Victoria). This means that with the same exposure to Covid-19 infection but also the same therapies of the United Arab Emirates, Australia could experience slightly less than 0.02% of the population being infected and perished as a result of the infection over one year. It may be added that vaccines do not offer 100% protection, especially against variants, as admitted by the Australian government when they write there are currently no grounds for an exemption from restrictions based on a person being vaccinated against Covid-19. Zinc and Covid-19 infection. Zn is certainly not a 100% effective therapy for Covid-19 infection. However, it has been shown that Zn help with Covid-19 infection. Zn deficiency has been associated with more serious consequences of Covid-19 infection. Zn supplementation is important in the prevention [17] , as well as the treatment in conjunction with antivirals such as Chloroquine or Hydroxychloroquine [17] . Regarding Zn Covid-19 studies, [17] reports of 15 studies where it is shown Zn supplementation matters in different phases of Covid-19 infection (Fig. 1) . Israel et al. [18] present a case-control study in a large population. Lower risk of hospitalization is associated with calcium + zinc supplements. Al Sulaiman et al. [19] propose a retrospective study of ICU patients showing lower mortality with zinc treatment. Asimi et al. (Velija and Al) [20] propose a retrospective study of Hashimoto's thyroiditis outpatients, with those taking vitamin D, zinc, and selenium, showing significantly lower hospitalization with treatment. Seet et al. [21] report improvements in prophylaxis with lower serious cases, lower symptomatic cases, and lower confirmed cases of Covid-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin. Thomas et al. [22] report a small RCT showing faster recovery with zinc and with vitamin C. Darban et al. [23] report a small RCT with 2 ICU patients, 10 treated with highdose vitamin C, melatonin, and zinc, not showing significant differences. Frontera et al. [24] propose a retrospective study of hospitalized patients showing 37% lower mortality with HCQ+zinc. Berrocal et al. [25] report a small retrospective study of hospitalized patients showing zinc deficiency associated with a higher ICU admission rate. Derwand et al. [26] report a retrospective study showing 79% lower mortality and 82% lower hospitalization with early HCQ+AZ+Zn. Jothimani [27] shows Covid-19 patients had significantly lower zinc levels. Yasui et al. [28] show in a retrospective study as significantly lower serum zinc levels are associated with severe Covid-19 cases. Yao et al. [29] show as Zn helps with the survival of hospitalized patients. Krishnan et al. [30] show in a small retrospective study of mechanically ventilated patients lower mortality with vitamin C, Page 4 of 9 J o u r n a l P r e -p r o o f vitamin D, HCQ, and zinc treatment. Carlucci et al. [31] show as the addition of Zn to HCQ+AZ reduces mortality, ICU admission, and the need for ventilation. Similar results are proposed by [32] , evidencing a correlation between Zn deficiency and more serious outcomes of Covid-19 infection. Here we argue as Zn supplementation may also be used as a preventive anti-inflammatory and de-toxic treatment during Covid-19 vaccination. These vaccines may generate local and systemic inflammatory responses. There may be also toxic effects of synthetic nucleosides and delivery components. Some Covid-19 mRNA vaccines use novel adjuvants such as lipid or polymer-based nanoparticles to protect and stabilize the mRNA and improve uptake [33] , [34] . The toxicological implications of the use of these substances have been only marginally considered. Zn is one substance that may help to mitigate the damage from Covid-19 vaccines and is thus worth considering in times of mass vaccination against Covid-19. Normal serum Zn is 0.66 to 1.10 mcg/mL [35] . Zinc metabolism: basic, clinical, and behavioral aspects Severe zinc deficiency in male and female rats Zinc: the biology and therapeutics of an ion Zinc transport in mammalian cells The physiological function of metallothionein Measurement of plasma metallothionein-I in the assessment of the zinc status of zinc-deficient and stressed rats Nutritional and physiological significance of metallothionein Zinc modulates mRNA levels of cytokines Zinc at cytotoxic concentrations affects posttranscriptional events of gene expression in cancer cells Plant microRNAs: biogenesis, homeostasis, and degradation. Frontiers in plant science What Are Zinc Supplements Good For? Benefits and More Australian Therapeutic Goods Administration (TGA) (2021), COVID-19 vaccine weekly safety report Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection Coronavirus explorer. ourworldindata.org/explorers/coronavirus-data-explorer NSW Health interim guidance on use of antiviral and immunomodulation therapy in COVID-19 Updates of Comprehensive COVID-19 Guideline for the Use of Healthcare Professionals in the Emirate of Abu Dhabi Zinc studies. c19zinc.com Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population Evaluation of Zinc Sulfate as an Adjunctive Therapy in COVID-19 Critically Ill Patients: a Two Center Propensity-score Matched Study Selenium, zinc, and vitamin D supplementation affect the clinical course of COVID-19 infection in Hashimoto's thyroiditis for COVID-19 prophylaxis: An open-label randomized trial Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z randomized clinical trial Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial Treatment with Zinc is associated with reduced in-hospital mortality among COVID-19 patients: a multi-center cohort study Zinc and Vitamin a Deficiency Predisposes to the Need for Intubation and Icu Admission in Patients With COVID-19 COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study COVID-19: Poor outcomes in patients with zinc deficiency Analysis of the predictive factors for a critical illness of COVID-19 during treatment-relationship between serum zinc level and critical illness of COVID-19− The minimal effect of zinc on the survival of hospitalized patients with COVID-19: an observational study Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients Assessment of the role of zinc in the prevention of COVID-19 infections and mortality: A retrospective study in the Asian and European population Nanomedicine and the COVID-19 vaccines mRNA vaccines-a new era in vaccinology Test ID: ZNS. Zinc, Serum Nutrition, immunity and COVID-19 Does vitamin D deficiency affect the immunogenic responses to influenza vaccination? A systematic review and meta-analysis Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial Trace mineral intake and deficiencies in older adults living in the community and institutions: A systematic review The authors have no conflict of interest to declare.