Vaccines No Match for Omicron and a Look at COVID-19 in Africa

Vaccines No Match for Omicron and a Look at COVID-19 in Africa

We’ve been living with COVID-19 now for more than two years, and questions continue to

arise about the best approach for prevention and treatment. I have never been asked about anything as much as the COVID-19 vaccines and never have I seen so much doubt and confusion among so many people. The emergence of the Omicron variant has made the issue more confusing and raises more questions about the efficacy of vaccines against COVID-19. Interpreting the reality of the effectiveness of these vaccines is complicated, especially when some of the new data is not robust and is often murky. Patients and doctors looking to the CDC for guidance in decision-making receive low-quality or outdated information. All too often, straightforward relative data – such as the benefits of normalizing vitamin D and zinc levels – is ignored. Please see my earlier blogs on Zinc and Vitamin D for more information here “Zinc the Most Important Nutrient for Immunity” and “There’s No Substitute for Sunlight: The Essential Influence of Nature’s Sunshine Vitamin on Health“

Adequate supply of vitamin D, zinc, as well as selenium, are essential for resistance to other viral infections, immune function, and reduced inflammation. Hence, it is suggested that nutrition intervention securing an adequate status might protect against SARS-CoV-2 and mitigate the course of COVID-19.[1]

A new study[2] from Columbia researchers, in collaboration with scientists at the University of Hong Kong, adds more evidence that the Omicron variant can evade the immune protection conferred by vaccines and natural infection. The new study tested the ability of antibodies generated by vaccination to neutralize the Omicron variant in laboratory assays that pitted antibodies against live viruses and against pseudo-viruses constructed in the lab to mimic Omicron. Antibodies from people double-vaccinated with any of the four most widely used vaccines—Moderna, Pfizer, AstraZeneca, and Johnson & Johnson—were significantly less effective at neutralizing the Omicron variant compared to the ancestral virus. Antibodies from previously infected individuals were even less likely to neutralize Omicron.

Individuals who received a booster shot of either of the two mRNA vaccines are likely to be better protected, although even their antibodies exhibited diminished neutralizing activity against Omicron. “The new results suggest that previously infected individuals and fully vaccinated individuals are at risk for infection with the Omicron variant,” says Ho. “Even a third booster shot may not adequately protect against Omicron infection.”[3]

Real-world data from the U.K. showed that efficacy of a third dose of a COVID-19 vaccine waned significantly at the 10-week mark, leaving boosted individuals at risk of infection with Omicron. In a December 23 U.K. Health Security Agency (HSA) technical briefing, vaccine efficacy against symptomatic infection generally fell to around 40% some 2.5 months after a booster dose.

Data from Israel also has suggested waning efficacy after a booster dose, though that country’s data pertains to the Delta variant. Last week, the expert panel advising the Israeli government recommended a fourth vaccine dose given at least 4 months after a third shot for certain groups: those ages 60 and up, immunocompromised people, and healthcare workers.

The HSA report did offer some good news — additional confirmation of other early findings of reduced illness severity with Omicron. It found about a 60% reduced risk of hospital admission with Omicron compared with Delta (HR 0.38, 95% CI 0.30-0.50) based on 70 hospital admissions with Omicron and 3,884 with Delta.[4] There was no data available to confirm whether those in the hospital were vaccinated or not.

When administered early in the course of infection, monoclonal antibodies can prevent many individuals from developing a severe COVID-19 infection. But a new study suggests that all the therapies currently in use and most in development are much less effective against Omicron, if they work at all.^[5]

The African Covid Conundrum: Low Vaccination Rate, Poverty, and Malnutrition, but a Lower Death Rate from COVID-19 (which appears to be over)

Preliminary findings from two South African clinical trials suggest the Omicron coronavirus variant has a much higher rate of “asymptomatic carriage” than earlier variants, which could explain why it has spread so rapidly across the globe.[6]

The latest data from the United Nations Development Programme (UNDP)^[7] shows that around half of people in high-income countries have been vaccinated while in low-income countries it is barely more than 1%.

As of January 10, 2022, confirmed cases of Covid-19 from 55 African countries reached 10,092,830,[8] while over 196,741,231 vaccinations have been administered across the continent,.  South Africa has the most reported cases at 3,353,106 with 90,587 deaths. Only 6% of Africa is vaccinated against COVID-19 and only 1 in 4 health workers in Africa have been fully vaccinated.^[9]

Decreased Severity of Disease during the First Global Omicron Variant COVID-19 Outbreak in a Large Hospital in Tshwane, South Africa

To date there have been more than 274 million reported cases and 5.3 million deaths. The Omicron variant first documented in the City of Tshwane, Gauteng Province, South Africa on  November 9, 2021, led to exponential increases in cases and a sharp rise in hospital admissions.

466 hospital COVID-19 admissions since November 14,  2021 were compared to 3976 prior admissions since May 4,  2020.

Ninety-eight patient records at peak bed occupancy during the outbreak were reviewed for primary indication for admission, clinical severity, oxygen supplementation level, vaccination and prior COVID-19 infection.

The estimated seroprevalence of hybrid immunity (immunity from prior infection and vaccine induced immunity) for the City of Tshwane is 66.7% (95% CI, 54.2 to 69.0). About

36% of adults aged 18 to 49 and 58% over age 50 in the Gauteng Province are vaccinated.

RESULTS

• Deaths and ICU admissions were 4.5% vs 21.3% (p<0.00001), and 1% vs 4.3% (p<0.00001); length of stay was 4.0 days vs 8.8 days; and mean age was 39 years vs 49 years for the Omicron and previous waves respectively.
• Admissions peaked and declined rapidly with peak bed occupancy at 51% of highest previous peak.
• Sixty three percent (63%) of patients in COVID-19 wards had incidental COVID-19 following a positive SARS-CoV-2 PCR test.
• Only one third (36) had COVID-19 pneumonia, of which 72% had mild to moderate disease. The remaining 38% required high care or ICU admission.
• Fewer than half (45%) of patients in COVID-19 wards compared to 99.5% in the first wave required oxygen supplementation.
• City and provincial rates show decoupling of cases, hospitalizations and deaths compared to previous waves, corroborating the clinical findings of milder omicron disease in the hospital. There was decreased severity of disease in the Omicron driven fourth wave in the City of Tshwane, its first global epicenter.INTRODUCTIONThe coronavirus disease 2019 (COVID-19) first reported in Wuhan China in December 2019 is a global pandemic that is threatening the health and wellbeing of people worldwide. To date there have been more than 274 million reported cases and 5.3 million deaths. The Omicron variant first documented in the City of Tshwane, Gauteng Province, South Africa on 9 November 2021 led to exponential increases in cases and a sharp rise in hospital admissions. The clinical profile of patients admitted at a large hospital in Tshwane is compared with previous waves.

What we know so far is that the Omicron wave has increased at a faster rate than previous waves, completely displacing the Delta variant within weeks and began its decline in both cases and hospital admissions in the fifth week following its commencement.  A plausible cause for the lower number of admissions and decreased severity is a decrease in pathogenicity of the highly mutated Omicron variant.

There are clear signs that case and admission rates in South-Africa may decline further over the next few weeks. If this pattern continues and is repeated globally, we are likely to see a complete decoupling of case and death rates suggesting that Omicron may be a harbinger of the end of the epidemic phase of the Covid pandemic ushering in its endemic phase.[10]

Meanwhile The CEO of Pfizer, Albert Bourla, has said that a vaccine for the highly transmissible Omicron variant of Covid-19 will be ready in March and that the pharmaceutical company has begun manufacturing the doses.  At the rate of transmissibility I am not sure we even need a Omicron vaccine by March.

CONCLUSION

There was decreased severity of disease in the Omicron driven fourth wave in the City of Tshwane, its first global epicentre.

Some important contributing factors to why Africa has done so well may include:

In many African countries, people spend more time outside than on other continents. Sunlight, fresh air, and vitamin D are all important to good health and immune status. 

Vitamin D insufficiency, for example, has been linked to a higher prevalence of infection and severity of COVID-19, implying that vitamin D supplementation could be beneficial as a preventive or therapeutic measure.[11]

Two New Studies add to the Overwhelming amount of Research on the Benefits of Healthy Vitamin D Levels and COVID-19 Severity, Hospitalizations, and Deaths.

The first study examined whether hospitalization with COVID-19 is more prevalent in individuals with lower vitamin D levels. The study (80,670 participants) included individuals with test results for serum 25-hydroxyvitamin D (25[OH]D) between April 1, 2020, and January 29, 2021, from 2 districts in Northwest England. The last 25(OH)D level in the previous 12 months was categorized as “deficient” if less than 25 nmol/L and “insufficient” if 25 to 50 nmol/L. Hospital admissions were 2.3 to 2.4 times higher among participants with serum 25(OH)D <50 nmol/L compared with those with normal serum 25(OH)D levels, without excess mortality risk.^[12]

The second study looked at vitamin D status and outcomes for hospitalized older patients with COVID-19. According to this study, older adults with vitamin D deficiency and COVID-19 demonstrate worse morbidity outcomes. Vitamin D status may be a useful prognosticator.^[13]

Africa also features the youngest population among global regions, with a median age of 19.7 years that is roughly half as young as that of the United States (38.5) and the United Kingdom (40.5), both of which have been hit hard by the pandemic.

Africa has a relatively low burden of noncommunicable diseases, such as cardiovascular disease, respiratory disease, and cancer, as well as obesity, which increase the risk of dying from COVID-19.  Exposure of people in Africa to the Bacillus Calmette-Guérin vaccination, which is administered against tuberculosis, could make them less vulnerable to COVID-19.^[14]

Herbal Medicine to the Rescue

Africa’s utilization of traditional herbal medicines in the response to COVID-19 may be a main factor in aiding recovery. Herbal medicine may not have a direct effect on the virus or reduce the risk of infection with it, but these products certainly stimulate the human immune system so that the body is better prepared to fight the disease.[15]

The use of traditional remedies in Africa is so deeply ingrained that most Malagasies, as they call themselves, would just as likely reach for an herbal cure to treat a headache or a stomachache as they would a western pharmaceutical product, says Tiana Andriamanana, the executive director of local conservation NGO Fanamby.

Andriamanana’s work often takes her to poor and rural areas where hospitals and pharmacies are hard to find, and conventional medicine is often unaffordable. “A lot of times there isn’t really a choice,” she says. “Traditional medicine is how we roll.” 

Andrianjara’s team combined artemisia with other ingredients to create an herbal tea and offered the decoction to patients who had tested positive for COVID-19. “We started with one, two [patients] and we found that it really reduced their symptoms,” he says. “They recovered quickly.” IMRA has not conducted any formal trials or tests; Andrianjara’s assessment comes only from observing the reactions of a handful of patients outside of a controlled setting.^[16]

“Africa has over 34 research institutions working on Traditional Medicine” says Dr. Falihery Razafindrabe, Pharmaceutical Adviser, Focal Point for Traditional Medicine, WHO Madagascar.

“I became herbalist by inheritance, I lived with my grandparents who were both herbalists. My grandfather treated men while my grandmother cared for girls and women using locally available plants and herbs found in our farm and within the community. This sparked my interest in plants at a young age and a call from my grandparents, I loved agriculture and developed interest in plants of any type but more so got interested on how some plants can be mixed together to heal a body disease by different methods of utilization i.e. boiling, soaking, burning, pounding, chewing, roasting, steaming etc.”

“My grandfather told me to pound hot pepper mixed with aloe leaves and Kendogensis Foetidissima and to add water before administering the concoction to the chicken, I noticed that after a few days the chicken were healed. This fascinated me, how can simple herbs heal, with encouragement from my grandparents, I started to successfully treat myself and my family members with assorted plant remedies whenever cases of coughs, headaches, chest congestions would arise,”  Mr. Martin Onyalo Odhiambo.

In April 2020, Zimbabwe Approved Herbal Treatment for COVID-19

In Zimbabwe, the government has authorized herbalists to treat coronavirus patients. The president of Zimbabwe Traditional Practitioners Association, Tribert Chishanyu, is happy that President Emmerson Mnangagwa‘s government is allowing herbalists to treat coronavirus-positive Zimbabweans.

“Traditional medicine practice is older… than science and it is accepted by the majority of Zimbabweans,” Chishanyu said, adding that, “If modern scientists are given opportunities to try whenever there is an emergency disease (outbreak), why can’t we do the same to traditional medicine practice? We are treating symptoms related to COVID-19, so by (some) chance we may be able to treat COVID-19.”

The African island nation Madagascar attracted a lot of attention last year when it announced it was promoting a drink containing artemisia annua plant extracts to combat coronavirus.

Tanzanian Health Minister Dorothy Gwajima held a press conference in March 2021 demonstrating how to make a drink with ginger, onions, lemon, and pepper, which she recommended to help boost the immune system and prevent COVID-19 infections.^[17]

President Rajoelina of Madagascar said last year that trials conducted on the Covid-Organics drink—which uses artemisia—showed its effectiveness against the disease.  But the exact composition of the drink is not known, although the government says more than 60% is derived from the artemisia plant. Mr. Rajoelina says among the additional plants is ravintsara, an indigenous plant of the laurel family. Madagascar also started producing capsules and a solution that can be injected, on which clinical trials were started.

A group of researchers investigated whether artemisia extracts and specific compounds which are extensively used for malaria in African countries could be responsible for the later emergence and lower than expected number of confirmed COVID-19 cases in these countries. This in vitro study revealed that all artemisinin-drug combinations inhibited the SARS-CoV-2 at expected maximum blood concentration at doses equivalent to those used for uncomplicated malaria.

Prior to the emergence of COVID-19, a study that included artemisia annua as an anti-SARS-CoV-1, was published in 2005. It reported that A. annua is one of the four herbs that significantly inhibited the in-vitro activity of the SARS-CoV-1 (strain BJ001) in a dose-dependent manner, with interferon-a (IFN-a) used as a positive control.^[18]

PubMed/MEDLINE, Scopus, and Google Scholar were searched for peer-reviewed articles that investigated the antiviral effects and mechanisms of artemisia annua and its phytochemicals against SARS-CoVs. Particularly, articles that evidenced the herb’s role in inhibiting the coronavirus-host proteins were favored. Nineteen studies were retrieved. From these, fourteen in silico molecular docking studies demonstrated potential inhibitory properties of artemisinins against coronavirus-host proteins including 3CL^PRO, S protein, N protein, E protein, cathepsin-L, helicase protein, nonstructural protein 3 (nsp3), nsp10, nsp14, nsp15, and glucose-regulated protein 78 receptor. The combination of A. annua’s biological properties, action on different signaling pathways and target proteins, and a multi-drug combined-therapy approach may synergistically inhibit SARS-CoV-2 and assist in COVID-19 treatment.

Summary of the Artemisia annua phytocompounds as potential SARS-CoV-2/host protein inhibitors. These compounds attained appreciable antiviral activity by inhibiting SARS-CoV-2/host proteins with binding scores of 7.0 kcal/mol. The stronger binding interaction among the artemisinins was reached by artesunate-N protein (!8.8 kcal/mol). The results were attained by in silico studies except those that are highlighted as in vitro studies (e.g., arteannuin B and dihydroartemisinin inhibited the N protein in vitro; artesunate inhibited N protein in vitro and in silico; and the rest of the compounds were in silico).

Potential mechanisms of Artemisia annua and its phytocompounds against SARS-CoV-2/COVID-19. The combination of A. annua’s biological properties, action on different signaling pathways, and target proteins may synergistically inhibit the SARS-CoV-2, decrease inflammation, modulate the host immune response, and alleviate the COVID-19 symptomatology.^[19]

Nigella Sativa

Nigella sativa is known by several names, including black cumin, black seed, and kalonji, and has been used to treat a wide range of ailments, including jaundice, conjunctivitis, rheumatism, diabetes, anorexia, stomach complications, intrinsic hemorrhage, asthma, cough, pneumonia, fever, bronchitis, pneumonia, and more. Thymoquinone, the most powerful phytochemical in black cumin, is responsible for the bulk of the spice’s therapeutic properties.[20]

In one study utilizing molecular docking, the authors uncovered new potential COVID-19 inhibitors using compounds from Nigella sativa L., a well-known therapeutic plant in North African communities and Islamic and Christian traditions.  The strongest candidates for COVID-19 treatment within Nigella appear to be nigellidine and α-hederin. Nigella sativa should be studied as a preventative measure against coronavirus infection.[21]

The Potential of Herbal Medicine Should be Explored

Herbs contain many different compounds (flavonoids, polyphenols, alkaloids, proanthocyanidins, and terpenoids), which are known to have antiviral activities, and are being tested for the treatment of SARS-CoV-2 infected patients. In the context of not having a proven medication for the prevention or treatment of COVID-19, patients depend on preventive and supportive care and symptomatic therapy and we should be providing more information on how to incorporate herbal medicine into their protocol. It is clear that many herbal extracts and natural products may help to treat the symptoms associated with SARS-CoV-2 infection.^[22]

I pray that we do not blindly place our trust in the systems and -isms of this world. Instead, may we pursue wisdom, including an openness to the healing that is offered by herbal medicine.

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[1] Alexander J, Tinkov A, Strand TA, Alehagen U, Skalny A, Aaseth J. Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19. Nutrients. 2020 Aug 7;12(8):2358. doi: 10.3390/nu12082358. PMID: 32784601; PMCID: PMC7468884.

[2] Sandile Cele, Laurelle Jackson, David S. Khoury, Khadija Khan, Thandeka Moyo-Gwete, Houriiyah Tegally, James Emmanuel San, Deborah Cromer, Cathrine Scheepers, Daniel Amoako, Farina Karim, Mallory Bernstein, Gila Lustig, Derseree Archary, Muneerah Smith, Yashica Ganga, Zesuliwe Jule, Kajal Reedoy,Shi-Hsia Hwa, Jennifer Giandhari, Jonathan M. Blackburn, Bernadett I. Gosnell, Salim S. Abdool Karim,Willem Hanekom, Network for Genomic Surveillance in, COMMIT-KZN Team, Anne von Gottberg, Jinal Bhiman, Richard J. Lessells, Mahomed-Yunus S. Moosa, Miles P. Davenport, Tulio de Oliveira, Penny L. Moore, Alex Sigal. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature, 2021; DOI: 10.1038/d41586-021-03824-5

[3] New study adds more evidence for omicron immune evasion, December 23, 2021, ScienceDaily, www.sciencedaily.com/releases/2021/12/211223151542.htm

[4] COVID Vaccine Booster Efficacy Against Infection May Fade Quickly— New U.K. data suggest steep drop-off in protection, potentially giving Omicron more power, by Kristina Fiore, Director of Enterprise & Investigative Reporting, MedPage Today December 28, 2021, ScienceDaily, 23 December 2021.

^[5] ., Sandile Cele, Laurelle Jackson, David S. Khoury, Khadija Khan, Thandeka Moyo-Gwete, Houriiyah Tegally, James Emmanuel San, Deborah Cromer, Cathrine Scheepers, Daniel Amoako, Farina Karim, Mallory Bernstein, Gila Lustig, Derseree Archary, Muneerah Smith, Yashica Ganga, Zesuliwe Jule, Kajal Reedoy, Shi-Hsia Hwa, Jennifer Giandhari, Jonathan M. Blackburn, Bernadett I. Gosnell, Salim S. Abdool Karim, Willem Hanekom, Network for Genomic Surveillance in, COMMIT-KZN Team, Anne von Gottberg, Jinal Bhiman, Richard J. Lessells, Mahomed-Yunus S. Moosa, Miles P. Davenport, Tulio de Oliveira, Penny L. Moore, Alex Sigal. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature, 2021; DOI: 10.1038/d41586-021-03824-5

[6] https://www.usnews.com/news/top-news/articles/2022-01-11/south-african-studies-suggest-omicron-has-higher-asymptomatic-carriage,

^[7] https://data.undp.org/vaccine-equity/, 12/28/2021

[8] https://allafrica.com/stories/202201100185.html

^[9] https://allafrica.com/stories/202112230140.html, December 23, 2021

[10] Abdullah, F et al. “Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, south africa.” International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, S1201-9712(21)01256-X. 28 Dec. 2021.

[11] Savant S., Srinivasan S., Kruthiventi A.K. Potential Nutraceuticals for COVID-19. Nutr. Diet. Suppl. 2021;13:25. doi: 10.2147/NDS.S294231.

^[12] Jude EB, Ling SF, Allcock R, Yeap BXY, Pappachan JM. Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-control Study. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4708-e4715. doi: 10.1210/clinem/dgab439. PMID: 34139758; PMCID: PMC8344535.

^[13] Baktash V, Hosack T, Patel N, Shah S, Kandiah P, Van den Abbeele K, Mandal AKJ, Missouris CG. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J. 2021 Jul;97(1149):442-447. doi: 10.1136/postgradmedj-2020-138712. Epub 2020 Aug 27. PMID: 32855214; PMCID: PMC7456620.

^[14] https://news.northeastern.edu/2019/08/12/global-health-researcher-helps-build-treatment-center-in-kenya-to-combat-neglected-tropical-disease-visceral-leishmaniasis/, Ian Thomsen, June 11, 2021

[15] Tagde P, Tagde S, Tagde P, Bhattacharya T, Monzur SM, Rahman MH, Otrisal P, Behl T, Ul Hassan SS, Abdel-Daim MM, Aleya L, Bungau S. Nutraceuticals and Herbs in Reducing the Risk and Improving the Treatment of COVID-19 by Targeting SARS-CoV-2. Biomedicines. 2021 Sep 18;9(9):1266. doi: 10.3390/biomedicines9091266. PMID: 34572452; PMCID: PMC8468567.

^[16] https://time.com/5840148/coronavirus-cure-covid-organic-madagascar/

^[17] https://www.devex.com/news/the-countries-that-don-t-want-the-covid-19-vaccine-992

^[16] https://time.com/5840148/coronavirus-cure-covid-organic-madagascar/

^[17] https://www.devex.com/news/the-countries-that-don-t-want-the-covid-19-vaccine-99243, 12/27/2021

^[18] Gendrot M, Duflot I, Boxberger M, Delandre O, Jardot P, Le Bideau M, et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J Infect Dis 2020;99:437–40.

^[19] Fuzimoto AD. An overview of the anti-SARS-CoV-2 properties of Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment. J Integr Med. 2021 Sep;19(5):375-388. doi: 10.1016/j.joim.2021.07.003. Epub 2021 Jul 22. PMID: 34479848; PMCID: PMC8378675.

[20] Sarkar C., Mondal M., Torequl Islam M., Martorell M., Docea A.O., Maroyi A., Sharifi-Rad J., Calina D. Potential Therapeutic Options for COVID-19: Current Status, Challenges, and Future Perspectives. Front. Pharmacol. 2020;11:572870. doi: 10.3389/fphar.2020.572870

[21] Islam M.T., Khan M.R., Mishra S.K. An updated literature-based review: Phytochemistry, pharmacology and therapeutic promises of Nigella sativa L. Orient. Pharm. Exp. Med. 2019;19:115–129. doi: 10.1007/s13596-019-00363-3.

^[22] Adhikari B, Marasini BP, Rayamajhee B, et al. Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review. Phytother Res. 2021;35(3):1298-1312. doi:10.1002/ptr.6893

43, 12/27/2021

^[18] Gendrot M, Duflot I, Boxberger M, Delandre O, Jardot P, Le Bideau M, et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J Infect Dis 2020;99:437–40.

^[19] Fuzimoto AD. An overview of the anti-SARS-CoV-2 properties of Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment. J Integr Med. 2021 Sep;19(5):375-388. doi: 10.1016/j.joim.2021.07.003. Epub 2021 Jul 22. PMID: 34479848; PMCID: PMC8378675.

[20] Sarkar C., Mondal M., Torequl Islam M., Martorell M., Docea A.O., Maroyi A., Sharifi-Rad J., Calina D. Potential Therapeutic Options for COVID-19: Current Status, Challenges, and Future Perspectives. Front. Pharmacol. 2020;11:572870. doi: 10.3389/fphar.2020.572870

[21] Islam M.T., Khan M.R., Mishra S.K. An updated literature-based review: Phytochemistry, pharmacology and therapeutic promises of Nigella sativa L. Orient. Pharm. Exp. Med. 2019;19:115–129. doi: 10.1007/s13596-019-00363-3.

^[22] Adhikari B, Marasini BP, Rayamajhee B, et al. Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review. Phytother Res. 2021;35(3):1298-1312. doi:10.1002/ptr.6893