While much of the public fanfare around new COVID-19 drugs has centered around the lupus drug, hydroxychloroquine, and a failed Ebola remedy, remdesivir, other researchers are keen to explore the potential of other time-worn remedies – although here, too, experts are urging extreme caution.   

Ivermectin, the antiparasitic drug that turned the tide in the West African fight against river blindness (onchocerciasis) some 30 years ago has been found to slow the growth in the laboratory of SARS-CoV-2, the virus behind COVID-19. Meanwhile, a widely circulated preprint study claiming that countries with mandatory Bacillus Calmette-Guérin (BCG) vaccination against tuberculosis may experience lower rates of COVID-19 cases and deaths has led to the initiation of at least two clinical trials on the prophylactic use of BCG in Australia and the Netherlands, with more countries planning on follow suit.

Still, the concentrations of ivermectin that were demonstrated as effective against SARS-CoV-2 in the laboratory cell culture experiments are “far beyond” dosage levels approved by the FDA to safely treat river blindness in humans, warned the Mectizan Donation Program, in an Expert Committee Statement, issued on Tuesday. High doses of ivermectin have shown “serious toxicity” in animal studies, they added.

In the laboratory trial, the single dose of ivermectin [Mectizan®] slashed the growth of SARS-CoV-2 by 5000-times within 48 hours, reported the study published in Antiviral Research last Friday. 

Clinical trials would be needed to determine if there is a dose of ivermectin that is both safe for humans and effective against the SARS-CoV-2, and even expedited human safety trials can take time, a WHO scientist told Health Policy Watch. 

“There is a long path from showing something works at certain concentrations in [cell culture studies] on the virus to showing that the required concentrations can be achieved in the target tissues in humans and are expected to be safe for humans,”  said the scientist.

Then, the drug would also have to be studied further in randomized controlled studies in COVID-19 patients, and must be proven to demonstrate “clinical benefit,” added the scientist. 

Millions of doses of the FDA-approved medication are donated every year to oncho-endemic countries through the Mectizan Donation Programme created by Merck Sharpe & Dohme (MSD), which developed the drug in collaboration with the TDR, the WHO-hosted Special Programme for Research and Training in Tropical Diseases, in the late 1970s. Ivermectin is typically administered once a year in communities of West Africa where onchocerciasis is endemic, to prevent the development of the disease, which can lead to blindness when it goes untreated. 

BCG Clinical Trials Beginning in Australia and Netherlands  – But Researchers Warn Against Complacency in Countries Where Vaccine is Widely Used 

Similarly, researchers have questioned the validity of the BCG vaccine study, urging for more robust studies on the effectiveness of the vaccine.

The initial pre-print study by researchers at the New York Institute of Technology found that in 28 middle- and high-income countries, which did not require BCG vaccination, there were also higher numbers of COVID-19 cases per capita and higher death rates than in countries that enforced universal BCG vaccination. BCG is a vaccine typically given to infants, which protects against tuberculosis in young children, although protection wanes by age 12. The vaccine has been demonstrated to induce a more general immune response, which may offer protection against other respiratory diseases. The study was published on the preprint server MedRxiv in mid-March, which means that it has not yet been peer-reviewed.

“Accepting these findings at face value has the potential for complacency in response to the pandemic, particularly in low- and middle-income countries [where BCG vaccination is highly prevalent]” warned infectious disease researchers Emily Maclean, Lena Faust, Sophie Huddart, and Anita Svadzian of McGill’s International TB Centre in Canada, in a searing critique published in Nature Microbiology Community. 

“The pre-print’s study design, timing of analysis and data collection, lack of adjustment for important confounders, and uncertain biological plausibility mean that we cannot view the paper’s findings as causal,”  Maclean told Health Policy Watch. 

Rather, she said, this type of ecological study, which only observes broad population level data, should be “hypothesis generating”. Under normal circumstances, such a study would spark more epidemiological studies and early phase clinical trials to test the vaccines’ safety and efficacy.

“However, given that we’re in extraordinary times, I think following up on promising vaccine leads is a good choice,” said Maclean, particularly because scientists already know the long-established vaccine is “safe for use” to humans.

“Ethically- and properly-conducted randomized control trials will allow us to see if BCG has a causal effect regarding COVID-19 morbidity and mortality,” she added. 

That’s exactly the step that some countries are taking. Phase III clinical trials to test the BCG vaccine in healthcare workers have begun in the Netherlands and in Australia, and researchers in the United States are also exploring ways to begin trials. The Inserm Research Director at the Institut Pasteur in Lille France, Camille Locht, is preparing for the implementation of a double-blind clinical trial in collaboration with Spain. 

Still, the vaccine is not a “panacea” warned Nigel Curtis, coordinator of the clinical trial in Australia, to the the New York Times. Both the Australian and the Dutch trials will aim to only assess whether the vaccine would reduce the duration of illness, thus allowing sick healthcare workers to recover more rapidly and return to work.

WHO Africa Region Hits 10,000 Cases

The WHO Africa region, which encompasses most of Sub-Saharan and Southern Africa, hit a sober new mark on Tuesday when the region surpassed 10,000 cases.

“COVID-19 has the potential not only to cause thousands of deaths, but to also unleash economic and social devastation. Its spread beyond major cities means the opening of a new front in our fight against this virus,” said WHO Regional Director for Africa Matshidiso Moeti in a press release.

Moeti urged for a “decentralized response” tailored to the local context across the continent. “Communities need to be empowered, and provincial and district levels of government need to ensure they have the resources and expertise to respond to outbreaks locally,” she added.

Of particular concern are countries with fragile health systems experiencing complex emergencies – some countries in Africa do not have the hospital bed capacity, enough ventilators, and trained personnel to take care of a surge of patients.

“Africa still has an opportunity to reduce and slow down disease transmission.  All countries must rapidly accelerate and scale up a comprehensive response to the pandemic, including an appropriate combination of proven public health and physical distancing measures,” said Ahmed Al-Mandhari, WHO’s Regional Director for the Eastern Mediterranean, which includes North African countries such as Egypt, Morocco, and Tunisia.

South Africa, with 1,749 cases and 13 deaths, has the highest number of cases, but the death rate so far is highest in Algeria with 205 deaths and 1,572 cases.

Image Credits: Mectizan Donation Programme, Y Tambe, Johns Hopkins CSSE.