A critical 500-person Cape Town trial, part of an international examination into whether the BCG vaccine protects against COVID-19, is under pressure from demands from a group of activists.
Bhekisisa reports that aCape Town scientists are hoping that a new study involving a common tuberculosis (TB) vaccine will show if it can help protect people at a high risk of COVID-19 from the disease and tell us more about how our immune system works. But, the trial has been criticised for allegedly failing to provide participants – many of whom are healthcare workers – with masks and gloves.
In May, the Cape Town clinical research organisation TASK began testing whether a TB jab – the Bacille Calmette-Guérin (BCG) vaccine that is usually given to newborns – could help protect hospital workers such as doctors, nurses, security guards and administration staff against serious COVID-19 disease.
As part of the 500-person trial in Cape Town’s Tygerberg Hospital, about half of volunteers will receive the shot while the other 50% are given a placebo shot of simple saline solution. After a year, scientists will compare the two groups to see if cases of COVID-19 were lower or milder in the group that got the BCG shot. TASK hopes to expand the study to ultimately include 2 000 volunteers.
Similar trials are underway in Australia and the Netherlands.
The BCG immunisation has been shown to protect young children from developing active TB. Although most of us carry the germ that causes TB, only about one in 10 people will fall sick and develop active TB, the US Centres for Disease Control and Prevention explain.
There is currently no evidence that BCG offers protection against COVID-19, the World Health Organisation says. However, a controversial study, released in March, catapulted the vaccine into the headlines after it claimed that countries with universal BCG vaccination had lower COVID-19 deaths. The research, which was never peer-reviewed, had major flaws. One was that it had been conducted before most countries, including South Africa, that use BCG, had seen many cases of the new coronavirus, argue researchers from Canada’s McGill International TB Centre in a post for the journal Nature.
Countries in Europe, such as Italy, the Netherlands and Belgium, where the research was conducted, do not give BCG jabs to babies as a rule, as TB infections rates are low. On the contrary, most countries in Africa, where TB is common, immunise babies with BCG at birth.
If studies on BCG eventually show that the common jab can help prevent or reduce serious cases of COVID-19, the results may also help shape relatively new ways of thinking about the immune system. But activists are concerned that the study isn’t doing enough to care for the people in it – or engage with them.
In the meantime, people may already be trying to get their hands-on BCG vaccinations without any proof they’ll protect them against COVID-19. A spike in demand for the shot could lead to shortages of the vaccine for children, warn experts.
Clinical trials in South Africa are heavily regulated. Before studies can begin, scientists must apply for permission from the national medicines regulator, the South African Health Products Regulatory Authority (Sahpra), and accredited expert committees – often based at universities – to ensure trials are conducted ethically.
The TASK study received approval from Sahpra as well as ethical sign off from the University of Cape Town and an independent research ethics committee at the firm Pharma-Ethics.
Clinical trials must also ensure that all participants receive a minimum standard of care and treatment, according to the World Medical Association’s Helsinki Declaration. But what constitutes that minimum standard of care – and whether that should be based on what’s locally or internationally available – remains debated.
On Friday, seven advocacy organisations, including the Vaccine Advocacy Resource Group, issued a statement saying that all COVID-19 clinical studies should ensure participants have access to free personal protective equipment (PPE), such as masks and gloves, as part of their standard of care — this includes in the TASK study.
Currently, none of the hospital workers in the TASK trial receive this kind of gear from the trial. Instead, they rely on the Western Cape health department, which has experienced shortages of masks since South Africa’s coronavirus outbreak started in March.
Caryn Upton is the scientist leading the TASK research. Upton says that neither the Cape Town trial or any of the other 10 studies looking at BCG and COVID-19 globally included or budgeted for the provision of PPE to volunteers.
“Essentially as healthcare workers in various different environments from cleaners all the way through to intensive care unit doctors, the provision of PPE, and the protection of these critical staff, is the responsibility of the state or the private institutions that are employing them,” she says. “A year of PPE for 1,000 participants basically makes the trial totally unfundable because that’s incredibly expensive.”
TASK recently approached the South African Medical Research Council (SAMRC) for funding to increase the number of people it could enrol in the study. Upton says the SAMRC is currently setting up a group of ethicists to discuss issues, including whether the trial should be providing protective gear.
“If we get funding for PPE – such as if the SAMRC wants to fund us – and included in that is funding for PPE, we are more than happy to provide PPE,” Upton says.
A Vaccine Advocacy Resource Group (VARG) founding member, Tian Johnson, who uses the pronoun they, says they also have concerns about how community engagement around the trial was conducted.
There are no international standards on community engagement, but the most recent 2006 guidelines from the South African national Health Department advise clinical trials to consider establishing a community advisory board. These bodies are composed of people from the community in which the trial is being held, for instance, religious or traditional leaders or trial participants. Today, most major HIV and TB clinical trials in South Africa have bodies such as these that help ensure communication between trial organisers and communities, via, for instance, regular community meetings.
Johnson says that when TASK was asked about what community engagement had been done, the organisation said it had posted information about the trial to a WhatsApp group and social media platforms. Johnson adds that TASK said that consultations had also been done with healthcare workers on internal TASK structures and with the civil society organisation, TB Proof, which represents healthcare workers affected by TB. “We brought on TB Proof to basically consult in the development of the protocol and also in terms of fulfilling the community engagement and recruitment,” says Upton. “They have a board, which has healthcare workers and community workers in it, and they represented our engagement with the healthcare worker community.”
But Johnson says this isn’t enough. “That’s not consultation,” says Johnson. “We need a process that allows for community and health sector engagement to help shape how the study is ultimately carried out.”
They explain: “None of us are saying that we don’t want the trial, or any other trial to happen… we’re just simply saying do it right. And right means ensuring that the trial is ethically sound and accountable to and owned by communities where research happens. We’ve learnt too much from HIV research for us to be having these conversations (about community ownership of research) in 2020.”
TB Proof says community engagement included discussing the trial with the COVID-19 People’s Coalition, an alliance of 300 NGOs, as well as the South African National AIDS Council (Sanac). Additionally, the TB non-profit held a 27 May meeting with members of the department of science and innovation, Sahpra and civil society.
Johnson was invited to chair this meeting, TB Proof explains. TB Proof Board Chair Helene-Mari van der Westhuizen in a statement said the organisation was surprised to see Friday’s statement from VARG and was under the impression that all concerns about the TASK trial except that regarding PPE had been resolved.
Van der Westhuizen says TASK gave a virtual presentation to Tygerberg staff on 28 April, which was also shared on a COVID-19 health worker Telegram group with more than 1,000 health care workers.
“TB Proof is advocating for adequate PPE provision to all health workers, not only those included in this trial,” van der Westhuizen argues. “The trial consortium has responded to civil society requests to include provision of PPE as part of this trial by proposing an additional ethics review and further engagement.”
She concludes: “TB Proof believes that if the current working conditions of health workers in South Africa is seen as “lack of standard of care”, this should not be addressed through adapting a trial but through making healthcare facilities safer for everyone.”
TB Proof is set to meet with civil society representatives, from the organisations that signed the statement, on Thursday to discuss the issues raised around the trial.
Although research on BCG released in March was flawed, it turns out researchers have been studying BCG’s potential to curb illnesses other than TB for years, in part because of a concept scientists call “trained immunity”. Our immune system is made up of different types of cells. When we get sick, these cells kick into action to try to fight infections.
But some researchers think that immunisations such as BCG and measles, that contain bits of live viruses – versus for instance, proteins made to look like viruses – help re-programme our immune cells to better respond to infections later. This, researchers argue, is even the case for infections other than the ones the vaccines were intended to fight, according to an article published earlier this year in Nature Reviews Immunology.
Thomas Scriba, deputy director of immunology at the South African Tuberculosis Vaccine Initiative: “There is … a part of your immune system that you are born with, it’s innate,” he says. “For a long time we thought you just have it, those cells do certain things and can’t adapt their behaviour. But it turns out that these innate cells can adapt a little through this process of trained immunity.”
Research in countries such as Guinea-Bissau argue the BCG vaccine helped reduce deaths from conditions such as malaria in newborns as well as reducing respiratory infections in teenagers in South Africa. The studies were published in 2017 and 2018 in the International Journal of Epidemiology and the New England Journal of Medicine.
But although the science seems to suggest “trained immunity” could be a concept worth looking at, it still can’t explain how it works, say researchers in a 2013 review in Trends in Immunology. That’s in part because most studies haven’t been designed to evaluate whether BCG vaccinations caused declines in illnesses other than TB, says Willem Hanekom, director of Africa Health Research Institute.
Although he says that the possibility that BCG could protect people against COVID-19 is a “nice hypothesis”, there is “precious little evidence to go on” that it will work. “The effects of BCG vaccination to prevent TB… the evidence is there. But it only works if you’ve not been exposed to TB before,” Hanekom explains.
A 2014 research review published in the journal of Clinical Infectious Disease found that BCG worked better to protect children against TB in northern countries, which typically have lower burdens of TB. Although more work is needed, scientists think that the jab may only work to prevent TB disease if people receive it before they are exposed to the TB germ – which is why in high TB burden countries like South Africa, vaccines happen soon after birth.
A 2010 study in the International Journal of Tuberculosis and Lung Disease found that 88% of about 1 000 people surveyed in Cape Town townships had latent TB – in other words, they had been infected with the TB germ, but had not fallen ill with it.
Meanwhile, effects of BCG on other illnesses have only really been described in very young children who have not been exposed to TB – unlike most South Africans.
Although studies in Guinea-Bissau looked promising, many other studies have been unable to replicate these results, sowing doubts among experts.
Hanekom concludes: “I cannot say with 100% (certainty) that (the BCG vaccine) is not going to have any effect, but it seems to only work when you are not infected with TB – and that is an important thing for me.”
Meanwhile, hype around the BCG jab’s possible role in fighting COVID-19, despite a lack of evidence, may already be having unintended consequences.
Upton says she is concerned that some healthcare workers who are not in the trial have tried to get re-vaccinated with the jab, even though they know there is no evidence that it will protect them from serious COVID-19 disease.
Upton says: “Without the supply chain being ready, without evidence even, we may run out of BCG and that will absolutely be a concern.”
In April, Sahpra said it had already seen an increased demand for the immunisation and warned that panicked people seeking out vaccinations could pose a public health risk. A 2016 mathematical model published in the journal BMC Medical estimated that shortages in BCG vaccine supply could lead to more than 100 000 deaths globally among children and adolescents.
Scriba warns: “Supply is actually still to some degree under pressure so it is really important that we protect the BCG vaccine supply for its intended use – vaccination of infants against TB – because that’s critical.”
[link url="https://bhekisisa.org/health-news-south-africa/2020-06-08-covid19-bcg-trials-south-africa-task-personal-protective-gear-trained-immunity/"]Bhekisisa report[/link]
[link url="https://www.medrxiv.org/content/10.1101/2020.03.24.20042937v1"]medRxiv abstract[/link]
[link url="https://naturemicrobiologycommunity.nature.com/users/36050-emily-maclean/posts/64892-universal-bcg-vaccination-and-protection-against-covid-19-critique-of-an-ecological-study"]Nature study[/link]
[link url="https://www.nature.com/articles/s41577-020-0285-6?proof=trueMay"]Nature Reviews Immunology abstract[/link]
[link url="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849087/"]International Journal of Epidemiology abstract[/link]
[link url="https://pubmed.ncbi.nlm.nih.gov/24336911/"]Journal of Clinical Infectious Diseases abstract[/link]
[link url="https://www.ingentaconnect.com/content/iuatld/ijtld/2010/00000014/00000004/art00007;jsessionid=64ktmoldbmi3d.x-ic-live-01"]International Journal of Tuberculosis and Lung Disease abstract[/link]
[link url="https://link.springer.com/article/10.1186/s12916-016-0685-4"]BMC Medicine mathematical model[/link]
This article was originally published by the Bhekisisa Centre for Health Journalism, bhekisisa.org