part from its new name, nothing really happened in the last week. New confirmed cases per day remained high, seemed to decline somewhat until it became clear that there was shortage of testing capacity. Definition adapted, and then the numbers of infected patients in the affected Chinese regions exploded. So, one question answered from previous blogs: it’s big in China and we may (still) not know everything that is happening there (or in some other countries).
In the meantime many scientists boarded a plane to WHO in Geneva to discuss the research that is needed. Some stayed at home to work on their HORIZON2020 submission with a research response towards the SARS-CoV-2 outbreak. A call opened on January 31st, and closed on February 12th!
The list of prioritized studies that WHO put on their website was:
- the natural history of the virus, its transmission and diagnosis;
- animal and environmental research on the origin of the virus, including management measures at the human-animal interface;
- epidemiological studies;
- clinical characterization and management of disease caused by the virus;
- infection prevention and control, including best ways to protect health care workers;
- research and development for candidate therapeutics and vaccines;
- ethical considerations for research;
- integration of social sciences into the outbreak response.
Not very surprising topics, but the one prominently put forward last week was “infection prevention and control, including best ways to protect health care workers”. The description of the first 138 COVID-19 patients in a Wuhan, see, smashed the reality of this outbreak in our face: 43% of the acquisitions had occurred in the hospital, both among patients and healthcare workers. Not all admitted patients had been recognized immediately as COVID-19 infected, and not all infection prevention measures were 100% effective. Easy to say, “that won’t happen in my place”, but I am not that confident. Simple things, like running out on masks, gowns and other protective clothing are real risks, if a similar outbreak size reaches us.
So, how to protect healthcare workers? A vaccine or another preventive medicine may not be ready in time (and if, who gets first?). Leaves us with out-of-the-box solutions.
This is one option: Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but many studies have shown its ability to induce potent protection against other infectious diseases: the so called non-specific effects. There are actually 3 RCTs in children and adults in which BCG reduced either mortality or respiratory tract infections with 38%-80%, and this was not due to protection against tuberculosis. The non-specific beneficial effects of BCG vaccination are due to epigenetic and metabolic reprogramming of innate immune cells such as myeloid cells and NK cells, leading to an increased antimicrobial activity, a process termed ‘trained immunity’, see.
BCG is widely available, cheap and safe, and this truly is an out-of-the-box idea, brought to me by Mihai Netea.
My question to the infection prevention society readership of this blog: Would a RCT with BCG among healthcare workers be 1) warranted and 2) ethically justified during a COVID-19 pandemic? Please cast your vote below:
If you already replaced healthcare workers by macaques, you might also consider intravenous BCG vaccination, see.
Reflections on Infection Prevention and Control 
This excellent systematic review (https://www.bmj.com/content/355/bmj.i5170.long) showed that only one of the four RCTs that have been conducted in infants to date had low risk of bias. That trial showed reduced overall mortality in infants with low birth weight who were given the BCG vaccine early in life in a high infant mortality setting; same for measles vaccination, but not DTP vaccination (increased risk). Observational birth cohort data found that BCG given at the same time as DTP is more beneficial than when the two vaccinations are given separately. None of the studies took all childhood vaccinations into account (nor the order in which they are given), and bias can be severe (the most vulnerable children are the least likely to be vaccinated; effect sizes likely differ significantly between high and low mortality settings). I know that much larger and better-controlled trials in infants are currently ongoing (e.g. the MIS BAIR trial in Melbourne) and I will watch this space with interest. I am less familiar with the clinical evidence in adults. These excellent studies by our Radboud colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382772/; https://doi.org/10.1016/j.chom.2017.12.010), in which a total of 25 volunteers received BCG vaccination and were subsequently challenged by an (attenuated) pathogen, showed some promising results, but also high inter-individual response variability and some adverse events. It seems to me that future studies in adults, even in healthy adults, should still be conducted in well-controlled settings and not in the context of a potentially overwhelming epidemic.
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But wouldn’t an overwhelming epidemic not offer a well-controlled setting? If you randomize before the epidemic and do serology afterwards? Randomizing individuals per site would balance to some extent hospital-exposure to infection, and a large sample would be needed to address heterogeneity in total disease exposure per individual.
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True, but do we have sufficient safety data in adults to vaccinate large numbers of individuals while only passively monitoring safety as we would normally do with established vaccines? Given the relative lack of data on safety and efficacy at this point in time, volunteers would presumably have to be screened for any comorbidities/medication use hat might make vaccination unsafe, undergo a rather complex informed consent process, and be pro-actively followed after vaccination to document AEs and deal with them adequately. This is what I meant with overwhelming. Hospital staff would be busy handling a large epidemic, and at the same time, have to worry about all that, none of which is ‘business as usual’.
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How many millions of healthy people have already received BCG vaccination?
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Children, sure. But I thought the recommendation is that adults have to be tuberculin skin test negative (for safety reasons, not efficacy reasons), and that the vaccine is not safe in pregnant women (in clinical trial settings, we tend to have to prove absence of pregnancy in such situations by pregnancy testing)? Furthermore, the idea of the trial you propose is about what happens when exposed to COVID-19 soon after BCG vaccination – the only thing we know about safety in similar ‘multiple exposure’ contexts is from the two Radboud studies (I think, not sure). I will shut up now; the real BCG experts should weigh in.
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