As the novel coronavirus pandemic spreads through vulnerable sections of populations around the world, with over 15 lakh cases globally, scientists are rushing to find a vaccine for COVID-19. Among several areas of focus—ranging from Ivermectin, which is used to treat head lice, to malaria drugs—is a potential connection between COVID-19 and the Bacillus Calmette–Guérin, or BCG vaccine, a widely–administered vaccine which has been used to immunise infants against tuberculosis for the last 80 years in developing countries. TB, an infectious bacterial disease primarily affecting the lungs, has been around for several millennia, infecting millions each year and endemic in many poor countries. Can the BCG vaccine now be put to use on these new COVID-19 frontlines?
While noting that there is “little evidence yet that the vaccine will blunt infection with the coronavirus,” the New York Times reported last week that a series of clinical trials may answer this question in the coming months. “On Monday, scientists in Melbourne, Australia, started administering the B.C.G. vaccine or a placebo to thousands of physicians, nurses, respiratory therapists and other health care workers — the first of several randomized controlled trials intended to test the vaccine’s effectiveness against the coronavirus,” the article reported. Other scientists are also studying whether there is a correlation between the BCG vaccine and fewer COVID-19 deaths in countries that have previously administered the vaccine.
In developing nations like India which have used the BCG vaccine, this connection is of great interest. Indians have wondered whether their previous use of the BCG vaccine has granted them an increased immunity from COVID-19. However, doctors have said that it is too early to establish a direct link between the BCG vaccine and COVID-19, and that large-scale epidemiological studies are needed before anything can be concluded.
On 8 April, I spoke to Kevin Urdahl, a doctor and a professor at the Center for Global Infectious Disease Research, a research center at the Seattle Children’s Hospital. Urdahl has been researching an effective TB vaccine for over 20 years through the Urdahl Lab, which is also based at the hospital. He offered a reality check on the role that BCG might play in the ongoing COVID-19 research and cautioned that we need to consider the impact of the BCG vaccine on our immune systems before we look at it as a potential safeguard against COVID-19.
Rajni George: Are you talking about the potential connection between COVID and TB in the United States?
Kevin Urdahl: People are talking about coronavirus all the time, that’s all that anyone is talking about. But I wouldn’t say that the connection between TB or BCG and coronavirus comes up much here. I think that part of the reason is that tuberculosis and BCG is much more on the minds of people in India than it is in the United States. We don’t use BCG here, most people don’t know people who are touched by TB, and that’s different in India.
RG: Is this something that you think is going to be discussed more, amongst your peers there?
KU: I think it will be. We [the Urdahl Lab] are involved in a large NIH [National Institutes of Health] consortium. The goal is to understand how immunity against TB works. To achieve this, we integrate work in small animal models, non-human primate models, and human studies. These last two days, we had a web-based kick-off meeting focused on our work in humans, and the NIH officers overseeing the program were on the line. We had 50 or 60 people on a web symposium across three continents. The intersection between coronavirus and TB was discussed, and we were told that there could be funds available if we had interesting ideas regarding this subject. So, these ideas were discussed in just the last couple of days.
RG: How long would proposals for this research take to be approved, and has the current situation changed how this is handled?
KU: Coronavirus research is being fast-tracked. In the US, this is an NIH initiative. Congress recently passed a stimulus package that included $945 million dedicated for coronavirus research. NIH is looking for proposals to review and fund quickly, and to fast-track these efforts. Right now, most research in the United States is closed down with the exception of coronavirus research which has potential to inform interventions that could curb the pandemic.
RG: Could you tell us more about this symposium you participated in?
KU: The name of the program is “Immune Mechanisms of Protection against Microbacterium tuberculosis.” We have a centre for that, it’s called IMPAc-TB.
This was a kick-off meeting for our group. There were European, African and American participants along with program officers from the NIH, discussing our plans going forward. Some of the discussions focused on how COVID-19 was impacting our research programme, and opportunities to study the intersection of COVID and TB as part of that.
RG: What might these plans look like? How can we go about using any connection between the BCG vaccine or TB and coronavirus effectively?
KU: We haven’t developed a proposal yet, but in general terms the questions are: how do co-infection with TB and COVID impact each other? Does a pre-existing TB infection make you have more severe or less severe symptoms from COVID, and vice versa? If you have a low-level TB infection and you get COVID, does that exacerbate your TB and make it worse? Recently there was a study in China, [titled, “Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity,” available on medRxiv, an online archive and distribution server for preprints in the medical, clinical and related health sciences] that reported that individuals with a positive test for TB infection, but who are not sick with TB disease, are more likely to get severe COVID disease. At this point this is a preliminary manuscript that is not yet peer-reviewed, but if it is true, this would be very important to know.
RG: Is the focus of these talks also on the BCG vaccination? People worldwide are discussing this as we consider all options.
KU: We didn’t discuss that in our talks yesterday, but we can talk about the rationale for that. The BCG vaccination is given to infants, usually in the first few days of life. Countries which have a large burden of TB continue to vaccinate with BCG, but we haven’t done it in the US since the early 60s. There have been a number of studies that show that the vaccine is primarily effective in infants and young children. Vaccinated infants get less severe TB, especially the most severe forms of TB, like TB meningitis and disseminated TB. In most cases, however, the protective effects of BCG are not long-lasting.
Vaccination at birth does not prevent TB in adolescents and adults. But it continues to be administered in most countries because it saves the lives of about 50,000–100,000 infants and young children every year. This is a lot of lives saved, but when you consider that over 1.2 million die of TB every year and most of those people were vaccinated as infants, it becomes apparent that BCG is not nearly effective enough. Also, babies aren’t the ones spreading the TB to other people. You have to have a certain form of TB and be coughing to spread the TB by aerosol to other people. Babies just don’t do that. The fact that the BCG vaccine doesn’t really have an effect on pulmonary TB in adolescents and adults and they’re the ones spreading it to other people, means that the vaccine hasn’t really done anything to curb the spread or transmission of TB.
RG: Is there a misconception that we are safer, having had this vaccine?
KU: I was not aware that that was a feeling. In general, the feeling of safety is not due to the vaccine at this point. Usually, acquiring TB requires prolonged contact with someone who has it; living with someone who has TB or being in the same room with them for many months, for example. It tends to propagate amongst impoverished people living in very close quarters. As people are spreading out and have bedrooms to themselves and larger houses, that is what really protects people. It’s more about your contact than the vaccine.
Back to the BCG vaccine. The idea that it could be helpful for coronavirus or other infections comes from studies of infants who get the BCG vaccine. Yes, they are saved from death and severe TB, but it also seems to have a non-specific effect against many other infections. Infants who are immunised with BCG at birth, compared to other infants, are less likely to have viral diarrhoeal diseases for instance, less likely to have pneumonia. They have less childhood mortality, less childhood death.
RG: Broadly, respiratory illnesses as well?
KU: Yes. The reason is that the BCG vaccine is a live, attenuated vaccine, which means that it is a live, crippled bacteria, that is related to TB but doesn’t cause TB disease. When you are immunised with BCG, it stays in your body for a period of time, we don’t really know if it’s weeks or months. During the time it’s in the infant’s body, it is replicating and stimulating the immune system non-specifically, such that immune cells that fight other infection become more robust and more inflammatory. When they encounter something that is not even TB, they can respond more robustly and in a more inflammatory manner, and might be able to deter that other infection that might give you pneumonia or diarrhoea and so forth. There is pretty good evidence that that is true in infants who have the BCG vaccine.
RG: Some experts are arguing for a more tailored approach to tackling COVID-19, asking for caution instead of assuming the BCG vaccine will help; others advocate for whatever will make the human host stronger, even if it is generic, at the global level. Where do you fall on this spectrum?
KU: There are a couple of problems that I see that might make this a risky option. First of all, part of the reason this works on infants, I think, is because infants’ immune systems are not very mature. They don’t mount a robust, inflammatory response when they see an infection, compared to an adult. This is why infants are more susceptible to a lot of infections. BCG helps their immune system mature faster, and become more robust and inflammatory. I think it works especially well in infants for this reason and in this non-specific manner. It is less clear how big a help that would be with adults who already have a mature immune system that is already robust and inflammatory. There is also the concern that it might push the adult immune system further, to be excessively robust and inflammatory.
The coronavirus itself is not what kills people. What kills people with coronavirus infection is an excessive, overly robust inflammatory response by the immune system that creates a cytokine storm. [A cytokine is a large group of proteins, peptides or glycoproteins that are secreted by specific cells of the immune system. A cytokine storm is an overreaction of the body’s immune system.] People die because their immune systems respond too robustly to the virus, in an overly inflammatory way. The very reason that BCG helps infants has the potential, in my mind, to push the immune system to respond non-specifically and excessively. This could actually be detrimental, and cause people to have more severe disease from the virus. The recent report from China that low-level TB infection is associated with severe COVID disease is concerning, because BCG is a live bacteria that is closely related to the TB bacteria and could have a similar effect on exacerbating severe COVID disease.
Nobody really knows until it’s tested. But I have significant concerns that this would be high risk. Most vaccines are more tailored to the infection. Most vaccines generate a very specific immune response to the infection that you are vaccinating against; it doesn’t have an impact on other infections and doesn’t boost your immune response in a non-specific way. I recognise that scientists are going to have different opinions about this. Some may think BCG immunisation could be beneficial for coronavirus infection, whereas others will think it’s too risky. I have to say that I am on the side that thinks that it might be too risky and I would not advocate doing a BCG vaccination trial for coronavirus. I think we would probably be better off waiting for a tailored vaccine that is specific for coronavirus, that doesn’t boost the immune response non-specifically, because I think that could be dangerous.
RG: How many others are voicing this note of caution in your field?
KU: I think there are some scientists saying the same thing that I am, maybe I said it a little more strongly. I don’t know. That’s the way these things go in science. Nobody knows for sure until you do the studies. The question is, is it worth taking the risk? We need to review everything we know about BCG and everything we know about how coronavirus causes disease. If it seems too risky, perhaps the trial should not even be done.
RG: You study “the barriers that prevent the immune system from eradicating the bacteria that causes tuberculosis”. Has there been any recent progress in the search for an effective TB vaccine? And is there any kind of similarity between these barriers that you are looking to overcome, and those we face with the novel coronavirus?
KU: I think coronavirus is quite different from TB. I’m hopeful there will be an effective vaccine for coronavirus in not much more than a year, that is tailored and specific to coronavirus. With most of these infections, we know how to get protection, and we know how to make vaccines to elicit these protective responses. Now we have a new virus, and we need to ramp up the tried and true ways to develop a vaccine for this type of virus. It takes a little time, but I’m confident we will do it and we will do it relatively quickly. For TB, it’s quite different.
RG: TB isn’t a virus.
KU: It’s not a virus, we still don’t know how exactly immunity to TB works. It’s much more complicated. It’s a bacteria that lives inside cells of our own body, and has developed strategies to persist in the body. We need more fundamental understanding of what the barriers are to immunity, and how to overcome those barriers.
That being said, in the last five years, I think there has been tremendous progress. We know now for sure that it’s possible to do better than BCG. There are examples in animal models of vaccines that can completely clear the TB bacteria from the body. That gives us the opportunity to study how that protective immunity works and understand how it’s mediated. Some people have questions about how translatable these particular vaccines will be for humans. There might be safety or feasibility issues that restrict their use in humans. But now that we have something that works in animals we can study it and try to understand how it works. This will enable us to know what part of the immune system to target, and this will help us to develop a vaccine for humans. We know that developing vaccines the way we have for other infections doesn’t work for TB. And just trying things doesn’t work either. We need to understand what we need to target to develop a TB vaccine that works well.
In the past year, the TB field got some exciting results about a promising new TB vaccine, M72:AS01E. This vaccine was administered to previously BCG-immunised adolescents as a booster, and it was shown to reduce the cases of active TB by about 50 percent for at least three years. Fifty percent is a modest number, and I think we’ll be able to do better than that. I don’t think this vaccine will be the final answer. Nevertheless, these results are exciting for two reasons. Even at 50 percent efficacy, it could save millions of lives while we are working to develop an even better vaccine. Also, it gives us an opportunity now to study immunity, and to understand how it is mediated so we can design a vaccine that is better.
RG: Is this vaccine being rolled out soon?
KU: It’s being moved forward into larger, phase three human trials, where its efficacy will be studied in a much larger, broader population. The first study of efficacy was a smaller phase two study. Now it needs to be done in a larger, broader study. Those studies are currently funded and being planned. If it validates what has been shown in the smaller study, it will likely be rolled out after that fact.
RG: TB is still a major killer, in the developing world. What are your thoughts on how much attention we give it versus how much attention we are giving threats like COVID-19?
KU: I think the COVID pandemic is very serious, and it needs to be taken very seriously. I don’t want anything I say to be misconstrued from that perspective. I think the global attention it is receiving and the social distancing and the quarantining, all of that is very warranted to curb the pandemic and lessen its impact. As bad as it has been, it has potential to be much, much worse, and I think these measures have already had an effect, and are already making a difference.
But regarding your question, even now, at the height of this, I think there are more people in the world dying every day of TB than of COVID-19, right now. And I think most people don’t realise that. Over 4,000 people per day die of TB. I don’t think we’ve reached 4,000 people per day who die of COVID. Not yet anyway. There is no doubt that TB does not get the attention that it should. I think we’ve kind of been numbed. This is a part of life that we just deal with every day, and it doesn’t need to be that way.
I think science has advanced to the point that we have the potential to overcome this very devastating disease, if it got the attention it deserved for how a big problem it really is. If people in societies really dedicated themselves to TB and gave it the resources it deserved, we could conquer this.
RG: It’s a disease that is more prevalent in developing countries. Isn’t that part of the problem?
KU: Yes. If we look at a lot of the countries that make the biggest investments in science, TB is often not considered a big problem in these countries, and it doesn’t rise to the top of the priority list. I think that’s been changing to some extent, gradually, over time, but we still have further to go.
It’s a small world, and there’s no such thing as, things that affect some people, but have no impact on other people. We are all connected. Maybe this COVID pandemic has a silver lining to it: this sense of connection that we all have to each other and to all people could emerge and have a carry-over effect for other very important diseases like TB.
This interview has been edited and condensed.
Correction: This interview incorrectly stated that a study titled “Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity” was published in the Medical Archives. It is in fact available on medRxiv, an online archive and distribution server for preprints in the medical, clinical and related health sciences. The Caravan regrets the error.