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Q&A: How vaccines can strengthen immune response beyond a specific disease

Live vaccines can give health effects beyond just protecting us from a specific disease and may even help us combat other infections such as Covid-19, according to Christine Stabell Benn, a professor in global health at the University of Southern Denmark.
Vaccines can train our innate immune system. Scientists like Christine Stabell Benn are now studying whether a TB vaccine confers protection against Covid-19. Image credit - Lone Morch

We often think about vaccines protecting us against a specific disease – training the immune system to recognise a particular threat and respond quickly if we are ever exposed to the disease. This is the adaptive immune system at work.

However, vaccines may also influence our immune system’s response to other diseases by training our innate immune system – the first line of defence against a broad range of infections.

Prof. Benn has studied the effects of childhood vaccines in low-income countries for over 20 years. She led the CHILIC project, which carried out clinical trials testing WHO policy on vaccines and vitamin A supplementation in Guinea-Bissau, and is studying the effect of the BCG (tuberculosis) and oral polio vaccines on Covid-19.

What effect do vaccines have on the immune system?

Our current understanding has historically been focused exclusively on what happens in terms of the specific memory that’s generated.

The whole idea with the vaccines is that you have an adaptive immune system that has memory. The innate immune system has never been ascribed any kind of memory. But in fact, that has been a simplistic view of the innate immune system.

What we are just recently learning is that there’s a lot more happening when a vaccine is given. It started with epidemiological observations at the population level, that is, by studying the effect of vaccines on overall health, and discovering that something is missing in this equation. We get effects on overall mortality that we cannot at all explain based on just the specific protective effect of the vaccine against the disease.

‘We get effects on overall mortality that we cannot at all explain based on just the specific protective effect of the vaccine against the disease.’

Professor Christine Stabell Benn, University of Southern Denmark

What types of vaccines have this effect?

All the live attenuated vaccines (created from a weakened form of a pathogen) we have studied have these beneficial nonspecific effects. They actually create a mild infection in the body and I think that’s key to their success. We have looked at BCG (a vaccine for tuberculosis), the measles vaccine – also in the form of the measles-mumps-rubella (MMR) vaccine – oral polio vaccine and the smallpox vaccine.

What additional effects have you seen from these vaccines?

One of the larger achievements with CHILIC was a study where low birth weight kids were randomised to (receive) BCG or no BCG. That was ethically justifiable by the fact that low birth weight kids would normally not get the BCG vaccine at birth; it’s postponed until they’ve gained more weight. In the first four weeks of life, we saw that overall mortality was reduced by a third in the BCG-vaccinated kids. This was due to a reduction in the risk of septicaemia and respiratory infections. So it had nothing to do with tuberculosis, which doesn’t kill babies in the first month of life.

(To understand better the immunological mechanisms) we gave Dutch volunteers either a BCG vaccine or a placebo. Four weeks later, we challenged them with a yellow fever vaccine and that is a pretty harsh live vaccine. It mimics getting an infection and you can measure the virus in the blood on day five after you get the vaccine. We could show that there was less yellow fever virus in the blood of those that received BCG four weeks prior. So we have here a proof-of-principle that a bacterial vaccine can alter how you handle a subsequent viral challenge.

What implications does this have on policies where live vaccines are being phased out, like the oral polio vaccine?

We, and other researchers also, have written a lot of letters and publications about this because it is a big concern. We can show that in Guinea Bissau, each dose of oral polio vaccine is associated with a reduction in child mortality of around 20%.

Other researchers have done back-to-back comparisons of oral polio vaccine and inactivated polio vaccine. Both trials found better health outcomes in those who got the oral polio vaccine.

Oral polio vaccine, in very rare circumstances – 1 in 2.7 million doses of OPV – (can lead to) cases of polio-vaccine-associated paralysis. That’s one of the reasons why the world is moving away from the oral polio vaccine. The other is the concern that it can mutate and become wild polio again.

My concern, and other people’s concern, is that once we stop using oral polio vaccine we will see mortality start to increase again, or at least the amazing decrease in all-cause mortality in low-income countries for the last decade is going to stop.

Do you think that live vaccines, such as BCG, can increase our protection against Covid-19?

There are two hypotheses out there. One is about giving BCG now, and seeing if it can prevent Covid in the following 6-12 months. The other hypothesis, which has been published in quite a few papers, claims that there is an association between countries with BCG childhood vaccination programme and less severe Covid-19.

I’m not convinced (by the second hypothesis). I mean, it would be wonderful if a vaccine given at birth could actually provide such long-term protection. It might provide some long-term protection, but still I find it a bit of a long stretch and the data quality is simply too poor.

We are conducting two trials with BCG vaccine in Denmark (for short-term protection against Covid-19 with healthcare workers and an elderly population).

We are also doing a randomised trial in Guinea-Bissau where we’re looking at oral polio vaccine. I would love to test it in Denmark also, but we are not allowed to use it here anymore. (Since Europe was declared polio-free in 2002, most EU countries have switched to using the inactivated polio vaccine, which does not contain live virus.) We’re using it in Bissau for adults above 50 (and tracking if coronavirus is picked up) to see if it mitigates the impact of Covid-19. 

The idea here (with these trials) is that their innate immune system will be so responsive that you will either completely fight off getting Covid or if you get it, you will have a very quick response to it and diminish the severity of the infection.

Are there other implications of your research on the current search for a coronavirus vaccine?

We have seen these beneficial nonspecific effects for live vaccines, but we have consistently seen that the non-live vaccines (like many of the frontrunner candidates for a coronavirus vaccine) do not have these effects.

It goes back to the immune system and what the vaccines do. We have now shown with Mihai Netea’s group (at Radboud University in the Netherlands) that the live vaccines can train the immune system and we have also shown now for four non-live vaccines that they induce tolerance in the innate immune system.

The net result is that if you take a Dutch woman and you vaccinate her with DTP (a non-live vaccine), and three months later, you take her (immune system) cells in a petri dish and you challenge them with various stimulants, then the cells are more lazy. So, you can train the innate immune system but you can also misdirect it, and we don’t know yet exactly how that happens.

The system for testing vaccines has been overtaken by our new understanding of how (the nonspecific effects of) vaccines work and how the immune system functions. We only look in the phase three (advanced) trials for specific effects of the vaccine and then in the first 14 days for plausible adverse events.

You could have a woman receiving this vaccine, and then three months later succumbing to bacterial pneumonia, and nobody in the world would ever count that, with the current system, as a side effect.

What I’m trying to advocate in Denmark is to roll out (a new coronavirus vaccine) in a randomised way. Let’s do it in a way where half of the target group gets the vaccine and the other half doesn’t get it and we can do some long-term follow-up, because that’s the only way to be sure.

The research in this article was partly funded by the EU’s European Research Council. If you liked this article, please consider sharing it on social media.

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