Beating COVID Is Child’s Play

In this video, Betsy Herold, MD, chief of the Division of Pediatric Infectious Disease at the Children’s Hospital at Montefiore and Albert Einstein College of Medicine in New York City, discusses new research on why children experience less severe COVID-19 infections and how it could lead to innovative therapeutics for infection moving forward.

The following is a transcript of her remarks:

We began looking at COVID-19 back in March of 2020, when it first really became apparent this was going to be a significant problem. At that time, mostly we were focused obviously in our own region — so in the Bronx and in New York in general. One of the first observations we made was that the disease seemed to be causing more severity in adults compared to children.

So in collaboration with colleagues here at Montefiore and Albert Einstein College of Medicine, as well as colleagues at Yale University, we began to collect samples from both adults and children who were being hospitalized with COVID to answer the question: What was different in the way children were responding to COVID compared to adults, and could we then learn from that to, perhaps in the future, help patients who are developing disease?

So we’ve completed and published two studies and are working on some additional ones right now. In those first studies, what we found is when you looked at the blood in the patients who were adults versus those who were children — and we divided them essentially also based on the disease presentation — so when we look at those three groups, the kids who do well, the adults who do well, and the adults who do poorly, there are clear differences.

The children overall had lower levels of what are called inflammatory cytokines. These are proteins that are secreted typically by immune cells, but they can be secreted by other cells in your body that cause inflammation. Now that by itself was not surprising. We already knew that clinically, that adults who were doing poorly were going to have higher levels of those proteins compared to adults who did well and compared to children.

But there were two proteins that really caught our eye and they became very interesting. And those are called IL [interleukin]-17A and interferon gamma. Now, the reason they were interesting is — it was the opposite — they were higher in the children compared to the adults — compared both to the adults who did well and the adults who did poorly. So that suggested that perhaps those proteins were being protective.

Now, there are many cells that can make these proteins, but to simplify the story, let’s just say that typically we think of them as being made by your T cells, which is part of your adaptive immune response. But when we collected T cells from a subset of patients, the T-cell responses to COVID – which, if that was the source of these “good guy” proteins, we’ll call them – would’ve been higher in the children. It actually was the opposite: they were higher in the adults.

So clearly that was not the source of those proteins that looked like they potentially were being protective. The other place that those proteins can come from is something called your innate immune system. Your innate immune system is really the first part of your immune system.

The first time any of us see a pathogen that we’ve never seen before, we all sort of have this immediate response in our body of an innate immune response — that can be proteins and cells that respond without having any memory of it [the pathogen]. That usually helps us in the first few days of infection.

Then our body starts to make what we call the adaptive immune response, which is specific for each different pathogen that we look at. And that includes your antibodies and your T cells. So since that interferon gamma and that IL-17A was not coming from the T cells, we thought those proteins are also made by innate cells, and maybe that’s where it’s coming from.

What that suggested to us was a model in which if you make a good enough innate response, then you maybe don’t need to make as much of that adaptive memory response, because you’ve gotten rid of the virus. The model that our data suggests, and has subsequently been validated by other groups as well looking at different patient populations, is that kids make a better initial innate adaptive response, which helps them, number one, recover from the virus more quickly, but number two, leads to them not needing to make quite as much of that adaptive response.

And some of that adaptive response actually is what’s contributing to the disease. When you have an “over-vigorous” – is the way I like to put it – adaptive response, too many T cells activated, maybe some of the antibodies in the process of trying to kill the infected cells can actually lead to more inflammation. And that leads to that ARDS [acute respiratory distress syndrome] kind of syndrome that we see in association with COVID.

So how do we use this knowledge to prevent or to treat infections as we move forward in the future? One concept there is to actually use the proteins that we and others have identified, some of these innate molecules, and actually administer those. And there have been a few clinical trials to look at giving interferon, for example, which is one of those families of proteins, to patients who have COVID. So far, that data has not been a home run yet.

But another way to think about this, and some people call this “trained immunity,” is to think why would children have a stronger innate immune response? One theory is that every time you have a viral infection, your innate response sort of gets turned on. And so maybe because children have more frequent viral infections, just your run-of-the-mill colds, their innate system is a little bit more turned on and it’s ready to go. There is some data in animal models that suggested that indeed is the case.

So some people have argued that vaccinations — not even just specific COVID vaccines, but that in general sort of mucosal vaccines, or other ways of turning on your innate immune system — might work to protect people against infections.

So I think this is a really important area of research. We don’t have all the answers quite yet.