William J. Muller, MD, PhD, discusses COVID-19 vaccinations for children and what is on the horizon for a potential RSV vaccine.
Contemporary Pediatrics®: Could you explain in some detail what caused the delay in allowing children 4 years and younger to be eligible for the COVID-19 vaccine?
William J. Muller, MD, PhD: The Pfizer/ BioNTech delay has been related to the second of the 2-dose series not inducing the same level of antibody response in younger children, those between the ages of 2 and 5 years. A lot of the pediatric studies have not been designed to show efficacy against preventing either symptomatic disease or hospitalization in this age group. Everybody is aware by now that children are not as severely affected as adults are by COVID-19. So it was reasonable for all the vaccine studies that I’m aware of in children to be designed to use surrogate end points—basically, how good are the immune responses produced?—and antibody levels are a reasonable surrogate for that. That’s the way that the companies have gone into studying these vaccines in children.
I think Pfizer/BioNTech was not expecting as low of an antibody response in that age group as they measured in later stages of the study. My understanding is they were encouraged by the FDA [US Food and Drug Administration] to ask for an authorization anyway, due to the Omicron surge. There was an expectation that maybe they could show some protection against either infection or some level of severity of disease, but that didn’t really hold up. And it may be that because they had a data cut-off, it was too soon in the Omicron surge for there to be an effect. Or it just may be that it’s very difficult to show protection from infection with any respiratory virus vaccine. This is true for influenza as well. As you know, the goal of most vaccinations is to keep you from getting so sick that you are hospitalized or worse, and because that’s an uncommon end point with children, you would need a huge study to show that there is that benefit.
So, in this case, the Pfizer/BioNTech response—which is appropriate—is that if the level of antibodies is too low, we may need a third dose in the age group of 2 to 5 years. That’s what they’re studying now, and it takes time to do that. They needed to bring all the participants back in for an additional dose, and they needed to get additional consent from the parents because that was not part of the initial study design. There are also concerns in adolescent and young adult males, in particular about possible cardiac effects of the mRNA vaccines, so that will be on their radar throughout the study. That added to the complexity and the amount of time it will take to get through all the data.
That’s for the Pfizer/BioNTech vaccine. We may not need 3 doses of the Moderna vaccine, which is studying 2 doses for children aged 6 months to 12 years. The expectation is that 2 doses will be sufficient to induce an immune response.
CP: As far as COVID-19 variants, going forward, where are we at in trying to be proactive?
WJM: The mRNA vaccine platforms are easily adapted to generating new variant vaccines. The technology that goes into putting a piece of mRNA into the lipid nanoparticle that is delivered as part of the vaccine doesn’t change when there’s a new variant; only the material that’s put into the vaccine would change. So from that standpoint, it’s not that difficult for a company to make a new vaccine for a variant.
Do the vaccines need to show the same level of efficacy? Probably not; I think they really need to show safety and some level of an immune response. All that said, it seems the existing vaccines now have a 3-dose series in adults; we don’t know necessarily yet for children if 2 or 3 doses will be necessary for all the mRNA vaccines, but there are reasonably good data that the immune responses induced may still provide a level of protection that is reasonable. Whenever there is a new variant, there are basic science laboratories in various parts of the world that are poised to immediately do studies with model systems in which they can put the variants into a virus that is not pathogenic and ask the question “Do the antibodies from some of the recipients of the vaccine provide some level of protection in a laboratory study?”
With the Omicron surge being so big, we were able to get a pretty good idea of whether people who had received the vaccine were significantly less likely to have significant consequences from infection. And the answer is that they seem to be much more protected from infection. Children aged 5 years and older who have been eligible for vaccination were really protected from hospitalization during the Omicron surge, and even at our hospital [Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois], we have good evidence that the increased number of hospitalizations in children was largely among either the unvaccinated or those who were not eligible for the vaccine.
CP: Do you foresee a time in the near future when the COVID-19 vaccine for adults and eligible children will be just part of the annual vaccination schedule, like with influenza?
WJM: I think there will be an expectation of a recommended vaccine for children and adults on some scheduled basis. And I think that the unanswered question right now is “Will we need it every year, like we recommend the influenza vaccine every year, or can it be spaced out over a longer time period?” It’s certainly too soon to tell if the current vaccines will offer lifelong protection. I don’t think I would expect that to be true. But, I don’t want to get too far off from what we know now.
CP: What about other COVID-19 vaccines?
WJM: More vaccines will become available. Recently, Sanofi and GSK [GlaxoSmithKline] asked for authorization for a protein-based vaccine for adults. As far as I know, the data
are not yet sufficient in children to ask for authorization. But that will give families a potential alternative, which may be beneficial in situations where, for example, somebody has an allergic reaction to mRNA vaccines. Another company, Novavax, is also making a protein-based vaccine, so there will be 2 additional protein-based options.
Currently, there is 1 other protein-based option under study, which is a vaccine being made from plants, Covifenz, from Medicago and GSK. [Editor’s note: As of this writing, Covifenz is approved for use in Canada for adults aged 18 to 64 years.1]. So, if somebody has objections to the manufacturing process associated with some vaccines, this could alleviate those concerns. I expect there to be more options within the COVID-19 vaccine area.
The other questions will involve alternative dosing schedules. There’s been some discussion recently about extending dosing between the first and second dose in adolescents and young adults. Early on in the pandemic, there were reasons to get the 2 doses close together. First, it made the studies go faster, and we needed something authorized quickly. That was a reasonable thing to do. Second, we wanted to get people protected sooner. That’s becoming less true as there is more population immunity. Maybe spacing out the doses [further] would be a practical approach.
CP: What about vaccines for other infectious diseases in pediatrics—is there anything of particular interest?
WJM: There certainly has been a lot of discussion recently about another illnesses of significant importance in pediatrics, notably RSV [respiratory syncytial virus]. Different strategies have been looked at to try to protect babies against severe disease from RSV infection. The first would be maternal vaccination—if the mom was able to get sufficient levels of antibodies, passive immunity could be passed from her to the baby. So far, those study findings have not necessarily shown protection. But as we learn more from the research, other vaccines might be developed to increase the mother’s ability to generate a protective response that doesn’t necessarily require the baby to get a separate immunization. I know that there are some studies as well that involve immunization of the baby, which could be active immunization for RSV—similar to the COVID-19 vaccine, in which the immune response that’s generated against the vaccine is what’s providing protection. And then there is passive immunity: That would provide protection against RSV by getting an antibody into the baby as opposed to inducing the production of antibodies. So, we will have to wait and see.
William J. Muller is an attending physician of infectious disease and scientific director of clinical and community trials at the Stanley Manne Children’s Research Institute at Ann & Robert H Lurie Children’s Hospital of Chicago and an associate professor of pediatric at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Medicago Covifenz COVID-19 vaccine. Government of Canada. Accessed March 2, 2022. https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/vaccines/medicago.html