This article is part of Harvard Medical School’s continuing coverage of COVID-19.

Experts from the Harvard Medical School-led Massachusetts Consortium on Pathogen Readiness, or MassCPR, respond to critical questions about the future of the COVID-19 pandemic, including what’s on the horizon for vaccines in young children, and what’s in store for the new omicron subvariant.

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  • Adrienne Randolph, HMS professor of anaesthesia; critical-care specialist and immunobiologist at Boston Children’s Hospital
  • Ofer Levy, HMS professor of pediatrics; director, Precision Vaccines Program, senior physician in infectious diseases, Boston Children’s Hospital
  • Jacob Lemieux, HMS instructor in medicine at Massachusetts General Hospital; co-lead of the MassCPR viral variants program
  • Jeremy Luban, professor of molecular medicine, biochemistry & molecular pharmacology at UMass Chan Medical School; co-lead of the MassCPR viral variants program
  • Bruce Walker, director of the Ragon Institute of MGH, MIT and Harvard; faculty co-lead of MassCPR

Harvard Medicine News: What can we expect regarding approval of the COVID-19 vaccine in children under 5?

Levy: It’s been announced publicly that on Feb.15, the FDA vaccine advisory committee will convene to decide whether to advise the FDA to authorize the Pfizer-BioNTech mRNA vaccine for children under 5 years of age. It’s a transparent process: the briefing document having to do with safety and efficacy will be shared with the committee members and will likely be made available to the public around Feb. 13, two days before the meeting.

The briefing document will summarize safety and efficacy data from the vaccine studies, which typically include several thousand children. The 20 or so committee members will scrutinize those data, listen to the CDC present the epidemiology evidence, hear commentary from the company, and listen to FDA biostatisticians present their analyses of the data. There will also be a public commentary phase. Then the committee members will discuss, comment, and take comments into consideration as they come to a decision. If and when the committee votes for an authorization, then it goes to the CDC to decide how to implement that.

In younger children, there are reasons in favor of and against initiating this kind of vaccine program. Some have pointed out that the risk of severe infection is relatively low in young children. On the other hand, omicron spreads so readily that even if only a small percentage of children develop clinically severe infection, you have to multiply that by millions and millions of children. In fact, nearly 20 million Americans are under the age of 5, so it’s a considerable population. Then there’s the question of how well these vaccines protect against transmission, which is likely not as well as they protect against severe illness. It’s going to be an interesting conversation. The FDA committee makes decisions on advising the agency whether a vaccine should be made available. A hot-button issue that is not in the purview of the FDA advisory committee is vaccine mandates, which brings together science, politics, and other dynamics—a very complicated set of considerations.

HM News: What have we learned about multisystem inflammatory syndrome in children (MIS-C), the rare inflammatory condition that develops in some children with COVID-19?

Randolph: We’re over two years into the pandemic, and over 7,000 cases of MIS-C have been reported to the CDC in the United States, although there are probably more that haven’t been captured. The hope was that the cases would go down, but it’s unclear if the frequency of MIS-C is really decreasing. This is because omicron has infected so many more children compared with the other strains of COVID-19, and the more children infected, the more who are going to be at risk of getting MIS-C.

In early 2021, we published a paper estimating that about three per 10,000 people under 21 who were infected with COVID-19 would develop MIS-C. We’re redoing that now with more recent data to get a better estimate. A report from France, where 75 percent of teenagers are vaccinated against COVID-19, found that the frequency of MIS-C in the 12 to 18 age range went down to almost nothing. We reported in the CDC’s Morbidity and Mortality Weekly Report that the estimated effectiveness of the vaccine for preventing MIS-C in 12-to-18-year olds is relatively high, at about 91 percent. We’re redoing that analysis now to include 5-to-11-year olds, as well as more 12-to-18-year olds, but it makes sense that the vaccine would prevent MIS-C because it induces antibody protection against the virus, thereby preventing the development of disease.

HM News: What questions remain about MIS-C?

Randolph: MIS-C is definitely associated with SARS-CoV-2 infection, but we don’t know what triggers it in susceptible children. Most of these children had asymptomatic infections or minimal symptoms and developed MIS-C three to six weeks later. We do know that some individuals are genetically predisposed to having this hyperinflammatory response, but there are a lot of hypotheses that need to be verified. For example, some data suggest that these patients have a reservoir of SARS-CoV-2 antigens in their blood that may precipitate ongoing inflammation. There is also a hypothesis that this may be the result of an autoimmune reaction. We’ve enrolled about 250 MIS-C patients in an immunobiology study, and we’re trying to validate some of the preliminary findings in more patients.

HM News: What is the latest on the BA.2 subvariant of omicron? Will there be another wave of COVID-19 driven by BA.2?

Lemieux: We have had a near-complete omicron epidemic now for a few weeks. The transition happened in December across the region and was caused by the BA.1 sublineage, which is part of the omicron classification by WHO. There have been places where another omicron sublineage, BA.2, which we’ve been talking about for several weeks, has taken over: the Philippines, India, Denmark, South Africa. These are examples of places that showcase a phenomenon that’s happening around the world, which is the steady takeover of BA.1 by BA.2. We hadn’t been seeing that in our region so much, but we are now seeing that here across the region: exponentially increasing rates of BA.2 here in the United States. It is still a very early signal, but the CDC estimates that at the present time, 3.6 percent of the current outbreak is BA.2.

As far as whether we are going to have a significant BA.2-driven outbreak, I think the answer is no—but maybe. If you look at what’s happening in South Africa, where the BA.1 epidemic has ended, and where we are now seeing a BA.2-predominant epidemic, the total case counts have not dropped to zero, and they haven’t dropped to their pre-BA.1 baseline. There continues to be ongoing transmission. If you look at places like the U.K., where the epidemic is an increasing proportion of BA.2, there is a shoulder of ongoing transmission. In other words, the rate of decline in cases is asymmetric and not equal to the rate of increase in cases, and that is likely driven by BA.2. I think that looking around us at the natural experiments that are being conducted is probably a more informative way to understand what the future holds for us in the United States, where BA.2 has come late. I think it paints a mixed picture. There will likely be some additional burden of transmission from BA.2, but the rate of increase will be slower in case counts than it otherwise may have been. There may be some peaks in some areas, but it’s not going to be a categorically different epidemic as it was when BA.1 surged through.

HM News: Now that COVID-19 cases are dropping, can we begin to consider a return to “normal”?

Lemieux: For me, I think one key thing that is missing—that I hope won’t be missing for too long—is widespread availability of easily distributable oral medications for COVID-19. Right now, at least in the adult population, Paxlovid, which is a combination of nirmatrelvir and ritonavir, has been authorized for use. We just don’t have it to prescribe yet in sufficient quantities, and there are some logistical issues with prescribing it. Ritonavir, one of the components of its coformulation, has a large number of drug-drug interactions, so this isn’t a medication that you can prescribe without taking a medical history and understanding what other medications the patient is on. Hopefully, that medication will become more available and others like it—hopefully ones with fewer complications in terms of drug-drug interactions but that maintain the incredible efficacy and ease of delivery that comes with oral medication. I think that’s a key metric.

A second challenge is that this is quickly transitioning into an epidemic of the vulnerable. The largely healthy, the immunized, can likely return to prepandemic life with little risk to life or limb, so to speak. The immunocompromised, despite vaccination, despite taking all precautions, remain at risk. These patients get hospitalized and there are terrible outcomes in a minority of cases. We have to remain cognizant that this is a highly lethal virus that remains in circulation for which first-line treatments are in short supply, and there is a subset of the population that remains extremely vulnerable. I think that we’re going to have to navigate this as a society, and it’s going to be a really difficult societal conversation. Of course, we all want to go back to prepandemic life, and we all want to have the most normal experience, but we also have vulnerable members of the population who are at ongoing risk for severe outcomes and even death.

Levy: I think that this spring will look a lot better than the winter, which tends to happen with the seasonality of a respiratory virus. The spring may be a time to take stock of the interventions that were put in place early in the pandemic. We need to assess the impact not just on the transmission of the virus and the burden of viral disease, but also on economic activity, social interactions, family life, and child education. We’re going to have to walk that balance. With some luck, spring and summer will look very good, and restrictions will be lessened to enable people to engage in more activities. We are, in fits and starts, making advances against this virus, but hopefully with vaccines that are more carefully tailored to the variants that are circulating year to year, increased supply of therapeutics, and thoughtful public policy that takes public health broadly into account by considering not just the impact of public health measures on viral transmission, but also their impact on the overall well-being of a society and its people, we will be on the right path.