This article is part of Harvard Medical School’s continuing coverage of the COVID-19 pandemic and related issues.
Members of the Harvard Medical School-led Massachusetts Consortium on Pathogen Readiness, or MassCPR, this week addressed key questions about COVID-19’s shifting landscape and its prevention and treatment in the context of new variants, flu infections, and respiratory syncytial virus, or RSV. The panel was moderated by Bruce Walker, faculty co-lead of MassCPR and director of the Ragon Institute of MGH, MIT and Harvard. It included:
- Amy Barczak, HMS assistant professor of medicine and an infectious disease specialist at Mass General and a faculty member of the Ragon Institute of MGH, MIT, and Harvard
- Bill Hanage, associate professor of epidemiology and co-director of the Center for Communicable Disease Dynamics at Harvard T.H. Chan School of Public Health
- Jake Lemieux, HMS assistant professor of medicine and an infectious disease specialist at Mass General and viral variants working group co-lead for MassCPR
- Jeremy Luban, professor of molecular medicine, biochemistry, and molecular biotechnology at UMass Chan Medical School and viral variants working group co-lead for MassCPR
- Kristin Moffitt, HMS assistant professor of pediatrics and a pediatric infectious disease specialist at Boston Children’s Hospital
Where do things stand at the moment with COVID-19 variants, influenza, and RSV?
Lemieux: We are definitely well into the winter surge of the “tripledemic.” In the United States, we’re seeing dashboard rates of COVID, RSV, and Influenza all rising or having recently risen. We’ve seen pretty dramatic increases in cases over the last two weeks, likely reflecting the holiday gathering season.
Remember, there’s a lot less testing. There’s a lot less reporting. So, we’re seeing these trends across the board in the test-positivity rate, the hospitalization rate, and alarmingly, also in the death rate, which has seen quite a jump as well. Overall, the picture is concerning and probably also not fully clear based on the data that we have available.
In Massachusetts, we have very good data on wastewater levels, and that’s showing that we’re at the highest level in the last nine months. Hopefully that trend reverses. But going into the holiday season, I think that’s very much an open question, and certainly for the next couple of weeks, I think it’s reasonable to anticipate that at least in Massachusetts case counts will rise. This is a BQ.1 and BQ1.1 epidemic at this time, and that’s very bad news for monoclonal antibodies.
The influenza data is also concerning. The influenza surveillance from the CDC shows that we’re accelerating early and at higher levels of hospitalizations than we’ve had for the past two years. There is similar CDC data on RSV. It does seem like that RSV epidemic has peaked, and we are fortunately seeing reduced activity.
We, in MassCPR and others, collaboratively have responded to the surge in RSV cases to provide some of the first and earliest genomic surveillance data, and it’s a striking pattern of a really heterogenous RSV surge of multiple sublineages, and their common ancestry seems to well predate COVID.
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Should people be wearing masks?
Lemieux: That’s a great question. Indoors I would think so, certainly. And also, where the gatherings are dense, where people are at higher risk, I would definitely consider it. I’m doing that.
Barczak: I think for many of us around the holidays, when we may be with elderly relatives or in particularly high-risk settings, masking is really important, and it’s a relatively easy intervention. So, I think a lot of us recommend it.
When do you think SARS-CoV-2 will reach an evolutionary plateau? Or is this just going to keep evolving?
Luban: It’s a complex question that has at least two parts. The good news is that in terms of severe disease protection, in terms of protection against going to the hospital or dying, that type of immunity that’s elicited by the vaccinations or from prior infection seems to be quite protective. There’s no evidence that the virus is evolving away from those immune protective mechanisms. This immunity against severe disease is likely derived from T cells, but there are also other types of immune cells and parts of the immune system that we still need to understand better.
The not-so-good news is that the antibodies that protect us from getting infected and prevent transmission of the virus — that’s clearly where the most pressure is put on the virus to change. That’s where most of the changes occur. Based on precedent of other coronaviruses that we’ve lived with all our lives that continue to come back in waves every two to three years and infect us despite neutralizing antibodies against the previous forms, I think it’s pretty likely that the antibody responses are going to continue to be a source of escape for SARS-CoV-2.
Most experts would predict that the virus has a yearly, or for all effects infinite, ability to escape antibody responses, and it seems very unlikely that we’re going to reach some absolute plateau on that front.
I also believe that the most important question going forward is: How often do we need to update vaccinations to prevent new infections?
What are the factors associated with repeat infections? And what do we know about the physiologic consequences of repeat infections?
Barczak: There are a few things that are clearly the highest contributors to risk. The first is how long has it been since an individual was previously infected. This matters. We know that immunity wanes and protection is a complicated thing, but clearly there’s a downslope in protection over time.
Your vaccination status also matters a lot. If you’re infected, and then you get another booster after that infection, that boost is quite protective. Whether or not you get an additional booster after infection can be associated with how likely you are to get a repeat infection.
People with certain immune conditions or on immunosuppressive treatments can be at an extremely high risk of getting a repeat infection. In addition to these host factors, there are viral factors at play. The match between the variant you were previously infected with and the circulating variant of the moment is really important in terms of whether or not you’re likely to get reinfected.
For people who have normal immune systems, it’s much less likely that they’re going to be reinfected with the same variant than with a new variant that is able to evade detection by antibodies against the earlier variant.
As far as consequences of repeat infections, this is something that’s been debated quite a bit. Recent data is converging to suggest that repeat infections do confer a cumulative risk of hospitalization, organ damage, or death. A previous episode of infection does not necessarily change the course of disease when you are reinfected.
It’s pretty clear that the people who are most at risk are those who are older, people who have baseline health issues, and people who have particular comorbidities like obesity or diabetes.
How comfortable should people feel if they’re getting together as a group over the holidays and they do antigen testing right before they meet? Are there strong data to suggest how much that mitigates risk?
Barczak: I think, in general, the accumulated data suggest that antigen testing is fairly accurate for identifying infection. I think it is a really good strategy. It’s easily available, and everyone can choose to do it, and hosts can make tests available.
Hanage: The way to think about it is that it’s cumulative risk reduction. We cannot get the risk to zero, but we can reduce risk markedly by vaccinating, by wearing masks where we want to, and if we don’t want to wear masks having people do a rapid test before they get together. I am going to be seeing my parents next week for the first time in three years, and I am certainly going to be carrying a bunch of rapid tests with me.
What about the shifting death trends? This doesn’t seem to be an ongoing pandemic of the unvaccinated. Can you make sense of these data?
Hanage: The fact is that people who are vaccinated can and do get infected. But the real issue is when they do get infected, they are much, much less likely to be severely ill as a result of the vaccination. Having said that, some vaccinated people can get pretty sick, particularly if they are older. Older people are not only more likely to die, they are also more likely to be vaccinated and boosted, which means that we tend to start seeing these spurious relationships. Yes, a lot of people who have died recently have been vaccinated. A lot of shoplifters are right-handed. That doesn’t mean that being right-handed makes you more likely to shoplift. Because so many of the most vulnerable people are also vaccinated, you can get this spurious link. The latest data from the CDC show that even though older people are more vulnerable in general, vaccinating them and boosting them really reduces their risk. In people between 65 and 80, vaccination reduces the risk of death eight-fold and in the over 80s nearly four-fold.
There are other ways to reduce risk, such as regular rapid testing in what you might call “high-consequence” environments — like nursing homes. That seems like a pretty obvious thing to do. Using these tests in places where they are most likely to be helpful is something we should be doing. And let’s not forget Paxlovid, a very useful drug, particularly in those people who are most likely to get severely ill.
As we just heard the monoclonal antibodies are not holding up so well against the new variants, so it’s that much more important to use the things we do have in our arsenal.
How are pediatric infections trending? What is the post-COVID situation in pediatrics, and where we stand with RSV on top of COVID?
Moffitt: Children’s hospitals, as everybody is aware, have been very, very, busy since late October, when we started to see the significant uptick in RSV. It was like an onslaught. I think a lot of us at Boston Children’s compared that to what adult hospitals were experiencing in the earliest waves of Covid.
We’re always prepared every respiratory viral season for an uptick in respiratory viral infections. But this really was something that was just of sheer volume in terms of the numbers of children experiencing RSV.
We’ve started to see the RSV case numbers go down. But we’re seeing a rapid uptick in influenza cases, and so we’re not feeling any relief of the strain quite yet.
Where is pediatric COVID continuing to play into that? Nationally, we’ve had over 170,000 pediatric admissions for COVID since August of 2020. We experienced the peak of pediatric COVID infections during the omicron surge, especially earlier this year. The latest data shows we have about 200 pediatric hospitalizations for a seven-day average — a substantial decrease from where we were during the peak, but it’s still substantial when you have this current stream on top of substantial RSV and influenza numbers. It’s been causing a lot of strain. The current CDC estimate is that about 86 percent of U.S. children under 17 have had a SARS-CoV-2 infection based on seroprevalence, or specific antibody presence in the blood. This translates to almost 62 million children. And reflects how woefully we are undercounting cases if we are just looking at testing data, which would indicate only 16 million have had a SARS-CoV-2 infection.
In terms of the consequences of COVID in children, there is one bit of positive news regarding multisystem inflammatory syndrome in children, known as MIS-C. This can develop about two to six weeks after infection and often requires ICU-level care. We saw a peak in MIS-C cases during the initial alpha variant surge. We had another peak during the delta surge. We saw one more peak of MIS-C cases during the earliest phase of the omicron surge in January 2022.
However, since then we’ve seen a significant decrease in MIS-C cases. We are talking to our pediatric ICU colleagues, and it’s very infrequent that we are seeing MIS-C anymore. It is not entirely clear why that is. Many of us are hopeful that perhaps MIS-C was unique to a patient’s first encounter with the virus, but that remains an unknown. It will be difficult to predict whether MIS-C cases might spike again until we better understand what causes MIS-C.
