We can’t get a break! Having battled SARS-CoV-2 for the past two years, the past few months have seen health care systems facing a “tridemic” comprising COVID, respiratory syncytial virus (RSV), and influenza. The national surge in RSV has been widely documented in the media as well as the peer-reviewed literature. A recent article from the Journal of the American Medical Association captured the sense of urgency among pediatricians: “This Is Our COVID” – What Physicians Need to Know About the Pediatric RSV Surge” (JAMA 2022;328:2096-98).

A much earlier than normal outbreak of RSV has stretched pediatric hospital resources nationwide (asamonitor.pub/3Xy4Aax). Abbasi from the University of Texas Health Science Center at San Antonio described the situation: “In a vacuum, that would probably not be the end of the world…. But it’s on top of a really, really high flu season on top of a global COVID-19 pandemic. So, it’s sort of this horrible three-layer ice cream cone that is putting a lot of burden on the pediatric systems in the region and nationally” (JAMA 2022;328:2096-98). Just as with COVID, the surge in RSV has been global (Figure 1).

What is behind this sudden surge in RSV? Some pediatricians have attributed it to “immunity debt.” Nonpharmaceutical interventions like masking and social distancing implemented in 2020 and 2021 to mitigate the transmission of COVID-19 prevented the typical exposure to pathogens. As a result, children did not develop immunity to the traditional panoply of childhood infectious diseases. Instead, respiratory infections that typically would have occurred throughout 2020 and 2021 appeared as a destructive wave in 2022.

RSV is one of the most prominent causes of lower respiratory tract infections, affecting nearly all children before the age of 2 (asamonitor.pub/3weGHbC). While RSV can cause infections among all age groups, the most severe infections typically occur in infants and young children. For most adults and older children, RSV infection does not pose a threat. However, severe infections are now increasing in the elderly and adults with comorbidities.

This concept of “immunity debt” was raised in a 2021 publication authored by the French Pediatric Infectious Disease Group, which observed that the “reduction of infectious contacts secondary to hygiene measures imposed by the pandemic may have led to a decreased immune training in children and possibly to a greater susceptibility to infections in children” (Infect Dis Now 2021;51:418-23). Presciently they noted that “low viral and bacterial exposures due to NPIs (non-pharmaceutical interventions) imposed by the COVID-19 pandemic raise concerns as we may witness strong pediatric epidemic rebounds once personal protection measures are lifted.”

The implementation of widespread masking and handwashing during the pandemic allowed for a comparison of the RSV disease activity during the pre-pandemic seasons to those during the pandemic. Typically, RSV disease activity peaks around December. During the pandemic, there was a dearth of RSV infection, except for a surge during summer 2021 when nonpharmaceutical interventions were relaxed. As noted by Bardsley and colleagues, “the absence of RSV activity in England during the winter of 2020-21 and then atypical activity in summer 2021 was unprecedented in the modern epidemiological era, and was most likely due to the introduction and subsequent relaxation of public health non-pharmaceutical interventions to mitigate the spread of COVID-19” (Lancet Infect Dis 2022;S1473-3099:00525-4). An accompanying commentary noted that “immunity debt” might be “an unintended consequence of non-pharmaceutical interventions” (Lancet Infect Dis 2022;S1473-3099:00544-8).

This concept of immunity debt is controversial. A robust rebuttal was published by the McGill University (Canada) Office for Science and Society (asamonitor.pub/3iKMRNK). The author, Jonathan Jarry, criticized the French Pediatric Infectious Disease Group for “boldly asserting the existence of an immunity debt in children” and “opening the floodgates.” As Mr. Jarry notes, following the publication by the French group, immunity debt “was being quoted in other papers and in media reports, and now we are led to believe that our immune system is just like a muscle: stop working it out and it will atrophy.”

The primary criticism of immunity debt is that “…children during the pandemic were not kept in sterile bubbles. They were in contact with microorganisms from the food that they ate, the soil that they played with, and the adults in their lives.” Mr. Jarry attributes the rise in pediatric RSV and other infections to nonimmune factors. “It’s not just RSV that is putting kids in the hospital but respiratory enteroviruses, influenza, and parainfluenza as well. These are viruses that many children were not exposed to {during the COVID lockdowns} … and there is now a lot of catching up to do.”

The only ground ceded by Mr. Jarry is that pregnant mothers may have had less exposure to RSV, which could theoretically have reduced cross-placental transfer of antibodies.

The best description of immune debt may be in George Carlin’s 1999 HBO special “You Are All Diseased” (asamonitor.pub/3wb7upy). Carlin notes that nobody growing up in his New York City neighborhood ever got sick. He attributes this disease resistance to the kids swimming in raw sewage in the Hudson River “to cool off” (asamonitor.pub/3XfYfQT). Carlin’s explanation of immune debt is spot on, including the logical fallacies (e.g., swimming in sewage is not a good idea).

Human RSV belongs to the genus Orthopneumovirus, which also includes bovine RSV and murine pneumonia virus (asamonitor.pub/3weGHbC). The genome of RSV consists of approximately 15,000 bases (roughly half the size of SARS-CoV-2) and encodes 11 proteins. The most relevant of these proteins clinically are the glycoprotein (RSV-G) and fusion protein (RSV-F). Together, these proteins mediate viral attachment and cellular entry (Nat Rev Microbiol 2019;17:233-45). They also serve as the epitopes for formation of neutralizing antibodies (Pathogens 2019;8:67).

Attempts at vaccine formation against RSV in the 1960s were spectacularly unsuccessful, increasing disease severity among those having RSV infections post-vaccination, which included the deaths of two children (Nature 2021 Dec;600:379-80). Enhanced infections following vaccination are usually the result of Fc receptor-mediated antibody dependent enhancement (Clin Diagn Lab Immunol 1994;1:670-7). Vaccine efficacy also may have been impaired if the formaldehyde used to deactivate the virus reacted with surface proteins (Nat Med 2006;12:905-7).

Several therapeutic interventions are on the horizon for RSV, including modern vaccines, monoclonal antibodies, and small molecule fusion inhibitors.

A recent study of the vaccine candidate RSVpreF found that vaccination reduced symptomatic infection and viral shedding, without any signals suggesting safety issues (N Engl J Med 2022;386:2377-86). RSVpreF was also evaluated in pregnant women (N Engl J Med 2022;386:1615-26). The authors found that “RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns.”

Monoclonal antibodies are being developed for treatment of severe RSV. One of the first is nirsevimab, a monoclonal that recognizes portions of the RSV fusion protein. A study in term and late preterm infants documented that a single dose given prior to the RSV season protected children from “medically attended RSV-associated lower respiratory tract infection” by a single dose of the antibody prior to the RSV season (N Engl J Med 2022;386:837-46). Additionally, the antibody produced “fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants.”

Lastly, small molecule fusion inhibitors are being investigated to treat RSV (Nat Commun 2017;8:167). Fusion inhibitors block RSV from entering cells.

Despite the debate over “immunity debt,” there is a good argument that the present RSV surge represents “catching up” on several years of RSV following relaxation of nonpharmaceutical interventions against COVID-19. As has happened with COVID-19 over the past three years, the surge in RSV is driving research into vaccines and novel therapeutics. We will be better prepared next time.

The good news is that new variants of RSV do not appear to be emerging, based on genomic sequencing data (asamonitor.pub/3XAgksl). This is very different from SARS-CoV-2, which mutates faster than we can develop monoclonal antibodies. The low mutation rate for RSV suggests that the RSV surge seen over the past few months is not likely to recur for some time.

Richard Simoneaux is a freelance writer with an MS in organic chemistry from Indiana University. He has more than 15 years of experience covering the pharmaceutical industry and an additional seven years as a laboratory-based medical chemist.