By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: The 2022-2023 northern hemisphere respiratory syncytial virus (RSV) season began with fury, crowding hospitals and making many young children extremely ill. Meanwhile, advancing research points to potential means of better preventing RSV infection.
SOURCES: Centers for Disease Control and Prevention. Increased respiratory virus activity, especially among children, early in the 2022-2023 fall and winter. Health Alert Network. emergency.cdc.gov/han/2022/han00479.asp
Park A. The troubling trends pointing to a severe flu and RSV season. Time. Oct. 25, 2022. time.com/6224268/severe-flu-season-rsv/
On Nov. 4, 2022, the Centers for Disease Control and Prevention (CDC) released a Health Advisory warning about an elevated respiratory disease risk for children that was “placing strain on healthcare systems.” Analysis of international data in the popular press suggests that the 2022-2023 winter respiratory season in the northern hemisphere could indeed be more severe than in other recent years. Already influenza diagnoses have been at record highs compared to previous seasons. Whatever reductions in influenza and respiratory syncytial virus (RSV) infections were seen during the COVID-19 pandemic seem to have been obliterated by rates even higher than in the pre-pandemic era. During October 2022, the number of influenza cases in the United States was more than twice as high as during any previous October in the past decade.
Similarly, the 2022 southern hemisphere influenza season in Australia also was severe. Influenza cases peaked two months earlier in Australia this year than in other recent years, and case numbers were the highest of the past seven years. Of course, COVID-19 has not disappeared yet either. The United States reports approximately 260,000 new COVID cases each week.
Alas, all those statistics pale compared to RSV. The RSV season has “opened” early and forcefully. Cases are nearly double the number seen last year. Why is the season shaping up with such viral strength? Part of the issue probably relates to lower rates of RSV and influenza during the COVID years when children (and adults) were masked and distanced. During the pandemic, older children were less likely to be exposed to RSV during their first year or two of life and had not built up immunity to protect them later. Another risk factor this respiratory season is that fewer influenza vaccine doses have been given in the United States than during the beginning of any of the three previous seasons.
COMMENTARY
The CDC warning and the data in the Time article are relevant and concerning, and they are anecdotally affirmed by hospital-based pediatricians. Hospital wards in North America, Europe, and the Middle East are full and even sometimes overflowing with sick children requiring inpatient care for RSV and influenza.
Essentially every child is infected with RSV during the first two years of life, often multiple times. RSV is the leading cause of lower respiratory tract-related hospitalization during the first year of life in the United States, with 16 times as many infants hospitalized with RSV as with influenza.1 Beyond the expected winter-time problems with RSV, this year’s “RSV season” is off to a particularly severe start.
There is no effective virus-specific curative treatment for RSV infection, and preventive efforts are essential. Severe RSV disease is most common in prematurely born infants, particularly those with chronic lung disease and/or congenital cardiac problems.1 Passive immunization of infants at most risk of RSV-related severe disease using anti-RSV monoclonal antibodies, such as palivizumab, reduces the risk of hospitalization by more than half.1 Palivizumab was approved for use in the United States in 1998, and recommendations for just which at-risk infants receive palivizumab have evolved over time.1 Palivizumab is effective for individual children, but recommendations are based on what is most cost-effective for at-risk subpopulation groups. The variations in who “should” receive monthly treatment with prophylactic palivizumab have evolved regarding age, gestational age, and cardiorespiratory risk factors.1 There are differences in the details of the recommendations by the American Academy of Pediatrics (AAP) and by the National Perinatal Association (NPA).1 As affirmed in 2019 and endorsed again this year by the CDC, the AAP recommends palivizumab only for babies born at less than 29 weeks’ gestational age, while the NPA, since 2018, recommends use in some at-risk children born at up to 35 weeks’ gestational age.1 A severe 2022-2023 RSV season might prompt less restrictive use of palivizumab.
A review article from Italy, released online in September 2022, provided good reminders of the value of non-pharmacologic measures in the prevention of RSV illness.2 RSV is spread via airborne droplets and via contact with contaminated objects.2 An indirect outcome of the COVID-19 pandemic was that physical distancing and hand hygiene led to marked reductions in the incidence of severe RSV infection. Breastfeeding of premature babies also is associated with reduced hospitalization for severe RSV illness.2
As reviewed earlier this year in Infectious Disease Alert, scientific advances offer optimism for additional (and less expensive than palivizumab) ways of preventing severe RSV disease.3 Subsequent recent publications, reviewed here now, demonstrate further advances as improved RSV prevention comes closer to reality.
New-generation monoclonal antibodies are being developed, some related to specific forms of RSV’s F protein.2,3 Nirsevimab and clesrovimab are such new-generation monoclonal antibodies that offer safety similar to that of palivizumab but with longer durations of protective efficacy (up to five months as opposed to three to four weeks with palivizumab).2 Thus, when available, a single intramuscular dose could provide passive protection of an infant for the entirety of the winter RSV season. These new monoclonal antibodies currently are undergoing Phase II and Phase III clinical trials.
Maternal vaccination against RSV during pregnancy also presumably could offer months of transplacentally provided passive protection to newborns. One study of vaccination during pregnancy showed significant increases in maternal anti-RSV antibody levels, yet without a change in risk for children.2 Another clinical trial of a related maternal vaccine is underway.2
The same F antigen at the center of monoclonal antibody studies also is the focus of active immunization research. Six active candidate RSV vaccines are undergoing Phase III trials.2 So far, though, five of these trials are in older adults and one is for pregnant women; development of infant vaccine trials still is pending.2 Even as human studies are underway, animal studies continue to refine the development of RSV vaccines. Researchers in the United States reported in October 2022 that a membrane-anchored form of the pre-F protein was more effective than a secreted form of the pre-F protein in providing pulmonary protection via intranasal vaccination of mice.4 The potential for these new vaccines prompted some authors to exclaim that “the future looks brighter.”2
Careful mathematical modeling explored the likely impact of various emerging RSV prevention strategies.5 Without specific pharmacologic prevention strategies, it was estimated that there would be 1.23 million medical visits of infants and toddlers each year in the United States for RSV-related disease, with 39,040 hospitalizations.5 Use of long-term monoclonal antibodies in all newborns (premature and full-term) would reduce medical visits and hospitalizations by about half.5 Palivizumab, relevant only for very premature infants, would only reduce overall medical visits and hospitalizations by 1% each year, while averting two deaths.5 Maternal vaccination during pregnancy would prevent about 10% of medical visits and hospitalizations and about 14 deaths each year in the United States.5 A separate prediction model affirmed the degree favorable effects for long-duration monoclonal antibody dosing of newborns and for maternal vaccination during pregnancy and, in addition, considered that active vaccination of infants was likely to be markedly less effective, since initiation of the vaccine effect likely would be delayed beyond the first months of life when severe disease is more common.6 Thus, while hospitals are busy with many children who are very sick with severe RSV infections this winter season, there is scientific progress offering hope that pending interventions will lead to marked reductions in RSV-related disease during future RSV seasons.
REFERENCES
- Krilov LR, Anderson EJ. Respiratory syncytial virus hospitalizations in US preterm infants after the 2014 change in immunoprophylaxis guidance by the American Academy of Pediatrics. J Perinatol 2020;40:1135-1144.
- Messina A, Germano C, Avellis V, et al. New strategies for the prevention of respiratory syncytial virus (RSV). Early Hum Dev 2022;174:105666.
- Fischer PR. Optimism for new interventions to prevent respiratory syncytial virus infections. Infectious Disease Alert 2022;41:54-56.
- Lamichhane P, Schmidt ME, Terhuja M, et al. A live single-cycle RSV vaccine expressing prefusion F protein. Virology 2022;577:51-64.
- Ektare V, Lang J, Choi Y, Finelli L. The clinical impact of multiple prevention strategies for respiratory syncytial virus infections in infants and high-risk toddlers in the United States. Vaccine 2022;40:6064-6073.
- Zheng Z, Weinberger DM, Pitzer VE. Predicted effectiveness of vaccines and extended half-life monoclonal antibodies against RSV hospitalizations in children. NPJ Vaccines 2022;7:127.
