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: Previous vaccines for respiratory syncytial virus infection in children caused more harm than good. However, new vaccines and new preventive monoclonal antibody treatments are nearing final stages of pre-licensure testing.
SOURCE: Abbasi J. RSV vaccines, finally within reach, could prevent tens of thousands of yearly deaths. JAMA 2021; Dec 29. doi: 10.1001/jama.2021.23772. [Online ahead of print].
In a new “Medical News and Perspectives” piece, Jennifer Abbasi provides a helpful historical review of failed efforts to prevent respiratory syncytial virus (RSV) infection and illness. She also provides pre-publication news about ongoing efforts to develop new agents to prevent RSV infection.
In a clinical trial in the mid-1960s, an investigational RSV vaccine was given to 23 children ages 2 to 7 months. Of these children, 18 became infected and required inpatient care. By contrast, only one of 21 RSV-infected children in a community comparison group required hospitalization. Two children in the RSV vaccine group died. Sadly, the vaccine prompted children, when subsequently exposed to natural RSV, to develop an exaggerated response to the infection with what is now called “enhanced respiratory disease.”
Twenty-five years later, two passive immunization products were used to prevent severe RSV disease in children considered to be at especially high risk of poor outcomes with RSV infection. One was RSV immune globulin (which is no longer used); the other was palivizumab, the first ever monoclonal antibody approved in the United States for an infectious disease. Palivizumab still is used for children at high risk — prematurely born babies, infants with chronic lung disease, and some infants with congenital heart disease.
Although no RSV vaccine has been developed, work continues. The author suggests that a vaccine for use in older vulnerable adults might be available soon and that maternal vaccination might follow. Along the way, a monoclonal antibody for use in all infants might be available even sooner.
RSV has been known to cause severe lung disease since the 1950s, but it wasn’t until this century that the global extent of RSV illness was fully recognized. RSV has been implicated as the most common cause of pneumonia, bronchiolitis, and other lower respiratory tract illnesses in preschool-age children. RSV is a leading cause of pediatric hospitalizations, especially during winter months, and it is reported to be the second leading cause of death during the first year of life in resource-limited countries. More than 100,000 children die of RSV each year. One expert says, “We have a pandemic every single winter, but we just deal with it.”
Essentially every child is infected with RSV by age 2 years. Then, reinfections are common, even though symptoms usually are mild. Nonetheless, about 14,000 older adults die each year in the United States because of RSV infections.
Structure-based vaccinology is a relatively new approach to vaccine development that involves determining the atomic structures of the antigen-antibody connections so vaccines can be targeted in structurally relevant ways. Of course, for SARS-CoV-2, the spike protein is the important structure for vaccine developers. For RSV, a fusion (F) protein is relevant. As it turns out, there are two forms of the F protein — a pre-fusion form and, after initial linkage of the viral and cell membranes, a post-fusion form. The pre-F antibodies achieve much higher neutralizing effects than do post-F antibodies, making the pre-F targets sensible for future vaccines, especially when incorporating stabilizing factors that prevent transformation to the post-F form. The problem with the 1960s RSV vaccine was not that it didn’t induce antibody development; rather, it induced the development of the wrong antibodies, antibodies that enhanced illness rather than reducing viral action.
A Phase I trial showed that there was good virus neutralizing activity up to 44 weeks after healthy adults received a new pre-F-related RSV vaccine. In fact, there are now 20 RSV vaccine clinical trials in progress, with about half targeting use in older adults and the other half either for children or to immunize mothers to protect children. Three vaccines currently are in Phase III trials, and each uses a stabilized pre-F protein.
The author suggests that within five years, effective RSV vaccines might be available for older adults, mothers, and children. Along the way, a new monoclonal antibody for use in all children (not just premature babies and infants with cardiac or airway disorders) might be available within two years.
COMMENTARY
With RSV season in full swing, this new article is timely — even though the new vaccines and monoclonal antibodies are not yet available. Children at most risk of severe RSV disease still can receive the currently available monoclonal antibody.
There was a figure with Abbasi’s article that summarized key features about clinical RSV illness. Unfortunately, it seems, the figure mentioned in its treatment section that medications could “treat other symptoms, such as wheezing.” It is not clear to what medication the figure refers, since bronchodilators are ineffective in treating children with RSV-associated wheezing (except for the rare infants with RSV who also have asthma).
In 2014, the American Academy of Pediatrics published a practice guideline about bronchiolitis, the most serious form of RSV infection in young children.1 The guideline advised that the diagnosis be based on history and physical exam (without needing radiographs).1 Treatment with bronchodilators, epinephrine, steroids, antibiotics, and chest physical therapy was not indicated.1 Since publication of the guidelines, children in the United States are less likely to receive bronchodilators for bronchiolitis than they were previously.2 However, children seen with bronchiolitis in emergency departments still often receive unnecessary treatments (bronchodilators in 26%, steroids in 6%, and antibiotics in 3%).2 For hospitalized children, bronchodilators are given to 50%, steroids to 18%, and antibiotics to 24%.2 While some of these children could have concurrent asthma and/or bacterial superinfection, it is likely that many of these treatments are not necessary. The figure in Abbasi’s paper seems to oversimplify management of bronchiolitis and to over-recommend bronchodilators in suggesting that treatment for wheezing is part of the standard care of RSV-infected patients.
Unnecessary treatments for bronchiolitis are not without cost.3 Even now (with more judicious use of bronchodilators, steroids, and antibiotics), costs of inpatient care for bronchiolitis are rising related to what seems to be overuse of high-flow nasal cannula oxygen in intensive care units.3 There still is the opportunity to provide less aggressive care for children with bronchiolitis at less cost without worsening outcomes.
REFERENCES
- Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline: The diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014;134:e1474-e1500.
- House SA, Marin JR, Hall M, Ralston SL. Trends over time in use of nonrecommended tests and treatments since publication of the American Academy of Pediatrics bronchiolitis guideline. JAMA Netw Open 2021;4:e2037356.
- Willer RJ, Coon ER, Harrison WN, Ralston SL. Trends in hospital costs and levels of services provided for children with bronchiolitis treated in children’s hospitals. JAMA Netw Open 2021;4:e2129920.
Previous vaccines for respiratory syncytial virus infection in children caused more harm than good. However, new vaccines and preventive monoclonal antibody treatments are nearing final stages of prelicensure testing.
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