“Often considered a disease seen in babies . . . many people are unaware that the virus can also cause serious complications in older adults or adults with underlying health conditions.”
- Hallie Levine, health and wellness journalist
“I never lose. I either win or I learn.”
- Nelson Mandela
The American Association for Respiratory Care recently declared October as the “National RSV Awareness Month.” Many Americans have never heard of Respiratory Syncytial Virus (RSV)—a little-known virus that is estimated to cause the death of 120,000 infants globally per year. In this Germ Gems post I discuss RSV with the goal of increasing awareness and reporting on some promising developments on the RSV vaccine front.
The toll of RSV infections in the U.S. For children under five years of age, RSV infection triggers an estimated 2.1 million outpatient visits and 58,000 hospitalizations with between 100-500 deaths each year. It is also estimated to cause about 177,000 hospitalizations and 14,000 deaths annually in adults over 65 years of age—a figure close to the fatalities due to influenza.
What is RSV? Identified in 1955, RSV is a highly contagious single-stranded RNA virus. Its name is derived from large cells known as syncytia that form when infected cells fuse. There are two subgroups of RSV, A and B, and several strains of both subgroups circulate during each seasonal epidemic. Outbreaks of RSV infections usually begin in October and run through April, overlapping almost perfectly with the annual flu season.
RSV infects virtually all children by the time they turn two. While RSV is the single most common cause of respiratory hospitalization in infants, it is an important pathogen in all age groups. Unfortunately, people can become repeatedly infected with RSV over their lifetime as they don’t develop long-lasting immunity.
Although the virus can live on surfaces for many hours and for 30 minutes or more on hands, RSV is spread primarily through contaminated respiratory droplets. Following initial infection via the eyes or nose, the virus infects the epithelial cells of the upper and lower respiratory tract, which causes inflammation, damage and obstruction of the airway, and manifests as bronchiolitis and pneumonia.
RSV infection has a wide variety of signs and symptoms ranging from a mild upper respiratory tract infection or a “common cold” to life-threatening lower respiratory tract infection requiring hospitalization and mechanical ventilation. Infants and older adults, especially those who are immunocompromised or with underlying cardiovascular disease, are at highest risk of severe and fatal disease.
The path to prevention of RSV infection. At present, there is no way to prevent RSV infection. Rigorous handwashing as a non-pharmaceutical intervention to prevent RSV is highly encouraged, but, of course, is insufficient. Unsurprisingly, research communities in academic centers and in the pharmaceutical industry have been working together to develop vaccines. The path to development of a RSV vaccine, however, has been especially rocky. Nonetheless, it has also been highly instructive and progress is being made.
Based on the prior successes of formalin-inactivated vaccines for influenza and polio, clinical trials for a RSV formalin-inactivated vaccine were conducted in the late 1960s. But there were unanticipated untoward reactions to the vaccine. Infants and toddlers immunized with the formalin-inactivated vaccine against RSV developed an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. For these reasons, the trials were stopped.
Subsequent research determined the cellular basis of this pathologic phenomenon, called “enhanced RSV disease (ERD),” is related to an altered, nonprotective antibody response involving aberrant CD4 helper and cytotoxic T lymphocytes. An extensive research collaboration ensued that ultimately led to a new way of thinking about vaccine development, called structure-based design, that was hailed by Science as a “top breakthrough of 2013.”
In recent years, vaccine designers determined that for RSV vaccines the target structural component of the virus is some form of stabilized fusion or “F” protein (antigen). Three of 20 clinical trials underway by GlaxoSmithKline, Janssen Pharmaceutical, and Pfizer all use pre-F antigen in their candidate RSV vaccines currently in phase 3 trials. Not to be outdone, Moderna began testing mRNA-1345—an investigational mRNA vaccine for RSV—in a phase 2 and 3 trials for older adults.
In addition to RSV vaccines, in the article in the New England Journal of Medicine on March 13, 2022, “Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants,” researchers reported the exciting results of a trial of nirsevimab, a monoclonal antibody to the RSV fusion protein. They found that a single injection of nirsevimab before the RSV season protected healthy pre-term and term infants from serious RSV-associated lower respiratory tract infection.
Never give up. Vaccine-mediated “Enhanced RSV disease (ERD),” which was the tragic outcome of the late 1960s trials, may have stopped many clinical researchers in their tracks. Fortunately, some very courageous and highly creative investigators persevered, learned from the unexpected results, and went on to develop “structure-based vaccine design.” As in many other areas of life, success in research requires perseverance. In the words of Asuncion Majas, MD, PhD, pediatric infectious disease specialist and associate professor of Nationwide Children’s Hospital and the Ohio State University College of Medicine, “The burden of RSV is tremendous. We just need to keep going and be patient and persistent.”