Respiratory Syncytial Virus (RSV) is a highly common and contagious virus that affects the respiratory tract. Nearly all children contract it by age two, yet for half a century, medical science could not field a safe and effective vaccine to prevent the most severe outcomes of infection. The lack of a preventative measure was a significant global challenge because the virus disproportionately affects the most vulnerable populations, namely infants and older adults.
The Severity of Respiratory Syncytial Virus
RSV is recognized as a leading cause of hospitalizations in infants globally, rivaling the flu in its potential for severe illness. While most healthy adults experience symptoms similar to a mild cold, the virus can quickly progress to dangerous lower respiratory tract infections in vulnerable groups. In children under five, RSV is the most common pathogen associated with acute lower respiratory infections, often manifesting as bronchiolitis or pneumonia.
Globally, RSV causes millions of hospitalizations each year, with a significant number of deaths among children younger than five, particularly in low- and middle-income countries. Infants under six months are at the highest risk for severe disease and death. The virus also poses a substantial threat to adults over 65, leading to an estimated 60,000 to 160,000 hospitalizations and thousands of deaths annually in the United States alone.
Decades of Scientific Roadblocks
The most significant setback in RSV vaccine development occurred in the 1960s with the trial of a formalin-inactivated vaccine (FI-RSV). The trial resulted in a tragic outcome, leading to a phenomenon known as Vaccine-Enhanced Respiratory Disease (VAED). Up to 80% of the vaccinated children who subsequently became infected with the wild-type virus required hospitalization with severe symptoms. Two toddlers in the trial died from this enhanced disease, causing a near-total halt to RSV vaccine research for decades. Analysis showed the FI-RSV vaccine created a non-protective antibody response and primed the immune system for a damaging inflammatory reaction upon natural infection.
Beyond the safety disaster, the virus presented a unique immunological challenge related to its key surface protein, the Fusion (F) glycoprotein. The F protein is the primary target for a protective immune response, but it exists in two distinct shapes: an unstable “prefusion” form and a stable “postfusion” form. The immune system’s most potent neutralizing antibodies are generated only in response to the unstable prefusion shape. Traditional vaccine methods caused the F protein to snap into its postfusion shape, which elicited the wrong kind of antibody response. For half a century, scientists struggled to stabilize the F protein in its elusive prefusion conformation outside of the virus.
Stabilizing the Target: The Prefusion F-Protein Discovery
The long-standing scientific roadblock was finally overcome through a breakthrough in structural biology achieved around 2013. Researchers at the National Institutes of Health (NIH) used advanced techniques to visualize the F protein at an atomic level, creating a detailed blueprint of its prefusion structure.
With the structure mapped out, scientists used computational and genetic engineering methods to chemically “lock” the F protein into its unstable prefusion state. This stabilization was achieved by introducing specific, targeted amino acid substitutions, often proline residues, into the protein’s structure. These engineered changes prevented the F protein from collapsing into its inactive postfusion shape, thus creating a highly effective vaccine antigen.
This stabilized prefusion F protein, often referred to as pre-F, allowed the development of safe and protective vaccines. By presenting the immune system with the correct shape of the protein, the new vaccine candidates elicited high levels of protective neutralizing antibodies. This robust and specific immune response successfully bypassed the aberrant, inflammatory immune priming that had caused the enhanced disease in the 1960s trial. The breakthrough transformed the RSV vaccine landscape.
Current Status of RSV Prevention
The scientific breakthrough of the prefusion F-protein has led to the recent introduction of effective prevention tools for the populations most at risk, providing protection through both active and passive immunization strategies. For older adults, new vaccines targeting the prefusion F-protein are now available, which actively stimulate the individual’s immune system to produce protective antibodies.
For infants, two primary methods of passive protection have been introduced. Maternal immunization involves administering a prefusion F-protein vaccine to a pregnant woman between 32 and 36 weeks of gestation. This allows the mother to produce protective antibodies that cross the placenta, offering the infant passive immunity for the first six months of life. The second strategy is the direct administration of a long-acting monoclonal antibody, such as nirsevimab, to the infant shortly after birth or at the start of the RSV season. This provides the baby with ready-made antibodies that offer immediate protection for the duration of the RSV season. These contemporary prevention tools have successfully addressed the historical problem.