By Zoe Katz

Over sixty years have passed since the respiratory syncytial virus (RSV) was first discovered, and after decades of failure, two vaccines have been approved for distribution in the United States.

To individuals with a competent immune system, infection with RSV presents as nothing but a cold. For those who are immunocompromised – including newborn babies, infants, and the elderly – infection can be deadly, resulting from inflammation (bronchiolitis) and infection (pneumonia) in the lungs¹. During normal breathing, air moves through the lungs by passing through small airways called bronchioles and airway sacks called alveoli in the lower respiratory tract. To get rid of the virus infection, host immune responses induce inflammation and increase mucus production². Together, this causes airway obstructions² and makes it more difficult to breathe. Each year, tens of thousands of children younger than five years old and adults over the age of 65 will be hospitalized; thousands will die from infection³. Historically, scientists recognized the significant disease burden RSV infection caused. Decades ago, scientists tried to develop a vaccine for RSV, with disastrous outcomes that halted vaccine development. However, the disease burden of RSV is still significant and continuously threatens the lives of newborns, infants, and the elderly. The lack of effective or affordable treatments pushed pharmaceutical companies to work tirelessly to develop vaccines against RSV, with little success – until this past summer. 

Vaccines for RSV were first tested in the 1960s. Before the advent of mRNA vaccines to initiate an immune response against a specific viral target protein, other methods were used to vaccinate people. Scientists used the fixative agent formalin to inactivate the whole RSV, called the formalin-inactivated RSV vaccine, FI-RSV. Formalin stabilizes surface viral proteins so that an immune response can be mounted against them. In 1966, the FI-RSV was administered to children across the United States in four clinical trials⁴. Afterwards, children were naturally exposed to RSV to test the efficacy of the vaccine. Instead of being protective, vaccination with the FI-RSV resulted in tragedy. Children experienced enhanced respiratory disease characterized by bronchopneumonia, wheezing, and fever, resulting in 80 percent of the vaccinated children being hospitalized⁵. Two of the vaccinated children, aged 14 and 16 months, died as a result of complications of RSV infection⁵. Years later, it was found that the immune response against FI-RSV induced production of antibodies that were targeted against a part of RSV that was not able to be effectively bound, known as post-F. Antibody binding affinity refers to the strength at which antibodies can bind to their targets. When antibodies exhibit high affinity, they are able to strongly bind and effectively neutralize RSV, preventing infection. The weak affinity antibodies found to be produced at great levels after vaccination with FI-RSV were not able to prevent RSV infection. Vaccination instead exaggerated lung inflammation and immune cell infiltration into the airways^4,5. As a result, vaccine development was stagnant after the tragedies from these clinical trials. Importantly, lessons learned from these trials and their tribulations allowed scientists to gain insight into what proteins should be targeted in future vaccines.

To develop an effective vaccine, it is crucial to understand how a virus infects and replicates inside its host and its constitutive host cells. For viruses to replicate, they must first enter a host cell and release their genetic material, either DNA or RNA. RSV is an RNA virus that is enveloped in a lipid bilayer, the same molecules that make up the outer cell membranes in human cells.  On this outer surface, RSV has two proteins embedded, the attachment (G) protein and fusion (F) protein. For viruses to infect cells, they must first attach to the host cell; this process is initiated by G. Following attachment, RSV, like other enveloped viruses, enters its host cells through a process called fusion. Mediated by F, the virus envelope and host cell lipid bilayer merge together, subsequently releasing the viral RNA into the host cell for replication. Importantly, F is found in two different conformations – pre-F and post-F. Pre-F is unstable and can refold easily, splaying out from the virus and helping RSV physically come into contact host cells in its vicinity. After embedding into the host cell membrane, pre-F adopts the post-F conformation, becoming stable and bringing the host and viral membranes together to initiate fusion (Figure 1)^2,6.

Although pre-F and post-F have structural similarities and are both found on infectious RSV, most of the neutralizing antibodies generated against RSV infection are directed against pre-F⁴. Neutralizing antibodies are involved in the specific immune response against invading pathogens such as RSV. They function to bind to the virus itself to prevent interactions of surface proteins – in this case, pre-F – with host cells, which prevents pre-F from initiating fusion and infection. Years after the FI-RSV vaccine clinical trials, it was discovered that most of the neutralizing antibodies produced were targeted against the post-F conformation of F, which caused them to not prevent infection, as shown in Figure 2⁵. Therefore, vaccines should be directed against pre-F instead of post-F.

Two pharmaceutical companies, GSK and Pfizer, took up the mantle to develop vaccines targeting RSV pre-F. Excitingly, on May 3^rd, 2023, the FDA approved the first RSV vaccine for adults aged 60 years and older. Phase III clinical trials found that the vaccine, called Arexvy, was 82 percent effective at preventing RSV-lower respiratory tract disease (RSV-LRTD) and 94 percent effective in preventing RSV infection after vaccination in older adults with underlying conditions⁷. Following suit, Pfizer’s vaccine, Abrysvo, for older adults was also approved in late May, 2023⁸.

Even more challenging than vaccinating adults is preventing RSV infection in newborn babies and infants. Newborn babies have very weak immune systems and lack the ability to protect themselves against RSV infection⁹. Their immune systems are too immature to respond to vaccines, even if one was approved. In a groundbreaking solution to protect infants against RSV, vaccines can now be administered during pregnancy, allowing antibodies generated after vaccination to cross the placenta to the fetus⁹. Abrysvo was granted a dual purpose – preventing RSV-LRTD in older adults, and also in infants from birth up to six months of age by immunizing their pregnant mothers at 32-36 weeks gestation⁹. It is the first and only maternal vaccine available to protect newborns, marking a very significant milestone for both scientific advancement and public safety.  

Viruses have always adversely affected humans, resulting in illness and death across the globe. To prevent infection, scientists develop antiviral medications and vaccines to target specific stages of viral life cycles, thus preventing infection or replication. By targeting the entry stages of the RSV life cycle, and by developing vaccines targeting the viral proteins involved in this process, infection can be severely inhibited. Following the tragic clinical trials of the 1960s, scientists were hesitant to develop and test vaccines. Regardless, scientists and the public recognize that vaccines are important in preventing tens of thousands of children and adults from being hospitalized and dying each year. To have not one, but two vaccines approved this year to help infants and older adults during the winter months is an incredible feat of scientific discovery, decades in the making. 

TL;DR 

• RSV infection causes thousands of hospitalizations and deaths each year.
• Hesitations following deadly RSV vaccine clinical trials in the 1960s led to stunted vaccine development over the past fifty years.
• This past summer, the first RSV vaccines were approved for distribution.

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Reference

1. RSV in Infants and Young Children. https://www.cdc.gov/rsv/high-risk/infants-young-children.html
2. Battles, M. B., & McLellan, J. S. (2019). Respiratory syncytial virus entry and how to block it. Nature Reviews Microbiology, 17(4), 233–245. https://doi.org/10.1038/s41579-019-0149-x
3. RSV Surveillance and Research. https://www.cdc.gov/rsv/research/index.html
4. Killikelly, A. M., Kanekiyo, M., & Graham, B. S. (2016). Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus. Scientific Reports, 6(1), 34108. https://doi.org/10.1038/srep34108 
5. Acosta, P. L., Caballero, M. T., & Polack, F. P. (2016). Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease. Clinical and Vaccine Immunology, 23(3), 189–195. https://doi.org/10.1128/CVI.00609-15 
6. Hu, M., Bogoyevitch, M. A., & Jans, D. A. (2020). Impact of Respiratory Syncytial Virus Infection on Host Functions: Implications for Antiviral Strategies. Physiological Reviews, 100(4), 1527–1594. https://doi.org/10.1152/physrev.00030.2019 
7. US FDA approves GSK’s Arexvy, the world’s first respiratory syncytial virus (RSV) vaccine for older adults. https://www.gsk.com/en-gb/media/press-releases/us-fda-approves-gsk-s-arexvy-the-world-s-first-respiratory-syncytial-virus-rsv-vaccine-for-older-adults/
8. U.S. FDA Approves ABRYSVO™, Pfizer’s Vaccine for the Prevention of Respiratory Syncytial Virus (RSV) in Infants Through Active Immunization of Pregnant Individuals 32-36 Weeks of Gestational Age. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-abrysvotm-pfizers-vaccine-prevention-0 
9. PrabhuDas, M., Adkins, B., Gans, H., King, C., Levy, O., Ramilo, O., & Siegrist, C.-A. (2011). Challenges in infant immunity: Implications for responses to infection and vaccines. Nature Immunology, 12(3), 189–194. https://doi.org/10.1038/ni0311-189 
10. Use of the Pfizer Respiratory Syncytial Virus Vaccine During Pregnancy for the Prevention of Respiratory Syncytial Virus–Associated Lower Respiratory Tract Disease in Infants: Recommendations of the Advisory Committee on Immunization Practices — United States, 2023. https://www.cdc.gov/mmwr/volumes/72/wr/mm7241e1.htm