FDA-approved vaccines for protection from severe respiratory syncytial virus (RSV) infection

Author: Morgan McCullough

Editors: Kylie VanDerMolen and Michaela Price, PhD

 

This article will describe the first vaccine, Arexvy, approved for prevention of lower respiratory tract disease arising from respiratory syncytial virus (RSV) infection. Approved by the Food and Drug Administration (FDA) in May of 2023, Arexvy is a product of GlaxoSmithKline (GSK). Here, I describe the burden of RSV, the history of RSV vaccine development, the clinical trial leading to Arexvy’s approval, and updates to the therapeutic landscape since May 2023, including additional vaccines now approved for use in pregnant women to prevent severe RSV disease in infant children.

What is RSV?

 RSV is a virus that circulates seasonally in temperate climates. In most adults, RSV infection is quite mild. However, those who suffer from pre-existing conditions, such as heart disease or weakened immune systems, are more likely to develop lower respiratory tract disease (LRTD) during RSV infection.1 LRTD refers to bronchiolitis (airway swelling) and pneumonia (inflammation and edema of the alveoli) that may develop as complications from severe RSV infection. 

Who is most at risk?

Because heart disease and weakened immune systems are more common in individuals aged 65 and older, RSV infection is more likely to lead to LRTD in this population.1,2 Among this high-risk group, there are 60,000-120,000 hospitalizations and 6,000-10,000 annual deaths from LRTD-associated RSV in the United States.3 Immunity derived from natural RSV infection wanes over time, meaning that re-infection may occur year after year, which presents a persistent risk of developing RSV-related LRTD in susceptible populations. 

Although older adults are at a high risk for developing severe RSV, the most vulnerable population for severe RSV is infants. Because RSV is so widespread, it is likely the first pathogen that infants encounter. Risk of LRTD from RSV is highest in newborns, with the risk of severe RSV infection decreasing as infants age.4 Most individuals are infected with RSV from a young age. In children 6 months and older and healthy adults, RSV infection is usually mild. However, RSV may cause serious disease in infants and young children with limited prior RSV exposure, with 75,000-150,000 hospitalizations5 and about 500 deaths6 caused by RSV infection per year in the United States, making RSV the leading cause of LRTD in infants. Further, RSV infection early in life is associated with subsequent development of asthma in children.7

For these reasons, scientists have spent decades chasing down a strategy to develop an RSV vaccine. Finally, in May of 2023, GSK was granted approval for their novel RSV vaccine, Arexvy, following presentation of evidence that Arexvy was safe and effective in preventing LRTD and severe LRTD in adults aged 60 and older.3 Subsequent updates to the therapeutic landscape have resulted in the ability for infants to gain immunity to RSV via their mothers.

The scientific obstacles to developing an RSV vaccine

Soon after RSV was discovered, a vaccine formulation was developed to induce immunity to the virus beginning in 1965. The vaccine formulation, termed “Lot 100”, was built on the technology of successful influenza and polio vaccines, where formalin was used to inactivate the virus before delivery with an adjuvant to excite the immune system.12 For reasons that remain unclear, the Lot 100 vaccine induced worse outcomes of natural RSV infection in children receiving the vaccine, with the youngest cohort of children experiencing a 16-fold increased hospitalization rate and two deaths.8 While the exact reasons that Lot 100 resulted in worse RSV outcomes are not entirely clear, this failure likely set back the development of the RSV vaccine for many years and proved that the development of immunity to RSV through vaccination would need to be more targeted than other inactivated vaccines.

A major obstacle to the development of an effective RSV vaccine was understanding which part of the virus the vaccine should target. When a virus infects cells in the human body, it takes over the host cells’ machinery to make more copies of itself before spreading to new cells. Early experimental RSV vaccines were unable to generate robust protection from RSV infection because they targeted a piece of the virus that only emerges after RSV initially infects cells.9 

In 2013, RSV researchers discovered a new target for RSV vaccines to improve their effectiveness in infection prevention. This protein, termed the prefusion F protein, is expressed by the virus before it infects host cells; thus, targeting this protein allows the immune system to recognize and attack RSV prior to infection.10 Discovery of the prefusion F protein set the stage for vaccine developers to use their already-robust vaccine pipelines to develop an RSV vaccine.

How Arexvy induces “memory” to RSV

Arexvy includes a stabilized form of the prefusion F protein (RSVPreF3), along with GSK’s adjuvant AS01E, which is included to promote an immune response to the prefusion F protein.11 AS01E contains 3-O-desacyl-4’-monophosphoryl lipid A (MPL), which is a lipopolysaccharide that has been detoxified, as well as Quillaja saponaria Molina, fraction 21 (QS-21), which is a triterpene glycoside purified from Quillaja saponaria Molina tree bark. Both of these components activate the immune system.12 

Following vaccination, the RSVPreF3 protein is taken up by cells of the immune system, which are stimulated by the AS01E adjuvant. This stimulation tells the cells of the immune system to initiate the process of developing memory to the viral RSVPreF3 protein, so that the immune system may recognize the RSV prefusion F protein and mount an efficient, effective response when natural infection occurs. Specifically, “memory” comes from the RSV-neutralizing antibodies that develop following vaccination. These antibodies then circulate throughout the body, where they may detect RSV and neutralize it before it causes (severe) infection. Thus, vaccination will allow the immune system to develop memory as it would during a natural infection, but without the illness or complications associated with natural infection.12 The mechanism of immune memory development is depicted in Figure 1.

Clinical trials leading to Arexvy approval

The phase III clinical trial leading to the FDA approval of Arexvy included 25,000 participants: half of which received Arexvy and half of which received a placebo. Among these participants, Arexvy reduced incidence of RSV-associated LRTD by 82.6% and reduced the incidence of severe RSV-associated LRTD by 94.1%. In this trial, 10 patients who received Arexvy and 4 patients who received placebo developed atrial fibrillation (irregular heartbeat). Further trials for Arexvy included 2,500 participants who were 60 years or older, which is a key patient population considering their susceptibility to RSV-related LRTD. Some participants were also vaccinated for the FDA-approved influenza vaccine at the time of RSV vaccination, and among these participants, two developed acute disseminated encephalomyelitis (a rare autoimmune disease where the brain and spinal cord become inflamed), leading to one death. In a separate study, one participant suffered from Guillain-Barre syndrome (autoimmune inflammation of the nerves) following Arexvy treatment. More common side effects included injection site pain, fatigue, muscle pain, headache, and joint stiffness/pain.3

Because RSV vaccines have the potential to provide “significant improvements in the […] prevention of serious conditions when compared to standard applications”, Arexvy was granted priority review. This process allows new drugs to finish the FDA review process in 6 months, as opposed to the 10 months necessary for standard review.13 The FDA approved Arexvy with the stipulation that GSK conducts postmarketing studies to understand the indicators for elevated risk of Guillain-Barre syndrome and acute disseminated encephalomyelitis. These postmarketing studies have resulted in an FDA mandate to require the inclusion of warnings regarding the development of Guillain-Barre syndrome in the prescribing information for Arexvy.14

RSV vaccines: updates since approval

Although immunity developed from natural RSV infection wanes over time, Arexvy is not currently administered annually, as it is too soon to understand how long immunity following vaccination lasts. Following approval of Arexvy in early May 2023, another RSV vaccine from Pfizer, Abrysvo, was approved weeks later at the end of May 2023 for use in adults 60 years of age or older.15 In May of 2024, Moderna was granted FDA approval for their RSV vaccine, mRESVIA, for the prevention of LRTD resulting from RSV in those 60 years of age and older.16 mRESVIA utilizes a similar mRNA platform as Moderna’s vaccines to protect against COVID-19. Indications for initial approval of RSV vaccines have been updated in subsequent years to better target those at risk for severe LRTD. These updates are outlined in Table 1. The CDC does not provide recommendations regarding choices in prescribing one vaccine over another, and which vaccine an individual receives could result from eligibility, personal preference, availability, and physician recommendations.

Abrysvo for prevention of RSV in infants

While initial RSV vaccine approvals focused on protection for elderly individuals, these approvals did not allow for the protection of those most vulnerable to severe RSV: infants. This is unsurprising, as the establishment of safety and efficacy in a population that has been exposed to RSV previously was desired prior to testing in more vulnerable populations. 

Due to failed clinical trials in infants, modern strategies for inducing protective immunity to RSV in infants has shifted from vaccinating infants to vaccinating pregnant individuals, who have likely encountered RSV before. Protection of infants via maternal vaccination occurs through transplacental antibody transfer. In August of 2023, Abrysvo was approved for use in pregnant individuals in the 32-36 week gestational age range to prevent LRTD resulting from RSV in infants following birth (Table 1).19 Immunity granted to infants via this route is estimated to last through the first four months of life, which is when risk of LRTD from RSV is highest. Among infants born to individuals vaccinated between 32-36 weeks of gestational age, newborn protection from LRTD from RSV was most robust, with Abrysvo reducing the risk of severe LRTD by 91.1% within the first 90 days (3 months) of birth and 76.5% within the first 180 days (6 months) of birth in clinical trials.19

What’s next?

Over 60 years following RSV’s initial discovery, approval of Arexvy represented a major step forward in preventing severe disease in vulnerable populations. As postmarketing monitoring studies on Arexvy and other RSV vaccines continue, prescribing information and recommendations may be updated to better serve populations affected by severe RSV infection. Early observational studies on the effectiveness of Arexvy and Abrysvo RSV vaccines are favorable, with both decreasing the incidence of infection, emergency department and urgent care visits, and hospitalizations among individuals 60 years of age and older22, indicating that these preventative therapies represent a major advancement in protecting those most vulnerable to severe RSV infection.

References:

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Publication Licenses for Figures:

Figure 1: Created in BioRender. Mccullough, M. (2025) https://BioRender.com/v25c042

Table 1: Created in BioRender. Mccullough, M. (2025) https://BioRender.com/d38l930 

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