On May 3, 2023, the U.S. Food and Drug Administration (FDA) approved Arexvy, the first respiratory syncytial virus (RSV) vaccine for use in the US to prevent lower respiratory tract disease caused by RSV in individuals 60 years of age and older.

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FDA approves the first RSV vaccine for use in the USA

The agency based its approval on data from the positive AReSVi-006 phase III trial that showed the vaccine’s exceptional efficacy in older adults, including those with underlying medical conditions, and in those with severe RSV disease.

GlaxoSmithKline Biologicals (GSK) funded this phase 3, randomised, placebo-controlled, observer-blind, multi-country study to demonstrate the efficacy of a single dose of GSK’s investigational vaccine in adults aged 60 years and above.

In an FDA news release, Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research noted that older adults, in particular those with underlying health conditions, such as heart or lung disease or weakened immune systems are at high risk for severe disease caused by RSV.

“Today’s approval of the first RSV vaccine is an important public health achievement to prevent a disease which can be life-threatening and reflects the FDA’s continued commitment to facilitating the development of safe and effective vaccines for use in the United States.” 

-Peter Marks

GSK, the developers of the vaccine characterised the FDA approval as “Ground Breaking”.

“It is a very big deal to have options available to prevent RSV disease” Miriam Vidal Valero, columnist of nature.com ( 3 May 2023) quoted Barney Graham, senior adviser for global-health-equity trials at Morehouse School of Medicine in Atlanta, Georgia, who spent his entire life in vaccine development related fields.

The technology underlying the RSV vaccine has been almost 60 years in the making. She revealed that Barney Graham spent the first 20 years primarily working out how to make a vaccine that could be safe. In India, the rates of RSV detection in various hospital- and community-based studies mostly done in children vary from 5% to 54% and from 8% to 15%, respectively.

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RSV: A highly contagious virus

“RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups. RSV circulation is seasonal, typically starting during the fall and peaking in the winter. In older adults, RSV is a common cause of lower respiratory tract disease (LRTD), which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs).”, FDA clarified in the news release.

According to the Centers for Disease Control and Prevention(CDC), each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalisations and 6,000-10,000 deaths among adults 65 years of age and older.

The (CDC) describes RSV as “a common respiratory virus that usually causes mild, cold-like symptoms.” Usually, the patients may have a runny nose, coughing, sneezing, loss of appetite and fever within a few days after getting infected. The only symptoms in very young, RSV-suffering infants may be irritability, decreased physical activity, and breathing difficulties.

“Most patients recover in a week or two, but RSV can be serious, especially for infants and older adults. RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia (infection of the lungs) in children younger than 1 year of age in the United States.”

-CDC

Most children get infected with RSV by 2 years of age; however, they may get re-infected throughout life, typically with mild or no symptoms. In older adults or those with coexisting conditions, RSV infection may cause lower respiratory tract disease and it may lead to more severe conditions of underlying diseases, hospitalisation, and death. According to the researchers, in 2019, RSV caused an estimated 5.2 million cases of acute respiratory infection, 470,000 hospitalisations, and 33,000 in-hospital deaths among adults 60 years of age or older in industrialised countries.

There is no specific treatment for RSV infection, though researchers are working to develop vaccines and antivirals (medicines that fight viruses)

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Barriers to RSV vaccine development

RSV is a clever and smart virus! Over a decade ago, Barney Graham who was then working at the Vaccine Research Centre, National Institute of Allergy and Infectious Diseases, National Institute of Health USA listed the major barriers to RSV vaccine development (Immunological Reviews, 2010). They include :

In 2019, Graham attempted to define Immunological goals for respiratory syncytial virus vaccine development (Science Direct, 59, August 2019):

“Defining the immunological goals for respiratory syncytial virus (RSV) vaccination requires an understanding of RSV biology and tropism, mechanisms of cell-to-cell spread and immunity, epidemiology, and transmission dynamics. The immunological goals for a particular vaccine would be product-specific based on antigen selection, delivery approach, and target population. There are many ways to achieve immunity against RSV infection involving innate and adaptive responses, hum oral, and cellular effector mechanisms, and mucosal and systemic responses.”, He said.

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The present study

Researchers are conducting an ongoing, randomised, placebo-controlled, phase 3 trial in 17 countries in Africa, Asia, Australia, Europe and North America. They followed the participants for three RSV seasons in the Northern Hemisphere and at least two consecutive RSV seasons in the Southern Hemisphere. The New England Journal of Medicine (NEJM, 2023; 388:595-608) published the present study carried out during the first RSV season in the Northern Hemisphere.

In the ongoing clinical trial, researchers from Italy, the USA, Canada, South Korea, Belgium, Germany and South Africa randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of Arexvy, the RSV vaccine or placebo before the RSV season.

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Results

24,966 participants received one dose of Arexvy (12,467 participants) or a placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed, RSV-related lower respiratory tract disease was 82.6% with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% against severe RSV-related lower respiratory tract disease (assessed based on clinical signs or by the investigator) and 71.7% against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). Researchers observed high vaccine efficacy in various age groups and participants with coexisting conditions.

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Side-effects

1. Arexvy was more reactogenic than placebo, but most adverse events were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.
2. Among a subset of these clinical trial participants, the most commonly reported side effects by individuals who received Arexvy were injection site pain, fatigue, muscle pain, headache and joint stiffness/pain.
3. Among all clinical trial participants, 10 participants who received Arexvy and 4 participants who received a placebo reported atrial fibrillation within 30 days of vaccination.
4. In two other studies, approximately 2,500 participants 60 years of age and older received Arexvy. In one of these studies, in which some participants received Arexvy concomitantly with an FDA-approved influenza vaccine, two participants developed acute disseminated encephalomyelitis (ADEM), a rare type of inflammation that affects the brain and spinal cord, seven and 22 days, respectively, after receiving Arexvy and the influenza vaccine. One of the participants who developed ADEM died.
5. In the other study, one participant developed Guillain-Barré syndrome (a rare disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) nine days after receiving Arexvy.

The FDA requires the company to conduct a post-marketing study to assess the signals of serious risks for Guillain-Barré syndrome and ADEM. In addition, although not an FDA requirement, the company has committed to assessing atrial fibrillation in the post-marketing study.

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Strengths and limitations of the study

“Strengths of the trial include its large sample size and the enrollment of a diverse older population (from different geographic areas and of various racial groups, ages, and statuses of coexisting conditions and frailty), which allow for extrapolation to the intended target population”, the researchers noted.

“Conducting the trial during the second year of the COVID-19 pandemic posed operational challenges. Moreover, public health measures to limit COVID-19 reduced the spread of RSV and altered the timing of the RSV season, with most cases of RSV-related acute respiratory infection occurring earlier in the season than expected. To mitigate these effects, we increased the sample size and started the trial in May, several months before the historical onset of the RSV season in the Northern Hemisphere” they clarified.

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Vaccine availability

A press release from GSK stated that in June 2023, the Advisory Committee on Immunisation Practices (ACIP) will make recommendations to the CDC on the appropriate use of the vaccine in the US. According to GSK, the vaccine will be available for older adults before the 2023/24 RSV season, which typically starts ahead of the winter months.

GSK said that in April 2023, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the vaccine for the prevention of Lower Respiratory Tract Disease (LRTD) caused by RSV in adults aged 60 years and older. GSK anticipates a final European regulatory decision in the coming months, while regulatory reviews are ongoing in Japan and several other countries.

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Experts’ comments on the vaccine

(The Science Media Centre, London, published the remarks from two experts before the journal published the paper.)

Dr Christopher Green, Associate Clinical Professor & Consultant Physician in Infectious Diseases, University of Birmingham revealed that RSV has been a target for vaccine development since researchers discovered it in the 1950s. The first vaccines developed in the 1960s used a formalin-inactivated version of the virus as a vaccine design, which then had also been used as a method to generate vaccines against other viruses.

However, the formalin-inactivated RSV (FI-RSV) vaccine when given to infants in the 1960s caused significant harm to many of the youngest recipients when they were infected with the real virus later that year, and two sadly died. Researchers have to work hard to understand why this happened before RSV vaccine research could resume. The FI-RSV vaccine appeared to prime an immune response to the real virus that was harmful in the youngest infants who had little/no previous exposure and natural immunity, unlike the older children and adults.

“Nonetheless, RSV vaccine development has always been an especially difficult and sensitive problem for this reason and many others that were less related to safety. We have not used formalin-inactivation as a way of making vaccines for use in humans for over 50 years but for RSV even today new RSV vaccine candidates undergo careful animal testing that includes RSV infection before the vaccine can be considered for testing in humans.” Dr Green

When GSK published a press release on the success of their vaccine for the elderly and the young, Dr Green described the development as a huge achievement after such a long time;

 

“Following on from results press released by Pfizer in August and data presented by Janssen at an RSV meeting in Belfast in September, these new results from GSK add to the sense that more than one highly effective vaccine to prevent serious respiratory illnesses caused by this virus in elderly people are well this side of the horizon.” 

-Prof Adam Finn, Professor of Paediatrics, University of Bristol

“With effective vaccines to prevent pneumonia caused by viruses like SARS CoV2, influenza and RSV as well as bacterial lung infections, the stage is set for further radical improvements in this area of preventative medicine in the near future.” 

-Prof Adam Finn, Professor of Paediatrics, University of Bristol

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Cost of RSV vaccine

“The approval makes GSK, which has been neck-and-neck with Pfizer (PFE.N) in RSV vaccine development, the first company to tap into a multi-billion-dollar market and also puts it ahead of rivals such as Moderna Inc (MRNA.O) and Bavarian Nordic (BAVA.CO),” Reuters reported on May 8th.

The agency estimates that the market for RSV vaccines to surpass $10 billion by 2030. Credit Suisse analysts expect $2.5 billion in peak sales for GSK's RSV vaccine for older adults. Chief Commercial Officer Luke Miels of GSK told Reuters that the company expects the vaccine to be available before the next RSV season in the United States. According to him, the vaccine would be priced above $120 per shot provided the data from a study, which is expected soon, shows that it offers protection for two RSV seasons.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and is a medical physicist with a specialisation in radiation safety and regulatory matters.