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First RSV jab for adults approved by FDA

The US Food & Drug Administration (FDA) has approved the first-ever vaccine for respiratory syncytial virus (RSV), marketed by GSK under the trade name of Arexvy and specifically indicated for preventing lower respiratory tract infections in people over 60.

Until now, there has been no vaccine to protect against RSV infection, a common scourge both for young children and older adults, reports MedPage Today.

An estimated 60 000 to 160 000 senior citizens in the US are admitted to hospital annually with RSV infections, with 6 000 to 10 000 deaths in this group being linked to the highly contagious virus.

“Older people, in particular those with underlying health conditions, like heart or lung disease or weakened immune systems, are at high risk of severe disease caused by RSV,” said Dr Peter Marks, director of the FDA’s Centre for Biologics Evaluation and Research.

Approval follows a strong endorsement earlier this year from the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), which voted 12-0 in support of the efficacy data presented by developer GSK, and 10-2 on safety.

Primary support for the approval came from the phase III AReSVi-006 (Adult Respiratory Syncytial Virus) trial involving 24 960 adults 60 and older who were randomised 1:1 to a single dose of the prefusion F protein vaccine or placebo.

Vaccine efficacy reached 82.6% against lower respiratory tract illness (96.95% CI 57.9-94.1) and 94.1% against severe cases (95% CI 62.4-99.9).

Seven people in the vaccine arm and 40 placebo recipients had lower respiratory symptoms or signs for at least 24 hours, along with a positive RSV test, meeting the study’s primary outcome measure. For severe illness, there was one case in the vaccine arm and 17 in the placebo arm. The vaccine performed similarly across subgroups: RSV A (84.6%), RSV B (80.9%), age 60-69 years (81.0%), and age 70-79 years (93.8%).

Adverse events included arm pain, fatigue, headache and myalgia; and no imbalances were seen between groups when it came to serious events.

The FDA also noted that among all clinical trial participants, atrial fibrillation within 30 days of injection was reported in 10 vaccine recipients versus four placebo recipients.

The agency is also requiring GSK to conduct a post-marketing study to assess for the risk of Guillain-Barré syndrome and acute disseminated encephalomyelitis (ADEM) after a cases of these rare but serious events turned up in trials.

While not a requirement, the company has also committed to follow the incidence of atrial fibrillation in its post-marketing study.

GSK said the vaccine would be available before the 2023/2024 RSV season, and that the CDC’s Advisory Committee on Immunisation Practices would weigh in on the RSV vaccine’s appropriate use in June.

More in the pipeline

However, it won’t be the only shot targeting the virus for long. Pfizer has also submitted its RSV vaccine in older adults for approval, and the FDA has until 31 May to make a decision.

Additionally, reports TIME, Moderna plans to request approval for its RSV vaccine, based on the same mRNA technology behind its Covid-19 vaccine, this year. (Johnson & Johnson-Janssen, which was also testing an RSV vaccine, stopped its late-stage trials in March.)

In coming months, the companies and FDA will also consider approving a Pfizer vaccine for babies, and Moderna is launching studies of its vaccine in paediatric populations.

Getting here has been a long journey, but one that has benefited from game-changing discoveries. Here’s how we got here.

In the 1980s, Paul Glezen, a microbiologist and immunologist at Baylor College of Medicine, made the first important discovery toward creating an RSV vaccine.

Doctors knew that while nearly every baby became infected with RSV by the time they were two, only a small percentage became sick enough from their infection to be hospitalised. Glezen guessed that most babies were benefiting from antibodies received passively from their mothers, helping their still undeveloped immune systems to fight off the virus.

To prove this, Glezen collected cord blood from thousands of babies born at Baylor’s maternity hospital, comparing those who ended up being hospitalised for RSV with those who were not. The babies who did not get admitted tended to have high levels of antibodies against the virus, while those who did not had lower levels.

“That was a fundamental breakthrough,” says Bill Gruber, senior vice-president of vaccine clinical research and development at Pfizer. “It indicated that if you could get the right antibodies to the babies, they would probably provide protection against RSV.”

That insight turned into an antibody treatment: an injectable shot known as palivizumab, or Synagis. This is currently the only antibody-based therapy for RSV, but it’s reserved for babies at highest risk of developing infections and requires five shots over the course of one viral season.

A vaccine that trains the immune system to fight the virus would have broader impact and could be more widely distributed to every newborn as part of their routine immunisations.

But after an early vaccine candidate failed to protect babies and instead led to worse illness, particularly among those who had never been exposed to the virus before getting immunised, development stalled for decades.

“That vaccine, which was given to infants, made things worse and set back research years and years,” says Dr Phil Dormitzer, global head of vaccines R&D at GSK.

Scientists working on another virus, parainfluenza virus, that also causes respiratory disease in babies, first introduced the idea that an effective vaccine against that pathogen should target a specific form taken by the virus just before it infects a cell.

Previous attempts to develop vaccines had targeted the wrong form of the RSV protein – one the virus made after it had infected cells. By then, the virus had already co-opted the cell’s machinery to make more copies of itself, and had launched a full scale infection, too late for any vaccine to have much effect.

Once the idea had been planted with the parainfluenza virus, “we assumed we could do the same thing with RSV, and that it would be easy to engineer”, said Dormitzer.

“But it turned out to be more difficult, and many frustrating years passed while we tried to do the same thing with RSV, with minor variations, and they weren’t working.”

Then, Barney Graham made a breakthrough discovery in 2013. An immunologist and virologist at the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, Graham had devoted years to unpacking how RSV worked.

He focused on understanding how the main RSV protein – that sets up a red flag for the immune system – was constructed. He successfully isolated a version of the protein that the virus made before infecting a cell, and in tests in animals and with human cells, this protein was far more potent in stimulating the immune system than previously isolated RSV proteins.

At Pfizer, Gruber, who had been Graham’s roommate at Rice University, learned of his friend’s discovery after reading Graham’s description in a journal. The two connected, and Gruber convinced Pfizer to license the technology.

The pharmaceutical giant put its scientists to work creating a stabilised form of the RSV protein that targeted not just one strain of the virus, but two – similar to how different versions of the influenza virus are included in each flu shot – to prompt the most wide ranging immune response possible.

GSK relied on its own strategies using recombinant technology to ensure the target RSV protein did not “flip to a form we didn’t want”, said Dormitzer. The engineering in GSK’s vaccine, he says, has advantages in that scientists can perform quality control to ensure that the RSV protein in the shot is pure and in the proper form, and gives them more control over how the vaccine can activate the immune system.

How RSV vaccines got sidelined by Covid-19

Graham was preparing to launch a trial of his RSV protein in a vaccine toward the end of 2019. But it turned out the first virus his theory would be tested against wouldn’t be RSV, but SARS-CoV-2.

Based on his work with RSV to that point, Graham was among the first to realise that the same approach he was testing for a new RSV vaccine could work for the novel coronavirus as well.

He asked his boss, Dr Anthony Fauci, director of NIAID, to allow him to test that idea and develop a prototype Covid-19 vaccine with a form of SARS-CoV-2.

NIAID had partnered with a small biotech called Moderna, to test this strategy. Not only did the company place its bets on the genetic code for the same form of the viral protein as Graham, but it also banked on a new way of delivering that information into the body using a genetic material known as mRNA.

Moderna scientists were convinced mRNA would be a better foundation for a vaccine, since the platform did not require growing any viral proteins but only relied on zeroing in on the right RNA sequence from the virus that would stimulate the immune system.

Graham’s advance allowed the immune system to generate a strong response to SARS-CoV-2 that surprised everyone. In the first studies in people, the Covid-19 vaccine was able to neutralise lab versions of SARS-CoV-2 with more than 90% efficacy.

Graham’s discovery, coupled with the mRNA platform’s flexibility and speed, set records for vaccine development. In under a year, scientists went from not knowing what SARS-CoV-2 was to having an effective vaccine directed against it.

Next steps for RSV vaccines

The success of those shots redirected scientists to bring their other vaccine candidates full circle, hopefully with similar results.

Building on the right form of the RSV protein that Graham’s group had identified, GSK scientists super-charged its vaccine for older people, many of whom have waning immune systems, with an accelerant known as an adjuvant, which makes foreign targets in vaccines more attractive to the immune system.

Pfizer also focused on a vaccine for adults at highest risk of RSV – the elderly – and used the same vaccine to also immunise pregnant women as a way to protect newborns.

“Some pregnant women could make antibodies to pass on to their infants: we needed to find how to give every pregnant woman that opportunity,” he said. In March, the company presented to an FDA panel of outside experts its encouraging late-stage results from human testing among older people.

That data showed the vaccine was around 67% effective in reducing RSV illness associated with at least two symptoms of infection, and had 85.7% efficacy in lowering more severe illness linked to at least three symptoms.

Pfizer’s next target will be immunising pregnant women against RSV, to protect their newborns.

In November 2022, the company announced encouraging results from its late-phase testing of the same vaccine used in older adults that was given to expectant moms. In that study, the vaccine was almost 82% efficacious in reducing the need for medical treatment of respiratory illness in the first 90 days after birth, and 69% efficacious in the first six months.

That study is ongoing, and Gruber says Pfizer’s scientists are hoping that vaccine could be given once during pregnancy to protect the newborn.

Dormitzer says that GSK’s RSV vaccine for older people probably won’t be applicable to pregnant women; early trials found a possible safety issue in this population, so the company stopped the study. “If we go with a vaccine directly in children, we would probably not use (the current formulation), because of what we saw in the 1960s,” he said.

“Right now, focusing on the older populations, we are immunising people who have all had RSV before, so there is no risk of seeing what happened in the 1960s.”

So far, GSK has found that protection from a single vaccination protects older people through an entire respiratory disease season, and potentially up to a year. In coming months, its scientists will know if that protection lasts longer, into a second season. Also coming could be combination vaccines targeting pairings of three of the major respiratory diseases that plague older people – flu, Covid-19 and RSV.

Study details

Respiratory Syncytial Virus (RSV) Prefusion F Protein Candidate Vaccine (RSVPreF3 OA) is Efficacious in Adults ≥ 60

Michael Ison, Alberto Papi, Joanne Langley, MD, Dong-Gun Lee, Isabel Leroux-Roels,  Federico Martinon-Torres, Tino Schwarz, Richard Van Zyl-Smit, PhD MD, Nancy Dezutter, Nathalie De Schrevel, et al.

Published in Open Forum Infectious Diseases (ID Week 2022) on 15 December 2022


RSV-associated acute respiratory infections (ARI), particularly lower respiratory tract diseases (LRTD), present a significant disease burden in older adults. Currently, there are no approved vaccines against RSV. We present results from an ongoing study designed to demonstrate the vaccine efficacy (VE) of the AS01E-adjuvanted RSVPreF3 OA in adults ≥ 60 YOA.

This ongoing, phase 3, observer-blind, placebo-controlled, multi-country study (NCT04886596) enrolled adults ≥ 60 YOA from the northern and southern hemispheres. Participants were randomized (1:1) to receive a single dose of RSVPreF3 OA or placebo before the RSV season. The primary objective was to demonstrate VE of a single dose of RSVPreF3 OA in preventing RSV-confirmed LRTD during one RSV season (criterion: lower limit of VE confidence interval [CI] > 20%). VE is reported also against severe RSV-confirmed LRTD, RSV-confirmed ARI, RSV-confirmed LRTD and RSV-confirmed ARI by RSV subtype (RSV-A and RSV-B), and RSV-confirmed LRTD by age, baseline comorbidity and frailty status. RSV-A/B was confirmed by quantitative RT-PCR.

A total of 26,664 participants were enrolled, of whom 24,966 (RSVPreF3 OA: 12,467; placebo: 12,499) were included in the exposed set and 24,960 (RSVPreF3 OA: 12,466; placebo: 12,494) in the efficacy analysis. The mean age was 69.5 (±6.5) years and 51.7% were women. Over a median follow-up of 6.7 months (maximum 10.1 months), 47 RSV-confirmed LRTD episodes were reported (RSVPreF3 OA: 7; placebo: 40), resulting in a VE of 82.6% (96.95% CI: 57.9–94.1), thus the primary objective was met. Consistently high VE across the clinical spectrum of RSV disease, from RSV-confirmed ARI (71.7% [95% CI: 56.2–82.3]) to severe RSV-confirmed LRTD (94.1% [95% CI: 62.4–99.9]) was observed. High VE was seen in different age groups and regardless of RSV subtype, baseline comorbidity or pre-frail status. Cumulative incidence curves for RSV-confirmed LRTD and RSV-confirmed ARI showed persistent efficacy throughout the follow-up.

A single RSVPreF3 OA dose is highly efficacious against RSV-confirmed LRTD and RSV-confirmed ARI in adults ≥ 60 YOA, regardless of RSV disease severity, RSV subtype, baseline comorbidity and pre-frail status.


OFID article – Respiratory Syncytial Virus (RSV) Prefusion F Protein Candidate Vaccine (RSVPreF3 OA) is Efficacious in Adults ≥ 60 (Open access)


MedPage Today article – FDA Approves First-Ever RSV Vaccine (Open access)



IME article – Why It Took So Long to Finally Get an RSV Vaccine (Open access)



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