Older adults first in line for RSV vaccines, but will they roll up their sleeves?

This coming fall and winter, older adults in the United States will face a decision: Should they roll up their sleeves to receive the world’s first approved vaccines against respiratory syncytial virus?

According to the CDC, the decision should be up to patients and their physicians.

Two RSV vaccines will join shots against influenza and COVID-19 in the armamentarium available to prevent a repeat of last year’s “tripledemic” of respiratory illnesses.

“The FDA approval of two new RSV vaccines for adults was a notable landmark in the effort to prevent this underappreciated infection that can rival influenza in producing serious respiratory illness each winter,”William Schaffner,MD,a Healio |Infectious Disease NewsEditorial Board member, professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center and medical director of the National Foundation for Infectious Diseases,said in an interview.

A twist came when the CDC, following advice from its Advisory Committee on Immunization Practices, recommended that RSV vaccination be based on “shared clinical decision-making” — that is, based on a discussion between patient and clinician about the benefits and risks.

“Although this is a broad recommendation, the ACIP stayed a small step shy from recommending RSV vaccine be given routinely to all older adults,” Schaffner said. “Why? Well, there are several reasons.”

We checked in with experts about the two vaccine approvals, the reasons for the CDC’s muted recommendation and what it all means for older patients in the U.S.

Back-to-back approvals

On May 3, the FDA approved the world’s first ever vaccine against RSV, GSK’s Arexvy, for adults aged 60 years or older. The approval was based on data from an ongoing randomized, placebo-controlled phase 3 trial, in which study participants will remain enrolled for three RSV seasons to assess the duration of efficacy and the safety of repeat vaccinations.

Available data showed that the vaccine reduced the risk for developing RSV-related lower respiratory tract disease by 82.6% and reduced the risk for developing severe RSV-related lower respiratory tract disease by 94.1%. It was well tolerated by trial participants, the company reported, with the most common side effects being injection site pain, fatigue, muscle pain, headache and joint stiffness or pain.

On May 31, the FDA approved a second RSV vaccine for adults aged 60 years or older, Pfizer’s Abrysvo. The approval was based on data from the randomized, double-blind, placebo-controlled phase 3 RENOIR trial, which is also ongoing to allow researchers to collect additional data from a second RSV season.

Data from approximately 37,000 people enrolled in the trial who were randomly assigned in a 1:1 ratio to receive the vaccine or placebo showed that the vaccine was 66.7% effective at preventing lower respiratory tract illness with two or more symptoms and 85.7% effective at preventing illness with three or more symptoms.

The approvals came with support from the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), although it was not unanimous. The advisory panel voted 7-4 that data supported the safety and efficacy of the Pfizer vaccine, 12-0 that data supported the efficacy of the GSK vaccine and 10-2 that data supported the GSK vaccine’s safety.

沙夫纳说,有一个特定的群patients who should receive the vaccines — particularly those who have chronic health conditions such as heart or lung disease or diabetes. Although the vaccines will be covered under Medicare Part D, he noted that not all Medicare recipients elect Part D, and that because of “administrative complexities,” some physicians’ offices do not provide immunizations covered by Part D. In that event, he said, patients can be referred to pharmacists for vaccination.

For other patients aged 60 to 64 years using other medical insurance programs, the new vaccines should be covered, “but it sometimes takes up to a year for new vaccines to be included,” Schaffner said.

‘The danger in plowing ahead’

During discussions before their votes, VRBPAC members questioned the number of older adults in both vaccine trials, as well as the lack of serious cases included in the data, which they said raised some concerns about safety and efficacy. Several also said they would have preferred to see a second year of data before voting.

“I was surprised that the vaccines were licensed, but at the same time, I was glad to see that the vaccines had demonstrated an advancement in the science. From that perspective, it is good,”David A. Nace, MD, MPH,clinicalchief of the division of geriatric medicine at the University of Pittsburgh and chief of medical affairs for the University of Pittsburgh Medical Center Senior Communities, said in an interview.

Nace is among the experts who would have liked to see more than one season of data on the vaccines.

“They were only studied in people over the course of one season,” Nace said. “The data that were released really reflected one experience over one RSV season and really looked at, for the most part, relatively healthy people in a community dwelling [or people with] stable comorbid medical problems.”

Nace said more data are needed on frail, older adults; adults aged 80 years or older; and people in long-term care. The GSK study included frail patients, but only a limited number and with a narrow definition of “frail,” he said.

“The tool they used was gait speed, and that's not a comprehensive measure of frailty,” Nace explained. “We can also argue about the cutoffs they use. A lot of geriatricians would disagree with what was defined as prefrail vs. frail vs. not frail. So, that population was really not adequately evaluated, and it wasn't even addressed in the Pfizer study.”

Another concern raised during discussions about the vaccines were the several cases of Guillain-Barré syndrome that developed in trial participants.

According to data shared with the FDA ahead of the VRBPAC vote, three cases occurred in the Pfizer study — one at 8 months that Nace said was likely not related, and two within 42 days, which he called “pretty striking.” In the GSK trial, there was one case that occurred in an earlier phase study within 42 days.

“They were pretty clearly associated with the vaccine and at a rate much higher than the background rate,” Nace said.

Nace acknowledged that the numbers were small, but said the outcomes were serious and that there is a need for longer term follow-up on participants to determine if the outcomes were related to the vaccine.

RSV vaccine research has only recently ramped up over the past decade after a long delay in activity following a deadly vaccine trial in the 1960s.

“The danger in plowing ahead and saying that everyone [aged 60 years or older] should get this is that if there is a safety concern, we would set vaccine policy in the United States back 30 years because no one would trust us,” he said. “This is a matter of trust, and for that we should not dogmatically push forward without making sure we have all the answers.”

Other questions could be sorted out with longer term data, according to Nace.

“How often should they get this vaccine? How long does that vaccine protection last — not just the antibody response, but the actual clinical effectiveness?” he said. “That really requires multiple years of study for us to be comfortable answering those questions.”

Amanda Cohn, MD,director of the CDC’s Division of Birth Defects and Infant Disorders and a voting member of the VRBPAC, said the data were “robust and demonstrate a potentially high effectiveness against RSV” but also said she would have liked to see another season of data.

“There really was not a substantial amount of severe disease among those that were studied, [giving] me pause about applying this to the general population ... but overall, I think that the data are very supportive of effectiveness,” Cohn said during the meeting.

‘May’ vs. ‘should’

Weeks after the FDA approvals, the ACIP voted to recommend that people aged 60 years or older “may” receive — not “should” receive — one of the two RSV vaccines in consultation with a clinician. Specifically, they voted 13-0 with one abstention to support this recommendation for people aged 60 to 64 years and 9-5 in support of the recommendation for adults aged 65 years or older.

The language of the recommendation is significant. By choosing “may” over “should,” the ACIP — and later the CDC, which supported the recommendation — chose to recommend that getting one of the vaccines be based on shared clinical decision-making. It is a designation the advisory committee has applied in the past to recommendations for meningococcal B, hepatitis B, HPV and pneumococcal vaccines in different age groups.

“The recommendation for shared clinical decision-making is intended to allow flexibility for providers and patients to consider individual risk for RSV disease, while taking into account patient preferences,” members of the ACIP and others wrote in the official recommendations published inMMWR.

“One of the best things about being a family physician is developing a strong relationship with patients. When it comes to vaccines, shared decision-making allows family physicians to work closely with their patients to determine whether a vaccine is right for them,”Tochi Iroku-Malize, MD, MPH,president of the American Academy of Family Physicians (AAFP), told Healio | Infectious Disease News.“This means looking at a patients’ entire health history, chronic conditions, and their risk for contracting RSV. Family physicians use that information to determine whether the patient a good candidate for the RSV vaccine.”

During public comments at a different ACIP meeting, a man speaking on behalf of an advocacy group for older patients expressed concern that the weaker recommendation would hurt RSV vaccine uptake, but Nace called it “exactly appropriate.”

“我们没有足够的证据说这是something that everyone should receive,” Nace said. “Based on the experience from the trials, it is suggested that there were benefits, but it really comes down to having a discussion with patients so that they make an informed decision around the risks and the benefits of the vaccines.”

Nace said it is difficult to anticipate how the language will impact getting shots into arms.

“But in all likelihood, the uptake will be less,” Nace said. “Our experience with hepatitis B with shared decision-making over 65 meant that not everybody got it. ... What we're hoping is that it's a more person-centered decision, which — in geriatrics — is one of the most important things we talk about. What matters most to the person? What is their assessment of the risks and benefits? Because this is not a decision like COVID, where the population health benefit is pretty clear. For RSV, we're still trying to figure that out.”

The RSV pipeline

Developing preventive therapies for RSV for all ages “continues to be an active area of translational investigation,” Schaffner said.

Another product has already been approved: the monoclonal antibody nirsevimab, licensed now as Beyfortus (AstraZeneca and Sanofi). The FDA approved nirsevimab in July for the prevention of RSV in newborns and infants born during or entering their first RSV season and for children up to age 24 months who remain vulnerable to severe illness from the virus through their second RSV season.

The FDA’s Antimicrobial Drugs Advisory Committee voted unanimously in June to recommend it for approval at an intramuscular injection of 50 mg for infants with a body weight less than 5 kg, and 100 mg for infants with a body weight of 5 kg or more.

On the other end of the spectrum, Bavarian Nordic announced in July that it was ending its RSV vaccine program after a phase 3 clinical trial of its candidate vaccine, MVA-BN RSV, failed to prevent RSV-related lower respiratory tract disease (LRTD) among adults aged 60 years or older.

“The final study results showed that the vaccine candidate had a 59% efficacy in preventing at least two predefined LRTD symptoms meeting one of the efficacy criteria of the study. However, when measuring more severe LRTD based on at least [three] predefined symptoms, the vaccine candidate only demonstrated a 42.9% efficacy and missed the coprimary endpoint of the study,” the company said.

Moderna also has an RSV vaccine candidate in late-stage development and has already initiated a rolling submission with the FDA, allowing the company to submit relevant data as they are collected, essentially streamlining the process of getting the vaccine, mRNA-1345, approved.

In January, the company announced that the messenger RNA-based vaccine met the primary endpoints of the phase 3 ConquerRSV trial, which enrolled approximately 37,000 adults aged 60 years or older from multiple countries. The results showed that the vaccine was 83.7% effective against RSV-associated LRTD as defined by two or more symptoms and 82.4% effective against RSV-associated LRTD as defined by three or more symptoms.

Data also showed that the vaccine was generally safe, with the most common side effects being injection-site pain, fatigue and headache.

Moderna is also testing mRNA-1345 in a phase 1 trial in pediatric populations to address the “significant disease burden” of RSV in children. As of July, the company said the trial is fully enrolled.

GSK and Pfizer are also assessing their vaccines among additional and more specific populations.

GSK is testing its vaccine in people aged 50 to 59 years, including those with underlying comorbidities, and is expecting results from that trial later this year.

Pfizer’s vaccine is already under FDA review to be given to pregnant people to protect their infants. In May, the company presented phase 3 data showing that, 90 days after birth, the vaccine’s efficacy was 57.1% against RSV-positive medically attended lower respiratory tract illness (MA-LRTI) and 81.8% against RSV-positive severe MA-LRTI in infants. The company recorded preterm birth or birth at less than 37 weeks’ gestation as one adverse event, which was reported in 5.7% of infants in the vaccine group and 4.7% of infants in the placebo group.

Based on these data, the VRBPAC voted 14-0 in May that the Pfizer vaccine was effective at preventing RSV in infants during their first 6 months when given to pregnant patients in the second or third trimester. Four advisors voted “no” in response to a second question on whether data demonstrated an adequate safety profile. An FDA decision regarding the maternal vaccine was expected in August.

‘An important first step’

Because the upcoming fall and winter months will mark the first RSV season with available vaccines, patients will undoubtedly have questions.

“The CDC’s recommendations mark an important first step,” Iroku-Malize said.“The vaccines are expected to be available to the public by this fall ahead of the next RSV season. Many patients will want to know whether the RSV vaccine is right for them, and their family doctor is here to answer questions and work together to make the best decision for their health.”

Schaffner said it will likely be a challenging respiratory diseases season given the recommendations for three separate respiratory vaccines for older adults, including the coming monovalent COVID-19 boosters. It will mean many discussions among health care workers and patients throughout the fall and winter months.

“Many doctors continue to become acquainted with the data accumulated over the past 15 to 20 years that RSV is ‘not just a pediatric virus,’ but one that also produces serious illness in their older adult patients,” Schaffner said. “The continuing education concerning RSV and the RSV vaccines is substantial, so this new information is streaming out into the medical community.”

Iroku-Malize said the most important thing to stress, though, is that “vaccines are safe, effective and save lives.”

“According to the CDC, between 60,000 to 120,000 adults aged 65 and older are hospitalized by RSV each year, and 6,000 to 10,000 die from the virus,” Iroku-Malize said. “With those jarring numbers in mind, the AAFP is hopeful that the CDC’s recommendation of RSV vaccines for adults 60 and older will lead to less serious illness and fewer hospitalizations and death from RSV.” –by Caitlyn Stulpin

References:

• Bavarian Nordic provides update on RSV vaccine program.https://www.bavarian-nordic.com/investor/news/news.aspx?news=6808. Published July 22, 2023. Accessed July 27, 2023.
• CDC. RSV surveillance and research.https://www.cdc.gov/rsv/research/index.html. Updated Oct. 28, 2022. Accessed July 12, 2023.
• FDA. FDA approves first respiratory syncytial virus (RSV) vaccine.https://www.fda.gov/news-events/press-announcements/fda-approves-first-respiratory-syncytial-virus-rsv-vaccine. Published May 3, 2023. Accessed July 11, 2023.
• FDA. Vaccines and Related Biological Products Advisory Committee February 28-March 1, 2023 meeting announcement.https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-february-28-march-1-2023-meeting. Accessed July 12, 2023.
• FDA. Vaccines and Related Biological Products Advisory Committee meeting – May 18, 2023. FDA briefing document.https://www.fda.gov/media/168185/download. Accessed July 11, 2023.
• Melgar M, et al.MMWRMorbMortalWklyRep.2023;doi:10.15585/mmwr.mm7229a4.
• Moderna announced global regulatory submissions for its respiratory syncytial virus (RSV) vaccine, MRNA-1345.https://investors.modernatx.com/news/news-details/2023/Moderna-Announces-Global-Regulatory-Submissions-For-Its-Respiratory-Syncytial-Virus-RSV-Vaccine-MRNA-1345/default.aspx. Published July 5, 2023. Accessed July 12, 2023.
• MVA-BN RSV phase 3 ongoing.https://www.bavarian-nordic.com/what-we-do/pipeline/rsv.aspx. Accessed July 12, 2022.
• U.S. FDA accepts biologics license application for Pfizer’s respiratory syncytial virus maternal vaccine candidate for priority review.https://www.pfizer.com/news/press-release/press-release-detail/us-fda-accepts-biologics-license-application-pfizers. Published Feb. 21, 2023. Accessed July 11, 2023.
• U.S. FDA approves ABRYSVO, Pfizer’s vaccine for the prevention of respiratory syncytial virus (RSV) in older adults.https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-abrysvotm-pfizers-vaccine-prevention. Published May 31, 2023. Accessed July 11, 2023.
• US FDA approves GSK’s Arexvy, the world’s first respiratory syncytial virus 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/. Published May 3, 2023. Accessed July 11, 2023.
• Walsh EE, et al.N Engl J Med. 2023;doi:10.1056/NEJMoa2213836.

For More Information:

Tochi Iroku-Malize, MD, MPH,can be reached via eholwick@aafp.org.

David A. Nace, MD, MPH,can be reached atnaceda@upmc.edu.

William Schaffner,MD,can be reached atwilliam.schaffner@vumc.org.