By Gary Evans, Medical Writer
With some concerns and caveats that put a strong emphasis on post-marketing surveillance, vaccine advisors for the Food and Drug Administration (FDA) have greenlit two vaccines against respiratory syncytial virus (RSV) infections in people aged 60 years and older.
Although widely and almost exclusively considered a pediatric infection, RSV causes about 177,000 hospitalizations and 14,000 deaths annually in the United States in those age 65 years of age and older, the National Foundation for Infectious Diseases (NFID) emphasized in a call-to-action report.1
Other studies have found that RSV rivals influenza in causing mortality in the elderly, since there is no vaccine and few established treatment options. “RSV infection can cause significant morbidity in hospitalized patients, with mortality rates up to 12%,” researchers report, adding, “The average age of RSV-infected patients was older than that of influenza patients (70 and 62 years, respectively). RSV patients were more likely to be residents of a long-term care facility or to have chronic obstructive pulmonary disease, pneumonia, or respiratory bacterial superinfection.”2
The two vaccines approved after two days of meetings of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) were the following:
Pfizer, Inc., submitted a Biologics License Application (BLA) to support licensure of RSVpreF (Abrysvo), with the proposed indication of prevention of acute respiratory disease and lower respiratory tract disease caused by RSV in individuals 60 years of age and older.
“The primary data to support the safety and efficacy of [Pfizer] RSVpreF in individuals 60 years of age and older consist of data from an ongoing multi-national Phase III randomized, double-blind, and placebo-controlled trial in 34,284 participants who were randomized to receive a single dose of RSVpreF (n = 17,215) or placebo (n = 17,069),” the FDA reported. “Vaccine efficacy (VE) in preventing laboratory-confirmed (lower respiratory tract disease [LRTD]) RSV with ≥ 3 symptoms was 85.7%, with two cases in the vaccine group and 14 cases in the placebo group.”
GlaxoSmithKline Biologicals submitted a BLA for an RSV adjuvanted vaccine RSVPreF3-AS01E (Arexvy) to prevent RSV-associated LRTD in adults 60 years of age and older. The GlaxoSmithKline vaccine studies included a total of 24,966 participants, of which 12,466 received the vaccine and 12,494 were placebo recipients. VE at the primary end point was 82.6%.
“This is amazing data that we have on efficacy for an RSV vaccine in this population and in this age group,” said Amanda Cohn, MD, liaison member representing the Centers for Disease Control and Prevention. “It looks like we have a vaccine that may work.”
Guillain-Barré Syndrome
Although the efficacy of the two vaccines generally was very strong, there were a few rare adverse events in the vaccine data. These include two cases of Guillain-Barré syndrome (GBS) in the Pfizer vaccine trials and one death as the result of acute disseminated encephalomyelitis in the GlaxoSmithKline studies, the FDA noted in a background document.
Although these adverse events are extremely rare, the appearance of GBS in particular is troubling. There is concern that vaccine skepticism and anti-vaccine sentiments will increase if an RSV vaccine is linked to GBS, an exceedingly uncommon autoimmune disorder that attacks the nervous system. This can result in weakness, tingling, and, in severe cases, paralysis.
GBS is not completely understood, but it has been seen in the aftermath of infections and in one infamous incident, influenza vaccinations.
That was during the disastrous public health response to the pseudo-pandemic of 1976. The government rolled out a vaccine in anticipation of a “swine flu” pandemic that never materialized. Immunization was associated with approximately one additional case of GBS per 100,000 people vaccinated, leading the public health response to be abruptly halted.
“I’m old enough to remember that,” said VRBPAC member Stanley Perlman, MD, PhD, of the University of Iowa. “I’m pretty concerned about the GBS after having the swine flu [incident] in the ‘70s and now living through all the COVID-19 vaccine stuff. We have abysmal booster rates because of people’s concerns — most of which are not valid. I’m very nervous about having any safety feature come up, even in the post-market surveys. It’ll affect both this [elderly] population and then uptake of [a future RSV] vaccine for babies.”
Trying to allay concerns, Joseph Toerner, MD, MPH, of FDA Vaccines Research said, “[The] FDA now has the authority to require post-marketing studies, [which] should be able to answer and best characterize the safety signal.”
The FDA background document clarified that Pfizer would have to agree to a post-market study if the RSV vaccine is licensed.
“There were two GBS cases among 19,942 vaccinated participants in the clinical studies submitted to the BLA,” the FDA stated. “In the context of a background rate of 1.5 to three cases per 100,000 people per year for GBS in the United States among adults > 60 years of age, the FDA has requested that the Applicant includes GBS and other immune-mediated demyelinating conditions in its Pharmacovigilance Plan (PVP) as an Important Potential Risk. To assess the risk of GBS and other immune-mediated demyelinating conditions among RSVpreF recipients post-licensure, FDA has requested that the Applicant propose a post-marketing safety study.”
VRBPAC approved the vaccines for biological license application, but they are not formally licensed yet and vaccine advisors for the CDC are expected to meet in the near term to weigh in as well.
Adverse Case Reports
Both companies submitted data from several ongoing studies, but a few rare adverse events were the subject of concern despite demonstrated efficacy against RSV.
Three serious adverse events in the RSVpreF group were considered to be possibly related to the study vaccine by the FDA. One was an event of hypersensitivity, not classified as anaphylaxis, beginning eight hours after vaccination and the other two were the aforementioned cases of GBS.
The case narrative for the three serious adverse events in the Pfizer RSVpreF group were described by the FDA as follows:
• A 61-year-old female experienced hypersensitivity of moderate severity that began eight hours after receipt of RSVpreF. The participant developed shortness of breath and chest pain, had loss of consciousness, and required hospitalization. She received a diagnosis of allergic drug reaction and her symptoms resolved five days after onset.
• A 66-year-old male with a past medical history of hypertension developed GBS, graded as life-threatening in severity, with onset of symptoms seven days after receipt of RSVpreF.
Prior to the onset of these symptoms, the participant had experienced a non-ST elevation myocardial infarction, not considered related to vaccination, on day 7.
He was hospitalized on days 7-8 for cardiac catheterization and angioplasty, and on day 8 developed lower back pain. On day 14, he developed bilateral lower extremity weakness, and, because of a fall, he was hospitalized. Physical examination and laboratory findings were consistent with the diagnosis of GBS.
He was treated with intravenous immune globulin, and five sessions of plasmapheresis. Symptoms improved and the event of GBS was resolving at the time of the last available report, approximately six months after symptom onset.
• A 66-year-old female with a past medical history of type 2 diabetes mellitus developed Miller Fisher syndrome, [a variant of GBS] graded as severe, with onset eight days after receipt of RSVpreF. The participant reported fatigue on day 9, sore throat on day 10, and ataxia on day 11.
On day 19, she was hospitalized for severe fatigue and unstable movements, and later developed diplopia, ataxia, and paresthesia of bilateral palms and soles. Ophthalmoplegia was seen on examination.
Her symptoms started to resolve on day 40, without treatment. On day 41, she was retrospectively diagnosed with Miller Fisher syndrome based on clinical course. The participant’s symptoms resolved completely approximately three months after symptom onset.
“I remain very concerned about GBS,” said VRBPAC temporary voting member Marie Griffin, MD, of Vanderbilt University. “I do feel confident that a post-marketing survey can pick it up, but it could be very bad for the adult vaccine program. I think these cases were very notable. One patient spent six months in the hospital. These are very devastating events.”
Daniel Feikin, MD, MSPH, a VRBPAC temporary voting member from Coppet, Switzerland, said waiting for more data as the studies continue is not likely to change the situation.
“I’d feel a bit more comfortable in doing a detailed safety follow-up post-market,” he said. “I don’t think a second season of data is going to help us. I’m not sure how that will give us more data on a GBS signal. This was a study of [about] 30,000 people, so I’m not sure where that data would come from except in a post-marketing setting.”
In the GlaxoSmithKline trials, there was “one death due to acute disseminated encephalomyelitis (also reported as a potential immune-mediated disease) [that] occurred in a participant 22 days after receiving concomitant RSVPreF3-AS01E and seasonal influenza (Fluarix Quadrivalent; GlaxoSmithKline),” the FDA said in the background paper. “[The] FDA considered the event to be possibly related to flu vaccination or RSVPreF3- AS01E vaccination,” adding “A 71-year-old male developed shaking and shivering and was hospitalized and diagnosed with acute disseminated encephalomyelitis seven days from the co-administration of the study vaccines. The participant died 22 days from the co-administration of the study vaccines.”
That case raised the question of whether there should be a specific message not to administer the flu shot and RSV vaccines together, although this has become a common practice with COVID-19 vaccines. That issue remains to be sorted out, but the bottom line is that the two vaccines were approved to move ahead in the review and regulatory process.
If they are licensed — and the safety concerns resolved — thousands of annual deaths as the result of RSV infection in the elderly could be prevented.
- National Foundation for Infectious Diseases. Call to action: Reducing the burden of RSV across the lifespan. Published January 2022. https://www.nfid.org/wp-content/uploads/2022/04/NFID-RSV-Call-to-Action.pdf
- Kwon YS, Park SH, Kim MA, et al. Risk of mortality associated with respiratory syncytial virus and influenza infection in adults. BMC Infect Dis 2017;17:785.
