FDA Flags Potential Guillain-Barre Risk With RSV Vaccine Candidates

Ahead of a 2-day meeting with FDA's vaccine advisors, reviewers at the agency highlighted a rare but potential risk for Guillain-Barré syndrome with two vaccine candidates for respiratory syncytial virus (RSV).

On Tuesday and Wednesday, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will recommend whether the risk-benefit profile with Pfizer and GSK's vaccine candidates support approval for reducing RSV-related lower respiratory tract infections in adults 60 and up.

Currently, no vaccines exist to protect against RSV infection. According to data from the CDC, an estimated 177,000 older adults in the U.S. were hospitalized due to RSV infections in 2017 alone, and 14,000 died.

In phase III trials, Pfizer and GSK's vaccine candidates demonstrated upwards of 66% efficacy against RSV-related infections involving multiple symptoms.

But with Pfizer's RSV prefusion F protein vaccine (RSVPreF), two cases of Guillain-Barré syndrome were observed at 7 and 8 days following vaccination among the nearly 20,000 participants who received the vaccine. FDA agreed with study investigators that the events were possibly related to the vaccine, according to a briefing document released ahead of the meeting.

Each year in the U.S., roughly 1.5-3.0 cases of Guillain-Barré syndrome occur per 100,000 people age 60 and older.

"Given the higher than background rate of GBS [Guillain-Barré syndrome] observed in the Phase 3 study, FDA will recommend a postmarketing study and enhanced surveillance for further evaluation of GBS and other immune-mediated demyelinating conditions with postmarketing use," wrote FDA staff.

In the case of GSK's RSV prefusion F protein vaccine (RSVPreF3 OA), among the more than 15,000 individuals who received the vaccine in multiple trials, one case of Guillain-Barré syndrome occurred 9 days after vaccination. Again here, the study investigator and FDA considered this to be "related to vaccination." GSK had already planned to include the rare neurological condition as a potential immune-mediated disease (pIMD) risk in its pharmacovigilance plan.

Pfizer RSV Vaccine Candidate

On Tuesday, the primary support to be presented for RSVpreF will come from the phase III RENOIR trial, which included 34,284 participants age 60 and up (mean age 68.3 years) randomized to either a single intramuscular injection dose of vaccine (120 µg) or placebo.

Vaccine efficacy reached 66.7% against two or more lower respiratory tract RSV symptoms (96.66% CI 28.8-85.8) and 85.7% against three or more symptoms (96.66% CI 32.0-98.7), meeting the co-primary endpoints of the study.

"While vaccine efficacy appears to be preserved among participants ≥80 years of age, and among participants with at least one at-risk condition for severe RSV, interpretation is limited by small sample size and low case numbers for these subgroups," noted FDA staff.

Data are not yet available on the durability of the vaccine, or how effective the vaccine is in frail or immunocompromised individuals, or against severe illness, given the limited follow-up duration of the trial.

Other than Guillain-Barré syndrome, safety signals also included atrial fibrillation (10 events in the study group and four with placebo), and an event of hypersensitivity in the vaccine group. Serious adverse events occurred in 2.3% of each group, while deaths occurred in 0.3% of each group, with none considered related to the study intervention.

GSK Vaccine Candidate

On Wednesday, advisors will hear findings from the AReSVi-006 (Adult Respiratory Syncytial Virus) trial as the primary support for GSK's vaccine candidate, RSVPreF3 OA. The study included 24,960 adults age 60 and older (mean 69.5 years) who were randomized 1:1 to the vaccine or placebo.

A single dose yielded a vaccine efficacy of 82.6% against lower respiratory tract illness (96.95% CI 57.9-94.1), meeting the study's primary endpoint, and vaccine efficacy landed at 94.1% against severe RSV illness (95% CI 62.4-99.9).

For the primary endpoint, the vaccine performed similarly across RSV subgroups and age groups:

• RSV A: 84.6%
• RSV B: 80.9%
• Age 60-69 years: 81.0%
• Age 70-79 years: 93.8%

Deaths occurred in 0.4% of the vaccine recipients and 0.5% of those receiving placebo, with none considered to be related to the intervention. FDA noted the following pIMDs as being possibly related to the RSV vaccine: Bell's palsy, pancytopenia, Graves' disease, gout, and psoriasis.

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