Another Investigational Vaccine Fails to Reduce RSV Infections

The latest investigational vaccine to be unsuccessful in targeting respiratory synctial virus (RSV) demonstrated immunogenic activity in older adults — without reducing their rate of infection.

Ann Falsey, MD (pictured), University of Rochester, New York, and colleagues reported results from a phase 2 clinical trial of a candidate vaccine (MED17510) containing the postfusion F protein of the RSV virus. The formulation also contained an adjuvant for the target population of older adults, who can be affected by the illness but have compromised response to vaccines from natural immunosenescence.

The F protein has been used with other RSV candidate vaccines as it is on the viral envelope, mediates viral entry into the host cell, and has previously been shown susceptible to serum neutralizing activity. There has yet to be a successful vaccine candidate against RSV, however. The most effective intervention has been use of monoclonal antibody palivisumab (Synagis), to bind postfusion F protein to prevent RSV disease in infants.

Faley and colleagues reported finding the candidate vaccine did promote an immunogenic response, but did not protect the older adults cohort from illness. The incidence of confirmed RSV illness occurring at least 14 days after dosing was 1.7% and 1.6% in the vaccine and placebo groups, respectively.

"The study appears to have failed because the vaccine did not generate adequate protective antibodies, either because antibodies to posfusion F were not qualitatively appropriately protective or because sufficiently high titres of anti-postfusion F neutralizing antibodies were not generated," researchers wrote.

In accompanying commentary, Joanne Langley, MD, Dalhousie University, Halifax, Nova Scotia, Canada, suggested that there may have been a missed opportunity in evaluating this candidate vaccine, with inherent inconsistencies in the primary efficacy measure of comparing infection rates in those receiving the vaccine or placebo.

"Year to year variation in RSV attack rates makes predicting this outcome measure particularly vexing," Langley wrote. "Protection might have been easier to detect in a different population, such as those with risk factors for severe RSV disease."

Langley's commentary is partially titled “The Work Continues,” and she gives credit to Falsey and colleagues for a study that "advances our understanding of the road ahead for RSV vaccine development in older adults."

The researchers also make this point, suggesting that future developments will be informed by their findings. Failure of the vaccine has “broad implications.”

"Our vaccine contained a potent toll-like receptor-4 agonist in a SE (stable emulsion) and a large quantity of antigen — close to the maximum that could feasibly be included in a vaccine — which suggests creating an improved postfusion F protein-based vaccine will be difficult. Inclusion of an F protein in the prefusion configuration may improve immunogenicity and efficacy," researchers wrote.

Falsey and colleagues also speculate that antibodies to the RSV G protein may be found to be protective, and considered for future development. They note, however, there will be difficulty in matching the highly variable G protein to circulating strains, and speculate that a successful program could involve periodic reformulation and inclusion of more than 1 genotype.

The study, "An Adjuvanted, Postfusion F Protein-Based Vaccine Did Not Prevent Respiratory Syncytial Virus Illness in Older Adults," was published online the Journal of Infectious Diseases last month.