More data needed before cell-based influenza vaccine considered for approval

Data from clinical trials of an investigational influenza vaccine that may potentially reduce manufacturing time were insufficient to garner support from the FDA’s Vaccines and Related Biologicals Advisory Committee today.

The investigational vaccine (Flublok, Protein Sciences) is a seasonal trivalent formulation, but is produced using a different process than the five currently licensed influenza vaccines in that virus is grown in cells instead of eggs.

The process relies on a baculovirus expression system, according to the manufacturers, who produced the vaccine by growing influenza virus in Spodoptera frugiperda insect cells, yielding recombinant influenza hemagluttinin antigens from influenza A H1, H3 and influenza B strains.

Manufacturing time from when a new virus is identified to completed vaccine product could be as short as two months using the cell-based approach, according to Manon Cox, PhD, chief operating officer at Protein Sciences, and production can be increased relatively quickly without the necessity of specially grown eggs.

“It would have certainly been helpful to have this vaccine available this fall,” Infectious Disease News Chief Medical Editor Theodore Eickhoff, MD, said at the meeting, adding that this process “offers a huge advantage over other trivalent influenza vaccines and is a breakthrough for the United States.”

Despite this, Eickhoff voted no in a six-to-five decision that available data did not support the vaccine’s effectiveness in adults aged 50 to 64 years, and no in nine-to-two decision that data did not support effectiveness in adults aged 65 and older.

"The numbers of subjects studied in those two older groups were, in my judgement, simply too small to make an informed decision," Eickhoff said.

Researchers were unable to draw meaningful conclusions from two separate safety and efficacy trials involving participants in these two age groups due to small case numbers and wide confidence intervals that resulted from mismatched vaccine and circulating influenza strains.

A phase-3 trial involving adults aged 18 to 49 was the only trial out of the four conducted that was sufficiently powered to test a formal null hypothesis of a clinical endpoint, and demonstrated a 44.8% vaccine efficacy against any influenza virus strain regardless of antigenic match (lower bound 95% CI: 24.4%).

Despite analyses of a safety database that consisted of 3,233 participants that indicated a similar frequency of adverse events among Flublok recipients compared with licensed influenza vaccine recipients, committee members voted 6-to-5 that the available safety data were insufficient. The vote came after some expressed concerns about a possible vaccine-related episode of pleuropericarditis in a 47-year-old man and an episode of vaccine related vasovagal syncope in a 57-year-old man.

“It’s not my sense that there’s a proven negative effect that would trump the benefits of this vaccine, but there is a significant signal with rare and serious adverse events that can’t be ruled out by the sample size we have,” said Thomas Flemming, PhD,committee member and professor of biostatistics at the University of Washington in Seattle.

Committee members called for a larger prelicensure study for patients aged 50 and older, a better safety database for patients aged 65 and older, and analyses of the relationship between repeat annual revaccinations and hypersensitivity. — by Nicole Blazek