Vaccines With Live Attenuated Virus May Face Greater Post-Marketing, Manufacturing Requirements

FDA advisory committee on May 7 will consider Porcine circovirus 1 found in GlaxoSmithKline's Rotarix as well as "adventitious" material found in two other vaccines.

Live attenuated virus vaccines may face additional post-marketing and manufacturing requirements after discovery of porcine circovirus 1 DNA sequences in GlaxoSmithKline's Rotarix rotavirus vaccine. FDA's Vaccines and Related Biological Products Advisory Committee will offer the agency advice on the issue on May 7.

The discovery of PCV1 in the product, announced by Eric Delwart of the University of California San Francisco in March, was quickly confirmed by FDA and GSK and led the agency to call for a temporary suspension in the vaccine's distribution, despite the fact that PCV1 poses no known risk of disease to the pigs it is found in, nor to human beings or any other animals, and may not even be able to reproduce in human cells (Also see "FDA Urges Suspension Of Glaxo's Rotarix Vaccine After PCV-1 Virus Is Detected" - Pink Sheet, 22 Mar, 2010.).

FDA's recommendation to doctors that they suspend use of the product has been criticized by some as overstepping its authority, but the agency argues that it is on firm legal footing and needs such enforcement flexibility to respond to emerging safety issues (see (Also see "Rotarix Response Illustrates FDA "Flexible" Approach To Meeting Public Health Goals" - Pink Sheet, 5 May, 2010.) ).

Three Vaccines With "Adventitious Viruses"

Whatever regulatory steps FDA decides to take, the moves will likely impact all live attenuated vaccines. At the time of the Rotarix suspension, FDA said that it had not found PCV1 in Merck's rotavirus vaccine RotaTeq , and the agency recommended that it be used instead.

But a subsequent study in the Journal of Virology lead authored by Delwart's colleague Joseph Victoria, found "adventitious viruses" in three of the eight live attenuated vaccines that were screened using "metagenomics and a pan-microbial microarray."

The researchers found Rotateq contained a single 276 nucleotide read with 96 percent identity to the simian retrovirus (SRV) genome and Merck's measles vaccine Attenuvax contained four reads covering 700 nucleotides of the avian leukosis virus (ALV) genome. Rotarix contained 6344 reads with 98 percent identity to pig circovirus 1 (PCV1), covering the complete circular genome.

The Rotatrix finding was the most concerning, but "recent testing by GSK indicated that PCV1 was also present in the early lots of Rotarix used in the extensive clinical trials that demonstrated the safety and efficacy of this vaccine," the authors note. "These trials indicate a lack of detectable pathogenic effects from PCV1 DNA on vaccinees."

Stronger Testing A Near Certainty

The article concludes by calling for more testing while stressing vaccine safety and efficacy. "The use of viral metagenomics and microarrays tests therefore seems warranted for the surveillance of products that are derived from cell cultures, plasma pools, or other biological sources and which may contain and transmit adventitious viruses. ... Given that live attenuated viral vaccines are safe, effective, and relatively inexpensive their use against human and animal pathogens should be encouraged."

Options for FDA to respond to the PCV1 concerns would be to beef up its recent final guidance on "Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications," released at the beginning of March (Also see "Experts Explore Ways to Strengthen Protection from Viral Contamination" - Pink Sheet, 1 Mar, 2010.).

"The power of the new methodology that was used to detect the PCV1 sequence suggests that such technologies may uncover the presence of adventitious agents that might not be detected with current methods," FDA notes. "Implementing routine use of such methods has benefits as well as challenges and risks."

The agency could also require sponsors of live attenuated vaccines to conduct more expansive - and thus expensive - post-marketing studies.

GSK and FDA researchers will give the committee their most recent findings and discuss current investigations into "whether the PCV1 DNA is particle associated, whether infectious PCV1 virus is present in the vaccine, and whether PCV1 is capable of replication in Vero cells or other mammalian cells, including human cell lines," FDA said.

"In addition, the committee will be informed of follow-up studies by GSK that are underway to assess the possibility of PCV1 replication in vaccine recipients by testing of stool and sera samples pre- and post-vaccination. Finally, an update on post-marketing safety data of Rotarix since licensure will be provided. [The panel] will be asked to discuss the significance of the most recent findings of PCV1 in Rotarix vaccine, the implications of the data for continued use of Rotarix, and the need for any additional experiments or data."

- Martin Berman-Gorvine ([email protected])