WASHINGTON — Methods are now available to produce influenza virus vaccines in a greater number of doses and with more up-to-date coverage of relevant strains than what is currently available, Peter Palese, Ph.D., said at a biodefense research meeting sponsored by the American Society for Microbiology.
In most instances, these methods can be applied to both killed (inactivated) and live (attenuated) vaccines, said Dr. Palese, chair of microbiology at Mount Sinai Medical Center, New York.
Viruses in killed vaccines are grown in embryonated eggs, purified, inactivated with formaldehyde, and usually then treated with a detergent to make the vaccine less pyrogenic. The recently approved live vaccines are grown in tissue culture at a lower temperature (25° C) and in embryonated eggs. This makes the virus temperature-sensitive and attenuated, limiting the virus to a few replication cycles in the upper respiratory tract.
New adjuvants should help reduce the amount of antigenic viral material in each vaccine dose that is needed to induce protective immunity, he said. With adjuvants, the antigenic mass in each dose could be reduced to anywhere from a fifth to a tenth of its current amount. Alum is the only adjuvant approved by the Food and Drug Administration for use in combination with some vaccines.
“This is an area where we really have to improve,” he said.
Each February, the FDA decides which strains should be included in vaccines for the next influenza season. Only the viruses that are circulating until the end of January can be considered in the decision. The FDA would make better decisions about which influenza isolates should be included in the vaccine if the decision could be delayed until May or June, Dr. Palese said.
Vaccines for the 2005–2006 season were trivalent with surface antigens from an influenza A H3N2 isolate from 2004, an older influenza A H1N1 isolate from 1999, and an influenza B isolate from 2002. One or two of the three components changes each flu season, Dr. Palese noted.
A new technique may let researchers adjust the viral antigens in vaccines and produce vaccines more quickly. It would work by inserting a combination of DNA copies of specific genes from a laboratory viral strain and genes for the hemagglutinin and neuraminidase antigens on currently circulating viruses into cells in a tissue culture. The resulting recombinant seed viruses could then be generated within 1 to 2 weeks for distribution to manufacturers for annual vaccine production.
This process allows more time to select the appropriate antigenic seed strains, he said.
Vaccine developers also may be able to use this process to engineer the influenza virus genome to express an altered version of nonstructural protein 1 (NS1). NS1 normally inhibits the interferon response of a host cell; viruses that lack NS1 cannot block interferon and, as a result, cannot replicate. Viruses with a truncated version of NS1 are still able to replicate, although not as easily as those with normal NS1, because the truncated protein induces an interferon response from the host cell. Viruses with truncated NS1 are attenuated and have been shown to immunize mice against challenges with high doses of active virus.
The viruses with truncated NS1 are highly immunogenic because interferon acts as an adjuvant by enhancing the production of immunoglobulins and contributing to the activation of dendritic cells required for antigen presentation. The robust immune response to these viruses could make it possible to scale down the amount of infectious agents in each dose by several orders of magnitude; many more doses could be manufactured in this way, Dr. Palese said.