Research ongoing to find improved influenza vaccine

BOSTON — The way in which influenza vaccines are made may be changing in the near future, based on new cutting-edge research presented here at the 49th Annual Meeting of the Infectious Diseases Society of America.

Wendy A. Keitel, MD, who is an associate professor in the department of molecular virology and microbiology at Baylor College of Medicine, said physicians have long voiced a concern about the efficacy and effectiveness of influenza vaccines.

During her presentation, she discussed the current and future strategies for improving influenza vaccine immunogenicity. These include quadrivalent vaccines, cell culture-grown vaccines and recombinant hemagglutinin (HA) vaccines.

“The major interest in these vaccines is the antibody to the HA because that has been the primary mediator of immunity against influenza,” Keitel said, adding that for inactivated vaccines, serum antibody seems to be the most predictive of protection against infection, whereas for live-attenuated vaccines, this relationship is less clear.

“There’s a more important component of mucosal immunity involved,” she said.

Regarding neuraminidase vaccines, “many of us believe there is promise in focusing more on looking at antigen dosing for neuraminidase and its contribution to prevention and infection,” Keitel said.

Possible solutions to the limitations of the current influenza vaccines include:

• Increasing the dose of antigen;
• Intradermal immunization;
• Quadrivalent vaccines; and
• Cell culture-based approaches.

The idea of increasing the dose of antigen is not new, Keitel said, “but it just took a little bit of persistence to get the idea to come to fruition.”

Previous research has shown that there is a dose-response for serum antibody responses and injection site reactions, and there is enhanced efficacy among those given high-dose vaccine.

In 1995, Kilbourne and colleagues found that doses of up to 135 mcg HA per strain given intramuscularly were safe and well tolerated but elicited higher rates of injection site reactions. Similar results were observed with a purified neuraminidase vaccine.

A 2008 study by Keitel and colleagues reported that increasing levels of HA significantly augmented serum and nasal wash antibody responses. Enhanced serum antibody responses vs. drifted strains have been observed, she said.

“We do need to wait for the results of trials assessing the efficacy of these higher doses to make sure this approach is sound. For that reason, the ACIP has not made a preference for the high dose vaccine in the elderly,” Keitel said.

In addition, she said intradermal immunization (also known as the Mantoux technique) provides efficient delivery to the dendritic cells.

Separate studies have shown that intradermal immunization with reduced doses of several vaccines elicits similar levels of antibody when compared with full-dose vaccine given intramuscularly. In addition, intradermal immunization using a microinjection system (0.1 mL) appears to elicit superior serum antibody responses vs. intramuscular immunization (0.5 mL) using similar doses of vaccine (15 mcg HA).

A disadvantage of the intradermal vaccine option is the increased frequency of local reactions compared with intramuscular vaccine.

“After looking at the research for a long time, it wasn’t until recently that convincing clinical trials were done to demonstrate that this could be accomplished,” Keitel said.

Quadrivalent vaccines include viruses belonging to two antigenically distinct influenza B lineages that have been circulating in recent years — B/Victoria and B/Yamagata — compared with the current vaccines that contain a single B strain, according to Keitel.

She also said the efficacy of LAIV in young children vs. same lineage, matched B strains equaled 86%; 55% for same lineage but drifted strain; 31% with different lineage and antigenically unrelated strain.

A study of healthy patients aged 18 to 64 years who were randomly assigned to receive one of two trivalent inactivated influenza vaccines containing different B lineages (B1=Brisbane-2009 and B2=Florida-2008) or a quadrivalent inactivated vaccine (QIV) containing both Bs had similar safety profiles.

The antibody responses in the QIV group were noninferior vs. all antigens when compared with the TIVs.

“You had a better immune response against both Bs, and you would expect this to happen,” Keitel said.

As for cell-culture based vaccines, she said there are currently at least 14 viral vaccines produced in cell culture, in contrast to the 95% or more of influenza vaccines that are grown in eggs. Cell culture-derived vaccines appear to be well tolerated and immunogenic-similar to egg-grown TIV.

Several influenza vaccines produced in cell culture have been licensed in the European Union, and the US Department of Health and Human Services is currently supporting development of cell-based production.

“This is to be responsive in the potential need to immunize the whole world against an unfolding pandemic virus,” she said.

Use of recombinant proteins for protection against influenza has been in development for some time, according to Keitel. The desired HA gene is cloned into an insect virus and then infect insect cells.

“These cells are a specially derived clonal cell from SF9 cell culture and express the HA in culture and purify,” she said. “We are re-inventing the wheel with HA vaccines.”

Disclosure: Dr. Keitel receives research support from Novartis.

For more information:

• Keitel W. Symposium 15. Presented at: IDSA 49th Annual Meeting; Oct. 20-13, 2011; Boston.
• Belshe RB. Vaccine. 2007;25:6755-6763.
• Belshe RB. Vaccine. 2010;28:2149-2156.
• Holland D. J Infect Dis. 2008;198:650-658.
• Keitel WA. J Infect Dis. 2008;198:1016-1018.
• Kilbourne ED. Vaccine. 1995;13:1799-1803.
• Perdue ML. Expert Rev Vaccines. 2011;10:1183-1194.

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