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
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
- 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
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
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
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.