Third meeting on influenza vaccines that induce broad spectrum and long-lasting immune responses, 3-4 December 2007, WHO HQ Geneva
On 3-4 December 2007, the Initiative for Vaccine Research (IVR) of the World Health Organization convened the third meeting on “Influenza vaccines that induce broad spectrum and long-lasting immune responses” as a follow-up to two previous meetings held on February 2004 and December 2005, respectively. The objectives of the meeting were to review the current status of research in the area of influenza vaccine strategies targeting vaccines which are able to induce broad spectrum and/or long-lasting immune responses and to provide cross-protection against divergent influenza virus strains. These new vaccines would overcome many of the problems currently we face with the seasonal vaccination strategy, based on annual interventions. They also would better meet the needs of developing countries and could contribute significantly to the control of an eventual influenza pandemic.
Considerable progress was made in the development of new adjuvants. At least, three manufacturers presented information on remarkable adjuvant activity of oil-in water emulsions. Supplementation of the split and subunit influenza vaccines with MF59 (Novartis), AS03 (GlaxoSmithKline Biologicals) or AF03 (Sanofi Pasteur) resulted in considerable improvement of immunogenicity, allowing very significant antigen-sparing and inducing broad-spectrum antibodies. New adjuvants, often based on TLR ligands, are being developed that can be added to a subunit vaccine or, better, covalently conjugated to the antigen. These new adjuvants greatly enhance the antibody response to subunit recombinant vaccines and probably open the way to the development of single-dose pandemic vaccines. Most of these new approaches, however, have yet to be tested outside of the mouse model.
The mechanism of broad-spectrum cross-protection observed after natural influenza virus infection can be explained, at least in part, by the production of secretory immunoglobulin A (SIgA), which, due to their polymeric nature, strongly cross-react with different influenza virus strains. One way to broaden and increase influenza vaccine protection would therefore be through the induction of mucosal SIgAs. The intranasal and the sub-lingual applications which elicit both mucosal and systemic immune responses were discussed at the meeting. Intradermal (ID) vaccination was also addressed. It was shown that the ID delivered vaccine at 0.1 mL dose induced similar levels of hemagglutination inhibition (HAI) antibodies to those elicited by the IM delivered vaccine at 0.5 mL dose, and that these antibodies cross-reacted with variant virus strains to similar degrees. These results are in line with previous observations that the ID route could allow substantial antigen sparing of the conventional inactivated influenza vaccine.
A review of the data on live attenuated influenza vaccines (LAIV) demonstrated a high level of protection including against drift variants, evidence of herd immunity through the vaccination of children and the potential for early, possibly interferon-based, protection shortly after vaccine administration. There is some evidence of greater protection than protection induced by inactivated vaccines; however, head-to-head comparisons are limited. Also, duration of protection by LAIVs and characterization of the immune memory they induce still need to be determined. Data on a different type of live attenuated influenza virus vaccine, based on a non replicative deletion mutant, was presented and discussed as well.
The meeting reviewed advantages and disadvantages of influenza vaccines based on conserved influenza virus proteins such as the NP and M2 proteins. These vaccines could be stockpiled as "pandemic" vaccines and might provide protective immunity prior to availability of HA-based, strain-matched vaccines; they also might be able to replace strain-matched seasonal vaccines and suppress the requirement for annual immunization. However, correlates of protection for these vaccines obviously are not the same as for HA vaccines and new standards and correlates of protection should be developed. The fact was emphasized that the only protection efficacy data available at this time with vaccines based on conserved influenza viral proteins have been obtained in animal models: their translation to protection in humans is missing and will be difficult to make. In the absence of known correlates of protection, it is most probable that vaccines based on conserved proteins will need to be directly tested in efficacy trials in human volunteers.
Within the session on new technologies for the development of influenza vaccines data were presented and discussed on the following approaches: virus–like particle vaccines, live recombinant influenza virus vaccines based on human adenovirus, modified vaccines with Ankara and Newcastle disease virus as vectors, as well as plant derived vaccines. Almost nothing is known at this time of the possible protective efficacy of these new types of vaccines in humans and much more has to be learnt on their immunogenicity and principal characteristics before they can be fully evaluated.
The meeting developed recommendations on further research in the area of cross-protective influenza vaccines.