Report of meeting on the development of influenza vaccines with broad spectrum and long-lasting immune responses, February 2004
The immunogenicity of currently available influenza vaccines – the inactivated influenza vaccine (IIV) and the live attenuated influenza vaccine (LAIV) – is measured by the level of antibodies raised against the two major viral surface glycoproteins, haemagglutinin (HA) and neuraminidase (NA) in serum and nasal secretions.
Because the antigenicity of these two viral proteins is constantly changing, the influenza vaccines are updated every year to contain the HA and NA influenza antigens currently circulating. When the vaccines contain antigens that are well matched with those in the circulating viral strains, they are very effective in preventing influenza in the majority of the population.
However, when those antigens are not well matched, the protection that follows vaccination is reduced.
Because the manufacturing and distribution process takes months, vaccine strains must be selected many months in advance of the influenza season to provide sufficient time to prepare and distribute the vaccine, a requirement that does not allow for the inclusion in the vaccine of viral strains that are identified too late to include in the manufacturing process. Other limitations of current vaccines include recommendations for yearly administration – a recommendation that will be hard to implement in industrialized countries, and even more difficult for developing countries – as well as their reduced protection in the elderly, the population at highest risk for influenza-related morbidity and mortality.
On 26–27 February 2004, the World Health Organization held a meeting on the “Development of influenza vaccines with broad spectrum and long-lasting immune responses” at its headquarters in Geneva, Switzerland. The main goal of this meeting was to examine available data and identify critical scientific issues and gaps in knowledge that need to be addressed to accelerate the development of new influenza vaccines capable of inducing broad spectrum and long-lasting immunity. Such vaccines would need to induce cross-protective immune responses against divergent influenza viruses and be acceptable for use in developing countries.
This is an important and timely initiative, especially in light of the current avian influenza outbreak in Asia and the serious concerns from international health authorities that one of the influenza viruses, newly emerged from the animal reservoir, might gain the ability to spread between humans and result in a pandemic. An influenza vaccine with a wide breadth of protection could protect against antigenically variant influenza viruses within a subtype; it could also protect the population, at least partially, from the antigenically novel viruses that cause pandemics. The components of such a vaccine would not need to be updated yearly because they would protect against virus strains not perfectly matched with the vaccine, making the manufacturing process more flexible and less time constrained. The availability of vaccines that protect against a broad spectrum of influenza virus and that induce a long-lasting immunity would permit the current yearly vaccination strategy to be revised to a schedule that is more feasible to implement in developing countries. Finally, a broad spectrum influenza vaccine might provide increased efficacy in the elderly.
Scientists from around the world presented a variety of options for enhancing the broad spectrum and long-lasting immune responses to vaccines. Initial presentations focused on general principles and problems to be addressed in the development of new and improved vaccines. The role of antihaemagglutinin (anti-HA) antibodies was reviewed, and the value of anti-HA antibodies as a surrogate for assessing significance of antigenic variation was discussed. The existence of heterotypic immunity to infection, with variants related to the vaccine virus, was emphasized and it was noted that increasing doses of HA correlate with increasing magnitude, duration and cross-reactivity of anti-HA immunity. The roles of immunity to NA and of anti-NA antibody in reducing the intensity and preventing infection were noted. The slower rate of antigenic variation of the NA, in combination with the established role of the level of anti-HA antibody in immunity, indicate a need to focus on induction of optimal antibody responses to these two antigens for the contribution they can make to an increased duration of immunity to antigenic variants within a subtype. A role for cytotoxic lymphocytes (CTL) and anti-HA and NA antibody in reducing the intensity and duration of viral shedding was considered. The role of M1, NP, and possibly other invariant antigens in induction of CTL responses was noted, as well as the potential of antibody to the invariant M2 protein. The importance of these invariant antigens in vaccines that could convey long-lasting immunity and immunity to pandemic viruses with novel HA and NA antigens, but antigenically conserved NP, M1, and M2 proteins, was provided as support for pursuing vaccine approaches that optimize responses to these conserved antigens.
The deficiencies of current inactivated influenza vaccines were reviewed. Among the deficiencies highlighted were the dependence on eggs and the difficult selection, manufacturing, formulation, testing, and distribution process. Furthermore, immunogenicity is relatively low for young children and the elderly, annual vaccination is recommended, vaccine is given parenterally, and protection is less than desired.
To combat many of the disadvantages of current vaccines and to identify options for improvement, the potential for mucosal delivery was discussed. Intranasal administration seems promising because administration of antigen to the mucosa is required for optimal IgA antibody responses and because the route can stimulate both mucosal and systemic immune responses. A mucosal delivery method may facilitate use of vaccine, particularly in developing countries. Evidence for greater heterotypic immunity of IgA antibody and for vaccines given by the nasal route was presented. The potential value for aerosol vaccination that would deliver vaccine to both the upper and lower respiratory tracts was discussed but the numerous hurdles to be surmounted for any acceptable method, including an optimal delivery system, concerns for inducing tolerance, a proper balance of IgA and IgG antibodies, and the need for adjuvants for optimising responses were emphasized.
Mucosal delivery took a recent setback with regulatory withdrawal of an approved intranasally-administered influenza vaccine containing virosomes and an E. coli enterotoxin because its use was associated with an increased risk of Bell’s Palsy. Nevertheless, the potential value of a mucosal delivery method is sufficient reason to continue study of this approach for vaccine delivery.
A variety of adjuvants is available for improving immune responses to vaccine and some of them were considered. An overview presentation identified the types and classes of adjuvants and emphasized that the choice of adjuvant depends on the proposed antigen, the type of immune response required and the target population. Virosomal vaccines containing IL–2 or CpG as an adjuvant have induced enhanced immune responses in clinical trials. In mice, cationic liposomes containing antigens are highly immunogenic without added adjuvants. ISCOMS can induce TH1 and TH2 responses and have induced long-lasting immunity and increased immune responses in both young and elderly populations.
Vaccines that specifically target conserved viral proteins were presented. Immunization with the M2 protein has induced homotypic and heterotypic immunity to infection of antigenic variants within a subtype, as well as to different influenza A subtypes. DNA vaccines inducing responses against the surface antigens induce homologous protection in animal models while DNA vaccines against conserved internal proteins (NP, M1) induce broad heterotypic immunity that includes influenza A viruses of a different subtype.
Influenza virus infection can induce both broad spectrum and long-lasting immunity against reinfection with an influenza virus within a subtype; this suggests that live attenuated influenza vaccines (LAIV) could theoretically be able to do this. In mice, ferrets and humans, LAIV have induced potent prevention against both matched and antigenically drifted viruses. Children, in particular, appear to benefit from LAIV but evidence for superiority over inactivated vaccines for adults is mixed.
Guidance in the use of animal models for vaccine development was presented. A sequence of models used at one site is mice, followed by ferrets and possibly non-human primates, before proceeding to clinical trials in humans.
A number of regulatory issues relating to new vaccines were cited. As new vaccines aimed at inducing specific immune responses are developed there will be a need for convincing data for regulatory authorities a) on new correlates of immunity and b) that demonstrate that cross-reactive and long-lasting immunity is induced. Efficacy studies in humans that provide this information are likely to be required for licensing in both Europe and the United States of America. For these developments, it will be necessary to establish new reagents and guidelines for their use. In so doing, it is important that international harmonization of regulatory requirements be promoted.
A final item emphasized is the important role that the WHO must play in facilitating international cooperation in the development of new and different vaccines and in promoting an understanding of the importance of influenza and the need for vaccination in all countries, including developing countries. Recommendations from meeting participants and abstracts of presentations are included below.