Scientific barriers to developing vaccines against avian influenza viruses

The increasing number of reports of direct transmission of avian influenza viruses to humans in the past few years and the ongoing outbreak of H5N1 influenza virus infections in birds and humans highlight the pandemic threat posed by avian influenza viruses.Although vaccination is the key strategy for the prevention of severe illness and death from pandemic influenza viruses and despite the long-term experience with vaccines against human influenza viruses, researchers face several obstacles in developing successful vaccines against avian influenza viruses.The haemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza viruses are the main targets of the protective immune response. Licensed influenza virus vaccines are designed to induce HA-specific antibody responses to protect the host from infection. However, the presence of 16 subtypes of HA and 9 subtypes of NA glycoproteins among avian influenza viruses and the genetic and antigenic diversity among each subtype in nature present several unique challenges for the generation of broadly cross-protective vaccines.Inactivated virus and live attenuated virus vaccines against pandemic influenza are being developed on the basis of plasmid-based reverse-genetics technology. Vaccines based on various other platforms, including live virus vectors and DNA vaccines, are also being developed and show promise in preclinical studies.The available data indicate that inactivated avian influenza virus vaccines are poorly immunogenic and require a high concentration of HA glycoprotein or co-administration with an adjuvant to achieve the desired antibody response in humans. The biological basis for the poor immunogenicity of avian HA glycoproteins is not well understood.Assays to measure the immune response to avian influenza viruses, in particular cell-mediated immune responses, are not available and the immune correlates of protection are not well understood. The choice of assay(s) for assessment of the immune response to pandemic influenza vaccines is a practical challenge in the evaluation of candidate vaccines.As it is difficult to predict which avian influenza virus will cross the species barrier and cause a future pandemic, a library of candidate vaccines of different subtypes must be generated and evaluated in animal models and humans.Although an ideal vaccine would prevent infection, a more realistic goal for a pandemic influenza vaccine might be to prevent severe illness and death.