Efficacious Vaccine Formulation System for Prophylactic Control of Influenza Pandemics
Influenza epidemics remain a burden for both human health and national economies, as witnessed by the recent advance of the pathogenic avian H5N1 influenza virus. While the numbers of human deaths in Europe has remained relatively low, the presence of such cases in Turkey demonstrates the danger posed by this virus. The avian H5N1 virus has now been detected in wild birds in numerous European countries, and the PANFLUVAC consortium is committed to creating an efficacious vaccine against this virus, to provide strong protection in a pandemic situation.
The overall aim of PANFLUVAC is to construct vaccine delivery systems for intranasal and parenteral vaccines. New H5N1 vaccines are to be based on well-established virosome technology - proven its worth for efficacious interpandemic vaccines - as well as whole virus vaccines. This will permit comparison of the intranasal virosomal vaccine with the whole virus vaccine. The vaccine potency will be enhanced by novel adjuvants targeting dendritic cells, offering both antigen-sparing potential and immunopotentiation characteristics. Both ISCOMs and lipopeptide adjuvants are already proven immunopotentiators, biosafe for humans. Certain of these have been employed with experimental influenza vaccines which allow the new H5N1 vaccines to be fast-tracked in their development. Accordingly, PANFLUVAC will generate the first H5N1 vaccine within the first 18 months of the project.
The PANFLUVAC project is also designed to facilitate rapid modification of the vaccine in the face of virus drift. Within the preclinical evaluation, the new vaccines will be tested for the degree of heterotypic cross protection they offer. PANFLUVAC offers a generic vaccine development system to provide safe and efficacious vaccines against influenza, fitting in with the European Commission's Working Paper on Community Influenza Pandemic Preparedness and Response Planning.[+] Read More
The avian H5N1 influenza virus is now spreading among the wild bird population in Europe, and infection of humans has already reached the borders of continental Europe. For a truly efficacious vaccine, one must consider the route of virus entry into the host (the respiratory tract), and host requirements for protective immune defences. That is, an ideal vaccine should induce both local (mucosal) and systemic (serum) immunity.
Currently, parenterally administered inactivated influenza vaccine is the best prophylactic control measure. However, parenteral vaccination does not ensure induction of local immunity in the respiratory tract - the route by which the virus infects humans - and from where it transmits to other individuals. Inducing mucosal immunity by vaccination would enhance control of both disease and transmission. Although mucosal immunisation has been studied, no acceptable intranasal vaccine against influenza is yet available. A major problem for the intranasal vaccine has been the adjuvant, which is required for efficient induction of immunity.
The WHO assessment of the risk to human health from the H5N1 avian influenza virus states: 'The disease in humans has no vaccine to confer protection and no specific treatment once illness becomes severe.' The WHO warning that 'outbreaks in birds pose a significant threat to human health', and that H5N1 'has the potential to ignite a global influenza pandemic in humans', has led to an urgent requirement for H5N1 pandemic influenza virus vaccines. The PANFLUVAC vaccines fit this requirement and allow for a rapid response to the entry of H5N1 into Europe, enforcing the WHO recommendation that 'trials of experimental influenza pandemic vaccines for humans be accelerated'.
PANFLUVAC is designed to construct a vaccine delivery and formulation to meet current and future influenza pandemics. The proposed H5N1 vaccine will be prepared with regard to the immediate needs, as identified above by the WHO. In addition, the project will generate the 'mock-up' library of vaccine reagents to meet the permanent threat from pandemic influenza. The overall aim is to construct the efficacious H5N1 vaccine, enhancing the capacity to protect the people of Europe both now and in the future, rather than just in the short term. The rapidly ageing European population, which is particularly vulnerable to influenza complications and influenza-related deaths, is a clear reminder of the need for better interpandemic as well as pandemic vaccines.
The project allows for 'robust scale-up of vaccine production', being coordinated by the leading group in virosomal technology - Crucell (partner 2 CRU). CRU holds the intellectual property rights for the application of ISCOMs for influenza vaccines. To this end, the project employs the latest advances in reverse genetics (partner 3 - National Biological Standards Board) - referred to in the Commission Working Paper (COM(2004)201 final). This allows for novel vaccines to be provided within a short time. Vaccine efficacy will be enhanced through application of novel formulations and adjuvants, in response to the requirement in the call for antigen-sparing strategies and the application of novel immunopotentiating agents. The proposed adjuvants, both current and under development, will provide the formulated vaccine with a potent immunogenicity. Moreover, these selected adjuvants target the dendritic cells, which are critically important for the activation of an efficacious immune response. This allows for the development of more efficacious vaccination and better usage of the vaccine available.
By promoting the vaccine to reach the target organs and cells more efficiently, lower doses of vaccine are required to maintain immunogenic concentrations. This increases the likelihood of manufacturing potential reaching demand, and reduces the risk of adverse side effects due to incorrect interaction with organs. It also responds to the Commission Working Paper (COM(2004)201 final), on development of a safe vaccine.
PANFLUVAC will create an efficacious vaccine inducing potent local and systemic immune responses to protect the host and prevent viral transmission. This is based on virosomal technology, together with a novel lipopeptide adjuvant targeting the critical cells of the immune system - dendritic cells. Consequently, PANFLUVAC will provide a particularly efficacious and safe vaccine against influenza virus (H5N1). In addition, the basis for efficacious intranasal and parenteral vaccines will be established, for future demands.
Considering the evolution of the avian H5N1 influenza virus and the threat it poses for initiating a human pandemic, an efficacious vaccine against this virus is urgently required. Accordingly, the PANFLUVAC project will construct an efficacious vaccine formulation to meet immediate and future needs for controlling influenza epidemics and pandemics. PANFLUVAC will deliver both an efficacious H5N1 vaccine and an inactivated whole virus vaccine within the first 18 months of the project. The vaccine is based on well-proven virosomal technology, together with a novel promising ISCOM and lipopeptide adjuvants. By investigating novel adjuvants, PANFLUVAC will provide the basis for the generation of efficacious and safe vaccines to combat both interpandemic seasonal influenza and influenza pandemics.
Many of the techniques being employed - including the adjuvants, virosomal vaccine delivery system and evaluation strategies - are applicable in a generic manner. The in vitro and ex vivo tests to be employed for immunological correlates of protection can be adapted easily for application to other vaccines. Certain of the formulations are patented, while others developed by the consortium will be subject to patent application. With the involvement of a number of SMEs in the project, patent application and Intellectual Property availability is at a high level. Overall, the main potential applications are the following: