Dose Sparing and Increased Immunogenicity for Vaccination Against Pandemic Influenza with Covaccine HT
The risk of a new influenza pandemic is emphasised by a WHO report documenting several hundreds of recent cases of human infection with a new virus strain and approximately 50% mortality. Control or prevention of a pandemic by emergency vaccination depends on availability of products with high efficacy and broad protection. The combination of an effective adjuvant and cell culture technologies for antigen production meets the requirements of a pandemic influenza vaccine.
The consortium of this FluVac project, among them proven and renowned experts in human vaccine development and influenza research, plans to deliver a prototype vaccine with proof-of-concept within 48 months. Optimal doses of inactivated, cell culture-derived whole influenza virus (H5N1) and CoVaccine HT as adjuvant will be tested in pre-clinical and clinical studies. In comparison to the widely used production system in eggs, production in cell culture offers the advantages of immediate and reliable availability of antigen of constant quality and with reduced risk of contamination.
The use of whole virus in a vaccine instead of subunits, is considered to induce broader protective immunity. The novel adjuvant CoVaccine HT has been shown to elicit high humoral and cellular responses against different types of antigens, including inactivated influenza virus, and in different animal species (mice, rats, rabbits, pigs, horses, primates, etc.). It is considered to be a promising candidate for a pandemic influenza vaccine. A Phase I trial, human challenge study and extensive immunological evaluation of the vaccine prototype will provide the information required for further development and registration (Scheme 1).[+] Read More
The impact of an influenza pandemic can be enormous as illustrated by the 'Spanish Flu' from 1918 to 1919 - one of the most dramatic events in human history with 20 to 40 million casualties worldwide. Influenza pandemics were caused by influenza virus A subtypes. Wild birds as the natural hosts can easily spread the virus and infect other animals and humans. Recently, a new highly pathogenic H5N1 strain of avian influenza A virus has become epidemic in birds in Asia and has been transmitted to European and African countries. Mortality rates among infected humans exceeded 50%, which is alarming. This H5N1 virus did not spread between humans, but once an influenza virus acquires the ability to transmit through respiratory droplets from one human to another it could spread within a few months around the world. The consequences of a pandemic outbreak could be enormous as it could disrupt daily life with tremendous social and economic effects and put a large burden on the health care system. High costs of anti-influenza drugs and limited availability thereof, implicates an urgent need for an affordable vaccine for the prevention and control of a pandemic influenza outbreak.
An adjuvant may compensate the shortcomings of the seasonal influenza vaccines for application during a pandemic. Firstly, an adjuvant may reduce considerably that antigen dose required to establish a certain level of immunity. Secondly, it may have a beneficial effect on the type, level and kinetic of the immune response. Thirdly, it may decrease the number of low-/non-responders thereby affording a higher degree of immunity in a susceptible population. Fourthly, it may enhance cross-protection to distinct influenza virus strains. Feasibility studies with CoVaccine HT, a sucrose fatty acid sulphate ester incorporated in a submicron emulsion of squalane-in-water exerted the ability to induce strong humoral and cellular immune responses against a wide range of antigens in various animal species and high efficacy in combination with low antigen dose (Fig. 1).
The combination of these technologies opens unique opportunities for preventing and controlling an influenza pandemic and the knowledge and expertise gained might be applicable to the design of other (types of) vaccines.
The consortium aims at a novel influenza vaccine formulation by combining a novel adjuvant CoVaccine HT and an inactivated, cell culture-derived, whole influenza virus (H5N1). Feasibility studies with the adjuvant indicated that CoVaccine HT is a promising candidate for emergency vaccines to establish high levels of immunity and to compensate for the limited availability of antigen.
The ultimate goal of the FluVac project is to prove safety and efficacy of a CoVaccine HT adjuvanted pandemic whole H5N1 virus vaccine in humans and to gain insight in its performance in animal models. After extensive preclinical evaluations, a vaccine with the optimal composition will be studied in a Phase I clinical trial and subsequently in a human challenge study. In parallel, the vaccines will be investigated in mouse models for neonates and elderly. The ambitious preclinical and clinical development plan addresses all known aspects of protective immunity against influenza.
Successful completion of the FluVac project and subsequent development and registration of the vaccine will have great benefits for the health of the European population. In addition, the project will contribute to the development of a novel generation of adjuvants and of improved vaccines to combat infectious diseases. The consortium is supported by the complementary know-how and technology of individual partners. The participants are renowned international experts in such areas as human (influenza) vaccine development, adjuvant development, neonatal immunity and influenza research i.e. Protherics (United Kingdom), OrganonBiosciences (the Netherlands), Retroscreen (United Kingdom), Landspitali University Hospital (Iceland) and Erasmus Medical Centre (the Netherlands).
A number of defined objectives will be pursued during the proposed project:
The FluVac consortium proposes a novel product for (pre-)pandemic vaccination by combining Protherics' proprietary adjuvant CoVaccine HT with OrganonBiosciences' H5N1 viral antigen produced in cell culture. Upon successful completion of clinical proof-of-concept studies, the consortium will pursue further clinical development.
Currently there are no adjuvanted Influenza vaccines licensed and marketed in the USA. MF59 and virosomes are licensed in Europe for epidemic and Al(OH)3 for pandemic influenza vaccine. The consortium envisages that this project will contribute to the urgent need of improved adjuvants for emergency vaccines. Knowledge and expertise gained will be useful to other types of vaccines.