Background, Objectives & Strategy

Background

Seasonal influenza occurs all over the world with an annual global attack rate estimated at 5 – 10% in adults and 20 – 30% in children, and causes about three to five million cases of severe illness and 250,000 to 500,000 deaths.  The most effective way to prevent the disease or severe outcome is vaccination.  However, as influenza viruses can accumulate three-four amino acids substitutions per year and frequently change antigenically to escape population immunity, current vaccines only offer limited protection against new variants and need to be administered annually.  As a consequence, persistent monitoring and selection of viruses, production, formulation and conduct of clinical trials to evaluate safety and immunogenicity of the new vaccines are necessary every year.  A major shortcoming is therefore that the relatively long production time results in a vaccine that does not always have a sufficient antigenic match with the epidemic strain.  

A significant advance in human infectious disease research would be the development of a new generation influenza vaccine that stimulates production of a robust, broadly neutralising antibody (bnAb) response, not only to drifted variants of seasonal influenza viruses, but preferably also to different influenza A virus subtypes that regularly infect birds and mammals and may be the basis of future influenza pandemics.  Thus, the development of a “universal” influenza vaccine that can provide broad coverage against different strains within a subtype or even across subtypes has become a key public health priority in both industrialised and low and middle income countries.

In order to address the problem of antigenic drift and annual vaccine reformulation, the EDUFLUVAC consortium proposes to develop a combinatorial immunisation strategy to educate the immune system towards cross recognition and coverage against antigenic drift in seasonal influenza virus exposure.

Objectives

To achieve this objective, EDUFLUVAC aims at developing a novel influenza vaccine candidate encompassing a combination of multiple influenza haemagglutinin (HA) or neuraminidase (NA) antigenic variants within a single (sub)type.  This vaccine concept, using the proven, modern technology of baculovirus-derived virus-like particles (VLPs), is expected to elicit a broad neutralising immunity that will confer longer-lasting and broader protection against multiple strains of influenza virus.

Strategy

The mechanism underlying the broadening of antibody responses is the increased relative concentration of common epitopes diluting out strain specific epitopes.  This will be achieved by testing the ability of a combination of historic HA variants to protect against a variety of modern isolates.  The overall strategy of the EDUFLUVAC project is to:

 

  1. Select HA and NA antigens representing antigenic drift within the H1, H3 and B (sub)types.
  2. Generate baculovirus vectors for expression of one or more HAs or NAs.
  3. Produce VLPs for immunological studies.
  4. Develop in process and final product development assays for product characterisation.
  5. Evaluate the immunogenicity and efficacy of VLPs in mice and explore the potential capacity of adjuvants to enhance the magnitude and longevity of the immune response.
  6. Evaluate the immunogenicity and efficacy of VLPs in ferrets and NHPs.
  7. Develop a complete Investigational Medicinal Product Dossier (IMPD) ready for transfer into cGMP VLPs clinical manufacturing for early phase clinical testing.