Efficient vaccine against pandemic influenza: combining DNA vaccination and targeted delivery to MHC class II molecules

Abstract

There are two major limitations to vaccine preparedness in the event of devastating influenza pandemics: the time needed to generate a vaccine and rapid generation of sufficient amounts. DNA vaccination could represent a solution to these problems, but efficacy needs to be enhanced. In a separate line of research, it has been established that targeting of vaccine molecules to antigen-presenting cells enhances immune responses. We have combined the two principles by constructing DNA vaccines that encode bivalent fusion proteins; these target hemagglutinin to MHC class II molecules on antigen-presenting cells. Such DNA vaccines rapidly induce hemagglutinin-specific antibodies and T cell responses in immunized mice. Responses are long-lasting and protect mice against challenge with influenza virus. In a pandemic situation, targeted DNA vaccines could be produced and tested within a month. The novel DNA vaccines could represent a solution to pandemic preparedness in the advent of novel influenza pandemics.

Keywords:

• antibodies
• APC targeting
• DNA vaccine
• influenza
• MHC II molecules
• vaccine

Financial & competing interests disclosure

The authors were supported by funding from K.G Jebsen Foundation, University of Oslo, the Helse Sør-Øst Regional Health Authority and the Research Counsil of Norway. G Grødeland is Inventor on patent applications filed on the Vaccibody vaccine molecules by the TTO offices of the University of Oslo and Oslo University Hospital, according to institutional rules. B Bogen is Inventor on patent applications filed on the Vaccibody vaccine molecules by the TTO offices of the University of Oslo and Oslo University Hospital, according to institutional rules. B Bogen is also head of the scientific panel and holds shares in the Vaccibody Co. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• For pandemic preparedness, novel vaccine formats that allow rapid production on demand, and that rapidly induce protective immune responses in vaccinated individuals, should be developed.

• DNA vaccines can be rapidly engineered, easily produced at low cost and are temperature stable.

• Unfortunately, DNA vaccines are generally hampered by low immunogenicity in larger animals and humans.

• Previously, it has been shown that targeting of protein antigen (Ag) to antigen-presenting cells (APC) increases immunogenicity.

• Here, we show that a combination of: DNA vaccination and Ag targeting to APC results in enhanced immune responses.

• This (DNA vaccination and Ag targeting to APC) is achieved by constructing vaccine plasmids that encode secreted fusion proteins with an ability to bind APC, thus loading APC with Ag.

• The vaccine format (Vaccibody) bivalently displays Ags and targeting units. The vaccine format allows expression of large Ags.

• Specifically, a DNA vaccine encoding a vaccine protein that incorporates influenza hemagglutinin, and targets MHC class II molecules on APC, substantially increases antibody and T cell responses in mice.

• A single DNA vaccination protects mice against a challenge with influenza virus as early as 8 days after vaccination.

• A single vaccination with the MHC II-targeted hemagglutinin induces long-lasting protection (>10 months).

• In addition to pandemic preparedness, the vaccine platform might be useful for development of vaccines with an ability to induce broadly protective responses against influenza virus (universal influenza vaccines).

• The vaccine platform might be easily adapted to Ags from various infectious pathogens.

Notes