19 Apr 2016

On the track of universal influenza vaccine

Almost every winter the seasonal flu is back and every year a new vaccine has to be designed. There are several forms of Influenza viruses in which mutations can occur, changing the antigenic signature at their surface: thus, despite the herd immunity induced by natural infection and vaccination, the immune system of individuals returns to a "naïve state" from one year to another. Influenza then continues to cause epidemics or pandemics with important morbidity and mortality. The strategy to develop a new vaccine every year is to use the strain of the previous years, hoping that the upcoming one will not be so different. Subsequently, the vaccine is efficient some years, less efficient some other years. To counteract this limitation, recent biomedical research has shown the interesting potential of broadly neutralizing antibodies as immunotherapy to prevent infection. In a paper published on 7 March 2016 in Scientific Reports, Sophie Valkenburg (principal investigator at HKU-Pasteur Research Pole) and co-workers describe the engineering of a HA mini-stem used as a vaccine to elicit broad and cross-group protection against influenza viruses. The study was conducted in collaboration with the Centre of Influenza Research (School of Public Health, HKU), the Molecular Biophysics Unit (Indian Institute of Science, Bangalore) and the Viral Pseudotype Unit (School of Pharmacy, University of Kent).

Full-length H5 HA sequence colored based on Q-score (left) and the H5 mini stem trimer (right). From Valkenburg and al., 2016.

HA, or hemagglutinin, is an antigenic glycoprotein expressed on the envelope of influenza viruses and involved in the binding of virus to the membrane of the cell being infected and the fusion of the viral envelope with the endosome membrane. It is composed of 2 domains, the HA head and the HA stem. Many current influenza vaccines target the HA head domain, but the antigenic drift and shift that affect this domain tend to make obsolete the antibody response they elicit. On the contrary, the HA stem domain is more conserved across HA subtypes and offers a larger proportion of target sites for broadly neutralizing antibodies. In this study, the research team developed and tested in mice a new H5-based HA stem immunogen designed from the influenza A H5N1 virus. It consists of a mini protein (1/4 of the full length HA) formed by 3 stem-derived fragments of H5 HA, mimicking the prefusion conformation and concentrating the conserved epitope of known broadly neutralizing antibodies. Vaccinations with this HA mini-stem successfully elicited high affinity stem-specific antibodies and conferred efficient protection against lethal heterologous influenza A viruses challenges. The team has demonstrated for the first time the in vivo protective potential of a vaccine designed from group 1 influenza virus against both group 1 (H5N1 and H1N1) and group 2 (H3N2) viruses. The antibody mediated vaccine protection has to be further investigated to determine if the HA stem-specific antibodies act by interfering with the virus life cycle during entry, fusion, replication, or by recruiting host immunity via antibody-dependent cellular cytotoxicity (ADCC) or complement activation. Nonetheless, the mini-stem protein vaccine being purified from E. coli it presents the potential for a rapid and large production. It is furthermore physically and chemically stable: transport and storage would not require any cold-chain, facilitating an easy deployment. This study therefore provides a promising strategic step on the way to "universal" influenza vaccine development.

The paper:

Valkenburg SA, Mallajosyula VV, Li OT, Chin AW, Carnell G, Temperton N, Varadarajan R, Poon LL (2016) Stalking influenza by vaccination with pre-fusion headless HA mini-stem. Sci Rep 6:22666