Engineering an intranasal universal influenza vaccine Influenza virus causes serious respiratory illness. Due to the high mutation rate in influenza genes, antigenic drift can create a new strain each year. Consequently there is significant economic burden to monitor virus activity and to create and distribute new influenza vaccines to the public each year. Furthermore, due to gene reassortment, a novel influenza subtype could emerge, which is virulent and has never circulated amongst humans, and could cause a devastating pandemic. It is therefore crucial that unlike current vaccines, more universal vaccination strategies be developed against influenza A that can protect against all influenza A subtypes. The 23 amino acid-long extracellular domain of the viral transmembrane protein M2 (M2e) found on human (h) influenza A viruses has remained highly conserved since the 1918 pandemic; and hM2e is thus considered a good candidate for the development of a universal influenza A vaccine. However, hM2e is poorly immunogenic. We have designed an intranasal delivery system for hM2e. Our studies show that by attaching hM2e to virus-mimicking gold nanoparticles (AuNPs) and by using CpG as a soluble adjuvant (AuNP- hM2e+sCpG vaccine) a broad heterosubtypic protection can be observed in Balb/c mice against human H1N1 and H3N2 influenza A strains, and the highly pathogenic avian influenza strain H5N1. However, the consensus amino acid sequence of M2e in human (h), avian (a), and swine (s) influenza viruses shows variability. Indeed our preliminary study shows that mice vaccinated intranasally by the AuNP-hM2e+sCpG vaccine are only partially protected against a lethal challenge by Anhui/1/2013 (H7N9), which is an avian reassortant virus, and whose M2e sequence has more homology to avian aM2e than hM2e. Amazingly, our vaccine can also induce M2e antibody response in C57BL/6 mice and CD-1 mice (an outbred strain), thus demonstrating an ability to be applicable to a genetically diverse population. We thus hypothesize that a multivalent vaccine based on AuNP?M2e+sCpG and comprising of hM2e, aM2e, and sM2e consensus sequences as antigens can be developed in to a broadly cross-protective, durable and safe influenza A vaccine that is effective in a genetically diverse population.
Our specific aims are: (i) Establish breadth of cross-protection in genetically diverse mouse strains and evaluate long term vaccine protection. (ii) Determine mechanism of immune stimulation by the vaccine. (iii) Determine biodistribution and safety of the vaccine. If successful these studies will provide the efficacy and safety data necessary to support moving the vaccine in to phase-I clinical trials.
This project focuses on the development of a universal influenza A vaccine that can enable protection against all influenza A strains, thus eliminating the need for yearly vaccinations against influenza, and the threat of influenza pandemics. Successful completion of the project may in the long run reduce much morbidity, especially amongst elderly and children.
