Progress Toward the Development of a Universal Influenza Vaccine
By Eric Toner, M.D., February 1, 2008
On January 3, 2008, Acambis plc, a British–American vaccine development company, issued a press release announcing positive preliminary results from two studies of its universal influenza vaccine, ACAM-FLU-A™.1
Currently available vaccines for influenza A primarily target specific antigenic sites on the hemagglutinin surface glycoprotein. These sites are constantly changing due to mutation. Therefore, vaccines developed against one influenza A strain may afford limited protection against another strain, even if they are closely related. For this reason, annual flu vaccination is needed to provide maximal protection. A “universal” influenza vaccine, on the other hand, is one that may provide immunity to many or all influenza A strains. To be successful, a universal vaccine must target an antigen that is highly conserved, which means that it changes very little from strain to strain.
ACAM-FLU-A™ is a recombinant vaccine in which the Hepatitis B core antigen is fused to the M2e region of the matrix-2 (M2) protein of the influenza virus envelope. M2 is a highly conserved protein that functions as a membrane ion channel and is essential for entry of the virus into host cells. It is the target of the adamantane class of influenza antiviral drugs (amantadine and rimantadaine), which are also known as M2 ion channel blockers. Antibodies to M2 have been demonstrated to protect mice from infection when challenged experimentally with influenza A virus. The M2e region is the extracellular portion of the M2 protein and is expressed on the surface of both the virus and infected host cells. Normally, M2 is not easily recognized by the immune system, as it is tucked below the relatively large, protruding hemagglutinin and neuraminidase glycoproteins. The hepatitis B core protein serves to present the M2e antigen to the immune system.2, 3
Acambis states in the press release that a randomized, double-blind, placebo-controlled Phase 1 clinical trial involving 79 human subjects was conducted at multiple centers in the U.S. The trial, which included four arms—vaccine alone, vaccine plus alum adjuvant, vaccine plus QS-21 adjuvant, and placebo—is reported in the press release to have demonstrated that the vaccine was well tolerated and immunogenic. These results have not yet been published in a scientific journal.
In the same press release, Acambis reported on an as-yet-unpublished pre-clinical study of ACAM-FLU-A™ against H5N1. In that study, 70% of vaccinated ferrets exposed to the Vietnam 2004 strain of H5N1 were protected. All of the animals in the placebo-treated control group died.
Before ACAM-FLU-A™ can be licensed, it will have to go through Phase 2 and 3 clinical testing to further establish safety and prove efficacy. This could take years, especially since correlates of immunity for influenza are poorly defined, and the U.S. Food and Drug Administration has licensed existing influenza vaccines based on antibodies to hemagglutinin.
Although these studies are preliminary, news of progress in the development of a universal influenza vaccine is encouraging. Widespread use of a vaccine that provides broad immunity to all influenza A viruses could mean the end of seasonal influenza and influenza pandemics as we know them.
Acambis press release January 3, 2008. Acambis reports positive data from trials of universal influenza A vaccine. http://www.acambis.co.uk/print.asp?id=2039. Accessed January 30, 2008.
Neirynck S, Deroo T, Saelens X et al. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999; 5:1157- 1163 http://www.nature.com/nm/journal/v5/n10/full/nm1099_1157.html. Accessed January 30, 2008.
Kilbourne E. What are the prospects for a universal influenza vaccine? Nat Med. 1999;5:1119-1120. http://www.nature.com/nm/journal/v5/n10/full/nm1099_1119.html. Accessed January 30, 2008.