Broad Spectrum Flu Antibodies Characterized
By Amesh A. Adalja, MD, March 6, 2009
Two teams of researchers recently and simultaneously reported the discovery and development of antibodies generated against invariate regions of the influenza virus.1,2 These developments are incremental steps toward a universal vaccine and/or treatment for a virus known for its mutability, reassortment, and recombination.
Dana-Farber Cancer Institute Researchers Discover Antibodies that Protect Mice from H5N1 and Many Other Influenza Viruses
Researchers from the Dana-Farber Cancer Institute screened 27 billion antibodies from an antibody library for activity against H5 hemagglutinin. Results of the study were recently published in Nature Structural & Molecular Biology. The team identified a group of 10 high affinity antibodies that bind to a “pocket” on the hemagglutinin molecule that is essential for membrane fusion. Three of these antibodies were then tested in a mouse challenge model in which mice were infected with a lethal dose of H5N1 influenza. Antibodies were administered either before or after infection with the virus; 80% to 100% of mice in both groups survived. Similar results were found whether the antibodies were given at 24, 48, or 72 hours after infection. Moreover, the antibodies prevented systemic spread of the virus.
The antibodies were also tested in-vitro against other influenza virus types and displayed neutralization ability against all group 1 influenza viruses that were tested, including H5 and H1. The H1 viruses include both the 1918 pandemic virus and the predominant strain of seasonal influenza in the U.S. for past last 2 years, which is now resistant to oseltamivir. The antibodies did not neutralize group 2 viruses, which include H3 and H7.1 H3 viruses have caused most seasonal influenza throughout the world since 1968, and H7 viruses have been responsible for a number of outbreaks of low pathogenic avian influenza.
Scripps Researchers Find Similar Results
A team of researchers from the Scripps Research Institute further characterized a potent antibody from a human subject who had been vaccinated against seasonal influenza. This antibody had been found to neutralize H5 type influenza viruses despite no known exposure to those viruses in the individual from which the antibody was isolated. The antibody was also found to neutralize other influenza viruses (H1, H2, H5, H6, H8, H9) and to protect mice from lethal challenges with both H5N1 and H1N1 viruses.3 In a study recently published in Science, the team further characterized the antibody with crystallographic studies and found it to bind to an area identical to that found by the Dana-Farber team, which is the area responsible for membrane fusion.2
What would a Universal Flu Countermeasure Mean?
A truly universal countermeasure against influenza would represent a leap forward in the treatment of this disease and would make pandemic preparedness a simpler, but still vital, process. Currently, pandemic mitigation strategies revolve around the use of both anti-viral medications and vaccines. As recent events have illustrated, the ability of the influenza virus to harbor drug resistant mutations and retain efficient transmissibility have rendered certain medications almost obsolete.4 Additionally, the antigenic drift of the virus makes it necessary to reconfigure the vaccine repertoire annually. A universal treatment or vaccine, targeting a non-varying region of the virus (i.e. the membrane fusion portion) would obviate the need to continually develop countervailing strategies to combat the genetic variation of the virus, which could lead to substantially lower capital and technology requirements for combating the influenza virus.
Sui J, Hwang WC, Perez S, et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nature Structural and Molecular Biology 2009;16:265-73. http://www.nature.com/nsmb/journal/vaop/ncurrent/abs/nsmb.1566.html. Accessed March 3, 2009.
Ekiert DC, Bhabha G, Elsliger M, et al. Antibody recognition of a highly conserved influenza virus epitope. Science 2009; [Epub ahead of print]. http://www.sciencemag.org/cgi/content/abstract/1171491. Accessed March 3, 2009.
Throsby M, van den Brink E, Jongeneelen M, Poon LLM, Alard P, et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE 2008;3(12): e3942. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003942. Accessed March 3, 2009.
Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009;301:1034-41. http://jama.ama-assn.org/cgi/content/full/2009.294. Accessed March 3, 2009.