H5N1 clinical trials are clinical trials concerning H5N1 vaccines, which are intended to provide immunization to influenza A virus subtype H5N1. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans.
Current status of H5N1 candidate vaccines Candidate vaccines were developed in the United States and the United Kingdom during 2003 for protection against the strain that was isolated from humans in Hong Kong in February 2003 but the 2003 strain died out in 2004 making the vaccine of little use. In April 2004, WHO made an H5N1 prototype seed strain available to manufacturers. In August 2006, WHO changed the prototype strains and now offers three new prototype strains which represent three of the six subclades of the clade 2 virus which have been responsible for many of the human cases that have occurred since 2005. The National Institute of Allergy and Infectious Diseases (NIAID) awarded H5N1 vaccine contracts to Aventis Pasteur (now Sanofi Pasteur) of Swiftwater, Pennsylvania, and to Chiron Corporation of Emeryville, California. Each manufacturer is using established techniques in which the virus is grown in eggs and then inactivated and further purified before being formulated into vaccines. "A universal influenza vaccine could provide protection against all types of influenza and would eliminate the need to develop individual vaccines to specific H and N virus types. Such a vaccine would not need to be reengineered each year and could protect against an emergent pandemic strain. Developing a universal vaccine requires that researchers identify conserved regions of the influenza virus that do not exhibit antigenic variability by strain or over time. A universal vaccine, ACAM-FLU-A, is being developed by the British company Acambis and is being researched by others as well. Acambis (meanwhile also acquired by Sanofi Pasteur) announced in early August 2005 that it has had successful results in animal testing. The vaccine focuses on the M2 viral protein, which does not change, rather than the surface hemagglutinin and neuraminidase proteins targeted by traditional flu vaccines. The universal vaccine is made through bacterial fermentation technology, which would greatly speed up the rate of production over that possible with culture in chicken eggs, plus the vaccine could be produced constantly, since its formulation would not change. Still, such a vaccine is years away from full testing, approval, and use." As of July 2007, phase I clinical trials on humans are underway in which a vaccine that focuses on the M2 viral protein "is being administered to a small group of healthy people in order to verify the safety of the product and to provide an initial insight into the vaccine’s effect on the human immune system." (See also Universal flu vaccines) The current development state of ACAM-FLU-A is unclear. In June 2006, the National Institutes of Health (NIH) began enrolling participants in a Phase 1 H5N1 study of an intranasal influenza vaccine candidate based on MedImmune's live, attenuated vaccine technology. Oct 2010 Inovio starts a phase I clinical trial of its H5N1 vaccine (VGX-3400X). Oct 2012 Novavax, Inc. pandemic influenza vaccine Phase I trials meet primary objectives.
Approved human H5N1 vaccines On April 17, 2007 the US FDA approved "Influenza Virus Vaccine, H5N1" by manufacturer Sanofi Pasteur Inc for manufacture at its Swiftwater, PA facility. In March 2006, Ferenc Gyurcsány, who was the prime minister of Hungary at the time, reported that Omninvest developed a vaccine to protect humans against the H5N1 influenza strain. The vaccine was approved by the country's national pharmaceutical institute for commercial production.
Results of trials Early results from H5N1 clinical trials showed poor immunogenicity compared to the 15-mcg dose that induces immunity in a seasonal flu vaccine. Trials in 2006 and 2007 using two 30-mcg doses produced unacceptable results while a 2006 trial using two doses of 90 mcg each achieved acceptable levels of protection. Current flu vaccine manufacturing plants can not produce enough pandemic flu vaccine at this high dose level. "Adjuvanted vaccines appear to hold the greatest promise for solving the grave supply-demand imbalance in pandemic influenza vaccine development. They come with obstacles—immunologic, regulatory, and commercial—but they also have generated more excitement than any other type of vaccine thus far. [In August 2007], scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion; after the second injection, even the lowest dose of 3.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007). And in September, Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company's own proprietary formula induced EU-accepted levels of protection after two doses of 1.9 mcg." The "GlaxoSmithKline-backed team that described an acceptable immune response after two adjuvanted 3.8-microgram (mcg) doses found that three fourths of their subjects were protected not only against the clade 1 Vietnam virus on which the vaccine was based, but against a drifted clade 2 virus from Indonesia as well [...] To achieve prepandemic vaccines, researchers would have to ascertain the right dose and dose interval, determine how long priming lasts, and solve the puzzle of measuring primed immunity. Further, regulatory authorities would have to determine the trial design that could deliver those answers, the public discussion that would be necessary for prepandemic vaccines to be accepted, and the safety data that would need to be gathered once the vaccines went into use".
Individual studies
Revaccination - January 2006 Study completion: January 2006 The purpose of this study is to determine whether having received an H5 vaccine in the past primes the immune system to respond rapidly to another dose of H5 vaccine. Subjects who participate in this study will have participated in a previous vaccine study (involving the A/Hong/Kong/97 virus) during the fall of 1998 at the University of Rochester.
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