MedImmune, Inc. has filed an investigational new drug application (IND) with the US Food and Drug Administration (FDA) to begin human clinical testing of a cell culture-based seasonal influenza vaccine using its proprietary live, attenuated, needle-free influenza vaccine technology. The filing represents a milestone under the terms of a five-year, $170-million contract with the US Department of Health and Human Services (HHS).
MedImmune's currently marketed influenza vaccine, FluMist (Influenza Virus Vaccine Live, Intranasal), is now made using chicken eggs, as are all other US-approved influenza vaccines. Vaccine manufacturers have been using eggs for production for decades; however, using chicken eggs as the production medium limits scalability in manufacturing and increases the potential risk of manufacturing delays or supply shortages. A severe outbreak of avian influenza could kill the flocks used to produce the eggs that would be used for vaccine production. To address these concerns, MedImmune will be applying state-of-the-art cell culture-based manufacturing methods to produce influenza vaccines without the need for chicken eggs. The success of this technology will reduce production times and substantially increase MedImmune's US-based manufacturing capacity to provide influenza vaccine to the US population. After adding the cell culture-based production capability for its influenza vaccine, MedImmune anticipates having the capacity to produce 300 million monovalent bulk doses of a pandemic vaccine annually by 2012.
"MedImmune is pleased to reach this important step in our collaboration with the US government," said James F. Young, president, research and development. "MedImmune's commitment to preparing the country to be protected against influenza illness annually and in the event of a pandemic is stronger than ever, and we are encouraged by the momentum of our research and development efforts."
Under the terms of the contract awarded earlier this year, MedImmune submitted a master product development plan to HHS on November 2, 2006 detailing the company's tactical approach from preclinical testing phases of its cell culture-based vaccine through regulatory licensure. The plan sets forth specific activities related to facility and manufacturing upgrade compliance, as well as vaccine development milestones. The first study of a cell culture- produced seasonal vaccine will characterize safety and immunogenicity in a placebo-controlled trial.
MedImmune is playing an important role in contributing to the nation's armamentarium against both annual seasonal and pandemic influenza. Each year, influenza is responsible for up to 60 million infections, (2) resulting in about 25 million doctors' office visits and hospital stays. (3) Between 1990 and 1999, about 36,000 Americans died from the flu and its complications each year. There is increasing concern that a particularly virulent strain of flu could create a national or worldwide pandemic, leading to high levels of illness, death, social disruption, and economic loss, according to the Centers for Disease Control and Prevention (CDC). MedImmune's research in the influenza field seeks to continue to market and develop products for the very real threats of existing seasonal influenza, while looking into the future at ways to protect Americans against even more dangerous forms of the virus.
MedImmune's other recent influenza vaccine development activities include: The FDA is currently reviewing a supplemental biologics licensing application (sBLA) to switch formulations from frozen FluMist, currently approved in healthy individuals 5 to 49 years of age, to the refrigerator-stable cold adapted influenza vaccine, trivalent (CAIV-T) formulation of FluMist for the same population. Pending timely approval, the company plans to launch the refrigerator-stable formulation for the 2007-2008 flu season.
MedImmune has also submitted a separate sBLA to the FDA seeking an expanded label for CAIV-T for use in children between 12 months and 59 months of age who do not have a history of wheezing or asthma. A response from the FDA for this sBLA is anticipated in the second quarter of 2007 and pending positive outcome, MedImmune plans to commercially provide CAIV-T for the expanded population for the 2007-2008 influenza season. The company is hopeful that the FDA will review the sBLA for CAIV-T label expansion expeditiously in order to prepare to vaccinate the children identified by the CDC as being at the highest risk of influenza disease as early as possible in the 2007-2008 season.
MedImmune received approval from the FDA in July 2006 to utilize reverse genetics technology in the development of seasonal and pandemic vaccines and has offered to license key intellectual property for this technology to governmental organizations and companies. For pandemic vaccines, reverse genetics can be particularly important because the technology allows vaccine manufacturers to work with a segment of the infectious pandemic virus strain's genome rather than directly with the infectious strain itself. Using this technology, it is also possible to make changes to the virus to make it less virulent.
In June 2006, MedImmune, in collaboration with the National Institute of Allergy and Infectious Diseases, initiated a phase 1 study of a monovalent, egg-based live, attenuated intranasal vaccine against the avian H5N1 under a cooperative research and development agreement (CRADA) with the National Institutes of Health (NIH). Under the CRADA, MedImmune is developing a library of prototype vaccines representing each HA subtype of pandemic potential and, in cooperation with the NIH, evaluating prototype vaccines in phase 1 clinical trials.
CAIV-T is an investigational intranasal, cold-adapted trivalent influenza vaccine. It is the next-generation, refrigerator-stable formulation of FluMist, which is a frozen, live attenuated cold-adapted trivalent influenza vaccine. To date, the safety, tolerability and efficacy of CAIV-T has been studied in both healthy and at-risk populations between the ages of 6 weeks and 98 years.
On May 1, 2006 at the Pediatric Academic Societies' annual meeting, MedImmune presented its pivotal phase 3 study for CAIV-T, entitled, "Comparison of the efficacy and safety of cold-adapted influenza vaccine, Trivalent With trivalent inactivated influenza vaccine in young children 5 to 59 Months of Age." The study included 8,475 children at 249 sites in 16 countries in North America, Europe, the Middle East and Asia. Study participants were randomized one-to-one to receive either CAIV-T or the flu shot during the 2004-2005 influenza season. Each participant also received a placebo nasal spray or placebo injection to preserve the double-blind design of the study. Participants were followed through the influenza season and evaluated to identify illnesses caused by influenza virus. The trial included more than 6,300 previously unvaccinated children with nearly 50 per cent of those children less than 2 years of age.
The results of this trial showed that CAIV-T was 55 per cent more effective than the trivalent injectable inactivated influenza vaccine (TIV) in reducing influenza illness caused by any influenza strain in children 6 months to 59 months of age, including both matched and mismatched strains. The influenza attack rate was 8.6 per cent for study participants receiving the flu shot compared to 3.9 per cent for those who received CAIV-T. Against matched strains alone, CAIV-T was 44 per cent more effective than the flu shot (attack rates: TIV = 2.4 per cent, CAIV-T = 1.4 per cent; P<0.001). In this study, CAIV-T also appeared to be 89 per cent more effective than the flu shot in reducing influenza illness caused by the matched H1N1 A strain (attack rates: TIV = 0.7 per cent, CAIV-T = 0.1 per cent; P<0.001) and 79 per cent more effective than the flu shot against the circulating mismatched H3N2 A strain (attack rates: TIV = 4.5 per cent, CAIV-T = 1.0 per cent; P<0.001). There were no cultures of mismatched H1N1 strains or matched H3N2 strains detected in the trial. While there were 16-per cent fewer children with illnesses associated with B strains in the CAIV-T group compared to TIV (attack rates: TIV = 3.5 per cent, CAIV-T = 3.0 per cent), this difference was not statistically significant.
In the study, the overall incidence of adverse events and serious adverse events was similar in both groups except for a higher incidence of runny nose and nasal congestion in CAIV-T recipients (4.4 - 11.1 per cent increase) and a higher incidence of injection site reactions in those receiving the flu shot (3.6 - 7.6 per cent increase). A statistically significant increase in the incidence of medically significant wheezing was seen in CAIV-T recipients 6 months to 23 months of age within 42 days following vaccination. Post-hoc analyses showed higher all-cause hospitalizations occurring through 180 days after vaccination in CAIV-T recipients 6 months to 11 months of age. Risk- benefit analyses showed a favorable profile for CAIV-T as compared to TIV in children 12 months to 59 months of age without a prior history of wheezing or asthma.
FluMist is indicated for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5 to 17 years of age, and healthy adults, 18 to 49 years of age. There are risks associated with all vaccines, including FluMist. Like any vaccine, FluMist does not protect 100 per cent of individuals vaccinated. In studies of people between the ages of 5 and 49 years, runny nose was the most commonly reported side effect. Other common side effects included various cold-like symptoms, such as headache, cough, sore throat, tiredness/weakness, irritability, and muscle aches.
FluMist should not be used, under any circumstances, in anyone with an allergy to any part of the vaccine, including eggs; in children and adolescents receiving aspirin therapy; in people who have a history of Guillain-Barre syndrome; and in people with known or suspected immune system problems. Pregnant women and people with certain medical conditions, asthma, or reactive airways disease should not get FluMist.