MedImmune Vaccines (formerly Aviron) has developed a cold-adapted live influenza virus vaccine [FluMist] that can be administered by nasal spray. FluMist is the first live virus influenza vaccine and also the first nasally administered vaccine to be marketed in the US. The vaccine will be formulated to contain live attenuated (att) influenza virus reassortants of the strains recommended by the US Public Health Service for each 'flu season. The vaccine is termed cold-adapted (ca) because the virus has been adapted to replicate efficiently at 25 degrees C in the nasal passages, which are below normal body temperature. The strains used in the seasonal vaccine will also be made temperature sensitive (ts) so that their replication is restricted at 37 degrees C (Type B strains) and 39 degrees C (Type A strains). The combined effect of the antigenic properties and the att, ca and ts phenotypes of the influenza strains contained in the vaccine enables the viruses to replicate in the nasopharynx to produce protective immunity. The original formulation of FluMist requires freezer storage throughout distribution. Because many international markets do not have distribution channels well suited to the sale of frozen vaccines, Wyeth and MedImmune are collaborating to develop a second generation, refrigerator-stable, liquid trivalent cold-adapted influenza vaccine (CAIV-T), which is in phase III trials. Initially, the frozen formulation will only be available in the US. For the 2003-2004 season, FluMist will contain A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like) and B/Hong Kong/330/2001. Aviron was acquired by MedImmune on 15 January 2002. Aviron is now a wholly-owned subsidiary of MedImmune and is called MedImmune Vaccines. Aviron acquired FluMist in March 1995 through a Co-operative Research and Development Agreement (CRADA) with the US NIAID, and a licensing agreement with the University of Michigan, Ann Arbor, USA. In June 2000, the CRADA was extended through to June 2003. Aviron holds exclusive worldwide rights to the vaccine except for Japan, where Kaketsuken Pharmaceuticals (also known as Chemo-Sero-Therapeutic Research Institute) is the licensee. Aviron signed a development and licensing agreement with Sang-A in Korea, which was to manufacture and market FluMist in South Korea. However, in 2000, Aviron terminated all rights and licences to Sang-A relating to FluMist. Sang-A responded by filing a suit against Aviron in August 2000, for breach of contract and unfair and deceptive business practices. Aviron filed a counter claim denying the allegations in late Sept 2001. In 1999, Aviron entered into an agreement with Wyeth-Lederle Vaccines for worldwide collaboration in the marketing of FluMist. Under the $US400 million agreement, Aviron granted Wyeth-Lederle Vaccines exclusive worldwide rights to market FluMist. Wyeth-Lederle Vaccines and Aviron (now Med-Immune Vaccines) will co-promote FluMist in the US, while Wyeth-Lederle Vaccines will have the exclusive right to market the product ex-US. Wyeth will hold marketing rights for up to 11 years. The collaboration excludes Korea, Australia, New Zealand and certain South Pacific countries. The companies will collaborate on the regulatory, clinical and marketing programmes for FluMist and both will manufacture liquid FluMist. MedImmune Vaccines is to receive an average of 40% of revenues from FluMist; the percentage will be higher in the US and lower in other markets. Aviron received a $US15 million upfront payment upon initiation of the agreement. In December 2000, Aviron received a $US15.5 million milestone payment from American Home Products (now Wyeth) after the US FDA accepted the BLA for FluMist. MedImmune Vaccines will receive a $US20 million milestone payment upon US FDA approval. Aviron also received an additional $US20 million in milestone payments for expaory body recommendations. MedImmune Vaccines is entitled to receive a $US10 million payment for submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines (now Wyeth Vaccines) had begun a phase II bridging study with a refrigerator-stable liquid formulation of FluMist in the Southern Hemisphere. The randomised single-blind trial is being conducted together with Aviron (now MedImmune Vaccines) and is intended to demonstrate clinical equivalence between frozen and liquid FluMist. At the time of the announcement, more than 500 children aged 1-3 years had been enrolled to receive either frozen or liquid FluMist. The final study population is approximately 1300. If clinical equivalence of the two forms of FluMist is demonstrated in this study, MedImmune Vaccines will be able to use data from trials of frozen FluMist in licence applications for international markets. Aviron submitted a Biologics Licence Application (BLA) to the US FDA in July 1998. The FDA rejected this application on the grounds of a lack of data on manufacturing, validation and stability. In June 1999, Aviron announced that it had completed a bridging study on FluMist designed to provide some of the manufacturing data required by the US FDA on FluMist prepared at one of two manufacturing sites. Preliminary analysis indicated that the results had met the company's objectives. The primary endpoint of the study was to demonstrate that the batch of FluMist blended and filled at Packaging Coordinators, Inc. in Philadelphia had similar immunogenicity for all three 1997-98 influenza strains as the vaccine used in earlier clinical trials, which was manufactured by Medeva Pharma (now Evans Vaccines, a subsidiary of PowderJect Pharmaceuticals) in England. The secondary endpoint was to show that these lots of FluMist had similar safety and tolerability profiles. Aviron then submitted a BLA in October 2000. However, in late July 2001, an FDA advisory committee declined to recommend approval of the vaccine, citing concerns with safety. Aviron subsequently received a Complete Response Letter from the FDA requesting additional clinical and manufacturing data. Aviron stated that it should be able to provide these data without conducting further clinical trials. In January 2002, Aviron submitted additional clinical and manufacturing data on FluMist to the US FDA. MedImmune received a second Complete Response Letter from the US FDA on 10 July 2002, requesting clarification and additional data relating to previously submitted information. One of the most significant issues raised by the US FDA was the exacerbated rate of asthma and wheezing in 18-35-month-old patients using FluMist. MedImmune is considering two options to address this issue; to either exclude patients with asthma and wheezing from the label, or to exclude 18- to 30-month-old patients from the proposed indication. On 26 August 2002, MedImmune reported that it had completed the submission of information requested by the US FDA for FluMist. On 17 December 2002, the US FDA's Vaccination and Related Biologicals Products Advisory Committee (VRBPAC) recommended that the FDA approve FluMist to prevent influenza in healthy children, adolescents and adults (ages 5-49 years). Even though the VRBPAC voted in favour of the product's safety in the 50- to 64-year age group, they believed that the data set on efficacy for this age group was insufficient. The committee has also recommended that head-to-head studies should be conducted comparing FluMist to the marketed trivalent inactivated vaccine. Additional clinical trials suggested by the VRBPAC were shedding studies to more clearly define the probability of transmitting the influenza vaccine virus to a high-risk patient and annual revaccination studies. On 30 January 2003, MedImmune announced that it had received a Complete Response Letter from the US FDA requesting clarification and additional information relating to data previously submitted. No additional clinical trials were requested. The company responded to the five questions contained in the letter on 7 February 2003. (ABSTRACT TRUNCATED)