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Influenza vaccine production technologies 20 December 2006 • Cost of establishment. The relatively high yield of the process means that a facility producing large quantities of vaccine can be established for a fraction of the capital investment required for plants producing IIV in eggs or cell culture. • Technology transfer. The technology required is straightforward and simple, both at the laboratory and industrial scale. Complex equipment and procedures are not required. • Speed. The time to establish and validate a plant capable of producing millions of doses is relatively short, less than two years. In addition, the time required for each vaccine-production cycle is shorter than with other methods. This fact, coupled with the high yield of the process means that the time taken to produce a vaccine following the declaration of a pandemic is less than with the other approaches. • Cost per dose. The process has a 15–30 fold higher yield per egg than the production of IIV in eggs or cell-culture. • Efficacy. Data suggest that a mucosally delivered live attenuated vaccine will induce more-relevant immune responses and, possibly, better protection than parenteral delivery of an inactivated vaccine. • Needle free delivery. LAIV is administered intra-nasally, either by spray or droplet. Use of sharps and the concomitant hazards of accidental needle-stick injury or improper use of needles are avoided. However, a number of key issues need to be resolved before this approach can be recommended for implementation. • Intellectual property and strain availability. A license to existing LAIV master vaccine strains will be needed. • Regulatory pathway. LAIVs are not likely to fulfil the standard CPMP immunological criteria for licensure. Therefore new immunological correlates may need to be established. Clarity on the regulatory requirements for approval is required. • Formulation and delivery. A formulation stable at 2–8°C needs to be developed along with suitable final containers and administration method. • Egg supply. LAIV production currently requires a supply of SPF eggs. This could be limiting, particularly during an avian-flu pandemic. Therefore, it needs to be established whether SPF eggs are a critical requirement. Cell culture production of LAIV would avoid this issue, but would require addressing the issues listed in section 10.2, namely IP, investment and regulatory uncertainty. 10.4 Action points and next steps In order to support these activities and address the issues listed above, WHO intends to: • Examine the IP landscape surrounding use of LAIV strains, and to ensure that vaccine strains are available. • Consult with reference laboratories such as National Institute for Biological Standards (NIBSC) to determine whether LAIV vaccine seed strains can be produced on a rolling basis. • Clarify the requirements for regulatory approval for new LAIV strains. In particular, to ascertain clinical-trial endpoints and requirements for the quality of eggs used for production. Page 28 of 34
Influenza vaccine production technologies 20 December 2006 11 References Belshe RB. 2004. Current status of live attenuated influenza virus vaccine in the US. Virus Res. 103(1-2): 177-185 Bresson JL, Perronne C, Launay O, Gerdil C, Saville M, Wood J, Hoschler K, Zambon MC. 2006. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 367(9523): 1657-1664. Buonagurio DA, Bechert TM, Yang CF, Shutyak L, D'Arco GA, Kazachkov Y, Wang HP, Rojas EA, O'Neill RE, Spaete RR, Coelingh KL, Zamb TJ, Sidhu MS, Udem SA.. 2006. Genetic stability of live, cold-adapted influenza virus components of the FluMist/CAIV-T vaccine throughout the manufacturing process. Vaccine 24(12): 2151-2160. Gerdil C. 2003. The annual production cycle for influenza vaccine. Vaccine 21: 1776-1779 Ghendon YZ, Markushin SG, Akopova II, Koptiaeva IB, Nechaeva EA, Mazurkova LA, Radaeva IF, Kolokoltseva TD. 2005. Development of cell culture (MDCK) live cold-adapted (CA) attenuated influenza vaccine. Vaccine 23(38): 4678-84 Glezen, W. 2004. Cold-adapted, live attenuated influenza vaccine. Expert Rev Vaccines.;3(2):131-9 Katz JM, Webster RG. 1989. Efficacy of inactivated influenza A virus (H3N2) vaccines grown in mammalian cells or embryonated eggs. J Infect Dis. 160(2): 191-198 Krattiger A, S Kowalski, R Eiss and A Taubman. 2006. Intellectual Property Management Strategies to Accelerate the Development and Access of Vaccines and Diagnostics: Case Studies on Pandemic Influenza, Malaria and SARS. Innovation Strategy Today 2(2):67-122. Lin J, Zhang J, Dong X, Fang H, Chen J, Su N, Gao Q, Zhang Z, Liu Y, Wang Z, Yang M, Sun R, Li C, Lin S, Ji M, Liu Y, Wang X, Wood J, Feng Z, Wang Y, Yin W. 2006. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 368(9540): 991-997. Nichol KL. 2001. Live attenuated influenza virus vaccines: new options for the prevention of influenza. Vaccine 19(31): 4373 - 4377 Nicholson KG. 2004. Limitations of currently available influenza vaccines. In “Report of meeting on the development of influenza vaccines with broad spectrum and long-lasting immune responses”, World Health Organization, Geneva, Switzerland, 26–27 February 2004. pp26-36. http://www.who.int/vaccine_research/documents/Report_Feb_04.pdf Rudenko LG, Arden NH, Grigorieva E, Naychin A, Rekstin A, Klimov AI, Donina S, Desheva J, Holman RC, DeGuzman A, Cox NJ, Katz JM. 2000. Immunogenicity and efficacy of Russian live attenuated and US inactivated influenza vaccines used alone and in combination in nursing home residents. Vaccine 19(2-3): 308-318. Stephenson I, Nicholson KG, Wood JM, Zambon MC, Katz JM. 2004. Confronting the avian influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 4(8): 499- 509. Stephenson I, Gust I, Pervikov Y and Kieny M-P. 2006. Development of vaccines against influenza H5. Lancet Infect Dis 6(8): 458-460. Page 29 of 34
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