Development of Lve Culture Influenza Vaccine (Thrust II)
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
3 Approved without Funding
State Research Center of Virology and Biotechnology VECTOR, Russia, Novosibirsk reg., Koltsovo
- Research Institute of Viral Preparations, Russia, Moscow
- Centers for Disease Control and Prevention (CDC) / National Center for Infectious Diseases, USA, GA, Atlanta\nNational Institute for Medical Research, UK, London\nTask Force for Child Survival and Development, USA, GA, Decatur\nBarts and The London, Queen Mary’s School of Medicine and Dentisty, UK, London\nInstitut Pasteur, France, Paris
Project summaryInfluenza now remains a serious health problem with an economic impact at the level of entire countries. The morbidity rate during annual influenza epidemics reaches 10–20% and is accompanied by a considerably high mortality (in the USA, approximately 20,000 persons per year) and an economic loss amounting to millions dollars. Children are most susceptible to the disease and are the major transmitters of influenza infection. It was also demonstrated that influenza morbidity is higher in the families with children. There are also data demonstrating that a massive vaccination of children decreases drastically the morbidity of unvaccinated persons of older age and even mortality rate of elderly persons. Thus, it may be inferred that massive vaccination of children against influenza may not only protect large number of children from infection and hospitalization, but also decrease essentially the morbidity and even mortality of unvaccinated population.
The experience of administering cold-adapted live influenza vaccine in Russia and the USA acquired so far demonstrates that this preparation displays the highest efficiency while vaccinating children, a somewhat lesser efficiency for adults, and low efficiency when administered to elderly. A simple administration route (intranasal) makes this preparation optimal for massive vaccinations, especially, for immunizing children. Note also that unlike inactivated influenza vaccines, the live vaccine is capable of protecting from infections with influenza virus antigenic variants. However, the live influenza vaccine used now has certain shortcomings. Its main disadvantage is use of chick embryos as a substrate while its manufacturing. As a result, the vaccine contains a considerable amount of chick embryo proteins, which can cause adverse reactions of children with allergy to these proteins as well as allergize vaccinees. The more so, as vaccination with the live vaccine is double and should be repeated annually. It is known that chick embryos are frequently contaminated with avian retroviruses, whose potential pathogenicity to humans is yet vague and required detailed studies. Therefore, only special pathogen-free chick embryos should be used for producing live influenza vaccine; however, they are rather expensive, thereby increasing essentially the price of the vaccine. Moreover, Russia lacks a farm for producing SPF chick embryos at all. In addition, chick embryos are nonstandard, preventing production of the vaccine at a necessary titer.
Since 2001, SRC VB Vector in collaboration with IVP under the ISTC Project No. 940B is involved in research connected with the development of technology for manufacturing cold-adapted live influenza vaccine using continuous MDCK cell culture cultivated in bioreactors on microcarriers in a serum-free medium as a substrate for propagation of the virus. Inoculation and working banks of MDCK cells were produced and certified at the national agency for control of immunobiological preparations, Tarasevich SISC. Optimal conditions for cultivation of the cells in bioreactors with a volume of 1–10 l using microcarriers and serum-free medium were selected as well as the optimal conditions for reproduction of cold-adapted influenza virus reassortants, allowing for producing the virus at titers up to 1010 EID50/ml. Conditions for stabilization and freeze-drying of the live trivalent vaccine were optimized, and pilot batches of the vaccine were manufactured. The relevant engineering and normative specifications for production of the vaccine were developed. The results obtained were used to prepare and submit the application for international patent on the method for manufacturing live culture influenza vaccine to the Russian Patenting Agency with a financial support of ISTC. Thus, the results obtained under the Thrust I of the ISTC Project No. 940B allow us to commence examining the safety and immunogenicity of pilot batches of the live culture trivalent influenza vaccine in clinical studies in volunteers.
The goal of Thrust II is (1) to study the safety and immunogenicity of the cold-adapted reassortant live influenza vaccine, produced according to the developed technology of growing influenza virus vaccine strains in MDCK cells cultivated in bioreactors using serum-free medium, in preclinical trials and in experiments in volunteers and (2) to obtain new cold-adapted master strains of types A and B influenza viruses that would be more optimal for vaccinating children.
These studies will allow us to commence extended clinical trials of the vaccine followed by introduction of the developed technology for manufacturing live culture cold-adapted influenza vaccine at SRC VB Vector and other facilities involved in production of immunobiological preparations.
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