Scientific Achievements

Investigations, focused on strengthening influenza and ARI surveillance in Russia and carried out within the Federal Influenza Centre and WHO National Influenza Centre in collaboration with a network of Russian Regional Base Laboratories, resulted in expansion of etiological and epidemiological monitoring of annual epidemics and enhancement of pandemic preparedness in Russia.

RII specialists made significant contribution to the theory of influenza and other ARI epidemic processes by revealing peculiar features of inter-pandemic period in Russia: decrease of annual influenza morbidity values, morbidity shift towards children, and higher rates of mixed etiology epidemics. Also, impact of demographic and ecological factors on epidemic intensity was demonstrated, link between influenza epidemics and mortality due to somatic diseases was analyzed.

Molecular and genetic analysis of influenza viruses circulating in Russia, followed by forecasting their variability trends, was conducted. Sequencing of full-size genome of influenza virus isolates, A(H5N1) included, was achieved with results submitted into GenBank. Studies on molecular mechanisms of influenza pathogenesis elucidated role of HA, NA & PB1-F2 virus proteins in reinforcing fibrinolytic and anticoagulant effect of blood plasma, and increasing tissue plasminogen activator activity level.

Comprehensive clinical studies to evaluate prophylactic efficacy and safety of live and inactivated influenza vaccines were realized at the RII Specialized Clinical Division. In view of pandemic concerns, RII specialists contributed significantly into influenza pandemic preparedness by developing vaccines against potential pandemic strains.

Among these, investigations focused on a novel approach in construction of live attenuated flu vaccine strains by deleting the non-structural NS1 protein (delNS1 viruses). Randomized double-blind placebo-controlled Phase I dose escalation study of two intranasal doses of reverse genetic constructed replication-deficient H5N1 vaccine confirmed safety, good tolerability and high immunogenic potential of a novel delNS1 pandemic vaccine candidate. The studies were carried out in the framework of the EU FLUVACC Project (collaborator — AVIR Green Hills Biotechnology AG, Vienna, Austria).

Promising results were obtained in Phase I/II prospective randomized clinical trials of OrniFlu vaccine (produced by FGUP NPO Microgen, Russia) against avian influenza. The vaccine, based on reassortant reference vaccine strain NIBRG-14 generated by reverse genetics at NIBSC, London, UK, and kindly provided to RII by Prof. J. Wood, was evaluated in different formulations in a two-dose regimen. The vaccine was submitted to registration in the Russian Federation. The possibility to replace double immunization by using a single dose of subunit H5N1 influenza vaccine, co-administered with recombinant human interferon-gamma Ingaron, was explored in further (Phase I) studies and suggested to be a viable approach to increase vaccine supplies in case of a pandemic situation.

Placebo-controlled prospective randomized clinical studies (Phase I/II) of pandemic vaccines based on A(H1N1) 2009 virus were conducted to evaluate two domestic (FGUP NPO Microgen production) vaccines including Pandeflu, an inactivated subunit adsorbed monovalent vaccine for intramuscular injection, based on A/California/7/2009(H1N1)v strain (recommended by WHO), and Influvir, a live monovalent intranasal vaccine based on /17/California/2009/38 (H1N1) strain (developed by Russian researchers on the basis of the reference strain). Both vaccines were registered to be used for immunization of adult population in the Russian Federation.

The first ever in Russia recombinant influenza virus strains, expressing mycobacterium protective protein ESAT-6, intended for tuberculosis prevention and treatment, were developed by RII researchers using reverse genetic technology. This approach appeared to be promising in generation of new specific tuberculosis vaccines. Results of pre-clinical investigations showed the novel tuberculosis vaccine to exceed a number of protective effect criteria of conventional BCG vaccine. It could be administered to children and subjects with immunosuppression. This invention was patent-protected (RU Patent 2318872 issued 10.03.2008) and could contribute to creation of vaccines against other infections and malignant neoplasms.

RII is a national leader in design and production of diagnostic reagents for influenza/ARI and other highly dangerous infections. Appropriate preparations and diagnostic kits are supplied to all regions of Russia. The Institute developed a range of means for specific detection of genome sequences, antigens and antibodies to current viruses, avian influenza included. With application of cell engineering, hybridomas producing monoclonal antibodies to biologically critical respiratory virus determinants for rapid differential influenza/ARI diagnosis were obtained. The design of highly specific monoclonal immunoreagents opens the way to next generation biotechnological systems with matrix protein biochips.

Among immunodiagnostic reagents, pilot series of diagnostic kits for A(H5N1) virus rapid diagnosis were developed and produced, serological techniques for indication of this influenza virus subtype were modified. The investigations resulting in creation of hybridomas secreting specific antibodies against pandemic influenza A(H1N1) virus were completed.

A significant progress was achieved in the field of novel antiviral drugs design. RII conducted studies to evaluate pathogenetic mechanisms of different chemical compounds (adamantane-based drugs, triterpenes, azoles, azines, etc). A variety of medicines, all either developed or undergone clinical testing at the RII, were approved and became widely used in current clinical practice: Algirem (rimantadine pediatric formulation) named Orvirem since 2008, interferon inducers Kagocel, Arbidol, Amixin, Cycloferon (2003 State Prize in Science and Technology), human alpha & gamma-recombinant interferon drugs (Alfaron, Ingaron). One of the latest products in the range was Dikvertoks (RU Patent 2380100), a dietary supplement based on antioxidant and immunostimulating components capable to significantly reduce influenza/ARI symptoms intensity during epidemic period.

Under the Federal Program, specialists of RII, jointly with the Ural Institute of Organic Particles, have designed an effective medicine Triazavirin, which shows high antiviral activity and broad action spectrum. Triazavirin Phase I clinical trials were successfully fulfilled, Phase II trials are currently in progress.