Inhalation Influenza Vaccine
Mucosal Influenza Virus Vaccine for Inhalation Application
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
3 Approved without Funding
Research Institute of Viral Preparations, Russia, Moscow
- Research Center of Toxicology and Hygienic Regulation of Biopreparations, Russia, Moscow reg., Serpukhov
- Hackensack University Medical Center, USA, New Jersey\nVeterinary Infections Disease Organization, Canada, SK, Saskatoon\nCenter for Immunology & Microbial Disease, USA, New York\nBarts and The London, Queen Mary’s School of Medicine and Dentisty, UK, London\nUniversity of Connecticut / Center of Excellence for Vaccine Research, USA, CT, Storrs
Project summaryInfluenza is still remaining an urgent problem for human health protection in many countries all over the world. The usual annual flu incidenсe rate during the outbreaks is about 10 per cent of the population, and it may be 4-6 fold increased during the pandemics. In fact, all flu outbreaks are resulted in sufficient mortality increasing. They are both dangerous for human health and disastrous for the economy of the country, as they are conditioned by the expenses for drugs, medical personnel service, hospitalization of patients as well as noticeable losses due to the people’s disablement.
With the aim of flu prophylaxis, inactivated vaccines are presently accepted. But in great majority of countries, the control of epidemics is most commonly limited by vaccination of high risk group people (humans of all ages having chronic ailments, and humans over 65). Strong incident decrease can be achieved only by mass vaccination of all groups of population, especially infants, who are considered to be the main flu infection deliverers.
The existent inactivated vaccines application for mass preventive influenza vaccination is rather problematic because of the high vaccine cost especially under parenteral method of application. Besides, the vaccines have shortcomings of their immunogenicity lack while elderly people vaccination, as well as weak ability to induce local immunity in the entrance gates of infection (nasopharynx).
Improvement of inactivated vaccines is possible due to including into their composition mucous-adhesive adjuvants, able to facilitate getting of sufficient amount of influenza antigen into mucous membranes cells of pharyngeal lymphatic circle, providing the induction of both humoral and local immunity. The inhalation method for vaccine delivery, we believe, ensures targeted vaccine delivery to the definite section of respiratory tract and is optimal for mass influenza prophylaxis.
The goal of the project.
The goal is to develop a mucous inactivated influenza virus vaccine for inhalation application.
In this connection, the development of mucosal influenza virus vaccine, capable of inducing not only systemic but also local immunity, and of being delivered to the entrance infection gates (nasopharinx) by the aerosol method, is considered to be of great scientific and practical importance.
It is planned to develop a mucosal inactivated influenza virus vaccine, capable of inducing both systemic and local immunity while both intranasal and inhalation method of administration, with the help of designed in Russia mucous-adhesive adjuvant in combination with one of interleukins.
At the initial stage of the project implementation it is suggested to optimize in laboratory animals the conditions to employ designed in Russia diphtheria toxin “Reditox”, having lost its toxicity, as a mucous-adhesive adjuvant while intranasal introduction of inactivated influenza virus vaccine. The recombinant toxoid “Reditox”, having deletion of N-end A-fragment of diphtheria toxin with size 28 amino-acid residues, but keeping C-end part of A-fragment (deletion of gene 5-end to Vsp 1-site) and full- size B-fragment, has entirely retained its receptory activity, and, consequently, is able to be a mucous-adhesive adjuvant and to stimulate actively the mucosal immune system. It is supposed to use at the same time a preparation of cholera toxin B-subunits as a control mucous adhesive one.
At the following stage it is planned to study the immune response following intranasal injection of inactivated influenza virus vaccine, containing diphtheria toxoid “Reditox”, as well as to study protective efficiency of the vaccine. It is expected to examine protective efficiency of the complex “inactivated influenza vaccine – Reditox “ in the experiments on virulent strains H1 and H3 of influenza A subtypes and virulent strains of influenza B, adapted for mice.
The next part of the work is related to the examination of mucous-adhesive properties and corrective effect of some interleukins under intranasal delivery of inactivated influenza virus vaccine, containing diphtheria toxoid “Reditox” and without it.
In the course of the project implementation it is planned to optimize the aerosol method for mucosal influenza virus administration in RCT& HRB laboratory installations. The optimal physics-chemical properties of the vaccine aerosol will be determined as well as the optimal aspirating doses and degree of aerosol preparation dispersion. It is also supposed to work out the technological regimes for vaccine conversion into aerosol, ensuring its delivery to the targeted section of respiratory tract.
A great number of biological and vaccinal preparations have been investigated recently in the RCT& HRB’ special aerosol chambers by the method of inhaling impact on laboratory animals. The instrumentation and techniques to control the concentration and aerosol particles size were developed and implanted in the Centre; a wide spectrum of modern now- how have been mastered to study the process of cellular and humoral immunity formation in pre- and post-inhalation vaccination period.
At the Laboratory for RNA- containing viruses genetics of the Research Institute for Viral Preparations at RAMS, prolonged refined investigations have been conducted to develop some new and improve the present influenza virus vaccines. In collaboration with the Veterinarian Academy, an inactivated hen influenza vaccine was developed and implanted. As a result of joint investigations with the Experimental Medicine Institute (EMI) at RAMS, adapted-to-cold recombinant influenza virus vaccine was designed and introduced. The investigation, conducted together with the EMI RAMS, as well as with WHO, CDC (Atlanta, USA), and Michigan University, manifested high efficiency of the formulation for the infants’ anti-flu prophylaxis (22). The Laboratory, the National Institute for Medical Investigations (London, GB), and CDC (Atlanta, USA), conducted jointly an intensive coverage of the influenza virus attenuation mechanisms. It was established, that the recombinant adapted-to-cold influenza virus intranasally delivered vaccine possessed high immunogenic activity and was able to induce both systemic and local immunity.
– new technology for mucosal inactivated influenza virus vaccine production with the use of diphtheria toxoid “Reditox” and exogenous cytokines as mucous-adhesive adjuvants;
– development of inhalation method for the vaccine application;
– data on safety and immunogenicity of mucosal influenza virus vaccine, obtained using experimental animals;
– test batches of the vaccine.
The mucosal influenza virus vaccine advantages are conditioned by its safety, simplicity of delivery, cost effectiveness, absence of tissues damage risk when inhalation application. The commercial benefit of the project is the possibility of the mucosal influenza vaccine mass production on the basis of the developed technique and the methodology for its application.
The present project entirely corresponds to the ISTC purposes and tasks. It facilitates weapon scientists’ reorientation to non-military activity and supports the development of the peaceful-aim technologies as well.The project implementation can contribute to the RCT&HRB and RIVP RAMS scientists’ joining the International Scientific Society.
Role of foreign collaborators:
– information exchange in the course of the project implementation;
– comments on technical reports, submitted to ISTC by the project participants.
Technical approach and methodology.
At the beginning of the work, the investigations will be focused on the analysis of immunologic efficiency of inactivated influenza virus vaccine, containing various concentration of diphtheria toxoid “Reditox” as a mucous-adhesive adjuvant when intranasal method of application. Various concentrations of cholera toxin B-subunits preparations will be used at the same time with the aim of control. It is planned to determine the basic properties of systemic and local immunity of immunized experimental animals. The work at the initial stage will make possible to determine the diphtheria toxoid efficiency as a mucous-adhesive adjuvant for mucosal inactivated influenza virus vaccine.
At the following stage it is planned to study protective efficiency of the inactivated influenza virus vaccine, containing diphtheria toxoid “Reditox”, under intranasal delivery in experimental animals. With this aim the immunized animals will be infected by the virulent strains of influenza A virus H1 and H3 subtypes and by influenza B virulent strains.
In the further investigations it is supposed to study the mucous-adhesive potential of some exogenous cytokines, and to examine the ability of such cytokines to correct the immune response in laboratory animals, immunized intranasally by the inactivated influenza virus vaccine. It is expected to study immunogenicity and protective efficiency of inactivated influenza virus vaccine, containing toxoid “Reditox” and one of the exogenous cytokines.
At the following stage it is planned to determine a more accurate composition of inactivated influenza vaccine, containing mucous-adhesive adjuvants, and to develop the technology for its production. A number of test vaccine batches will be produced.
The technique for inhalation vaccine delivery is supposed to be examined extensively in experimental animals using aerosol installations of the RCT& HRB (Serpukhov, Moscow region). The technological regimes for vaccine conversion into aerosol, ensuring its delivery to the targeted section of respiratory tract, will be worked out. It is planned to optimize physics-chemical properties of the vaccine aerosol, as well as aspirating dose and aerosol preparation degree of dispersion.
At the final stage it is expected to optimize the inhalation method for mucosal influenza virus vaccine delivery using the RCT&HRB aerosol installations with experimental animals.
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