LIVE ATTENUATED INFLUENZA VIRUS (LAIV) VACCINE

The Live Attenuated Influenza Virus (LAIV) vaccine was in-licensed from the IEM in St Petersburg, Russia where it has been approved and used, in its present trivalent form, for over a decade in many millions of people - children, adults and the elderly.

The LAIV vaccine is administered by nasal spray and induces a rapid immune response in the mucosal lining of the nose and pharynx.  The vaccines are based on ‘Master Donor Strains’ that have been rendered ‘cold adapted’ and temperature sensitive, such that they will not replicate readily at temperatures above 33°C, as found in the lungs.  The administration of the live vaccine stimulates a broad mucosal, cellular and humoral immune response (all of which are required to optimise the effective prevention of influenza), without causing the disease. The LAIV influenza vaccine is marketed as NasovacÔ in India by the Serum Institute of India.

BioDiem has exclusive rights to commercialize the LAIV technology outside Russia and the Commonwealth of Independent States.  Unlike the more traditional influenza vaccinations which are injected, the LAIV vaccine is a nasal spray and contains live viruses. However, the viruses are attenuated (weakened) and do not cause serious illness.

Each year the strains of flu circulating in the population change. The diagram shows how the LAIV vaccine is produced so that it is effective against the relevant strains that year, as recommended by the World Health Organization each year.

The Live Attenuated Influenza Virus vaccine has a number of advantages. Extensive clinical trials and over fifty years use in Russia have established the safety and efficacy profile of the LAIV vaccine. The LAIV vaccine is suitable for rapid production via cell-based manufacture giving a high yield and can also be manufactured using eggs with an increased yield compared to other vaccine technologies.

One major advantage of the LAIV vaccine over the standard flu shot is that it is a nasal spray so does not require injections or trained personnel. This makes it easier to use and administer. It also appears that vaccination using the LAIV offers immunological advantages in that it produces immunity similar to natural infection thus creating a broader immune response involving mucosal, humoral and cellular immunity. Inactivated vaccines do not induce mucosal immunity.

It has been shown in several studies that the LAIV vaccine provides better herd immunity than inactivated vaccines. In particular, in the Novgorod school study, it was observed that influenza morbidity was significantly lower among non-vaccinated pupils and staff, where more than 50% pupils were vaccinated, compared with those schools, where pupils received inactivated influenza vaccine. [Rudenko L.G., Slepushkin A.N., Monto A.S., et al., Efficacy of live attenuated and inactivated influenza vaccines in school children, J. Infect Dis. 168 (1993) 881-887]

It has been demonstrated in Russian clinical trials that the LAIV vaccine provided 59% protection in situations in which the epidemic influenza strain was different from the vaccine strain virus (”cross-protection”) [Grigorieva E.P., Drinevsky V.P., Doroshenko E.M., Erofeeva M.K.,  Desheva J.A., Maksakova V.L., Rudenko L.G., Efficacy of live attenuated cold-adapted reassortant influenza vaccine during the circulation of drift influenza viruses. Epidemiology and vaccinal prevention, 2009, 1 (44), 45-53]

BioDiem’s LAIV provides broad protection against “drifted” variants of influenza. In years where the vaccine strain has not exactly matched the circulating strain of influenza, the standard inactivated flu shot has provided protection at little more than placebo rates. This is important because the WHO strain selection for seasonal vaccines is based on expectation of what strains will circulate which is extremely difficult to predict into the future.

CELL- BASED manufacture of LAIV INFLUENZA VACCINE

First in human and Proof of Concept clinical trials have been completed in Europe for an LAIV vaccine manufactured using a mammalian cell-based method.

EGG- BASED manufacture of LAIV INFLUENZA VACCINE

Collaborations with the Institute of Experimental Medicine, St Petersburg, the World Health Organization and other international groups such as the Program for Appropriate Technology in Health (PATH) for the development of seasonal and pandemic influenza LAIV vaccines are in place.

World Health Organization (WHO) Program

BioDiem contributes to the WHO's Global Pandemic Influenza Action Plan by licensing the WHO to transfer an egg-based live attenuated influenza virus (LAIV) vaccine production technology to developing country manufacturers.

The agreement is a non-exclusive licence designed to support wider distribution of the LAIV influenza vaccine in developing countries. Whereas public sector usage is royalty-free, royalties will flow to Biodiem directly from private sector sales. BioDiem has authorised the Institute of Experimental Medicine (IEM) to supply LAIV reassortants to the WHO for use by its sublicencees. The vaccines developed through the WHO program are manufactured using eggs.  In September 2009, the WHO issued sublicences to the LAIV technology to two companies: the Serum Institute of India, Pune, India and the Government Pharmaceutical Office, Bangkok, Thailand.

In July 2010 the Serum Institute of India launched its H1N1 (swine flu) pandemic vaccine, called Nasovac™, in India. This vaccine is a result of the WHO collaboration using BioDiem’s technology. BioDiem receives royalty payments on sales of this product in the private market.

It is anticipated that the Government Pharmaceutical Office of Thailand will launch its pandemic vaccine into the Thai market in 2011.

Facilitated by a grant from the WHO, work has commenced on a new laboratory fit-out at the Institute of Experimental Medicine to allow the Institute to handle highly pathogenic influenza strains e.g. H5N1 (avian or bird flu). Any material generated will be also be made available for use in developing countries under the World Health Organization’s Global Pandemic Influenza Action Plan to Increase Vaccine Supply. 

The arrangement with the WHO gives BioDiem the opportunity to realize an early flow of income from royalties on sales in the private market in developing countries.

In 2009 the Institute of Experimental Medicine (IEM), the originator of BioDiem’s Live Attenuated Influenza Virus (LAIV) technology, entered into a development and collaboration agreement with the PATH, an international non-profit organization, to develop a prototype pandemic LAIV vaccine for use in developing countries. The aim of this collaboration is to speed the development of live attenuated influenza vaccines that can be a safe, low-cost, and highly effective method for enabling real-time response against an influenza pandemic which is likely to hit developing countries hardest.

Under this agreement, nonclinical studies of the LAIV vaccine against pandemic H5N1 (avian) and H7N3 (avian) influenza strains were successfully completed. The vaccine against the avian H5N1 influenza strain is scheduled to enter early stage clinical trials in 2012.

Co-operative Research and Development Agreement (CRADA)

The Cooperative Research and Development Agreement (CRADA) between BioDiem and the US Center for Disease Control and Prevention (CDC) aims to develop a vaccine candidate against the H5N1 avian influenza based on BioDiem’s technology. Preclinical studies to assess the infectivity, immunogenicity and protective efficacy of the H5N1 LAIV versus the standard inactivated influenza vaccine have been successfully completed. The results support the value of the LAIV vaccine technology in protection against the H5N1 virus. In particular it was demonstrated that the cell-based manufacturing method, which allows rapid scale up in the case of a pandemic, produced successful results and that the LAIV vaccine provided greater cross-protection against variants of the H5N1 virus than the inactivated vaccine. Previous published work demonstrated the efficacy of cell-produced LAIV vaccine vs. egg-produced vaccine in ferret studies.

LAIV VECTOR

Viruses have the ability to generate proteins prolifically. Viral vectors are viruses which are used as a delivery tool for proteins (antigens or epitopes) in vaccines. They deliver the specific proteins to elicit an immune response in the person vaccinated. The resulting vaccines can target a wide range of diseases depending on the choice of antigen or epitope which is presented. Various viruses have been engineered for vaccine design to produce specific proteins of diseases unrelated to the virus that generate a protective immune response to the unrelated disease. Unfortunately these viruses often have disadvantages. For example, they are weak and therefore safe, but often too weak to generate the strong immune response needed.

The LAIV vector research aims to produce a platform technology to assist in the design of vaccines for different diseases including cancers.  The initial phase of the laboratory work will be to ascertain the feasibility of the approach. The advantage of the LAIV virus technology is that it has a documented safety profile from its use in Russia over many years and through its use in the European clinical trial program as an influenza vaccine. BioDiem has access to GMP virus materials (LAIV) will enhance the value of the vector project. There are a number of critical steps in the project including importation and regulatory approvals for the biological starting materials, and the confirmation of the feasibility of using the LAIV, the ‘flu virus itself, as a vector in an artificial model. Following this successful demonstration, specific cancer and infectious diseases will be targeted in animal models i.e. nasopharyngeal carcinoma and respiratory syncytial virus, respectively.

Nasopharyngeal carcinoma (NPC) is a cancer originating in the nasopharynx, the uppermost region of the throat, where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck in its occurrence, causes and treatment. It is strongly related to Epstein-Barr virus infection, which is associated with glandular fever.  The prevalence of NPC is greatest in Asia, and is vastly more common in certain regions of East Asia and Africa than elsewhere.

Respiratory Syncytial Virus (RSV) is a common childhood respiratory infection and is the single most important cause of severe respiratory illness in infants and young children and the major cause of infantile bronchiolitis (inflammation of the small airways in the lung). It is the most frequent cause of hospitalization of infants and young children in industrialized countries. In the USA alone, from 85,000 to 144,000 infants with RSV infections are hospitalized annually, resulting in 20%-25% of pneumonia cases and up to 70% of bronchiolitis cases in the hospital. The global burden of RSV is estimated at 64 million cases and 160,000 deaths every year.