PART B: INFORMATION ABOUT THE RELEASE APPLICATION TO BE INCLUDED ON THE PUBLIC REGISTER
B1. The name and address of the applicant.
One MedImmune Way
Gaithersburg, MD 20878
B2. The full or general description of the genetically modified organisms in relation to which the application is being made.
The GMO, MEDI-534 (b/h PIV3/RSV F2), is a recombinant vaccine which expresses human PIV3 fusion (F) and hemagglutinin-neuraminidase (HN) proteins in a bovine PIV3 virus genomic backbone. In addition, the human RSV fusion protein (RSV F) has been engineered into the genome. Thus, the bPIV3 backbone is used to deliver antigens thought to be protective against both RSV and hPIV3 infection.
MEDI-534 is an intranasal vaccine for the prevention of lower respiratory tract disease caused by RSV and hPIV3 in young infants. This study is being conducted to evaluate the safety and immune response of this vaccine in healthy 6 to <24 month-old children and in 2 month-old infants.
In animal model systems, MEDI-534 has been shown to be safe and well-tolerated. MEDI-534 has been previously evaluated in two completed Phase 1 clinical trials in the United States. Overall, the data from clinical testing in healthy adults and RSV and PIV3 seropositive children 1 to 9 years of age suggest that MEDI-534 has an acceptable safety profile and restricted replication in seropositive subjects. MEDI-534 is also currently being evaluated in an on-going Phase 1 study that evaluates the safety, tolerability, immunogenicity and shedding of MEDI-534 in seronegative children 6 to <24 months of age. A preliminary blinded evaluation after 2 doses of MEDI-534 indicates that the vaccine was well tolerated in hRSV and hPIV3 seronegative infants 6 to <24 months of age. This study is currently enrolling subjects within the United States. The study which is proposed in this application is an international study and is currently enrolling subjects in the United States.
B3. The location(s) at which the genetically modified organisms will be released.
The following clinical study sites within Scotland will be used:
The GMO will be administered at the Castlemilk Health Centre, 71 Dougrie Drive, Glasgow, G45 9AW, United Kingdom.
The GMO will be administered at the Royal Aberdeen Children's Hospital , Westburn Road , Aberdeen , AB25 2ZG, United Kingdom.
The GMO will be administered at the Queen Mother's Hospital, Dalnair Street, Yorkhill, Glasgow, G3 8SJ, United Kingdom.
The GMO will be administered at the Southern General Hospital Maternity Unit, 1345 Govan Road, Glasgow, G51 4TF, United Kingdom.
The GMO will be administered at the Royal Hospital for Sick Children, Dalnair Street, Yorkhill, Glasgow, G3 8SJ, United Kingdom.
B4. The general purpose or details of the purpose for which the genetically modified organisms will be released.
The objectives of this study are to describe the safety, immune response and viral shedding of multiple doses of MEDI-534 in RSV and PIV3 seronegative children 6 to < 24 months of age and in infants 2 months of age. The study will be conducted in North America, South America, Europe, Africa, and Australia/New Zealand and is currently ongoing in the United States.
The intention of this study is to add to scientific/clinical knowledge by continuing to expand the safety profile of MEDI-534 in both young seronegative children 6- 24 months of age and infants 2 months of age. Additionally, evaluation of the immune response generated by administration of multiple doses of MEDI-534 will provide an initial indication of the biological activity of MEDI-534. The dosage that will be used for further development will be selected based on data from this trial.
No vaccine exists for the prevention of RSV or hPIV3 infections and disease. Because RSV and hPIV3 infects and can cause disease in otherwise healthy infants, the development of vaccines for the prevention of RSV disease is a public health priority (WHO 2007).
B5. The foreseen dates of the release.
It is anticipated that enrollment of study MI-CP178 will begin in the EU in April 2009 and will be completed by March 2012. However, based on data generated in this and other studies, MedImmune envisions requesting permission to conduct further studies to evaluate the vaccine's clinical efficacy.
B6. The methods and plans for monitoring the genetically modified organisms and for emergency response.
The MEDI-534 vaccine has been shown to be safe and well tolerated in animals and in adults and children 1 to 9 years of age. Safety monitoring of the study subjects will be conducted through the duration of the study, and study subjects will have regular safety assessments. Study subjects will also be monitored for their immune response following administration with the MEDI-534 vaccine through the collection of blood samples at pre-defined timepoints throughout the study.
Study subjects will be administered either MEDI-534 vaccine or a placebo intranasally. Because the MEDI-534 vaccine is a live vaccine, replication of the vaccine virus in the nasal passages is required to generate an immune response. Thus, it is expected that RSV and PIV3 naïve recipients will shed vaccine virus through nasal secretions. Study subjects will therefore be monitored for viral shedding by the collection of nasal wash specimens at defined intervals during the study, and during any unscheduled illness visits.
The MEDI-534 vaccine can be identified by genetic analysis in samples taken from study subjects. The MEDI-534 vaccine cannot persist in the environment on its own and can easily be decontaminated using common household disinfectants, such as bleach. All clinical study sites where the study will be conducted are licensed healthcare facilities and have standard facility controls in place for administration of paediatric vaccines, collection of samples and clinical evaluation of study subjects. MEDI-534 has been classified as a BioSafety Level 1 organism in the United States and does not require any special safety containment above universal precautions.
B7. The evaluation of the environmental impact of the genetically modified organisms, in particular any pathogenic and/or ecologically disruptive effects.
MEDI-534 vaccine is a live, attenuated virus that requires a specific host cell for replication. The virus does not persist in the environment and can only remain infectious outside of a host cell for no more than 8 hours. Other factors such as sunlight and heat will further decrease its chance of survival outside a host cell. It is susceptible to common disinfectants and cleaning agents. MEDI-534 is considered to have minimal potential hazard to clinical site personnel and the environment. No laboratory manipulation of MEDI-534 vaccine or placebo will be conducted at the clinical study sites. Procedures are in place for the shipping, storage, administration and disposal of MEDI-534, and appropriate site training is conducted on study procedures.
MEDI-534 has been shown to be safe and well-tolerated in nonclinical studies and in clinical studies conducted in the United States in adults and seropositive children. Clinical study MI-CP178, the same study proposed under this application, has also been initiated in the United States. MEDI-534 is also currently being evaluated in an on-going Phase 1 study that evaluates the safety, tolerability, immunogenicity and shedding of MEDI-534 in seronegative children 6 to <24 months of age (study MI-CP149). A preliminary evaluation after 2 doses of MEDI-534 at the lowest dose indicates that the vaccine was well tolerated in RSV and PIV3 seronegative infants 6 to <24 months of age.
Replication of MEDI-534 in the nasal mucosa is required to generate an immune response. Thus, it is expected that RSV and PIV3 naïve recipients will shed vaccine virus through nasal secretions. Although viral shedding is very restricted in seropositive individuals, the magnitude and duration of viral shedding for MEDI-534 in RSV and PIV3 seronegative children is still unknown. Shedding of MEDI-534 leading to secondary transmission is possible with potential secondary transmission to vulnerable populations such as pregnant women, immunocompromised individuals and seronegative children. The study exclusion criteria outlined in the protocol exclude subjects from participation if they have the potential to come into contact with individuals considered to be at risk for secondary transmission of MEDI-534 should a subject shed vaccine virus. These exclusion criteria provide a guideline for the extent of contact that should be avoided to minimize the risk of transmission to these populations. RSV and PIV3 are endemic throughout the world and all people can expect to be serially exposed on an annual basis.
During the conduct of the study, subject safety will be monitored by the collection of solicited symptoms, adverse events, serious adverse events, concomitant medication use, medically attended lower respiratory illness, and significant new medical conditions. Additionally, viral shedding will be monitored by the collection of nasal wash specimens at defined intervals and during illness visits, and immunogenicity will be evaluated through the collection of serum samples at defined intervals.
The bPIV3 strain that serves as a backbone for the MEDI-534 vaccine naturally occurs in cows and has been shown to cause respiratory disease in seronegative calves. bPIV3 is endemic throughout the world. Virulence of MEDI-534 in bovines has not been studied; however, transmission to animals would require the sharing of nasal secretions from vaccinated infants with the animal. No evidence exists of MEDI-534 being transmitted from humans to animals or vice versa. MEDI-534 is not expected to infect microbes or plant cells. The study vaccine will be administered at standard healthcare facilities where paediatric vaccines are commonly administered. It is not anticipated that the study vaccine or any waste associated with study procedures will affect the surrounding ecosystem.