Double-blind, Randomized, Controlled Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine

Double-blind, Randomized, Controlled Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine

A Dbl-blind,Randomized,Controlled,Phase IIb Field Trial in 12-47 Month-old Children in Western Kenya to Eval the Efficacy,Safety and Immunogenicity of the FMP1/AS02A Malaria Vaccine vs Rabies Vaccine

The PATH Malaria Vaccine Initiative (MVI), United States Agency for International Development (USAID), GlaxoSmithKline, Kenya Medical Research Institute, Walter Reed Army Institute of Research (WRAIR)

This trial is currently evaluating one candidate malaria vaccine, FMP1/AS02A. This candidate malaria vaccine is being developed for the routine immunization of infants and children living in malaria-endemic areas. This vaccine would offer protection against malaria disease due to the parasite Plasmodium falciparum. Prior to the start of this study, FMP1/AS02A had been given to approximately 60 malaria-naïve adults and 40 adults and 90 children living in malaria-endemic regions. This study will investigate whether the candidate vaccine prevents malaria disease for 6 months post-vaccination. One half of the enrolled subjects will receive FMP1/AS02A and the other half rabies vaccine (RabAvert).

Field trial of a candidate antigen/adjuvant conducted at one study center with 12 outlying (satellite) field stations. Subjects were screened no more than 45 days prior to the first inoculation and were randomized on the first day of vaccination 1:1 between two arms (FMP1/AS02A and rabies vaccine). The planned immunization schedule was 0, 1, and 2 months for both study arms; however, the 4-week intervals between doses could be extended for up to 2 additional weeks if temporary suspension was deemed advisable due to serious adverse events (SAEs) or other concerns. Vaccinations were administered intramuscularly (IM) in the left anterolateral thigh muscle unless a compelling reason for using an alternate injection site was evident. Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). Follow-up of SAEs continued for study duration. Active case detection occurred during the Efficacy Follow-up Period (169 days, starting 14 days after the third vaccination (Day 71)), active case detection commenced with visits approximately every 28 days to the Walter Reed Project Kombewa clinic and terminated after 6 months (approximately Day 240). The primary study analysis for all endpoints was completed on the cleaned Efficacy Follow-up Period database after a data-lock-point. The Addendum Efficacy Follow-up Period (125 days) started with the end of the Efficacy Follow-up Period (approximately Day 240) and active case detection commenced with visits approximately every 28 days to the Walter Reed Project Kombewa Clinic and terminated after 10 months (approximately Day 364). The study addendum analysis for all endpoints was completed after the Addendum Efficacy Follow-up Period database after a data-lock-point. Malaria cases were detected actively and passively. Active case detection was handled through scheduled (1) facilitated participant visits to the Kombewa Clinic and (2) field worker visits to participant homes. Passive case detection was handled through unscheduled, self-presentation of participants to the Kombewa Clinic. At scheduled clinic visits, blood samples were taken from all subjects to determine parasite density and hemoglobin levels. At home visits, subjects with fever or other illness within the 24 hours were transported to the clinic for collection of blood samples.

Subjects were screened no more than 45 days prior to the first inoculation and were randomized on the first day of vaccination 1:1 between two arms (FMP1/AS02A and rabies vaccine (RabAvert)).

Both study participants and those investigators responsible for evaluation of the endpoints will be blinded as to who receives the test article versus the comparator. On vaccination days, the comparator vaccine will be in the same package as received from the manufacturer. After agitation it will appear clear and pink. The FMP1 antigen and the AS02A adjuvant will be packaged separately. The reconstituted FMPI antigen in the AS02A adjuvant/diluent will have a milky white appearance. Because the vaccines will have a markedly different appearance, contents of the syringe will be concealed as described later in this section. The two vaccine preparation teams, consisting of the study pharmacist, pharmacy assistants, and drug manager (an experienced nurse, clinician, or pharmacist), will be responsible for vaccine preparation. They will also verify that the proper vaccine and vaccine dose is prepared and delivered to each subject.

FMP1/AS02A candidate malaria vaccine was administered IM in the left anterolateral thigh muscle at 0, 1, and 2 months

Subjects Time to First Clinical Episode of P Falciparum Malaria During the Efficacy Follow-up Period Adjusted for Time at Risk - Intent to Treat (ITT) Population

Days to first clinical episode of P falciparum malaria during the efficacy f/u period for ITT population Time at Risk adjusted for: SA= study absence MT= malaria treatment SA MT= study absence and malaria treatment Case Definitions: Primary = >37.5°C with presence of a density of asexual stage P. falciparum >50K parasites/µL blood Secondary (200) = >37.5°C with presence of a density of asexual stage P. falciparum >200K parasites/µL blood Secondary (100) = >37.5°C with presence of a density of asexual stage P. falciparum >100K parasites/µL blood Secondary (10) = >37.5°C with presence of a density of asexual stage P. falciparum >10K parasites/µL blood Secondary (0) = >37.5°C with presence of a density of asexual stage P. falciparum >0 parasites/µL blood Secondary (0*) = >37.5°C OR history of fever in the last 24 hrs with presence of a density of asexual stage P. falciparum >0 parasites/µL blood

Time to First Clinical Episode of P Falciparum Malaria During the Efficacy Follow-up Period Adjusted for Time at Risk - According to Protocol (ATP) Population

Days to first clinical episode of P falciparum malaria during the efficacy f/u period for ATP population Time at Risk adjusted for: SA= study absence MT= malaria treatment SA MT= study absence and malaria treatment Case Definitions: Primary = >37.5°C with presence of a density of asexual stage P. falciparum >50K parasites/µL blood Secondary (200) = >37.5°C with presence of a density of asexual stage P. falciparum >200K parasites/µL blood Secondary (100) = >37.5°C with presence of a density of asexual stage P. falciparum >100K parasites/µL blood Secondary (10) = >37.5°C with presence of a density of asexual stage P. falciparum >10K parasites/µL blood Secondary (0) = >37.5°C with presence of a density of asexual stage P. falciparum >0 parasites/µL blood Secondary (0*) = >37.5°C OR history of fever in the last 24 hrs with presence of a density of asexual stage P. falciparum >0 parasites/µL blood

Vaccine-Related Solicited Symptoms During 7-day Follow-up Period by Immunization - Intent to Treat (ITT) Population

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Vaccine-Related Solicited Symptoms During 7-day Follow-up Period by Immunization - According to Protocol (ATP) Population

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Number of Patients Who Showed Symptoms, Unsolicited Adverse Events, and Serious Adverse Events by Immunization

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). Follow-up of SAEs continued for study duration (364 days)

vaccination day plus post-vaccine days 1, 2, 3, and 6; 30 day follow-up for unsolicited events and follow-up for SAEs to continue for duration of study (364 days)

Vaccine-Related Local and Systemic Solicited Adverse Events by Immunization - According to Protocol (ATP)

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Each subject participated in the study approximately 14 months with 7-day follow-up for solicited adverse events (five visits: vaccination day plus post-vaccination days 1, 2, 3, and 6) and 30-day follow-up for unsolicited events (vaccination day plus 29 subsequent days). I1 = Immunization 1 I2 = Immunization 2 I3 = Immunization 3

Inclusion Criteria: All subjects must satisfy the following criteria at study entry: A healthy male or female child, 12 to 47 months of age on the day of screening Written informed consent obtained from at least one parent/guardian before study start Available to participate for the study duration (about 14 months) Exclusion Criteria: Acute disease at the time of entry into the study that in the opinion of the investigator may pose a threat to the subject Prior receipt of a rabies vaccine or any investigational vaccine Use of any investigational drug or vaccine other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use up to 30 days after the third dose Administration of chronic (defined as more than 14 days) immunosuppressants or other immune-modifying drugs within six months of vaccination. (For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day. Inhaled and topical steroids are allowed) Administration or anticipated administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine(s) with the exception of tetanus toxoid Previous vaccination with a vaccine containing MPL or QS21 (e.g., RTS,S/AS02A) Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection. (No HIV test will be performed as part of this study.) History of allergic reactions or anaphylaxis to immunizations or to any vaccine components, such as eggs History of surgical splenectomy Administration of immunoglobulins, blood transfusions, or any other blood products within the six months preceding the first dose of study vaccine or planned administration during the study period Simultaneous participation in any other clinical trial Acute or chronic cardiovascular, pulmonary, hepatic, or renal condition that in the opinion of the PI, may increase the risk to the subject from participating in the study Any other condition or circumstance that in the opinion of the investigator may pose a threat to the subject

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