Safety, Immunogenicity and Efficacy Against of a Combined Malaria Vaccine in Healthy Malaria-naïve Adults

Study Overview
=================
Brief Summary
-----------------
This study will evaluate whether administration of two investigational malaria vaccines (257049 and Ad35.CS.01 vaccines) combined in one immunization schedule increases protection against malaria infection as compared to protection induced by the 257049 vaccine alone. The study will also evaluate the safety and the immune response to the new combination of the two experimental malaria vaccines.

Detailed Description
-----------------
Approximately 168 healthy, malaria-naïve volunteers aged 18 - 50 years, divided into 2 groups (84 in each group), will receive either one dose of Ad35.CS.01 followed by two doses of 257049 at monthly intervals or 3 doses of 257049 vaccine at monthly intervals. Of these, a maximum of 138 vaccinated volunteers will be challenged with P. falciparum infected mosquitoes. The challenge will occur 2 weeks following the third immunization. A group of up to 18 infectivity controls will begin participation in the study at the challenge stage. These controls receive no vaccine and are enrolled for malaria-challenge only in order to provide comparison group for vaccinated individuals.

Official Title
-----------------
Safety, Immunogenicity and Efficacy Against Malaria in the Sporozoite Challenge Model of One Dose of Ad35.CS.01 Malaria Vaccine Followed by Two Doses of Malaria 257049 Vaccine in Healthy Malaria-naïve Adults

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Biological: Crucell's replication deficient adenovirus type 35 circumsporozoite malaria vaccine (Ad35.CS.01)
* Biological: GSK Biologicals' malaria vaccine 257049 (2 doses)
* Biological: GSK Biologicals' malaria vaccine 257049 (3 doses)
* Other: Sporozoite challenge


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes can and will comply with the requirements of the protocol. A male or non-pregnant female 18 to 50 years of age at the time of first vaccination. Written informed consent obtained from the subject before screening procedures. Free of obvious health problems as established by medical history and clinical examination before entering into the study. Available to participate for the duration of the study. Female subjects of non-childbearing potential. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate Food and Drug Administration (FDA)-approved contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate FDA-approved contraception during the entire treatment period and for 2 months after completion of the vaccination series and/or malaria challenge. Pass a comprehension assessment test. Exclusion Criteria: Use of any investigational or non-registered product within 30 days preceding the first dose of study vaccine, or planned use of any investigational or non-registered product other than the study vaccines during the study period. Planned administration/ administration of a vaccine not foreseen by the study protocol within 7 days of the first dose of vaccines. Prior receipt of an investigational malaria or adenovirus vaccine. Chronic use of antibiotics with antimalarial effects. History of malaria chemoprophylaxis within 60 days prior to vaccination. Any history of malaria. Planned travel to malaria endemic areas during the study period. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s) including latex. History of allergic disease or reactions likely to be exacerbated by chloroquine. History of psoriasis and porphyria, which may be exacerbated after chloroquine treatment. Current use of medications known to cause drug reactions to chloroquine, such as antacids and kaolin. Any history of anaphylaxis in reaction to any previous vaccination. History of severe reactions to mosquito bites. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Chronic administration of immunosuppressants or other immune modifying drugs within six months prior to first vaccine dose. Any confirmed or suspected immunosuppressive or immunodeficient condition, including immunodeficiency virus (HIV) infection. Family history of congenital or hereditary immunodeficiency. History of splenectomy. Major congenital defects or serious chronic illness. History of any neurological disorders or seizures. Acute disease and/or fever at the time of enrollment. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Any abnormal baseline laboratory screening tests. Evidence of increased cardiovascular disease risk, moderate or high, according to the NHANES I criteria. An abnormal baseline screening electrocardiogram (EKG). Hepatomegaly, right upper quadrant abdominal pain or tenderness. Personal history of autoimmune disease. Seropositive for hepatitis B surface antigen or Hepatitis C virus (antibodies to HCV). Pregnant or lactating female. Female who intends to become pregnant during the study or planning to discontinue contraceptive measures. Suspected or known current alcohol abuse. Chronic or active intravenous drug use. History of blood donation within 56 days preceding enrolment. Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ad35.CS.01 Group<br>Healthy male or non-pregnant female subjects, aged 18 to 50 years, were administered one dose of Ad35.CS.01 vaccine at Month 0, and 2 doses of GSK257049 at Months 1 and 2 intramuscularly in the deltoid of the non-dominant arm. The duration of the study was approximately 11 months for vaccinated subjects. | Biological: Crucell's replication deficient adenovirus type 35 circumsporozoite malaria vaccine (Ad35.CS.01)<br>* One dose will be administered intramuscularly at Study Day 0.<br>Biological: GSK Biologicals' malaria vaccine 257049 (2 doses)<br>* Two doses will be administered intramuscularly at monthly intervals<br>|
| Experimental: GSK257049 Group<br>Healthy male or non-pregnant female subjects, aged 18 to 50 years, were administered 3 doses of GSK257049 vaccine at Months 0, 1 and 2 intramuscularly in the deltoid of the non-dominant arm. The duration of the study was approximately 11 months for vaccinated subjects. | Biological: GSK Biologicals' malaria vaccine 257049 (3 doses)<br>* Three doses will be administered intramuscularly at monthly intervals<br>|
| Experimental: Control Group<br>Healthy male or non-pregnant female subjects, aged 18 to 50 years, were volunteers who did not receive any immunization but were subjected to the sporozoite challenge. The duration of the study was approximately 8 months for infectivity control subjects. | Other: Sporozoite challenge<br>* Subjects were challenged with sporozoite-infected mosquitoes to determine whether immune protective response had been induced by vaccination.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Plasmodium Falciparum Parasitemia Following Sporozoite Challenge | P. falciparum parasitemia was defined as a positive blood slide. | 28 days following sporozoite challenge (Day 105) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, pain that prevented normal every day activities. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | Within the 7-day (Day 0 - Day 6) follow-up period post-vaccination | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were chills, fatigue, gastrointestinal symptoms, headache and temperature [defined as axillary temperature equal to or above (≥) 38 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade.Grade 3 Chills = rigors [uncontrollable shivering more than (>) 15 seconds]. Grade 3 Fatigue, Gastrointestinal symptoms and Headache = symptoms that prevented normal activity. Grade 3 fever = fever higher than (>) 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | Within the 7-day (Day 0 - Day 6) follow-up period post-vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within the 30-day (Day 0 - Day 29) follow-up period post-vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within the 30-day (Day 0 - Day 29) follow-up period post-challenge | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | Throughout the study period (Day 0 - Day 236) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days Until the Onset of P. Falciparum Parasitemia Following Sporozoite Challenge | The onset of P. falciparum parasitemia was defined by a positive blood slide. | From day of challenge (Day 0) up to 159 days post-challenge | 
| Anti-circumsporozoite Protein (Anti-CS) Antibody Titers | Titers are presented as geometric mean titers (GMTs) and are measured in titers. Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore GMTs for this group are presented as from Day 77. | 28 days post-dose 1 (Day 28), 28 days post-dose 2 (Day 56), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Anti-hepatitis B (Anti-HBs) Antibody Titers | Titers are presented as geometric mean titers (GMTs) and are measured in titers. Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore GMTs for this group are presented as from Day 77. | 28 days post-dose 1 (Day 28), 28 days post-dose 2 (Day 56), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Anti-Adenovirus Type 35 (Ad35) Neutralizing Antibody Titers at Specified Time Points | Titers are presented as geometric mean titers (GMTs) and are measured in titers. Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore GMTs for this group are presented as from Day 77. | 28 days post-dose 1 (Day 28), 28 days post-dose 2 (Day 56), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Frequency of CS (Total CS or Repeat)-Specific CD4+ T-cells | CS-specific CD4+ T-cells expressing at least 2 cytokines/activation markers between IL-2, IFN-γ, TNF-α and CD40-L are presented here. Analysis was performed via intra-cellular staining (ICS) assays, data are presented as frequency of T-cells per million peripheral blood mononuclear cells (PBMCs).Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore the frequency for this group is presented as from Day 77. | 14 days post-dose 1 (Day 14), 14 days post-dose 2 (Day 42), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Frequency of CS (Total CS or Repeat)-Specific CD8+ T Cells | CS-specific CD8+ T-cells expressing at least 2 cytokines/activation markers between IL-2, IFN-γ, TNF-α and CD40-L are presented here. Analysis was performed via intra-cellular staining (ICS) assays, data are presented as frequency of T-cells per million peripheral blood mononuclear cells (PBMC). Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore the frequency for this group is presented as from Day 77. | 14 days post-dose 1 (Day 14), 14 days post-dose 2 (Day 42), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Frequency of HBs-specific CD4+ T-cells | HB-specific CD4+ T-cells expressing at least 2 cytokines/activation markers between IL-2, IFN-γ, TNF-α and CD40-L are presented here. Analysis was performed via intra-cellular staining (ICS) assays, data are presented as frequency of T-cells per million peripheral blood mononuclear cells (PBMCs). Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore the frequency for this group is presented as from Day 77. | 14 days post-dose 1 (Day 14), 14 days post-dose 2 (Day 42), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Frequency of CS-specific T-cells Producing IFN-γ | The analysis was performed via Enzyme-Linked Immunospot (ELISPOT) full length assay. Data are presented as the number of spots per million peripheral blood mononuclear cells (PBMCs). Volunteers from Control Group did not receive any immunization, but were subjected to the sporozoite challenge, therefore the frequency for this group is presented as from Day 77. | 14 days post-dose 1 (Day 14), 14 days post-dose 2 (Day 42), 21 days post-dose 3 (Day 77 = Day of challenge), 28 days post-challenge (Day 105), 63 days post-challenge (Day 140), 159 days post-challenge (Day 236) | 
| Frequency of CS-specific T-cells Producing IFN-γ | The analysis was performed via Enzyme-Linked Immunospot (ELISPOT) N-terminal assay. Data are presented as the number of spots per million peripheral blood mononuclear cells (PBMCs). | 14 days post-dose 1 (Day 14) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
safety, Vaccine, Phase 1/2, immunogenicity, Malaria, efficacy, sporozoite challenge