Efficacy, Safety and Immunogenicity Study of GlaxoSmithKline(GSK) Biologicals' Candidate Malaria Vaccine 257049 in the Sporozoite Challenge Model in Healthy Malaria-naïve Adults

This protocol posting has been amended to reflect changes in Amendment 1 of the Protocol (20 April 2014).

Rationale for Protocol Amendment 1:

• In order to assess whether protection is maintained over time, and assess boostability, the protocol has been amended to incorporate another sporozoite challenge, after a single boost of 1/5th standard dose of RTS,S/AS01B, or no boost.

Study design:

• Dependent upon enrolment date during the screening period, the study duration will be approximately 19 months for each vaccinated subject in the delayed fractional dose group, 14 months for each vaccinated subject in the 0, 1, 2-month group, 7 months for each infectivity control subject in the challenge phase and 6 months for each infectivity control subject in the rechallenge phase.
• Vaccination schedules:

• 0, 1, 7-month followed by sporozoite challenge 21 days (3 weeks) after the third vaccination, with subsequent boosting/no boosting at Booster Phase Study Day 0 followed by sporozoite rechallenge 3 weeks post boost/no boost.
• 0, 1, 2-month followed by sporozoite challenge 21 days (3 weeks) after the third vaccination, with subsequent boosting/no boosting at Booster Phase Study Day 0 followed by sporozoite rechallenge 3 weeks post boost/no boost.
• Safety and immunogenicity will be evaluated during the study up to 3 months after rechallenge (Booster Phase Study Day 105).
• Treatment allocation:

• Non-randomized for primary phase; subjects will be enrolled to different study groups in a consecutive manner, to ensure the day of sporozoite challenge (conducted over two days) is the same for all.
• For the booster and rechallenge phase, subjects unprotected during the first challenge will receive a 1/5th RTS,S/AS01B booster dose while subjects from each group who were protected in the first challenge will be randomized to receive a 1/5th RTS,S/AS01B booster dose or no booster dose.

This protocol posting has been amended to reflect changes in Amendment 2 of the Protocol (08 January 2015) Rationale for Protocol Amendment 2: In order to have sufficient blood samples for future assay development or testing, evaluation of Hepatitis B (HBs) cellular-mediated immunogenicity (CMI) was de-prioritised from a secondary outcome measure to a tertiary secondary outcome measure and will only be conducted if sufficient cells are available from the thawn cryotube(s) that will be used for circumsporozoite protein (CS) testing.

Inclusion criteria

Inclusion criteria

for enrolment to the primary phase:

• Subjects who, in the opinion of the investigator, 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 (approximately 15 months per vaccinated subject in the delayed fractional dose group, approximately 10 months per vaccinated subject in the 0, 1, 2-month schedule and approximately 7 months per subject in the infectivity control group).
• Female subjects of non-childbearing potential may be enrolled in the study.

• Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause.
• Female subjects of childbearing potential may be enrolled in the study, if the subject:

• has practiced adequate 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.

Inclusion criteria

for enrolment to the booster phase:

• Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written informed consent obtained from the subject before screening procedures.
• Subjects vaccinated in the primary phase of the study (not applicable to new infectivity controls), having undergone sporozoite challenge during the primary phase of the study.
• Available to participate for the duration of the booster phase of the study (approximately 3 months).
• Female subjects of non-childbearing potential may be enrolled in the study.

• Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause.
• Female subjects of childbearing potential may be enrolled in the booster phase of the study, if the subject:

• has practiced adequate FDA-approved contraception for 30 days prior to day of booster vaccination, and
• has a negative pregnancy test on the day of booster vaccination, and
• has agreed to continue adequate FDA-approved contraception during the entire treatment period and for 2 months after completion of the booster vaccination and/or malaria rechallenge.

Exclusion criteria

For enrolment to the primary & booster phase:

• Any confirmed or suspected immunosuppressive or immunodeficient condition, including immunodeficiency virus (HIV) infection.
• Acute disease and/or fever at the time of enrolment to booster phase.

• 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.
• Fever is defined as temperature ≥ 38.0°C (100.4°F) on oral, axillary or tympanic setting. The preferred route for recording temperature in this study will be oral.
• Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.
• Evidence of increased cardiovascular disease risk, "moderate" or "high", according to the National health and nutrition examination survey I (NHANES I) criteria.

Note: NHANES I criteria will be applied for all subjects including subjects aged 18-35 years old.

• An abnormal baseline screening electrocardiogram (EKG), defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm excluding isolated premature atrial contractions; right or left bundle branch block; or advanced A-V heart block.
• Female who intends to become pregnant during the study or planning to discontinue contraceptive measures.

For enrolment to the primary phase:

• Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use 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 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.
• 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. For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 20 mg/day. Inhaled and topical steroids are allowed.
• Family history of congenital or hereditary immunodeficiency.
• History of splenectomy.
• Major congenital defects or serious chronic illness.
• History of any neurological disorders or seizures, except for a single episode of simple febrile seizure in childhood.
• Any abnormal baseline laboratory screening tests: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), creatinine, hemoglobin, platelet count, total white blood cell count, out of normal range as defined in the protocol.
• Hepatomegaly, right upper quadrant abdominal pain or tenderness.
• Personal history of autoimmune disease.
• Seropositive for hepatitis B surface antigen or Hepatitis C virus.
• Pregnant or lactating female.
• 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.

For enrolment to the booster phase:

• Planned use of any investigational or non-registered product other than the study vaccine during the study period.
• Planned administration/administration of a vaccine not foreseen by the study protocol within 7 days of booster dose of study vaccine.
• Planned administration of immunoglobulins and/or any blood products during the study period.
• An abnormal baseline laboratory screening test, graded 2 or more as defined in the protocol.
• Any abnormal baseline laboratory screening tests out of normal range as defined in the protocol and of clinical concern according to the Principal Investigator.
• Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in the booster phase of the study.