Study of Malaria Vaccine RTS,S/AS01E in Plasmodium Falciparum-infected and Uninfected Adults Pre-treated With Anti-malarial Therapy

Phase 2

Completed

Conditions: Plasmodium Falciparum

Interventions: Biological: Abhayrab rabies vaccine
Biological: Malaria Vaccine RTS,S/AS01E
Drug: Dihydroartemisinin-piperaquine (DHA/Pip)
Drug: Artemether / Lumefantrine
Drug: Primaquine

Registration Number: NCT04661579

Lead Sponsor: PATH

Brief Summary: The main goal of this study is to assess the efficacy of RTS,S/AS01E, a candidate vaccine against malaria caused by Plasmodium falciparum (P. falciparum), in adults positive for P. falciparum at the start of the study, but treated with anti-malarial medications to clear the parasite before receiving multiple doses of the vaccine. The goal is to overcome the reduced vaccine efficacy (hypo-responsiveness to the vaccine) reported in actively or chronically infected adults.

Detailed Description: PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the burden of malaria disease in children and contribute to malaria elimination. GSK has developed a candidate vaccine against malaria caused by P. falciparum called RTS,S/AS01E. The vaccine has been shown to be safe in multiple trials and efficacy data in pediatric populations has led to a pilot implementation program in three African countries including Kenya. The RTS,S/AS01E vaccine mechanism of action is presumed to work on the initial sporozoite and liver stages of P. falciparum infection through neutralization of the circumsporozoite (CS) antigen on parasites invading after a mosquito bite in individuals immunized with the RTS,S/AS01E vaccine. In order to inform whether a vaccine such as RTS,S/AS01E may have a future role in malaria elimination, it will be important to establish vaccine efficacy in adults in Sub-Saharan Africa who are reservoirs of parasites and who contribute to ongoing malaria transmission. However, in previous trials, the vaccine has been less effective in adults who have had malaria before. There are probably multiple reasons for this, but one possible reason that is probably very important is that prior infection with malaria or an infection with malaria for long periods, even without symptoms of the disease, can prevent the vaccine from working properly.

This study postulates that treatment of infection prior to immunization can reset the immune response leading to an improved vaccine efficacy. To evaluate this hypothesis, the study will recruit 5 groups. Groups 1 and 4 will have asymptomatic infection with P. falciparum as measured by a highly sensitive polymerase chain reaction (PCR) assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the primary objective of evaluating the vaccine efficacy of RTS,S/AS01E relative to the rabies vaccine in this context. Groups 2 and 5 will be negative for asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the secondary objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Group 3 will have asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay but will not be treated with antimalarial medications prior to immunization with the RTS,S/AS01E vaccine; the immunological profile of this group and groups 1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives include safety assessments.

The study will include an initial immunization period (vaccine given on 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations) followed by 6-12 months of follow-up (varying based on the number of events),

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 620

Inclusion Criteria

Provision of signed or thumb printed and dated informed consent form
Stated willingness to comply with all study procedures and availability for the duration of the study
Male or female between 18 and 55 years of age, inclusive
In good general health as evidenced by medical history and clinical examination before entering the study
Ability to take oral medication and be willing to adhere to the medication regimen
For females, she must be of non-childbearing potential or use appropriate measures to prevent pregnancy for 30 days prior to vaccination through 2 months after completion of the vaccine series. Non-childbearing potential means she is surgically sterilized or at least one year post-menopausal. Appropriate measures to prevent pregnancy include abstinence or adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant or Depo-Provera). Clinical trial site staff will assist with provision of acceptable birth control for study entry and will discuss with volunteer at screening visit.

Exclusion Criteria

Planned administration/administration of a vaccine not foreseen by the study protocol from within 30 days before the first dose of study vaccine until 30 days after the last dose of study vaccine.†

† In the context of the COVID-19 pandemic, the administration of the COVID-19 vaccine will be allowed as an exception to this exclusion criteria as follows. The study team will work with the participant to attempt to have any COVID-19 vaccine administration occur 30 days or more before or after study vaccinations. When this is not possible, COVID-19 vaccination will be allowed 10 days or more before or after study vaccination. Intervals shorter than 10 days can be allowed on a case-by-case basis in discussion with the sponsor.
Any prior receipt of any rabies vaccine or experimental malaria vaccine.
Confirmed or suspected significant immunosuppressive or immunodeficient condition as determined by the investigator, including clinical stage 3 or 4 human immunodeficiency virus (HIV) infection.
A family history of congenital or hereditary immunodeficiency.
History of allergic reactions, significant immunoglobulin E (IgE)-mediated events or anaphylaxis to previous immunizations.
History of any neurologic disorders.
Acute disease (defined as the presence of a moderate or severe illness with or without fever), including acute malaria, at the time of enrolment. All vaccines can be administered to persons with a minor illness, such as diarrhea or mild upper respiratory infection without fever, i.e. Oral temperature < 37.5°C*. Individuals excluded with acute disease, including acute malaria, can become eligible again after complete recovery of the illness, including appropriate treatment as applicable, and can be rescreened at a later date. *Temperature readings may be taken by site staff either using either oral, axillary, or infrared thermal thermometers during clinic or field visits, while subjects enrolled in the reactogenicity cohort will be supplied with oral thermometers for the purposes of recording their own temperature measurements in the memory aid over 7 days after each vaccination.
Acute or chronic, clinically significant pulmonary, cardiovascular (including cardiac arrythmias) , hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory screening tests.
History of homozygous sickle cell disease (Hgb SS).
Any clinically significant laboratory abnormalities as determined by the investigator on screening labs.
History of splenectomy.
Administration of immunoglobulins, blood transfusions or other blood products within the three months preceding the first dose of study vaccine or planned administration during the study period.
Pregnant (i.e. a positive pregnancy test) or lactating female during immunization phase of the study (refer to section 2.3 for rationale). If a woman becomes pregnant after all vaccinations are complete, she will not be excluded from the remainder of the study.
Female planning to become pregnant or planning to discontinue contraceptive precautions during the vaccination phase.
History of chronic alcohol consumption and/or drug abuse.
Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose (for corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed).
Major congenital defects or serious chronic illness.
Simultaneous participation in any other clinical trial [apart from participation in the Health and Demographics Surveillance System (HDSS) network].
Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine	Artemether / Lumefantrine	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine	Artemether / Lumefantrine	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine	Artemether / Lumefantrine	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine	Dihydroartemisinin-piperaquine (DHA/Pip)	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine	Abhayrab rabies vaccine	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine	Malaria Vaccine RTS,S/AS01E	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine	Dihydroartemisinin-piperaquine (DHA/Pip)	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine	Malaria Vaccine RTS,S/AS01E	Participants with detectable P. falciparum parasitemia at baseline did not receive any anti-malarial medications to clear parasites. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. This group is included only for immunological assessment and not for vaccine efficacy.
Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine	Malaria Vaccine RTS,S/AS01E	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine	Dihydroartemisinin-piperaquine (DHA/Pip)	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine	Dihydroartemisinin-piperaquine (DHA/Pip)	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine	Abhayrab rabies vaccine	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine	Artemether / Lumefantrine	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine	Primaquine	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine	Primaquine	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine	Primaquine	Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine	Primaquine	Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.

Primary Outcome Measures

Name	Time	Method
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4	The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.	Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive polymerase chain reaction (PCR) (Plasmodium falciparum/ Pan-Plasmodium 18S ribosomal ribonucleic acid (rRNA) laboratory developed test \[LDT\]) that can detect sub-clinical parasitemia at the US Army Medical Research Directorate-Africa (USAMRD-A) / Kenya Medical Research Institute (KEMRI) laboratories in Kisumu, Kenya. A positive PCR result from blood samples collected during the ADI was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.

Secondary Outcome Measures

Name	Time	Method
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5	The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.	Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive PCR (Plasmodium falciparum/ Pan-Plasmodium 18S rRNA LDT) that can detect sub-clinical parasitemia. A positive PCR result from blood samples collected during the ADI phase was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.
Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3	Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination)	The RTS,S antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen. Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) were measured from blood samples of participants in Groups 1, 2 and 3 using standard enzyme-linked immunosorbent assays (ELISA) at Walter Reed Army Institute of Research (WRAIR), in Silver Spring, MD, United States.
Number of Participants With Serious Adverse Events (SAEs)	From first dose to end of study, up to 65 weeks.	An adverse event is any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. A serious adverse event is any adverse event that: * Resulted in death, * Was life-threatening, * Resulted in disability/incapacity, * Required hospitalization or prolongation of existing hospitalization, * Resulted in disability/incapacity. * Resulted in a congenital anomaly and / or birth defect.
Number of Participants With Unsolicited Adverse Events	Within 28 days after each vaccination.	An adverse event is defined as any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study staff during study visits or those identified during review of medical records or source documents. Solicited AEs with an onset after the seven-day solicitation period were also considered unsolicited AEs.
Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3	Baseline, Day 29 (28 days after first vaccination) and Day 225 (28 days after third vaccination)	The RTS,S vaccine antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen, hence anti-HBsAg antibodies were also measured. Anti-hepatitis B surface antigen antibodies were assessed at the International AIDS Vaccine Initiative Human Immunology Laboratory (IAVI-HIL) at Imperial College, London, UK, using a commercially available ELISA kit.
Number of Participants With Solicited Local and Systemic Adverse Events (AEs)	Within 7 days after each vaccination.	Solicited AEs are pre-specified local and systemic AEs that occur relatively more frequently or are known to be associated with immunization, which are monitored actively as potential indicators of vaccine reactogenicity. Solicited local and general AEs were collected among RTS,S vaccinated groups in the first 50 participants enrolled in Groups 1 and 2 and all participants enrolled in Group 3 (Reactogenicity Cohort) for seven days (day of vaccination and six subsequent days) after each dose of vaccine. Local (injection site) adverse events are defined as: * Pain at injection site * Swelling at injection site Systemic adverse events are defined as: * Fever (temperature ≥ 37.5°C) * Headache * Gastrointestinal problems * Fatigue * Muscle ache
Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3	Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination)	Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) measured by standard enzyme-linked immunosorbent assays (ELISA) for participants in Groups 1, 2 and 3. To measure antibody-antigen avidity (strength of binding) ELISA was performed with and without urea (to dissociate the antigen-antibody complex). The avidity index is calculated by dividing the serum titer obtained in the presence of the urea by the serum titer without urea.