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

A Phase 2b Randomized, Open-label, Controlled, Single Center Study in Plasmodium Falciparum-infected and Uninfected Adults Age 18-55 Years Old in Kenya to Evaluate the Efficacy of the Delayed, Fractional Dose RTS,S/AS01E Malaria Vaccine in Subjects Treated With Artemisinin Combination Therapy Plus Primaquine

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.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum
• Intervention / Treatment: Biological: Malaria Vaccine RTS,S/AS01E; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Drug: Artemether / Lumefantrine; Drug: Primaquine; Biological: Abhayrab rabies vaccine

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),

• Study Type: Interventional
• Enrollment (Actual): 620
• Phase: Phase 2

Contacts and Locations

Study Locations

• Kenya
  • Kisumu County
    • Kisumu, Kisumu County, Kenya, 40100
      • Lucas O Tina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E 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 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.	Biological: Malaria Vaccine RTS,S/AS01E; RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization.; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.; Drug: Artemether / Lumefantrine; Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.; Other Names: Coartem®; Drug: Primaquine; One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.
Experimental: Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E 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 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.	Biological: Malaria Vaccine RTS,S/AS01E; RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization.; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.; Drug: Artemether / Lumefantrine; Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.; Other Names: Coartem®; Drug: Primaquine; One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.
Experimental: Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine; 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.	Biological: Malaria Vaccine RTS,S/AS01E; RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization.
Placebo Comparator: Group 4: Positive Parasitemia; Anti-malarial Treatment + 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.	Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.; Drug: Artemether / Lumefantrine; Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.; Other Names: Coartem®; Drug: Primaquine; One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.; Biological: Abhayrab rabies vaccine; Abhayrab rabies vaccine, 0.5 mL, contains 2.5 IU rabies antigen.
Placebo Comparator: Group 5: No Parasitemia, Anti-malarial Prophylaxis + 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.	Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.; Drug: Artemether / Lumefantrine; Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.; Other Names: Coartem®; Drug: Primaquine; One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.; Biological: Abhayrab rabies vaccine; Abhayrab rabies vaccine, 0.5 mL, contains 2.5 IU rabies antigen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5	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.	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.
Number of Participants With Serious Adverse Events (SAEs)	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.	From first dose to end of study, up to 65 weeks.
Number of Participants With Solicited Local and Systemic Adverse Events (AEs)	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	Within 7 days after each vaccination.
Number of Participants With Unsolicited Adverse Events	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.	Within 28 days after each vaccination.
Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3	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.	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)
Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3	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.	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)
Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3	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.	Baseline, Day 29 (28 days after first vaccination) and Day 225 (28 days after third vaccination)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Anti-rabies antibodies	Anti-rabies antibodies at specified timepoints in a subset of subjects in Groups 4 and 5.	Specified timepoints up to 32 weeks.
Exploratory: Cell-mediated immune responses	Cell-mediated immune responses in subjects administered RTS,S/AS01E (Groups 1, 2, and 3) will be descriptive in nature.	Specified timepoints up to 32 weeks.
Exploratory: RNA transcriptional responses	RNA transcriptional responses for all subjects in Groups 1 - 5.	Specified timepoints up to 32 weeks.
Exploratory: Human Leukocyte Antigen (HLA) typing	HLA typing in subjects administered RTS,S/AS01E (Groups 1, 2, and 3).	Up to 53 weeks.
Exploratory: Malaria Cross-sectional prevalence at end of study	Cross-sectional malaria PCR/DBS at Study Termination visit in Groups 1 - 5.	Results determined time period between approximately week 46 and up to approximately week 77.

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: GlaxoSmithKline; Kenya Medical Research Institute; US Army Medical Research Directorate-Africa - Walter Reed Army Institute of Research; FHI Clinical SA Proprietary Limited; DF/Net
• Investigators: Principal Investigator: Lucas O Tina, MD, MTM&H, Kombewa Clinical Research Center

Publications and helpful links

General Publications

• RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014 Jul 29;11(7):e1001685. doi: 10.1371/journal.pmed.1001685. eCollection 2014 Jul.
• Kester KE, Cummings JF, Ofori-Anyinam O, Ockenhouse CF, Krzych U, Moris P, Schwenk R, Nielsen RA, Debebe Z, Pinelis E, Juompan L, Williams J, Dowler M, Stewart VA, Wirtz RA, Dubois MC, Lievens M, Cohen J, Ballou WR, Heppner DG Jr; RTS,S Vaccine Evaluation Group. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis. 2009 Aug 1;200(3):337-46. doi: 10.1086/600120.
• Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, Kathcart AK, Hauns KD, Komisar JL, Qabar AN, Davidson SA, Dutta S, Griffith ME, Magee CD, Wojnarski M, Livezey JR, Kress AT, Waterman PE, Jongert E, Wille-Reece U, Volkmuth W, Emerling D, Robinson WH, Lievens M, Morelle D, Lee CK, Yassin-Rajkumar B, Weltzin R, Cohen J, Paris RM, Waters NC, Birkett AJ, Kaslow DC, Ballou WR, Ockenhouse CF, Vekemans J. Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study. J Infect Dis. 2016 Sep 1;214(5):762-71. doi: 10.1093/infdis/jiw237. Epub 2016 Jun 13.
• Polhemus ME, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S, Cummings JF, Kester KE, Ockenhouse CF, Stewart A, Ofori-Anyinam O, Ramboer I, Cahill CP, Lievens M, Dubois MC, Demoitie MA, Leach A, Cohen J, Ballou WR, Heppner DG Jr. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS One. 2009 Jul 31;4(7):e6465. doi: 10.1371/journal.pone.0006465.
• Keitany GJ, Kim KS, Krishnamurty AT, Hondowicz BD, Hahn WO, Dambrauskas N, Sather DN, Vaughan AM, Kappe SHI, Pepper M. Blood Stage Malaria Disrupts Humoral Immunity to the Pre-erythrocytic Stage Circumsporozoite Protein. Cell Rep. 2016 Dec 20;17(12):3193-3205. doi: 10.1016/j.celrep.2016.11.060.
• Illingworth J, Butler NS, Roetynck S, Mwacharo J, Pierce SK, Bejon P, Crompton PD, Marsh K, Ndungu FM. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol. 2013 Feb 1;190(3):1038-47. doi: 10.4049/jimmunol.1202438. Epub 2012 Dec 21.
• Freeman GJ, Sharpe AH. A new therapeutic strategy for malaria: targeting T cell exhaustion. Nat Immunol. 2012 Jan 19;13(2):113-5. doi: 10.1038/ni.2211.
• Weiss GE, Crompton PD, Li S, Walsh LA, Moir S, Traore B, Kayentao K, Ongoiba A, Doumbo OK, Pierce SK. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area. J Immunol. 2009 Aug 1;183(3):2176-82. doi: 10.4049/jimmunol.0901297. Epub 2009 Jul 10.
• Weiss GE, Traore B, Kayentao K, Ongoiba A, Doumbo S, Doumtabe D, Kone Y, Dia S, Guindo A, Traore A, Huang CY, Miura K, Mircetic M, Li S, Baughman A, Narum DL, Miller LH, Doumbo OK, Pierce SK, Crompton PD. The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. 2010 May 20;6(5):e1000912. doi: 10.1371/journal.ppat.1000912.
• Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK, Tygrett LT, Waldschmidt TJ, Crompton PD, Harty JT. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol. 2011 Dec 11;13(2):188-95. doi: 10.1038/ni.2180.
• Nielsen CM, Vekemans J, Lievens M, Kester KE, Regules JA, Ockenhouse CF. RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype. Vaccine. 2018 Mar 14;36(12):1637-1642. doi: 10.1016/j.vaccine.2018.01.069. Epub 2018 Feb 10.
• RTS,S Clinical Trials Partnership; Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, Methogo BG, Doucka Y, Flamen A, Mordmuller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Nhamuave A, Quelhas D, Bassat Q, Mandjate S, Macete E, Alonso P, Abdulla S, Salim N, Juma O, Shomari M, Shubis K, Machera F, Hamad AS, Minja R, Mtoro A, Sykes A, Ahmed S, Urassa AM, Ali AM, Mwangoka G, Tanner M, Tinto H, D'Alessandro U, Sorgho H, Valea I, Tahita MC, Kabore W, Ouedraogo S, Sandrine Y, Guiguemde RT, Ouedraogo JB, Hamel MJ, Kariuki S, Odero C, Oneko M, Otieno K, Awino N, Omoto J, Williamson J, Muturi-Kioi V, Laserson KF, Slutsker L, Otieno W, Otieno L, Nekoye O, Gondi S, Otieno A, Ogutu B, Wasuna R, Owira V, Jones D, Onyango AA, Njuguna P, Chilengi R, Akoo P, Kerubo C, Gitaka J, Maingi C, Lang T, Olotu A, Tsofa B, Bejon P, Peshu N, Marsh K, Owusu-Agyei S, Asante KP, Osei-Kwakye K, Boahen O, Ayamba S, Kayan K, Owusu-Ofori R, Dosoo D, Asante I, Adjei G, Adjei G, Chandramohan D, Greenwood B, Lusingu J, Gesase S, Malabeja A, Abdul O, Kilavo H, Mahende C, Liheluka E, Lemnge M, Theander T, Drakeley C, Ansong D, Agbenyega T, Adjei S, Boateng HO, Rettig T, Bawa J, Sylverken J, Sambian D, Agyekum A, Owusu L, Martinson F, Hoffman I, Mvalo T, Kamthunzi P, Nkomo R, Msika A, Jumbe A, Chome N, Nyakuipa D, Chintedza J, Ballou WR, Bruls M, Cohen J, Guerra Y, Jongert E, Lapierre D, Leach A, Lievens M, Ofori-Anyinam O, Vekemans J, Carter T, Leboulleux D, Loucq C, Radford A, Savarese B, Schellenberg D, Sillman M, Vansadia P. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011 Nov 17;365(20):1863-75. doi: 10.1056/NEJMoa1102287. Epub 2011 Oct 18.
• RTS,S Clinical Trials Partnership; Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BG, Kabwende AL, Adegnika AA, Mordmuller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Machevo S, Acacio S, Bulo H, Sigauque B, Macete E, Alonso P, Abdulla S, Salim N, Minja R, Mpina M, Ahmed S, Ali AM, Mtoro AT, Hamad AS, Mutani P, Tanner M, Tinto H, D'Alessandro U, Sorgho H, Valea I, Bihoun B, Guiraud I, Kabore B, Sombie O, Guiguemde RT, Ouedraogo JB, Hamel MJ, Kariuki S, Oneko M, Odero C, Otieno K, Awino N, McMorrow M, Muturi-Kioi V, Laserson KF, Slutsker L, Otieno W, Otieno L, Otsyula N, Gondi S, Otieno A, Owira V, Oguk E, Odongo G, Woods JB, Ogutu B, Njuguna P, Chilengi R, Akoo P, Kerubo C, Maingi C, Lang T, Olotu A, Bejon P, Marsh K, Mwambingu G, Owusu-Agyei S, Asante KP, Osei-Kwakye K, Boahen O, Dosoo D, Asante I, Adjei G, Kwara E, Chandramohan D, Greenwood B, Lusingu J, Gesase S, Malabeja A, Abdul O, Mahende C, Liheluka E, Malle L, Lemnge M, Theander TG, Drakeley C, Ansong D, Agbenyega T, Adjei S, Boateng HO, Rettig T, Bawa J, Sylverken J, Sambian D, Sarfo A, Agyekum A, Martinson F, Hoffman I, Mvalo T, Kamthunzi P, Nkomo R, Tembo T, Tegha G, Tsidya M, Kilembe J, Chawinga C, Ballou WR, Cohen J, Guerra Y, Jongert E, Lapierre D, Leach A, Lievens M, Ofori-Anyinam O, Olivier A, Vekemans J, Carter T, Kaslow D, Leboulleux D, Loucq C, Radford A, Savarese B, Schellenberg D, Sillman M, Vansadia P. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med. 2012 Dec 13;367(24):2284-95. doi: 10.1056/NEJMoa1208394. Epub 2012 Nov 9.
• RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23. Erratum In: Lancet. 2015 Jul 4;386(9988):30. doi: 10.1016/S0140-6736(15)60643-2.
• Moorthy VS, Ballou WR. Immunological mechanisms underlying protection mediated by RTS,S: a review of the available data. Malar J. 2009 Dec 30;8:312. doi: 10.1186/1475-2875-8-312.
• Wykes MN, Horne-Debets JM, Leow CY, Karunarathne DS. Malaria drives T cells to exhaustion. Front Microbiol. 2014 May 27;5:249. doi: 10.3389/fmicb.2014.00249. eCollection 2014.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2020
• Primary Completion (Actual): June 22, 2022
• Study Completion (Actual): August 17, 2022

Study Registration Dates

• First Submitted: October 26, 2020
• First Submitted That Met QC Criteria: December 3, 2020
• First Posted (Actual): December 10, 2020

Study Record Updates

• Last Update Posted (Actual): July 19, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: RTS,S/AS01E; hypo-immuno-responsiveness; open-label randomized study; Phase 2b; Kenyan adults; anti-malarials; fractional dose RTS,S/AS01E
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Physiological Effects of Drugs; Anti-Infective Agents; Immunologic Factors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Vaccines; Lumefantrine; Artemether; Primaquine; Artemether, Lumefantrine Drug Combination; Piperaquine; Artenimol
• Other Study ID Numbers: CVIA 078; PACTR202006896481432 (Registry Identifier: Pan African Clinical Trial Registry)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No