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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 620
- 试验地点
- 1
- 主要终点
- Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4
研究概览
简要总结
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.
详细描述
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),
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Malaria Vaccine RTS,S/AS01E (Biological)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA/Pip) (Drug)
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.
干预措施: Artemether / Lumefantrine (Drug)
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.
干预措施: Primaquine (Drug)
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.
干预措施: Malaria Vaccine RTS,S/AS01E (Biological)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA/Pip) (Drug)
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.
干预措施: Artemether / Lumefantrine (Drug)
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.
干预措施: Primaquine (Drug)
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.
干预措施: Malaria Vaccine RTS,S/AS01E (Biological)
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.
干预措施: Abhayrab rabies vaccine (Biological)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA/Pip) (Drug)
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.
干预措施: Artemether / Lumefantrine (Drug)
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.
干预措施: Primaquine (Drug)
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.
干预措施: Abhayrab rabies vaccine (Biological)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA/Pip) (Drug)
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.
干预措施: Artemether / Lumefantrine (Drug)
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.
干预措施: Primaquine (Drug)
结局指标
主要结局
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4
时间窗: 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.
次要结局
- 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.)
- 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))
- Number of Participants With Serious Adverse Events (SAEs)(From first dose to end of study, up to 65 weeks.)
- Number of Participants With Unsolicited Adverse Events(Within 28 days after each vaccination.)
- 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))
- Number of Participants With Solicited Local and Systemic Adverse Events (AEs)(Within 7 days after each vaccination.)
- 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))