RTS,S/AS01E Hypo-immuno-responsiveness Study

Study Overview
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Brief Summary
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The proposed trial design has been developed to answer several questions related to the nature of RTS,S vaccine efficacy in African adults that may be influenced by concurrent and/or past P. falciparum infection leading to a state of immunologic hypo-responsiveness. The proposed study design encompasses five groups. Three groups (Groups 1, 2, and 3) will be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th fractional dose. Two groups (Groups 4 and 5) will be administered a comparator vaccine on a 0, 1, 7 month schedule.

Detailed Description
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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 Plasmodium falciparum, 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 in endemic regions compared to challenge studies. While the cause of this is likely multi-factorial, there is a degree of immunologic hypo-responsiveness that occurs in endemic regions that may impede the development of a protective immune response following immunization that is presumed to be related to chronic infection. 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 PCR assay (planned assay is an RNA-based polymerase chain reaction (PCR) though the backup utilizes both RNA and DNA PCR, see protocol for details) 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 (including anti-CS and cell-mediated immune responses) of this group and groups 1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives include safety assessments and other exploratory objectives defined in this protocol. A total of 619 subjects will be enrolled (164 in groups 1 and 4, 128 in groups 2 and 5, and 35 in group 3) over a period of 6 months and will participate in the study for 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), with the primary and secondary efficacy endpoints of time to first malaria infection by PCR. Total duration expected to be 20.5-26.5 months. Those groups receiving antimalarial medications (1, 2, 3, 4) will receive either dihydroartemisinin-piperaquine or artemether/lumefantrine and low-dose primaquine as described in the protocol.

Official Title
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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

Conditions
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Plasmodium Falciparum

Intervention / Treatment
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* Biological: RTS,S/AS01E
* Biological: Abhayrab rabies vaccine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Three groups (Groups 1, 2, and 3) will be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th fractional dose. Two groups (Groups 4 and 5) will be administered a comparator vaccine on a 0, 1, 7 month schedule.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Positive baseline parasitemia, antimalarial treatment, RTS,S/AS01E vaccine<br>Group 1 subjects have detectable P. falciparum parasitemia at baseline measured by PCR. Anti-malarial treatment with Dihydroartemisinin-piperaquine (DHA/Pip) to clear asexual stage and young gametocyte parasites plus low dose primaquine (LD PQ) to clear mature gametocytes will be given 4 weeks prior to immunization with RTS,S/AS01E. A 2nd course of DHA/Pip plus Primaquine will be given 2 weeks before second RTS,S/AS01E immunization. One week before 3rd RTS,S/AS01E immunization, a three-day course of Artemether/lumefantrine (A/L) plus Primaquine will be administered to clear infection. Rationale for administration of A/L is its preferred shortened half-life allowing for evaluation of vaccine efficacy thereby excluding any confounder effect due to prolonged anti-malarial effect of drug. | Biological: RTS,S/AS01E<br>* Vaccine<br>|
| Experimental: Group 2: Negative baseline parasitemia, antimalarial prophylaxis, RTS,S/AS01E vaccine<br>Group 2 subjects have no detectable P. falciparum parasitemia as measured by PCR at enrolment. It is proposed to initiate anti-malarial chemoprevention to subjects (prophylaxis effect) with DHA/Pip plus LD PQ 4 weeks prior to immunization with RTS,S/AS01E. A 2nd course of DHA/Pip plus Primaquine will be given 2 weeks before second RTS,S/AS01E immunization. One week before 3rd RTS,S/AS01E immunization, a three-day course of A/L plus Primaquine will be administered to clear infection. | Biological: RTS,S/AS01E<br>* Vaccine<br>|
| Experimental: Group 3: Positive baseline parasitemia, RTS,S/AS01E vaccine<br>Group 3 subjects have detectable P. falciparum parasitemia at baseline measured by PCR but will not receive any anti-malarial medications to clear PCR-positive parasites. This group includes 35 subjects and is included only for immunological assessment and not for vaccine efficacy. Subjects in Group 3 will be administered RTS,S/AS01E three times on a 0, 1, 7 month schedule. | Biological: RTS,S/AS01E<br>* Vaccine<br>|
| Placebo Comparator: Group 4: Positive baseline parasitemia, antimalarial treatment, rabies vaccine<br>Group 4 subjects have detectable P. falciparum parasitemia at baseline measured by PCR (note any positive result from PCR will be considered positive for purposes of group selection and study endpoints as with Group 1) and will receive DHA/Pip , Primaquine, and A/L on the same schedule as subjects in group 1. Subjects in Group 4 will be administered Abhayrab rabies vaccine on a 0, 1, 7 month schedule. | Biological: Abhayrab rabies vaccine<br>* Vaccine<br>|
| Placebo Comparator: Group 5: Negative baseline parasitemia, antimalarial prophylaxis, rabies vaccine<br>Group 5 subjects have no detectable P. falciparum parasitemia as measured by PCR at enrolment and will receive DHA/Pip, Primaquine, and A/L on the same schedule as subjects in group 2. Subjects in Group 5 will be administered Abhayrab rabies vaccine on a 0, 1, 7 month schedule. | Biological: Abhayrab rabies vaccine<br>* Vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Efficacy: Malaria infection by PCR in Groups 1 and 4 | The time to first malaria infection by PCR after completing vaccination in Groups 1 and 4. | Start of active detection of infection phase at approximately week 30 until up to 77 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Efficacy: Malaria infection by PCR in Groups 2 and 5 | The time to first malaria infection by PCR after completing vaccination in Groups 2 and 5. | Start of active detection of infection phase at approximately week 30 until up to 77 weeks. | 
| Safety parameters: Incidence of Serious Adverse Events (SAEs) as assessed by meeting SAE definition per protocol | Frequency count and proportion of subjects reporting serious adverse events (SAEs) during the whole study period. SAEs are defined as adverse events which: Results in death, Is life-threatening, Results in disability/incapacity, Requires hospitalization or prolongation of existing hospitalization, Results in disability/incapacity. Results in a congenital anomaly and / or birth defect. | From Dose 1 to study conclusion. | 
| Safety parameters: Incidence of solicited local and systemic adverse events as assessed by definition of events per protocol | Frequency count and proportion of subjects reporting solicited local and systemic adverse events within 7 days after each vaccination. 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. | 
| Safety parameters: Incidence of unsolicited adverse events as assessed by definition of events per protocol | Frequency count and proportion of subjects reporting 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. | Within 28 days after each vaccination. | 
| Immunogenicity: Anti-circumsporozoite (CS) antibody | Anti-circumsporozoite (CS) antibody levels and avidity at specified time points. | Specific timepoints up to 53 weeks. | 
| Immunogenicity: Hepatitis B surface antibody (HBsAb) | Hepatitis B surface antibody (HBsAb) levels at specified time points. | Specific timepoints up to 53 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RTS,S/AS01E, hypo-immuno-responsiveness, open-label randomized study, Phase 2b, Kenyan adults, anti-malarials, fractional dose RTS,S/AS01E