Safety, Tolerability and Efficacy of PfSPZ Vaccine in Healthy Children and Infants 5 Months - 9 Years Living in Kenya

Malaria Clinical Trial

Official title:

Safety, Tolerability and Efficacy of PfSPZ Vaccine Administered by Direct Venous Inoculation (DVI) to Healthy Children and Infants 5 Months Through 9 Years of Age Living in an Area of High Malaria Transmission in Western Kenya: Age De-escalation and Dose Escalation and a Double Blind, Randomized Placebo-Controlled Trial for Safety and Efficacy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02687373
• Other study ID #: KEMRI/SERU/CGHR/017/3129
• Secondary ID: CDC IRB Protocol
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 21, 2016
• Est. completion date: August 14, 2018

Study information

• Verified date: April 2019
• Source: Sanaria Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be conducted in Siaya County in Nyanza Province, western Kenya. Healthy children aged 5 months through 9 years of age living within approximately 10 km of the study clinic(s) (Siaya County Referral Hospital, or Wagai dispensary, a government health facility in Wagai division) will be eligible for participation in Part 1; healthy infants aged 5 months - 12 months inclusive will be eligible for Part 2.

Description:

Part 1: Age De-Escalation and Dose Escalation Part 1 of this trial is a randomized blinded evaluation of the safety and tolerability of PfSPZ Vaccine administered by DVI in healthy children and infants living in an area of high malaria transmission. A maximum of 156 children from 5 months to 9 years inclusive at vaccination will be enrolled and randomized to receive vaccine or normal saline (NS) placebo by DVI. Total participation time in the dose escalation trial ranges from 5-16 weeks per participant from screening visit to close out or 4 - 12 weeks from enrolment to close out.

Vaccination will begin in the 5-9 year age group at a dosage of 4.5 x10^5 PfSPZ. A single vaccination will be administered by DVI to each of 12 participants aged 5-9 years (inclusive) of age, 8 receiving PfSPZ vaccine and 4 participants receiving NS placebo by DVI, with treatment allocation randomized and double-blind. Once the initial dose has been shown to be well tolerated and without safety concerns, the next higher dose of 9.0 x 10^5 PfSPZ will be administered to a second group of 5-9 year olds. Once this has been shown to be well tolerated and without safety concerns, the highest dose of 1.8 x 10^6 PfSPZ will be given to a third group of 5-9 year olds and concurrently the lowest dose (1.35 x10^5) will be given to a same-sized group of younger children aged 13-59 months. Two weeks later, this dose will be escalated to 2.7 x10^5 PfSPZ in a second group of children aged 13-59 months. Only once this dose is shown to be well-tolerated and without safety concerns will PfSPZ Vaccine, at the lowest dose, be given to infants aged 5 - 12 months. Within each age group, dosages will increase stepwise until they reach 1.8 x 10^6 PfSPZ, with the initiation of each group staggered by at least 2 weeks, provided that no safety thresholds are surpassed. In each dosage level, the PfSPZ Vaccine or placebo will be provided to a limited number of participants each day (e.g. 3 participants from one age group on days 1 through 4). The PfSPZ Vaccine dose will only be increased to the next dose level when safety has been assessed in subjects of the first group. The same procedures will be followed for all doses. Children in all age groups who are enrolled to receive the 2 highest doses, i.e. 9.0 x 10^5 or 1.8 x 10^6 PfSPZ, or placebo, will receive a second vaccination of the same dose after 8 weeks, provided the first vaccination at this dose level did not show safety signals.

Part 2: Safety and Efficacy Part of this study will be conducted in the outpatient areas of Siaya County Referral Hospital, a large referral hospital in western Kenya and in Wagai dispensary. A maximum of 416 infants from 5 M to 12 M inclusive at vaccination will be enrolled into this safety and efficacy trial and randomized to receive PfSPZ Vaccine at a dose determined during Part 1 of the trial (dose escalation), but likely to be 4.5x10^5, 9.0 x10^5and 1.8 x 10^6 administered x 3 doses ; and NS placebo administered x 3 doses, all by DVI administered at 8 week intervals.

Participants (N = 416, with 104 in each study arm) will be randomly assigned in a double blinded fashion to receive one of the following PfSPZ Vaccine regimes:

Group 1 (N=104): The highest dose that is determined to be safe and well tolerated in the Part 1 trial, administered in 3 doses by DVI at 0, 8 and 16 weeks. Likely dosage will be 1.8 x 10^6 PfSPZ per dose.

Group 2 (N=104): The second highest dose, which is half of the highest dose, administered in 3 doses by DVI at 0, 8 and 16 weeks. Likely dosage will be 9.0 x 10^5 PfSPZ per dose.

Group 3 (N=104): A lower dose (half of the second highest dose) administered in 3 doses by DVI at 0, 8, 16 weeks. Likely dosage will be 4.5x 10^5 PfSPZ per dose.

Group 4 (N=104): A placebo arm, will receive NS by DVI, 3 times at 8 week intervals.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 337
• Est. completion date: August 14, 2018
• Est. primary completion date: August 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Months to 9 Years

Eligibility

Inclusion Criteria:

• Healthy children 5 months - 9 years inclusive (Part 1) and healthy infants 5-12 months inclusive (Part 2)

• HIV negative

• Able to participate for the duration of the study.

• Parents/guardians over the age of 18 years able and willing to provide informed consent/permission. The consent/permission will be in writing. For adult parents or guardians who are illiterate, an impartial witness can sign the consent/permission form on behalf of the parent and the parent/guardian will provide a thumb print.

Exclusion Criteria:

• Positive HIV test or breastfeeding infants or children of a known HIV positive mother (per Kenyan guidelines, these HIV exposed breastfeeding children should be on cotrimoxazole)

• Refusal of HIV testing

• Elevated ALT (liver function test) =2x ULN ( ALT >84 U/L)

• Abnormal hematological parameters defined as: hemoglobin < 8 g/dl, WBC <1500 / mm3, neutrophils <750/ mm3, platelet count <75.000/ mm3

• Abnormal renal function test with creatinine >0.9 mg/dL

• Known sickle cell disease and other inherited blood cell disorders like thalassemia and G6PD deficiency

• Current use of systemic immunosuppressant pharmacotherapy

• Current significant medical condition (cardiac, hepatic, renal, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination

• History of a splenectomy

• History of neurologic disorder (including seizures, other than uncomplicated febrile seizures)

• Known allergy to any component of the vaccine formulation, history of anaphylactic response to mosquito-bites, or known allergy to first or second line anti-malarials used to treat malaria

• Plan to participate in another investigational vaccine/drug research during or within 1 month of this study end

• Prior participation in a malaria vaccine trial

• Participation in the PfSPZ Vaccine Trial Part 1 (for Part 2 only)

• History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives

• Child/orphan in institutional care

Related Conditions & MeSH terms

• Malaria

Intervention

Biological:
• PfSPZ Vaccine
Aseptic, purified, cryopreserved, radiation-attenuated Plasmodium falciparum sporozoites

Other:
• Normal Saline
0.9% Sodium chloride

Locations

Country	Name	City	State
Kenya	Center for Global Health Research, KEMRI	Kisian	Siaya County

Sponsors (5)

Lead Sponsor	Collaborator
Sanaria Inc.	Centers for Disease Control and Prevention, Kenya Medical Research Institute, National Institutes of Health (NIH), University of Maryland

Country where clinical trial is conducted

Kenya, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ratio of Pf +BS in experimental arm to Pf +BS in placebo arm to determine efficacy against Pf infection at certain parasite thresholds in each study arm	Passive and active surveillance for naturally acquired Pf infection, measured by blood smear microscopy, during 12 months following the last dose in each study arm will be performed and the Pf infection by blood smear at parasite density >400 or >5000 parasites per microliter between each dose study arm and placebo will be compared.	2 weeks to 12 months after last vaccination
Other	Ratio of Pf +BS in experimental arm to Pf +BS in placebo arm to determine efficacy against clinical malaria and malaria hospitalization in each study arm	Passive and active surveillance for naturally acquired Pf infection of > 5000 parasites per microliter measured by blood smear microscopy associated with fever (clinical malaria) and/or hospitalization as well as hospitalization for severe malarial anemia, during 12 months following the last dose in each study arm will be performed and each study arm will be compared with the placebo group.	2 weeks to 12 months after last vaccination
Other	Effect of vaccination on anemia	Measure hemoglobin at 6 months and 12 months after the last vaccination and compare hemoglobin levels in each study arm with the placebo group.	6 months and 12 months after last vaccination
Primary	Part 1 - Incidence and type of adverse events (AE)	Incidence and type of solicited and unsolicited adverse events including breakthrough malaria infections and clinical laboratory assessments (hematological, liver and renal function) will be collected within 28 days after each vaccination. Proportions of participants with AEs and frequencies of individual AEs will be calculated and compared against participants in the same age category and dose group receiving placebo.	Collected from day of each vaccination until day 28 post vaccination
Primary	Part 1 - Incidence and type of possibly/probably or definitely related serious adverse events (SAEs)	Incidence of all hospitalizations, deaths, disabilities caused by at least possibly related SAEs during study participation	Collected from day of first vaccination until close out visit (28 days for 3 lower doses, 84 days for 2 higher doses)
Primary	Part 1 - Assessment of Pf-specific antibodies in the different age categories and to the different vaccine doses	Collection of blood samples for antibodies on day 8 after each vaccination. Following vaccination serum will be taken and an assessment of Plasmodium falciparum (Pf)f-specific antibodies against specific malaria proteins such as the circumsporozoite protein (CSP) PfCSP and whole Pf sporozoites (SPZ) will be determined by enzyme-linked immunosorbent assay (ELISA) and automated immunofluorescence assay (aIFA) respectively.	Collected 1 week after each vaccination
Primary	Part 2 - Incidence and type of adverse events in infants 5-12 months of age following administration of PfSPZ Vaccine	Incidence and type of solicited and unsolicited adverse events including breakthrough malaria infections and clinical laboratory assessments (hematological, liver and renal function) will be collected during 28 days after each vaccination.	Collected from day of each vaccination until day 28 post vaccination
Primary	Part 2 - Incidence and type of possibly/probably or definitely related serious adverse events (SAEs) following administration of PfSPZ Vaccine	Incidence of all hospitalizations, deaths, disabilities caused by at least possibly related to the study product during the 12-month follow-up period.	Collected from day of first vaccination through the 12-month follow-up period.
Primary	Part 2 - Assessment of Pf-specific antibodies in infants of 5-12 months to three vaccinations of PfSPZ Vaccine	Collection of blood samples for antibodies on day 8 after vaccination 1 and 2 and day 15 after the third PfSPZ vaccination. Following vaccination serum will be taken and an assessment of Plasmodium falciparum (Pf)f-specific antibodies against specific malaria proteins such as the circumsporozoite protein (CSP) PfCSP and whole Pf sporozoites (SPZ) will be determined by enzyme-linked immunosorbent assay (ELISA) and automated immunofluorescence assay (aIFA) respectively.	Collected 1 week after the first and second vaccination and 2 weeks after the third vaccination.
Primary	Part 2 - Ratio of Pf positive blood smear (+BS) in experimental arm to Pf +BS in placebo arm to determine efficacy of PfSPZ Vaccine during 6 months after last dose	Efficacy against malaria infection of PfSPZ Vaccine administered to infants 5-12 months of age in 3 doses by passive and active surveillance for naturally acquired Pf infection, measured by blood smear microscopy, during 6 months following the last vaccine dose.	2 weeks to 6 months after the last vaccine dose
Secondary	Part 2 - Ratio of Pf +BS in experimental arm to Pf +BS in placebo arm to determine efficacy of PfSPZ Vaccine during 12 months after last dose	Efficacy against malaria of PfSPZ Vaccine administered to infants 5-12 months of age in 3 doses by passive and active surveillance for naturally acquired Pf infection, measured by blood smear microscopy, during 12 months following the last vaccine dose will be performed and the prevalence ratio of the prevalence of malaria infection by blood smear between each dose study arm and placebo will be compared.	2 weeks to 12 months after the last vaccine dose
Secondary	Part 2 - Ratio of Pf positive PCR in experimental arm to Pf positive PCR in placebo arm to determine efficacy against submicroscopic malaria infection of PfSPZ Vaccine following 6 and 12 months after the last dose	Efficacy against submicroscopic malaria infection of PfSPZ Vaccine administered to infants 5-12 months of age in 3 doses by passive and active surveillance for naturally acquired Pf infection, measured by PCR, during 6 and 12 months following the last vaccine dose.	2 weeks to 6 and 12 months after the last vaccine dose
Secondary	Part 2 - Assessment of Pf-specific antibodies, parasite-specific T cell responses and RNA sequencing.	Collection of blood samples for Anti PfSPZ antibodies and RNA sequencing at different time points. Following vaccination serum will be taken and an assessment of Plasmodium falciparum (Pf)f-specific antibodies against specific malaria proteins such as the circumsporozoite protein (CSP) PfCSP and whole Pf sporozoites (SPZ) will be determined by enzyme-linked immunosorbent assay (ELISA) and automated immunofluorescence assay (aIFA). For assessment of parasite-specific T cell responses, PBMCs will be assessed by multi-parameter flow cytometry and / or ELISPOT, and intracellular cytokine staining. RNA sequencing from whole blood will be performed by processing the RNA and performing deep sequencing. Analysis of gene expression will be performed to develop biomarkers and predictors of protection.	Before the first vaccination, 1 week after vaccination 1 and 2, 2 weeks after vaccination 3 and at 6 months and 12 months after the last vaccination
Secondary	Part 2 - Assessment of Pf-specific antibodies, parasite-specific T cell responses and RNA sequencing to determine correlation of immune response with efficacy	Comparison of the immune response at different time points and the protection against naturally acquired Pf infection. Following vaccination serum will be taken and an assessment of Plasmodium falciparum (Pf)f-specific antibodies against specific malaria proteins such as the circumsporozoite protein (CSP) PfCSP and whole Pf sporozoites (SPZ) will be determined by enzyme-linked immunosorbent assay (ELISA) and automated immunofluorescence assay (aIFA). For assessment of parasite-specific T cell responses, PBMCs will be assessed by multi-parameter flow cytometry and / or ELISPOT, and intracellular cytokine staining. RNA sequencing from whole blood will be performed by processing the RNA and performing deep sequencing. Analysis of gene expression will be performed to develop biomarkers and predictors of protection.	Entire study period