Clinical trial NCT02687373: Safety, Tolerability and Efficacy of PfSPZ Vaccine in Healthy Children and Infants 5 Months - 9 Years Living in Kenya
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malaria
Keywords: Plasmodium falciparum
PfSPZ Vaccine
Lead sponsor: Sanaria Inc.
Sponsor class: INDUSTRY
Collaborators: name: Kenya Medical Research Institute
name: Centers for Disease Control and Prevention
name: National Institutes of Health (NIH)
name: University of Maryland
First posted: 2016-02-22
Enrollment: 337
Sex: ALL
Minimum age (years): 5
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1 - Incidence and type of adverse events (AE)
timeFrame: Collected from day of each vaccination until day 28 post vaccination
measure: Part 1 - Incidence and type of possibly/probably or definitely related serious adverse events (SAEs)
timeFrame: Collected from day of first vaccination until close out visit (28 days for 3 lower doses, 84 days for 2 higher doses)
measure: Part 1 - Assessment of Pf-specific antibodies in the different age categories and to the different vaccine doses
timeFrame: Collected 1 week after each vaccination
measure: Part 2 - Incidence and type of adverse events in infants 5-12 months of age following administration of PfSPZ Vaccine
timeFrame: Collected from day of each vaccination until day 28 post vaccination
measure: Part 2 - Incidence and type of possibly/probably or definitely related serious adverse events (SAEs) following administration of PfSPZ Vaccine
timeFrame: Collected from day of first vaccination through the 12-month follow-up period.
measure: Part 2 - Assessment of Pf-specific antibodies in infants of 5-12 months to three vaccinations of PfSPZ Vaccine
timeFrame: Collected 1 week after the first and second vaccination and 2 weeks after the third vaccination.
measure: 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
timeFrame: 2 weeks to 6 months after the last vaccine dose
Secondary outcomes:
measure: 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
timeFrame: 2 weeks to 12 months after the last vaccine dose
measure: 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
timeFrame: 2 weeks to 6 and 12 months after the last vaccine dose
measure: Part 2 - Assessment of Pf-specific antibodies, parasite-specific T cell responses and RNA sequencing.
timeFrame: 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
measure: Part 2 - Assessment of Pf-specific antibodies, parasite-specific T cell responses and RNA sequencing to determine correlation of immune response with efficacy
timeFrame: Entire study period
Other outcomes:
measure: 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
timeFrame: 2 weeks to 12 months after last vaccination
measure: 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
timeFrame: 2 weeks to 12 months after last vaccination
measure: Effect of vaccination on anemia
timeFrame: 6 months and 12 months after last vaccination
Locations:
city: Kisian
country: Kenya
facility: Center for Global Health Research, KEMRI
state: Siaya County
Study officials:
affiliation: Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya
name: Martina Oneko, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Oneko M, Steinhardt LC, Yego R, Wiegand RE, Swanson PA, Kc N, Akach D, Sang T, Gutman JR, Nzuu EL, Dungani A, Kim Lee Sim B, Oloo PN, Otieno K, Bii DK, Billingsley PF, James ER, Kariuki S, Samuels AM, Jongo S, Chebore W, Abdulla S, Daubenberger C, Mpina M, Styers D, Potter GE, Abarbanell G, Richie TL, Hoffman SL, Seder RA. Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial. Nat Med. 2021 Sep;27(9):1636-1645. doi: 10.1038/s41591-021-01470-y. Epub 2021 Sep 13.
citation: Oneko M, Cherop YR, Sang T, Gutman JR, Wiegand R, Nyang'au EM, Odila AD, Akach D, Hamel MJ, Samuels AM, Kariuki S, Abebe Y, Nzuu EL, Wijayalath W, James ER, Sim BKL, Billingsley PF, Richie TL, Hoffman SL, Seder RA, Steinhardt LC. Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya. Vaccine. 2020 Jun 15;38(29):4592-4600. doi: 10.1016/j.vaccine.2020.05.008. Epub 2020 May 19.
citation: Steinhardt LC, Richie TL, Yego R, Akach D, Hamel MJ, Gutman JR, Wiegand RE, Nzuu EL, Dungani A, Kc N, Murshedkar T, Church LWP, Sim BKL, Billingsley PF, James ER, Abebe Y, Kariuki S, Samuels AM, Otieno K, Sang T, Kachur SP, Styers D, Schlessman K, Abarbanell G, Hoffman SL, Seder RA, Oneko M. Safety, Tolerability, and Immunogenicity of Plasmodium falciparum Sporozoite Vaccine Administered by Direct Venous Inoculation to Infants and Young Children: Findings From an Age De-escalation, Dose-Escalation, Double-blind, Randomized Controlled Study in Western Kenya. Clin Infect Dis. 2020 Aug 14;71(4):1063-1071. doi: 10.1093/cid/ciz925.