Two regimens of PfSPZ Vaccine in Mali, Africa #18-I-N084 An ongoing two regimen study is designed to explore two accelerated regimens of vaccination, a regimen used in the previous study (0, 8, 16 wks) and a shortened regimen (0, 1, 4 wks). A total of 210 participants were enrolled in Ouelessebougou, Mali and started vaccinations in Jun 2018 with the 3rd vaccination administered in Sep 2018. Participants have been followed to assess vaccine efficacy against natural transmission during the rainy season. The main objectives of these studies are: 1. To assess the incidence and severity of local and systemic adverse events following PfSPZ Vaccine administration; 2. Characterize the immunological responses associated with protection; 3. Determine the protective efficacy measured by natural exposure to malaria and via controlled human malaria infection (CHMI). In FY2019, a booster vaccination was successfully administered to 142 participants who remain on long-term follow-up. WOCBP PfSPZ Vaccine in Mali, Africa #19-I-N113 This is a randomized, double blind, placebo-controlled study to assess the safety, tolerability, immunogenicity, and protective efficacy of PfSPZ Vaccine in healthy women of child bearing potential (WOCBP). Enrolled women receive pregnancy prevention during vaccination, but report plans to become pregnant in the near future. The primary objective of this study is to assess the safety and tolerability of PfSPZ Vaccine primary series in healthy Malian WOCBP when administered at 1, 8, 29 days at two different doses (9 x105and 1.8 x106). This study began enrollment and vaccination in FY2019 and is currently ongoing. PfSPZ CVac-PYR2 #17-I-0067 The approach of combining the administration of non-attenuated Pf sporozoites (PfSPZ) with the administration of an antimalarial drug to attenuate the PfSPZ in vivo is known as chemoprophylaxis vaccination (Sanaria PfSPZ-CVac). We designed a series of nonhuman primate studies and human clinical trials in 2015 to optimize and assess the safety, immunogenicity, and protective efficacy of PfSPZ-CVac in healthy US adults. This collaboration between LMIV (NIAID) and Sanaria, Inc begun under a U01 grant at the NIH Clinical Center. The main objective of the CVac-PYR2 #17-I-0067 study conducted at the Clinical Center was to compare CVac using pyrimethamine (new regimen) to CVac using chloroquine (established approach) for the following key endpoints: 1. Incidence and severity of local and systemic adverse events following PfSPZ CVac administration 2. Immunological responses associated with protection, and 3. Protective efficacy measured against controlled human malaria infection (CHMI) with homologous and heterologous P. falciparum sporozoites In FY 2019, the CVac-PYR2 #17-I-0067 study conducted at the Clinical Center completed the final vaccinations, CHMI, and follow-up visits. Results showed that a high dose of PfSPZ Challenge NF54 with either pyrimethamine (PYR) or chloroquine (CQ) against homologous (NF54) and heterologous (7G8) CHMI were safe and well-tolerated. Additionally, in both PfSPZ-CVac-PYR and PfSPZ-CVac-CQ groups, high levels of sterile immunity against homologous or heterologous CHMI were observed 3 months after last vaccine administration. PfSPZ CVac-Mali #19-I-0099 The unprecedented results from the above Phase I study were sufficiently encouraging to justify a follow-up trial that has begun in Bancoumana, Mali (PfSPZ CVac-Mali #19-I-0099) in FY2019 as well. This Phase 1/2 randomized double-blind placebo-controlled study will determine the safety and protective efficacy against naturally transmitted Plasmodium falciparum (Pf) malaria infection of Sanaria PfSPZ Challenge NF54 administered by direct venous inoculation (DVI), combined with pyrimethamine (PYR) or chloroquine (CQ) treatment. The study began screening participants in May 2019. The pilot phase randomized and enrolled a total of 12 participants on 23 May 2019. The pilot arms (n=12) received artemether/lumefantrine approximately 14 days prior to the first immunization to clear any existing parasitemias. Clearance was done to avoid the immunomodulatory effect of parasitemia on vaccine take. 4.0x105 PfSPZ of PfSPZ Challenge (NF54) was administered to three groups of four research subjects by DVI on 09 June 2019. One group received PYR as the partner drug on day 0, the second group received PYR as the partner drug on days +2 and +3, and the third group received CQ as the partner drug on days -2 and +5. All study medications and vaccinations were safe and very well-tolerated. Participants were actively followed for safety and parasitemia breakthrough evaluation until 12 days post-injection. As discussed in the previous DSMB meeting on 20 June, there was no breakthrough parasitemia detected in any research participant and all sensitive blood smears (20 1 cm passes rather than 5 passes) from 7 to 12 days post-vaccination were negative. LMIV qPCRs were collected during the same timepoints and will be completed retrospectively. All participants were treated with artemether/lumefantrine beginning on 12 days post-vaccination and have been taken off study to clear any subpatent parasitemias. PILOT ARM schedule: completed 1. Arm 1a: PfSPZ-CVac (PYR) with PYR administered on day 0 (n=4) 2. Arm 2a: PfSPZ-CVac (PYR) with PYR administered on days 2 and 3 (n=4) 3. Arm 3a: PfSPZ-CVac (CQ) with CQ administered on days -2 and +5 (n=4) With the favorable results of the pilot phase, the main phase of the study was cleared to proceed. The main phase participants were to undergo 3 vaccinations approximately 1 month apart while on PYR or CQ treatment. However, due to slow recruitment, the protocol was amended to allow for the study to be split into 2 years with the PYR arms along with their controls occurring this year and the CQ arms along with their controls beginning next year in 2020. The amendment was approved on 12 July 2019, at which time all participants previously enrolled into the CQ arms were re-randomized into the PYR arms to participate in the study this year. MAIN ARM schedule (1st year): ongoing 1. Arm 1b: PfSPZ-CVac (PYR) with PYR administered on day 0 (n=90) 2. Arm 2b: PfSPZ-CVac (PYR) with PYR administered on days 2 and 3 (n=60) 3. Arm 4a: Normal saline control with PYR administered on day 0 (n=54) 4. Arm 4b: Normal saline control with PYR administered on days 2 and 3 (n=36) MAIN ARM schedule (2nd year): planned to begin early 2020 1. Arm 3b: PfSPZ CVac (CQ) with weekly CQ (n=90) 2. Arm 4c: Normal saline control with weekly CQ (n=90) The main phase (1st year study) has randomized and enrolled 226 participants to date with 224 participants (PYR arms + controls) undergoing vaccination #1 of 3 with 4.0x105 PfSPZ of PfSPZ Challenge (NF54) beginning on 09 July. All study medications and vaccinations have been safe and very well-tolerated. Participants were actively followed for safety and parasitemia breakthrough with daily blood smears for evaluation from 7 days post to until 9 days post injection. During this monitoring period, if participants reported symptoms of malaria, a sensitive blood smear (20 1cm passes rather than 5 passes) was read in real time. There have been seven symptomatic smears completed to date with all reported negative. All routine blood smears were also negative. LMIV qPCRs were collected during the same timepoints and will be completed retrospectively.
