NCT03917654

Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali

Safety, Immunogenicity and Efficacy of Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 1,301 (actual)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: All
• Age: 1 Year
• Healthy volunteers: Not accepted

Summary

Background: Malaria affects many people in Mali and other parts of Africa. It is spread by mosquito bites. Malaria can make people sick or can lead to death. Scientists want to learn if a vaccine can stop it from spreading to other people. Objective: To test how well an experimental malaria vaccine works to decrease malaria infections. Eligibility: Healthy people ages 5 and older who live in Doneguebougou, Mali, and surrounding areas Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests EKG Participants will be randomly assigned to get either the experimental vaccine or an approved vaccine. They will not know which they are getting. Participants will have a visit about a week before their first vaccine. They will take a medicine that kills malaria. They will take it at the clinic the next 2 days. Participants ages 5-8 will take the drug again 2 weeks before their third vaccine. Participants get the vaccine through a needle in the arm. They will have visits 1, 3, 7, and 14 days after. They will have blood tests or finger pricks. Participants will get another vaccine 1 and 6 months later. Participants will have blood tests once a month. At these visits they may also have urines tests or mosquito feeds. For the feeds a cup full of mosquitoes will be placed on arms or legs for 15-20 minutes. Participants will have visits twice a month for 4 months after their last vaccine.

Detailed description

A vaccine to interrupt malaria transmission (VIMT), targeting disruption of both human and mosquito transmission, would be a valuable tool for local elimination or eradication of this disease. One strategy to design a VIMT is using components that block transmission of malaria to mosquitoes, such as Pfs230. Pfs230, a surface antigen of intracellular gametocytes, as well as extracellular gametes and zygotes in the mosquito stage of Plasmodium falciparum, is currently the leading candidate in clinical trials for a malaria transmission-blocking vaccine (TBV). Recombinant Pfs230D1M has been conjugated to a recombinant Pseudomonas aeruginosa ExoProtein A (EPA) and adjuvanted with AS01. When formulated in AS01, results from a recent first-in-human trial demonstrated that Pfs230-EPA induces functional transmission-reducing, and in a significant proportion of vaccinees, transmission-blocking serum activity that can be measured for months, the vaccine is well-tolerated and safe in adults, and our recent natural history data clearly indicate that children play a disproportionate role in malaria transmission. The next step in the development of Pfs230D1M-EPA as a TBV is therefore to conduct an age de-escalation trial to ensure that the vaccine is safe to administer to children and then to conduct a community clinical trial to assess efficacy in family groups. This Phase 2 study will first determine safety and tolerability of Pfs230D1M-EPA/AS01 in healthy Malian children of decreasing ages: 9-18 years old, followed by 5-8 years old. A total of 60 subjects will be enrolled in Doneguebougou, Mali, West Africa. Children will be recruited from compounds/family that have agreed to participate in the main phase of the study and will enroll in a staggered manner to receive either Pfs230D1M-EPA/AS01 vaccine or comparator as assigned by their compound block randomization. Prior to receipt of vaccination #1, all subjects will receive a full treatment course of artemether/lumefantrine (AL). Safety and tolerability will be monitored and reported as local and systemic adverse events (AEs) and serious adverse events (SAEs) and reviewed by DSMB, sponsor, medical monitors, and study team prior to proceeding with enrollment of the main phase. If there are no safety concerns, in a staggered manner, the main phase will begin enrollment of approximately 137 compounds/vaccine units (about 1500 vaccinees + about 400 under 5 years of age for parasite surveillance). Children enrolled during the pilot safety phase will join their main phase compounds/family for vaccination #3. Prior to receipt of first vaccination, all subjects will receive a full treatment course of AL. All vaccinated subjects will be monitored for safety and tolerability. Immunogenicity outcomes will be antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) against recombinant Pfs230D1M. Functional activity of the induced antibodies will be assessed by standard membrane feeding assays in select samples. Vaccine activity will be measured in children 9-18 years of age who will undergo direct skin feeds (DSF) starting 2 weeks post vaccination #3 for a total of 8 DSFs. Prior to scheduled last vaccination in members of the compound/family, children 1-4 years of age and vaccinated children 5-8 years of age will receive a full treatment course of AL prior to the expected start of the transmission season and will then be followed every 2 weeks by blood smear (BS) along with all vaccinated children. Children 9-18 years of age will also be assessed for vaccine efficacy, but as a separate analysis from those 1-8 years of age. In Year 2, those who received vaccination during Year 1 (5 years of age and older at enrollment), if eligible and still on study, will receive a single fourth vaccination per their vaccine unit (VU) blinded arm assignment. No new individuals will be enrolled. Again, children 1-4 years of age and vaccinated children 5-8 years of age will receive a full treatment course of AL prior to the expected start of the transmission season and will then be followed every 2 weeks by BS along with all vaccinated children. Children 9-18 years of age will also be assessed for vaccine efficacy against parasitemia, but as a separate analysis from those 1-8 years of age. Immunogenicity outcomes will be antibody responses as measured by ELISA against recombinant Pfs230D1M. Functional activity of the induced antibodies will be assessed by standard membrane feeding assays in select samples. Vaccine activity will be measured in children 9-18 years of age who will undergo DSF starting 2 weeks post vaccination #4 for a total of 10 DSFs.

Conditions

• Malaria

Interventions

Type	Name	Description
BIOLOGICAL	Pfs230D1M-EPA/AS01	The Pfs230D1M-EPA was formulated as conjugated Pfs230D1M in 4 mM phosphate-buffered saline (PBS) to a 2X dilution of the high dose (160 (Micro)g/mL in 0.5 mL volume) in cGMP compliance at Walter Reed Bioproduction facility in April 2016 and will be provided as a single use vial. AS01B adjuvant was manufactured for use in the SHINGRIX vaccine by GSK
BIOLOGICAL	HAVRIX	HAVRIX (Hepatitis A Vaccine; HAV) is produced by GSK and is a sterile suspension of inactivated virus for IM administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. HAVRIX is FDA approved for active immunization against disease caused by HAV for persons 12 months of age and older.
BIOLOGICAL	TYPHIM Vi (Salmonella typhi vaccine)	TYPHIM Vi (Typhoid Vi Polysaccharide Vaccine), produced by Sanofi Pasteur SA, for IM use, is a sterile solution containing the cell surface Vi polysaccharide extracted from Salmonella enterica serovar Typhi, S typhi Ty2 strain (inactivated, subunit vaccine). TYPHIM Vi vaccine is indicated for active immunization for the prevention of typhoid fever caused by S typhi and is FDA approved for use in persons 2 years of age or older
BIOLOGICAL	Menactra	Menactra (Sanofi Pasteur) is a sterile, intramuscularly administered vaccine that contains Neisseria meningitidis serogroup A, C, Y, and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. No preservative or adjuvant is added during the manufacturing process. Menactra is FDA approved for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 (but does not protect against serotype B) for use in individuals 9 months through 55 years of age.
BIOLOGICAL	AVAXIM	AVAXIM - Pediatric \[Hepatitis A Vaccine Inactivated\] is a sterile, whitish, cloudy suspension. The active ingredient is a purified and formaldehyde-inactivated hepatitis A virus (HAV) obtained from the GBM strain, cultured on MRC-5 human diploid cells. HAV is adsorbed onto aluminum.

Timeline

• Start date: 2019-04-24
• Primary completion: 2021-07-30
• Completion: 2022-10-31
• First posted: 2019-04-17
• Last updated: 2024-10-22
• Results posted: 2022-08-23

Locations

1 site across 1 country: Mali

Regulatory

• FDA-regulated drug study