Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults

Abstract

Abstract.We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. Twenty- to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial. Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naïve Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects. Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.

Role of Human Pegivirus Infections in Whole P. falciparum Sporozoite Vaccination and Controlled Human Malaria Infection in African Volunteers

“…Strikingly, the comparison of PfSPZ vaccine-induced antibody titers specific for the P. falciparum circumsporozoite protein (PfCSP) showed significantly lower titers in malaria preexposed than malaria-naive individuals immunized with the PfSPZ Vaccine using comparable regimen [8]- [11]. These differences in PfSPZ vaccine-induced immunity was also observed between vaccinees residing in malaria endemic countries including Tanzania, Mali and Equatorial Guinea [11]- [13].…”

“…Serum samples for anti-PfCSP antibody evaluation were collected before vaccination (baseline) and days post last vaccination. Anti-PfCSP total IgG levels were measured by enzyme linked immunosorbent assay (ELISA) as described [11,31,32].…”

“…An efficacious malaria vaccine could alleviate malaria disease burden, prevent malaria related deaths, contain the spread of drug resistant malaria parasites and might even support the aim of malaria elimination [3]- [5].However, these vaccine development efforts are challenged by an incomplete understanding of the immune mediators leading to highly protective, long-lasting vaccine induced immunity in the field [6]. A number of studies testing metabolically active, purified, cryopreserved and radiation-attenuated whole sporozoites of P. falciparum as vaccine approach (PfSPZ Vaccine) have been published recently [7]- [11].…”

Plasmodium falciparum pre-erythrocytic stage vaccine development

“…The vaccine was well-tolerated in a clinical trial in Malí [24], having 29% efficacy against heterologous strains during 24-week (~ 6 month) follow-up without incurring in any serious local or systemic adverse events (AE). Effectiveness 3 to 24 weeks (~ 1 to 6 months) after the last immunization was evaluated by homologous intravenous CHMI which showed that 20% of the subjects who received 5 doses of 2.7 × 10 5 PfSPZ had become fully protected [25].…”

“…Higher Abs responses in children and infants who had been less exposed to P. falciparum [28] and subjects living in non-endemic areas [27] suggested that Africans' reduced immune responses were due to immunoregulation following long-term exposure to P. falciparum infection [24,25]. All such efforts have shown that PfSPZ efficacy in adults who have not had prior exposure to P. falciparum depends on the administration route (to induce tissue resident T cells in the liver) and the dose (which determines the degree of protection durability against homologous and heterologous challenge).…”