Multi-Dose Priming Regimens of PfSPZ Vaccine: Safety and Efficacy against Controlled Human Malaria Infection in Equatoguinean Adults

Abstract

Plasmodium falciparum sporozoites (PfSPZ) Vaccine is composed of radiation-attenuated, aseptic, purified cryopreserved PfSPZ. Multiple clinical trials empirically assessing two to six doses have shown multi-dose priming (—two to four doses the first week) to be optimal for protection in both 4- and 16-week regimens. In this randomized, double-blind, normal saline (NS), placebo-controlled trial, four groups (G) of 18- to 32-year-old Equatoguineans received multi-dose priming regimens with or without a delayed final dose at 4 or 16 weeks (9 × 105 PfSPZ/dose). The regimens were G1: days 1, 3, 5, 7, and 113; G2: days 1, 3, 5, and 7; G3: days 1, 3, 5, 7, and 29; and G4: days 1, 8, and 29). All doses were 9 × 105 PfSPZ. Tolerability, safety, immunogenicity, and vaccine efficacy (VE) against homologous-controlled human malaria infection (CHMI) 6–7 weeks after vaccination were assessed to down-select the best regimen. All four regimens were safe and well tolerated, with no significant differences in adverse events (AEs) between vaccinees (N = 84) and NS controls (N = 20) or between regimens. Out of 19 controls, 13 developed Pf parasitemia by quantitative polymerase chain reaction (qPCR) after CHMI. Only the vaccine regimen administered on study days 1, 8, and 29 gave significant protection (7/21 vaccinees versus 13/19 controls infected, VE 51.3%, P = 0.03, Barnard’s test, two-tailed). There were no significant differences in antibodies against Pf circumporozoite protein (PfCSP), a major SPZ antigen, between protected and nonprotected vaccinees or controls pre-CHMI. The six controls not developing Pf parasitemia had significantly higher antibodies to blood stage antigens Pf exported protein 1 (PfEXP1) and Pf merozoite surface protein 1 (PfMSP1) than the controls who developed parasitemia, suggesting naturally acquired immunity against Pf-limited infections in controls. This study identified a safe, protective, 4-week, multi-dose prime vaccination regimen for assessment in future trials of PfSPZ Vaccine.

A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection

“…More than 6000 doses of PfSPZ of PfSPZ Vaccine containg 5.2 billion PfSPZ have been administered to > 2000 subjects aged 5 months to 61 years in 20 clinical trials in Africa, Europe, and the US without documenting a breakthrough infection. In double blind placebo-controlled trials, including 12 conducted in Africa, there have been no significant differences in adverse events or laboratory abnormalities between vaccinees and normal saline controls 16 , 18 , 20 , 21 , 26 – 29 . The near absence of reactogenicity of PfSPZ Vaccine was confirmed in a recent trial completed in Kenyan infants who were administered three doses of 4.5 × 10 5 , 9.0 × 10 5 , or 1.8 × 10 6 PfSPZ, the latter twice the dose administered to adults in the current study 27 , 28 .…”

“…The key component of the down-selected regimen may be the two sequential doses in the first week – multidose priming. Prior work indicates that this approach enhances the VE of PfSPZ Vaccine compared to single dose priming 22 , 29 . Because the PfSPZ in PfSPZ Vaccine do not replicate, administering two or more doses in a short period of time may better mimic the typical live attenuated vaccines used against many pathogens, which generally replicate over the course of several days before containment by nascent immune responses.…”

Five decades of clinical assessment of whole-sporozoite malaria vaccines

“…In this study, four multi-dose priming regimens, with or without delayed boosting, were evaluated, all of which using doses of 9 x 10 5 PfSPZ delivered iv: days 1, 3, 5, 7 and 113; days 1, 3, 5 and 7; days 1, 3, 5, 7 and 29; and days 1, 8, and 29. A significant 51.3% protection was only observed for the regimen in which the vaccine was administered on a 4-week schedule, on days 1, 8, and 29 ( 63 ). The delayed boosting immunization schedule yielded a protective efficacy of ~40%, which is similar to that observed in the USA trial ( 62 ), but was not statistically significant ( 63 ).…”

“…A significant 51.3% protection was only observed for the regimen in which the vaccine was administered on a 4-week schedule, on days 1, 8, and 29 ( 63 ). The delayed boosting immunization schedule yielded a protective efficacy of ~40%, which is similar to that observed in the USA trial ( 62 ), but was not statistically significant ( 63 ). Perhaps surprisingly, protection afforded by the 2-dose multi-prime regimen (days 1, 8, and 29; 51.3%) was higher than that afforded by 4-dose multi-prime (days 1, 3, 5, 7 and 29; 10.7%), clearly a matter that demands additional investigation.…”

Rethinking detection of pre-existing and intervening Plasmodium infections in malaria clinical trials

“…Clinical trials are critical for evaluating candidate malaria vaccines and drugs. Such trials are routinely conducted in malaria-endemic sites as field efficacy trials (1)(2)(3)(4)(5) and in both endemic and non-endemic sites as controlled human malaria infection (CHMI) studies (6)(7)(8)(9). In all cases, it is generally accepted that the Plasmodium infection status of the participants is established at the time of trial enrollment.…”