Efficacy, T cell activation and antibody responses in accelerated Plasmodium falciparum sporozoite chemoprophylaxis vaccine regimens

Abstract

Repeated direct venous inoculation of Plasmodium falciparum sporozoites (PfSPZ) together with antimalarial chemoprophylaxis (PfSPZ–CVac) is the most potent way to induce sterile immunity against P. falciparum infection in malaria-naive volunteers. However, established schedules are complex and long. Here, we tested two accelerated three-dose schedules (28- and 10-day regimen) assessing efficacy by controlled human malaria infection (CHMI) against placebo, comparing vaccine-specific T cell and antibody responses by antigen-reactive T cell enrichment (ARTE) and protein microarray, respectively. Both regimens were similarly efficacious (67 and 63% vaccine efficacy) but different in the induction of vaccine-specific T cells and antibodies. The 10-day regimen resulted in higher numbers of antigen-specific CD4+ effector memory pro-inflammatory T cells and a broader antibody response compared with the 28-day regimen. Usually in nature, P. falciparum liver stage lasts about 6.5 days. The short vaccination-interval of the 10-day regimen prolongs the time of continuous exposure to liver-stage parasites, which may explain the stronger response. Besides dose and number of vaccinations, duration of liver-stage exposure is a factor to optimize PfSPZ–CVac immunogenicity.

Positive-unlabeled learning identifies vaccine candidate antigens in the malaria parasite Plasmodium falciparum

“…Reticulocyte binding homolog 5 (RH5) is expressed in the blood stage, functions as an invasion ligand, and is currently under malaria vaccine development 66 , 67 . Merozoite surface protein 5 (MSP5) is expressed in sporozoites, late liver stages, and in blood stage parasites, and has recently been shown to elicit antibodies strongly associated with protection following vaccination with PfSPZ sporozoite vaccines 68 . P230, in the 6-cysteine protein family, is expressed and located on the surface of gametocytes 69 .…”

Sporozoite immunization: innovative translational science to support the fight against malaria

“…Both condensed regimens used the 5.12 × 10 4 PfSPZ dose. VE at 10 weeks against homologous CHMI was 63% (5/8 protected) for the 5-day interval regimen and 67% (6/9 protected) for 14-day interval regimen, compared to 100% for the gold standard 28-day intervals, indicating that shortening the interval led to a loss of VE [ 8 , 203 ]. Of note, the administration of three doses of CQ at the same time as the administration of PfSPZ Challenge in the 5-day interval regimen proved effective in clearing all transient parasitemias.…”

“…Finally, azithromycin stops parasite development late during the liver stages and has been successfully used in rodents [ 205 ]. A single dose of 2 g extended-release azithromycin on the day of DVI led to blood stage parasitemia and the approach was therefore abandoned, as multiple dosings with azithromycin during immunization to prevent parasitemia was deemed impractical [ 203 ].…”

“…This scheduled the second immunization during the period of transient parasitemia caused by the first ( Figure 7 ), and the third immunization during the period of transient parasitemia caused by the second. None of the seven participants undergoing homologous CHMI 3 weeks later was protected [ 127 ], in contrast to the ITM trial in which three doses of 5.12 × 10 4 PfSPZ at five-day intervals protected 5/8 (63%) participants [ 8 , 203 ]. This abrogation of protection presumably resulted from the immunosuppressive effects of parasitemia on vaccine take [ 127 ], discussed further below.…”

Five decades of clinical assessment of whole-sporozoite malaria vaccines

“…Homologous CHMI was performed by iv administration of PfSPZ Challenge (PfNF54) 10 weeks after the last immunization. The two immunization regimens yielded similar protective efficacies of 67 and 63% for 28- and 10-day vaccination schedules, respectively, but the latter resulted in more pronounced cellular and humoral immune responses than the former ( 122 ). Collectively, these results pave the way for further development of an effective condensed regimen of PfSPZ-CVac immunization, capable of eliciting protective immunity in the field.…”