Safety and Immunogenicity of Radiation-Attenuated PfSPZ Vaccine in Equatoguinean Infants, Children, and Adults

Abstract

The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults < 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8 × 106 or 2.7 × 106 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6-11 months and 1-5, 6-10, 11-17, 18-35, and 36-61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6-61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group (P ≥ 0.17). There were no significant differences between vaccinees and controls with respect to the rates or severity of unsolicited AEs or laboratory abnormalities. Development of antibodies to P. falciparum circumsporozoite protein occurred in 67/69 vaccinees (97%) and 0/15 controls. Median antibody levels were highest in infants and 1-5-year-olds and declined progressively with age. Antibody responses in children were greater than in adults protected against controlled human malaria infection. Robust immunogenicity, combined with a benign AE profile, indicates children are an ideal target for immunization with PfSPZ Vaccine.

Trial registration: ClinicalTrials.gov NCT02859350.

Figure 1.

CONSORT diagram—study enrollment, group allocation, and analysis populations. CVac = non-attenuated PfSPZ attenuated in vivo by coadministration of chloroquine; NS = normal saline; PfSPZ = Plasmodium falciparum sporozoites.

Figure 2.

Net OD 1.0 IgG antibodies to PfCSP by ELISA 14 days after the third immunization with PfSPZ Vaccine or normal saline, by group. Horizontal arms represent medians and are bracketed by the interquartile range. Each point represents the results for a unique participant. Filled circles (⬤) represent participants not infected after CHMI; open circles (○) represent participants who were infected after CHMI (ages 18–35 years only). Crossed circles (⊗) represent participants who did not undergo CHMI, and open triangles (Δ) represent participants who received placebo. Net OD antibody levels were significantly different between vaccinees and placebo recipients in 18–35-year-olds (P < 0.001), 11–17-year-olds (P = 0.002), and 6–10-year-olds (P = 0.002) but not 36–61-year-olds (P = 0.11, Mann-Whitney two-sided test). No sera were available from controls in the 1–5-year-old and 6–11-month-old age groups. CHMI = controlled human malaria infection; PfCSP = Plasmodium falciparum (Pf) circumsporozoite protein; PfSPZ = Plasmodium falciparum sporozoites.

Figure 3.

Comparison of Net OD 1.0 anti–PfCSP antibody levels in infants and children with levels in 18–35-year-old adults protected against Plasmodium falciparum parasitemia after CHMI. Horizontal arms represent medians and are bracketed by the interquartile range. Each point represents the results for a unique participant. Filled circles (⬤) represent participants not infected after CHMI; crossed circles (⊗) represent participants who did not undergo CHMI. Median antibody levels were significantly higher than the median for protected adults for children ages 6–11 months and 1–5 and 6–10 years. CHMI = controlled human malaria infection; PfCSP = Plasmodium falciparum circumsporozoite protein; PfSPZ = Plasmodium falciparum sporozoites.