Safety and Differential Antibody and T-Cell Responses to the Plasmodium falciparum Sporozoite Malaria Vaccine, PfSPZ Vaccine, by Age in Tanzanian Adults, Adolescents, Children, and Infants

Abstract

In 2016, there were more cases and deaths caused by malaria globally than in 2015. An effective vaccine would be an ideal additional tool for reducing malaria's impact. Sanaria^® PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups. We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Because all age groups received three doses of 9.0 × 10⁵ PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults. T-cell responses were highest in 6-10-year olds after one dose and 1-5-year olds after three doses; infants had no significant positive T-cell responses. The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea. Because PfSPZ Vaccine-induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.

Figure 1.

Volunteer participation (CONSORT 2010 Diagram). Once allocated, no volunteers were removed, lost to follow-up, or excluded from analysis. This figure appears in color at www.ajtmh.org.

Figure 2.

Proportion of volunteers experiencing solicited adverse events (AEs) during the 7 days after each immunization. Ninety-one of 93 volunteers injected at least once experienced no solicited AEs during the 7 days after each immunization. One volunteer experienced three Grade 1 local AEs (yellow bar) and one volunteer experienced Grade 2 temperature elevation (38.5°C) after each immunization accompanied by mild (Grade 1) chills, fatigue, headache, and malaise (blue bar). These AEs are further described in the text. This figure appears in color at www.ajtmh.org.

Figure 3.

Difference between postimmunization and preimmunization antibody results. Antibody assay results by dose in Plasmodium falciparum circumsporozoite protein enzyme-linked immunosorbent assay (A–C), immunofluorescence assay (D–F), and inhibition of sporozoite invasion (G–I) assays. Results were obtained by subtracting preimmune values from the values obtained from sera drawn 2 weeks after the third dose. For the 9.0 × 10⁵ Plasmodium falciparum sporozoite dose (B, E, and H), previously assessed results from clinical trial VRC 314, conducted in the United States with the same dosage regimen and in the same laboratory with the same assays as in the BSPZV2 trial assays, are shown as a comparison. For the VRC 314 trial the filled in circles indicate protected volunteers and the empty circles the unprotected volunteers. Medians with interquartile ranges are shown.

Figure 4.

Plasmodium falciparum sporozoites (PfSPZ)-specific memory CD4 T-cell responses pre- and postvaccination. Percent of memory CD4 T cells in the blood expressing interferon gamma (IFN-γ) interleukin 2 (IL-2) or tumor necrosis factor alpha (TNF-α) at preimmunization or 2 weeks after the first and third doses of PfSPZ Vaccine (9.0 × 10⁵). Results are the percentage of cytokine-producing cells after incubation with PfSPZ minus the percentage of cytokine-producing cells after incubation with vaccine diluent (medium with 1% human serum albumin). Bars indicate median values within each group. Differences within each age group between pre- and postvaccination groups were assessed by two-way ANOVA with Dunnett’s correction for multiple comparisons. *P < 0.05, **P < 0.01, ****P < 0.0001. Previously measured results from clinical trial VRC 314 conducted in the United States with the same dosage regimen and the same assay conducted in the same laboratory as for the BSPZV2 trial assays are shown as a comparison. This figure appears in color at www.ajtmh.org.