DISCUSSION
fever, malaria-exposed, seizures, Seizures, parasitemia
EVENT, PARASITEMIA, SPONTANEOUS ABORTION, MISCARRIAGE, COMPLICATIONS, GENERALIZED SEIZURE
This age escalation/de-escalation trial performed in malaria-exposed adults, children, and infants on Bioko Island, Equatorial Guinea, is the second trial to assess the safety, tolerability, and immunogenicity of PfSPZ Vaccine in infants, children, and adults and the first trial in older adults. To address vaccine safety, NS was chosen as a rigorous placebo control that can be safely administered by DVI. The frequency of local or systemic AEs was not significantly different between PfSPZ Vaccine and NS in all age groups combined or in each age group assessed individually (As in other studies of PfSPZ Vaccine, DVI was well tolerated as a procedure. All participants in the vaccine and NS arms were successfully injected, requiring only a single needle stick in 91%. Success with the first attempt was lower in the 1–5-year-old (85%) and 6–11-month-old (80%) age groups than it was in 6–61-year-olds (95%), similar to what was previously reported in Tanzania (87% in 1–5-year-olds and 63% in 6–12-month-oldsPain was subjectively rated by participants as mild or none in 93% of the injections in participants aged 6 years and above (There were two possibly related SAEs in the clinical trial. One was a solitary generalized seizure in a 15-year-old boy with no history of seizures, who was described as previously healthy. Seizures after immunization are reported with most licensed vaccines but are generally regarded as infrequent and typically associated with fever, although published trials frequently combine both types (with/without fever), blurring the distinction.The second SAE was a spontaneous abortion at 9 weeks of pregnancy in a 19-year-old woman. By history, her last menstrual period was approximately 2 weeks prior to her first dose of PfSPZ Vaccine, implying conception occurred concurrently with administration of her first dose of PfSPZ Vaccine. Prior to this event, only one pregnancy had occurred in any trials of PfSPZ Vaccine (unpublished data); this participant had a positive urine pregnancy test 43 days after her fourth (final) immunization and 28 days after undergoing CHMI. This pregnancy was electively terminated 6 days later. Two additional pregnancies occurred during this trial, one of which produced a healthy child at 37.5 weeks. The second pregnancy was associated with complications determined by blinded study staff to be unrelated to immunization. The cumulative probability of miscarriage through 28 weeks’ gestation has been calculated at 18.9% in western Kenya,Compared with the 18–35-year-old group, antibody responses to PfSPZ Vaccine correlated inversely with age in the younger age groups, with maximum antibody levels in the 1–5-year-old age group, despite a higher vaccine dose administered to adults. Similar findings have been reported in Tanzania,Antibody levels were higher in males than in females in children < 11 years of age and higher in females than males in participants ≥ 11 years of age, but neither difference was statistically significant. The latter finding is consistent with a meta-analysis of 11 previous clinical trials showing higher antibody responses in postpubertal females than males.Field trials with PfSPZ Vaccine in Mali and Burkina Faso, with data from men and women combined, have demonstrated a correlation between PfCSP antibody levels after immunization and protection from naturally transmitted Antibody levels likely contribute to early VE by the neutralization of SPZ but, more importantly, may serve as a marker for protection that is mechanistically tied to cellular immune responses. A relationship between antibody levels and cell-mediate protection could result from Fc-mediated interactions, for example. Cellular immunity is thought to underpin the long-lasting immunity to naturally transmitted Notably, field protection has been achieved only in studies where trial participants were cleared of parasitemia prior to first immunization to eliminate the immunosuppressive properties of preexisting parasitemia. To realize the potential benefit of vaccination implied by the robust antibody responses of infants and children compared with adults in the current study, clearing parasitemia prior to immunization will likely be required. Only one study of PfSPZ Vaccine in a pediatric population has been published to date.Limitations of this study include the relatively small sample sizes, making it difficult to identify potential small differences in the rates of AEs between vaccinees and controls. Additional results, however, from a similarly designed trial in malaria-exposed Tanzanian infants, children, and adultsThere were no significant differences in AEs between vaccinated participants and controls. There was no indication of an increased frequency of AEs in young children and infants compared with older children or adults. Regarding immunogenicity, the trial showed the same inverse relationship between age and antibody levels as shown in a prior study in Tanzania, with levels in all pediatric age groups equal to or exceeding levels measured in adults protected after CHMI. These findings support the ongoing development of PfSPZ Vaccine to prevent 