Discussion
fever, swelling, malaria, pain, headache, autoimmune disease
MALARIA, EVENTS, AUTOIMMUNE DISEASE
In this study, the safety, reactogenicity and immunogenicity of three doses of the malaria vaccine candidate BK-SE36/CpG intramuscularly administered at Days 0, 28 and 112, were evaluated in 135 healthy African adults and children exposed to the parasite The vaccine was well tolerated in all three cohorts. No subject experienced a SUSAR, Grade 3 vaccine-related AE, or AE that led to trial withdrawal. The five SAEs that occurred during the trial (52-226 days post vaccination) were all inpatient hospitalizations due to malaria.AEs were more common in the vaccine arm, but were mostly Grade 1 events. The most common local symptoms were mild or moderate injection site pain or swelling; systemic symptoms were mostly headache and fever. All solicited vaccine-related AEs resolved spontaneously within 3 days after onset; unsolicited vaccine-related AEs resolved within 3 weeks. In all cohorts, the proportion of subjects that experienced AEFIs was higher in the BK-SE36/CpG arm than in the control arm. Most were of short duration, Grade 1 or Grade 2, except for two Grade 3 events (alanine aminotransferase increased and aspartate aminotransferase increased) in one subject in Cohort 1 (resolved 21 and 247 days from onset, respectively) unlikely to be related to vaccination. Four other Grade 3 AEs that occurred during the trial resolved 7-63 days from onset; all were unlikely to be or not related to vaccination.Large variations were observed in haematology and biochemical tests and were considered to be not clinically significant. Due to theoretical concerns related to the potential of CpG ODN to evoke or unmask underlying autoimmune disease (Frequent fluctuations or early elevations in ANA, anti-dsDNA and ANCA were observed in both the BK-SE36/CpG and control arm but none were considered to be associated with any clinically significant signs or symptoms. No evidence of autoimmune disease was noted in subjects that were positive for any of the markers. No subjects were also positive for at least two markers at the same time. The results are similar to the Phase 1a trial in malaria naïve adults where relatively non-specific and frequent fluctuations from baseline in ANA levels did occur in both the CpG and non-CpG groups (BK-SE36/CpG was immunogenic in all three cohorts. Despite the relatively small sample size, mean anti-SE36 antibody titres were higher in the BK-SE36/CpG arm compared to control arm. The highest response was observed in the youngest cohort. Anti-SE36 IgG antibodies were detected before vaccination in all arms across all cohorts suggesting seropositivity as a result of natural Improved vaccine immunogenicity with the use of CpG-ODN (K3) was reflected in both the rapid seroconversion rates and the high titres obtained in all age cohorts. It is difficult to compare results since trials were conducted in different populations and dosing schedule. Nevertheless, if one compares 4 weeks post Dose 2 response in Ugandan adults (21-32 years-old) using BK-SE36 (In BK-SE36 vaccinees, a third dose resulted in higher immune responses, either 6- (There have been reports that increased immunogenicity did not always correlate with In conclusion, our results confirmed the safety profile of BK-SE36/CpG observed in malaria naïve adults living in Japan (