Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults

Abstract

Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

Keywords: adenovirus; circumsporozoite; malaria; vaccine.

Figure 1. Schedule of events and outcome measures. Baseline screening assessments included complete blood counts; serum chemistries; hepatic enzymes; urinalysis; serologies for HIV, HCV, and HBV; and pregnancy testing. During post-vaccine safety visits, each subject’s memory aid was reviewed for adverse events. The primary outcome measure was the frequency and severity of local and systemic adverse events. Secondary outcome measures included anti-CS antibody titers (ELISA) and neutralizing antibody titers to adenovirus type 35.

Figure 2. CONSORT Flow Diagram of Study Participants. In total, 62/72 subjects completed all vaccinations and follow-up visits. Reasons for voluntary withdrawal include loss to follow-up, concern about risks and study procedures, and insufficient time to complete study visits. Reasons for investigator withdrawal include non-compliance due to participation in another trial (1), dosing error (1), and adverse reactions to vaccine (4). Adverse events leading to withdrawal occurred exclusively in the Ad35.CS.01 10¹¹ vp/mL dosage group.

Figure 3. Reactogenicity following each dose of Ad35.CS.01 vaccine at increasing doses. Local and systemic reactions appeared to increase with ascending dosages, but not with multiple administrations. (A)Pain; (B)Erythema;(C)Induration; (D)Malaise; (E)Myalgia; (F)Nausea; (G)Fever; and (H)Headache

Figure 4. Geometric mean Ad35 Neutralizing antibody titers at baseline, 1 mo, 2 mo, 6 mo, and 7 mo following first vaccination. Negative responses are set at 8 IC90, calculated as half the lower limit of quantification, whiskers indicate 95% CI.