Malaria vaccine candidate based on Duffy-binding protein elicits strain transcending functional antibodies in a Phase I trial

Abstract

Reticulocyte invasion by Plasmodium vivax requires interaction of the Duffy-binding protein (PvDBP) with host Duffy antigen receptor for chemokines (DARCs). The binding domain of PvDBP maps to a cysteine-rich region referred to as region II (PvDBPII). Blocking this interaction offers a potential path to prevent P. vivax blood-stage growth and P. vivax malaria. This forms the rationale for development of a vaccine based on PvDBPII. Here we report results of a Phase I randomized trial to evaluate the safety and immunogenicity of recombinant PvDBPII formulated with glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). Thirty-six malaria-naive, healthy Indian male subjects aged 18-45 years were assigned into three cohorts corresponding to doses of 10, 25 and 50 µg of PvDBPII formulated with 5 µg of GLA-SE. Each cohort included nine PvDBPII/GLA-SE vaccinees and three hepatitis B control vaccine recipients. Each subject received the assigned vaccine intramuscularly on days 0, 28 and 56, and was followed up till day 180. No serious AE was reported and PvDBPII/GLA-SE was well-tolerated and safe. Analysis by ELISA showed that all three doses of PvDBPII elicited antigen-specific binding-inhibitory antibodies. The 50 µg dose elicited antibodies against PvDBPII that had the highest binding-inhibitory titres and were most persistent. Importantly, the antibody responses were strain transcending and blocked receptor binding of diverse PvDBP alleles. These results support further clinical development of PvDBPII/GLA-SE to evaluate efficacy against sporozoite or blood-stage challenge in controlled human malaria infection (CHMI) models and against natural P. vivax challenge in malaria endemic areas.

Fig. 1

Flow chart of study design and volunteer recruitment

Fig. 2

Humoral response to immunization with PvDBPII formulated with GLA-SE. a Kinetics of PvDBPII-specific Geometric Mean antibody titres for all Study Groups (PP Population). Geometric mean antibody levels (U/mL) to PvDBPII measured by ELISA in sera collected from groups immunized with 10, 25, or 50 μg PvDBPII/GLA-SE and Hepatitis B vaccine. Study participants were immunized on Days 0, 28 and 56, and sera were collected on Days 0, 28, 56, 84 and 180. Antibody levels measured by ELISA were expressed as Geometric Mean Titres (GMT) with 95% confidence interval for the nine subjects. b Serum IgG subclass responses to PvDBPII in three PvDBPII dose groups (PP Population). Geometric means with SD are shown

Fig. 3

Reactivity of sera from PvDBPII immunized subjects with P. vivax-infected erythrocytes obtained from vivax malaria patients. Representative images are shown from each of the three PvDBPII dose groups (PP Population)

Fig. 4

Inhibition of binding of recombinant PvDBPII variants to the Duffy antigen receptor for chemokines (DARC) using an ELISA-based assay. a Mean percentage binding inhibition at Day 84 and Day 180 for sera from groups immunized with PvDBPII (Sal I) at 10, 25 and 50 µg, and tested at a 1:10 sera dilution (PP Population). b 50% Binding-inhibitory titres for inhibition of PvDBPII-DARC binding using Day 84 and Day 180 sera from groups immunized with 10, 25 and 50 μg of PvDBPII formulated with GLA-SE. c Inhibition of DARC binding by PvDBPII variants using sera from groups immunized with 10, 25 and 50 μg of PvDBPII formulated with GLA-SE. Means with standard deviations are shown