Addition of blood-stage antibody enhances anti-sporozoite antibody protection in a humanized mouse model of Plasmodium falciparum infection

Malaria continues to exact a high disease burden worldwide, and improved vaccines and therapeutics are desperately needed. Both licensed vaccines target only the circumsporozoite protein (CSP) expressed during early stages of Plasmodium falciparum infection. Vaccines targeting the subsequent blood stage, in particular those based on RH5, are also showing clinical promise. Concrete data demonstrating the utility of a combination of antigens are lacking. Using a humanized liver mouse model, we show that anti-CSP monoclonal antibodies (mAbs) lose protection below ∼30 μg/mL serum concentration and plateau above ∼60 μg/mL. Yet breakthrough infections have multiple logs fewer parasites emerging from the liver. The addition of an anti-RH5 blood stage mAb to a partially protective anti-CSP mAb yields additional benefits by controlling the ensuing blood stage parasitemia to a transient and extremely low-level infection. These results provide the proof-of-concept evidence that multi-stage antibodies may be more protective compared to a single stage approach.