Assessment of Antibody Protection against Malaria Sporozoites Must Be Done by Mosquito Injection of Sporozoites

To the Editor-in-Chief:

I read with much interest the insightful article by Mueller et al1 on genetically attenuated malaria sporozoites used for induction of pre-erythrocytic immunity in mice. On the basis of elegant experiments with genetically modified mice, the authors convincingly show that T cells and interferon-γ (IFN-γ) are important effectors in mice immunized with genetically attenuated sporozoites, which as they note have been previously shown with radiation-attenuated sporozoites.2,3,4,5 However, Mueller et al1 overlook an important aspect of the biology of malaria parasites when they conclude that anti-sporozoite antibodies “play a minor protective role” and that B cells are not protective in the absence of IFN-γ. They report that immunization of mice unable to express IFN-γ resulted in a strong anti-sporozoite antibody titer, but the mice were not protected against challenge with wild-type sporozoites. They cite the earlier studies done by immunization with irradiated sporozoites, which they contend also demonstrate the minor protective role played by anti-sporozoite antibodies.2,3,4,5 Thus, they conclude “that antibodies cannot compensate for IFN-γ deficiency.”

The problem with this study and the earlier studies is that challenge was by intravenous injection of sporozoites, whereas natural challenge is by mosquito injection. Recent work has consistently shown that most or all mosquito-transmitted sporozoites are not deposited in the blood circulation but in avascular portions of the skin, from where their motility enables them to invade dermal blood vessels.6,7,8,9,10,11 Sporozoites injected directly into the circulation (as in the study by Mueller et al1) can invade hepatocytes within a few minutes12; thus, there is little time for antibodies to have an effect. Their use of intravenous challenge is perfectly appropriate for their assessment of the T-cell and IFN-γ immune mechanisms that act against infected hepatocytes. However, sporozoites injected by mosquitoes do not leave the skin rapidly6,7,8,10,11; thus, there is more time for anti-sporozoite antibodies to act by immobilizing sporozoites13 deposited into the skin and preventing these sporozoites from entering the circulation.8 I suggest that unless these authors are able to show that mice with high antibody levels are unprotected against a normal mosquito bite challenge, their conclusion regarding antibodies being relatively nonprotective is unsustainable.