Long-lasting and sterile homologous protection against malaria can be achieved by exposure of malaria-naive volunteers under chemoprophylaxis to Plasmodium falciparum-infected mosquitoes (CPS-immunization). While CPS-induced antibodies neutralize sporozoite infectivity in vitro and in vivo, antibody-mediated effector mechanisms are still poorly understood. Here, it was investigated whether complement contributes to CPS-induced pre-erythrocytic immunity.Sera collected before and after CPS-immunization in the presence of active or inactive complement were assessed for recognition of homologous NF54 and heterologous NF135.C10 sporozoites, complement fixation, sporozoite lysis, and possible subsequent effects on in vitro sporozoite infectivity in human hepatocytes. CPS-immunization induced sporozoite-specific IgM (p<0.0001) and IgG (p=0.001) antibodies with complement-fixing capacity (p<0.0001). Sporozoite lysis (p=0.017), traversal (p<0.0001) and hepatocyte invasion inhibition (p<0.0001) by CPS-induced antibodies were strongly enhanced in the presence of active complement. Complement-mediated invasion inhibition in the presence of CPS-induced antibodies negatively correlated with cumulative parasitaemia during CPS-immunizations (p=0.013). While IgG antibodies similarly recognized homologous and heterologous sporozoites, IgM binding to heterologous sporozoites was reduced (p=0.023). Although CPS-induced antibodies did not differ in their ability to fix complement, lyse sporozoites or inhibit traversal of homologous and heterologous sporozoites, heterologous sporozoite invasion was more strongly inhibited in the presence of active complement (p=0.008).These findings demonstrate that CPS-induced antibodies have complement-fixing activity, thereby significantly further enhancing functional inhibition of homologous and heterologous sporozoite infectivity in vitro The combined data highlight the importance of complement as an additional immune effector mechanism in pre-erythrocytic immunity after whole-parasite immunization against Plasmodium falciparum malaria.
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