Abstract
ABSTRACTLong-lasting and sterile homologous protection against malaria can be achieved by the exposure of malaria-naive volunteers under chemoprophylaxis to Plasmodium falciparum-infected mosquitoes (chemoprophylaxis and sporozoite [CPS] immunization). While CPS-induced antibodies neutralize sporozoite infectivity in vitro and in vivo, antibody-mediated effector mechanisms are still poorly understood. Here, we investigated whether complement contributes to CPS-induced preerythrocytic immunity. Sera collected before and after CPS immunization in the presence of active or inactive complement were assessed for the 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 capacities (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 parasitemia 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 abilities to fix complement, lyse sporozoites, or inhibit the 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 the 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 preerythrocytic immunity after whole-parasite immunization against Plasmodium falciparum malaria.
Highlights
Long-lasting and sterile homologous protection against malaria can be achieved by the exposure of malaria-naive volunteers under chemoprophylaxis to Plasmodium falciparum-infected mosquitoes
Specific IgG and IgM antibodies against the dominant circumsporozoite protein (CSP) were induced (P ϭ 0.0026 and P ϭ 0.0012) (Fig. S1C and S1D) and were positively correlated (P ϭ 0.0194) (Fig. S2B)
The present study shows that CPS immunization with P. falciparum NF54 sporozoites induces complement-fixing antibodies that are capable of activating the classical complement pathway, resulting in membrane-compromised sporozoites and a further reduction of homologous and heterologous sporozoite infectivity in vitro
Summary
Long-lasting and sterile homologous protection against malaria can be achieved by the exposure of malaria-naive volunteers under chemoprophylaxis to Plasmodium falciparum-infected mosquitoes (chemoprophylaxis and sporozoite [CPS] immunization). While achieving sterile immunity by subunit vaccination has proven to be difficult [7,8,9], long-lasting and sterile protection against a homologous P. falciparum malaria infection can be accomplished experimentally by whole-parasite immunization with live attenuated sporozoites This can be achieved in healthy human volunteers by the intravenous injection of 150,000 cryopreserved sporozoites (PfSPZCVac) [10] or by exposure to bites of 30 to 45 P. falciparum-infected mosquitoes under chloroquine chemoprophylaxis (chemoprophylaxis and sporozoites [CPS]) [11, 12]. We studied whether antibody-dependent complement activation contributes to preerythrocytic-antibody-mediated protective immunity against P. falciparum malaria sporozoites induced by CPS immunization To this end, CPS-induced antibodies were assessed for their functional capacity to fix complement proteins on sporozoites, induce sporozoite lysis, and further impact in vitro hepatocyte traversal and invasion by sporozoites in the presence of active complement, tested for both the homologous NF54 strain the genetically and geographically distinct NF135.C10 parasite clone
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