Editors' ChoiceMalaria

Antibodies complement malaria

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ec56
DOI: 10.1126/scitranslmed.aab0842

In 2012, there were over 207 million cases of malaria, which resulted in the death of an estimated 789,000 people. Malaria is caused by the transmission of the parasite Plasmodium falciparum from mosquitos to humans. Symptoms include fatigue, headaches, nausea, and vomiting with cyclical recurrences of chills and fever that can ultimately progress to seizures, coma, and in some cases, death. Despite being the subject of intense research for over a century, there is currently no vaccine to prevent malaria infection. There are currently two vaccine candidates that are in clinical trials. However, there is a lack of immune correlates of protection that has hampered the evaluation of these vaccines. In a recent paper, immune correlates that conferred protection from malaria in humans were identified.

It is well established that antibodies play a major role in immunity to malaria. However, the mechanisms mediating protection have been unclear. Human antibodies that correlate with protection are primarily cytophilic and of the subclasses IgG1 and IgG3, raising the possibility that complement might play a role in the effector function of these protective antibodies. The complement system is composed of multiple serum proteins that, when activated, form a membrane attack complex on the surface of offending microorganisms to kill them. Whereas complement proteins have no specificity on their own, antibodies can direct them to particular organisms. To address the involvement of complement in the ability of antibodies to induce immunity to malaria, Boyle et al. isolated anti–Plasmodium falciparum antibodies from individuals who had been exposed to malaria and tested their ability to prevent parasite invasion of red blood cells (RBCs) in the presence of complement. Interestingly, when antibodies were incubated with serum containing intact complement proteins, there was significant protection from parasite invasion of human RBCs. However, in the absence of complement, these same antibodies were ineffective, demonstrating the importance of the complement cascade for host resistance to malaria.

To obtain epidemiological evidence of antibody-mediated complement fixation in immunity to malaria, the authors tested antibodies in 206 children, 5 to 14 years of age, who lived in a malaria endemic area. All children were treated for malaria at enrollment and then monitored over 6 months. Complement deposition on antibodies was very high in most individuals and positively correlated with increased age. Interestingly, when individuals were separated into groups of high, medium, and low complement activity, there was a stronger association between high responders, fewer symptomatic episodes, and lower parasitic burden compared with low or medium responders. These data suggest that antibody-mediated complement limits blood stage replication of P. falciparum and provides greater protection against disease. Finally, the authors demonstrate that one of the vaccine candidates currently in clinical trials, MSP-2, induces antibody-mediated complement in individuals immunized with this formulation. More importantly, these antibodies that arise from this vaccine are capable of inhibiting invasion of RBCs by the malaria parasite. These exciting results uncover an important immune mechanism required for protection from malaria and highlight that focusing on targets and strategies for inducing complement fixing antibodies might be the key to designing efficacious vaccines.

M. J. Boyle et al., Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity 42, 580–590 (2015). [Abstract]

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