Naturally acquired blocking human monoclonal antibodies toPlasmodium vivaxreticulocyte binding protein 2b

Abstract

Plasmodium vivax preferentially invades reticulocytes and recognition of these cells is mediated by P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) binding to human Transferrin receptor 1 (TfR1) and Transferrin (Tf). Longitudinal cohort studies in Papua New Guinea, Thailand and Brazil show that PvRBP2b antibodies are correlated with protection against P. vivax infection and disease. Here, we isolated and characterized anti-PvRBP2b human monoclonal antibodies from two individuals in Cambodia with natural P. vivax infection. These antibodies bind with high affinities and map to different regions of PvRBP2b. Several human antibodies blocked PvRBP2b binding to reticulocytes and inhibited complex formation with human TfR1-Tf. We describe different structural mechanisms for functional inhibition, including either steric hindrance with TfR1-Tf or the reticulocyte membrane. These results show that naturally acquired human antibodies against PvRBP2b can inhibit its function which is important for P. vivax invasion.

Untangling population structure and genetic diversity of reticulocyte binding protein 2b (PvRBP2b) erythrocytic stage vaccine candidate in worldwide Plasmodium vivax isolates

“…Isolation and characterization of anti-PvRBP2b human monoclonal antibodies (mAbs) in Cambodian patients proved the inhibitory role of naturally acquired antibodies against P . vivax invasion [ 19 ]. The majority of PvRBP2b human mAbs were connected to epitopes within amino acids 169–470, and 470–652, and only two mAbs were related to 969–1454 residues [ 19 ].…”

“…vivax invasion [ 19 ]. The majority of PvRBP2b human mAbs were connected to epitopes within amino acids 169–470, and 470–652, and only two mAbs were related to 969–1454 residues [ 19 ]. To know whether antigenic diversity and amino acid replacements can impact on the recognition of epitopes by antibodies, epitope prediction was performed and the results showed that of 44 substitutions, 14 replacements were located in the linear and conformational B-cell epitopes.…”

“…These mutations may hamper on the vaccine designed based on reference alleles. In this regard, in a recent study has been shown that the binding activity of a monoclonal antibody against PvRBP2b antigen may be influenced by K363 and G382 polymorphisms in N-terminal domain [ 19 ]. Interestingly these mutations were observed in Iranian and worldwide isolate ( Table 6 ) and should be considered in vaccine design perhaps by including different variants to cover all mutations in these positions.…”

“…Besides, Chan et al, declared that one (237235) out of four detected human antibody sets is located in a conserved region within the N-terminal domain. They found that this monoclonal antibody bind to amino acids 171, 173, 174, 193, 203, 231, 235, 238, 239, 241, 434, 437, 438, 441, 445 and 448 on the PvRBP2b antigen [ 19 ]. Interestingly, no polymorphism was detected in the mentioned positions of the analyzed worldwide sequences, which should be considered for PvRBP2b-based vaccine design.…”

“…vivax infections within the previous nine months in Thailand, Peru, and Brazil regions [ 18 ]. Furthermore, it has been shown that naturally acquired human antibodies against N-terminus of PvRBP2b can inhibit parasite invasion [ 19 ]. Therefore, due to the significant high polymorphisms [ 10 ] and potential to induce immune responses against PvRBP2b [ 12 , 15 – 19 ], the N-terminal and a part of C-terminal region of pvrbp2b was considered for further analysis in the present study.…”