Global distribution of single amino acid polymorphisms in Plasmodium vivax Duffy-binding-like domain and implications for vaccine development efforts

Abstract

Plasmodium vivax ( Pv ) malaria continues to be geographically widespread with approximately 15 million worldwide cases annually. Along with other proteins, Duffy-binding proteins (DBPs) are used by plasmodium for RBC invasion and the parasite-encoded receptor binding regions lie in their Duffy-binding-like (DBL) domains—thus making it a prime vaccine candidate. This study explores the sequence diversity in Pv DBL globally, with an emphasis on India as it remains a major contributor to the global Pv malaria burden. Based on 1358 Pv DBL protein sequences available in NCBI, we identified 140 polymorphic sites within 315 residues of Pv DBL. Alarmingly, country-wise mapping of SAAPs from field isolates revealed varied and distinct polymorphic profiles for different nations. We report here 31 polymorphic residue positions in the global SAAP profile, most of which map to the Pv DBL subdomain 2 ( α 1– α 6). A distinct clustering of SAAPs distal to the DARC-binding sites is indicative of immune evasive strategies by the parasite. Analyses of Pv DBL-neutralizing antibody complexes revealed that between 24% and 54% of interface residues are polymorphic. This work provides a framework to recce and expand the polymorphic space coverage in Pv DBLs as this has direct implications for vaccine development studies. It also emphasizes the significance of surveying global SAAP distributions before or alongside the identification of vaccine candidates.

Plasmodium vivax Duffy Binding Protein-Based Vaccine: a Distant Dream

“…(iv) A strain transcending Pv DBPII-based vaccine demands a globally conserved epitope. Mittal et al , in their global Single Amino Acid Polymorphism (SAAP) data analysis reported that from the four Pv DBL–mAb complex structures, 2 out of the 4 purported neutralizing mAbs do not bind near the supposed dimer interface ( Mittal et al., 2020 ). Such discoveries points towards the fact that a vaccine against P. vivax could have more impact if above challenges of Pv DBPII (as the lone candidate) were considered.…”

“…(2014) . Although these structural and biophysical studies provide deep insight into Pv DBPII-DARC engagement, further studies are required to assess these models as this region is prone to polymorphisms ( Mittal et al., 2020 ) and as a result, the inherent variability in Pv DBL might render the Pv DBP-based vaccines inefficacious. Further, Yogavel et al.…”

“…A step-wise binding model has also been proposed which involves receptor-induced PvDBPII dimerization facilitating the formation of a heterotrimer that eventually employs a second DARC molecule to form a heterotetramer (PDB: 4NUU and 4NUV) Batchelor et al (2014). Although these structural and biophysical studies provide deep insight into PvDBPII-DARC engagement, further studies are required to assess these models as this region is prone to polymorphisms (Mittal et al, 2020) and as a result, the inherent variability in PvDBL might render the PvDBP-based vaccines inefficacious. Further, Yogavel et al reported the existence of two binding sites in PvDBPII, a) Site 1 which includes residues K266, K270, R273 and K347 and, b) Site 2 including residues K242, R243 and H325 (from PDB: 3RRC, 4NUU and 4NUV) (Yogavel et al, 2018).…”

Structural insights into global mutations in the ligand-binding domain of VAR2CSA and its implications on placental malaria vaccine

“…Similar concerns are also being addressed for COVID-19 vaccines whose efficacy may be altered against new variants having SNPs (Harvey et al, 2021). Similarly, a recent study on Plasmodium vivax DBL (Duffy-binding like) protein that binds to DARC (Duffy antigen receptor for chemokines) receptor for invasion into red blood cells showed inherent variability in its sequences worldwide, which may act as a limitation for the development of an effective, universal vaccine (Mittal et al, 2020). Thus, it is clear that region-wise or country-wise polymorphism analysis in the ligand-binding domain of VAR2CSA must be covered for vaccine development.…”

Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets

“…Inherent variability in genomic sequences of drug and vaccine targets can be a shortcoming in the design and development of effective therapies as the targets will be naturally resistant (compromised) [ 24 , 25 ]. Any amino acid change, particularly at the active site of a drug target, can induce alterations in the structural features which will alter its interaction with the drug and can lead to weak or no binding.…”