Sequence analysis of Plasmodium vivax Duffy binding proteins reveals the presence of unique haplotypes and diversifying selection in Ethiopian isolates

Abstract Background Red blood cell invasion by the Plasmodium vivax merozoite requires interaction between the Duffy antigen receptor for chemokines (DARC) and the P. vivax Duffy-binding protein II (PvDBPII). Given that the disruption of this interaction prevents P. vivax blood-stage infection, a PvDBP-based vaccine development has been well recognized. However, the polymorphic nature of PvDBPII prevents a strain transcending immune response and complicates attempts to design a vaccine. Methods Twenty-three P. vivax clinical isolates collected from three areas of Ethiopia were sequenced at the pvdbpII locus. A total of 392 global pvdbpII sequences from seven P. vivax endemic countries were also retrieved from the NCBI archive for comparative analysis of genetic diversity, departure from neutrality, linkage disequilibrium, genetic differentiation, PvDBP polymorphisms, recombination and population structure of the parasite population. To establish a haplotype relationship a network was constructed using the median joining algorithm. Results A total of 110 variable sites were found, of which 44 were parsimony informative. For Ethiopian isolates there were 12 variable sites of which 10 were parsimony informative. These parsimony informative variants resulted in 10 nonsynonymous mutations. The overall haplotype diversity for global isolates was 0.9596; however, the haplotype diversity was 0.874 for Ethiopia. Fst values for genetic revealed Ethiopian isolates were closest to Indian isolates as well as to Sri Lankan and Sudanese isolates but further away from Mexican, Papua New Guinean and South Korean isolates. There was a total of 136 haplotypes from the 415 global isolates included for this study. Haplotype prevalence ranged from 36.76% to 0.7%, from this 74.2% were represented by single parasite isolates. None of the Ethiopian isolates grouped with the Sal I reference haplotype. From the total observed nonsynonymous mutations 13 mapped to experimentally verified epitope sequences. Including 10 non-synonymous mutations from Ethiopia. However, all the polymorphic regions in Ethiopian isolates were located away from DARC, responsible for junction formation. Conclusion The results of this study are concurrent with the multivalent vaccine approach to design an effective treatment. However, the presence of novel haplotypes in Ethiopian isolates that were not shared by other global sequences warrant further investigation.

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Insights into Cross-species Evolution of Novel Human Coronavirus 2019-nCoV and Defining Immune Determinants for Vaccine Development

10.1101/2020.01.29.925867 ◽

2020 ◽

Cited By ~ 19

Author(s):

Arunachalam Ramaiah ◽

Vaithilingaraja Arumugaswami

Keyword(s):

Binding Affinity ◽

Vaccine Development ◽

Asia Pacific ◽

Potential Candidate ◽

T Cell Epitopes ◽

Live Animal ◽

Synonymous Mutations ◽

Wide Range ◽

Novel Coronavirus ◽

N Proteins

ABSTRACTNovel Coronavirus (nCoV) outbreak in the city of Wuhan, China during December 2019, has now spread to various countries across the globe triggering a heightened containment effort. This human pathogen is a member of betacoronavirus genus carrying 30 kilobase of single positive-sense RNA genome. Understanding the evolution, zoonotic transmission, and source of this novel virus would help accelerating containment and prevention efforts. The present study reported detailed analysis of 2019-nCoV genome evolution and potential candidate peptides for vaccine development. This nCoV genotype might have been evolved from a bat-CoV by accumulating non-synonymous mutations, indels, and recombination events. Structural proteins Spike (S), and Membrane (M) had extensive mutational changes, whereas Envelope (E) and Nucleocapsid (N) proteins were very conserved suggesting differential selection pressures exerted on 2019-nCoV during evolution. Interestingly, 2019-nCoV Spike protein contains a 39 nucleotide sequence insertion relative to SARS-like bat-SL-CoVZC45/2017. Furthermore, we identified eight high binding affinity (HBA) CD4 T-cell epitopes in the S, E, M and N proteins, which can be commonly recognized by HLA-DR alleles of Asia and Asia-Pacific Region population. These immunodominant epitopes can be incorporated in universal subunit CoV vaccine. Diverse HLA types and variations in the epitope binding affinity may contribute to the wide range of immunopathological outcomes of circulating virus in humans. Our findings emphasize the requirement for continuous surveillance of CoV strains in live animal markets to better understand the viral adaptation to human host and to develop practical solutions to prevent the emergence of novel pathogenic CoV strains.

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Genetic Diversity and Natural Selection of Plasmodium vivax Duffy Binding Protein-II From China-Myanmar Border of Yunnan Province, China

Frontiers in Microbiology ◽

10.3389/fmicb.2021.758061 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tian-Qi Shi ◽

Hai-Mo Shen ◽

Shen-Bo Chen ◽

Kokouvi Kassegne ◽

Yan-Bing Cui ◽

...

Keyword(s):

Genetic Diversity ◽

Population Structure ◽

Natural Selection ◽

Genetic Differentiation ◽

Positive Selection ◽

Plasmodium Vivax ◽

Yunnan Province ◽

Duffy Binding Protein ◽

Synonymous Mutations ◽

Selection Of

Malaria incidence has declined dramatically over the past decade and China was certified malaria-free in 2021. However, the presence of malaria in border areas and the importation of cases of malaria parasites are major challenges for the consolidation of the achievements made by China. Plasmodium vivax Duffy binding protein (PvDBP) performs a significant role in erythrocyte invasion, and is considered a promising P. vivax vaccine. However, the highly polymorphic region of PvDBP (PvDBP-II) impedes the development of blood-stage vaccine against P. vivax. In this study, we investigated the genetic diversity and natural selection of PvDBP-II among 124 P. vivax isolates collected from the China-Myanmar border (CMB) in Yunnan Province, China, during 2009–2011. To compare genetic diversity, natural selection, and population structure with CMB isolates, 85 pvdbp-II sequences of eastern Myanmar isolates were obtained from GenBank. In addition, global sequences of pvdbp-II were retrieved from GenBank to establish genetic differentiation relationships and networks with the CMB isolates. In total, 22 single nucleotide polymorphisms reflected in 20 non-synonymous and two synonymous mutations were identified. The overall nucleotide diversity of PvDBP-II from the 124 CMB isolates was 0.0059 with 21 haplotypes identified (Hd = 0.91). The high ratio of non-synonymous to synonymous mutations suggests that PvDBP-II had evolved under positive selection. Population structure analysis of the CMB and eastern Myanmar isolates were optimally grouped into five sub-populations (K = 5). Polymorphisms of PvDBP-II display that CMB isolates were genetically diverse. Mutation, recombination, and positive selection promote polymorphism of PvDBP-II of P. vivax population. Although low-level genetic differentiation in eastern Myanmar was identified along with the more effective malaria control measures, the complexity of population structure in malaria parasites has maintained. In conclusion, findings from this study advance knowledge of the understanding of the dynamic of P. vivax population, which will contribute to guiding the rational design of a PvDBP-II based vaccine.

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Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

Microorganisms ◽

10.3390/microorganisms7100402 ◽

2019 ◽

Vol 7 (10) ◽

pp. 402

Author(s):

Titus Abiola Olukitibi ◽

Zhujun Ao ◽

Mona Mahmoudi ◽

Gary A. Kobinger ◽

Xiaojian Yao

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Ebola Virus ◽

Vaccine Development ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immunological Approach ◽

Vaccine Approach ◽

Acquired Immune Responses ◽

Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

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Production of recombinant PvDBPII, receptor binding domain of Plasmodium vivax Duffy binding protein, and evaluation of immunogenicity to identify an adjuvant formulation for vaccine development

Protein Expression and Purification ◽

10.1016/j.pep.2015.06.011 ◽

2017 ◽

Vol 136 ◽

pp. 52-57 ◽

Cited By ~ 7

Author(s):

Rukmini Bhardwaj ◽

Ahmad Rushdi Shakri ◽

Dhiraj Hans ◽

Pankaj Gupta ◽

Carmen Fernandez-Becerra ◽

...

Keyword(s):

Plasmodium Vivax ◽

Receptor Binding ◽

Vaccine Development ◽

Binding Protein ◽

Binding Domain ◽

Receptor Binding Domain ◽

Duffy Binding Protein

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Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies

Infection and Immunity ◽

10.1128/iai.01036-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 1089-1095 ◽

Cited By ~ 64

Author(s):

Patchanee Chootong ◽

Francis B. Ntumngia ◽

Kelley M. VanBuskirk ◽

Jia Xainli ◽

Jennifer L. Cole-Tobian ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

High Titer ◽

Blood Stage ◽

Duffy Binding Protein ◽

Linear Peptide ◽

Binding Function ◽

Blood Stage Infection ◽

Erythrocyte Binding ◽

Linear Epitopes

ABSTRACT Plasmodium vivax Duffy binding protein (DBP) is a merozoite microneme ligand vital for blood-stage infection, which makes it an important candidate vaccine for antibody-mediated immunity against vivax malaria. A differential screen with a linear peptide array compared the reactivities of noninhibitory and inhibitory high-titer human immune sera to identify target epitopes associated with protective immunity. Naturally acquired anti-DBP-specific serologic responses observed in the residents of a region of Papua New Guinea where P. vivax is highly endemic exhibited significant changes in DBP-specific titers over time. The anti-DBP functional inhibition for each serum ranged from complete inhibition to no inhibition even for high-titer responders to the DBP, indicating that epitope specificity is important. Inhibitory immune human antibodies identified specific B-cell linear epitopes on the DBP (SalI) ligand domain that showed significant correlations with inhibitory responses. Affinity-purified naturally acquired antibodies on these epitopes inhibited the DBP erythrocyte binding function greatly, confirming the protective value of specific epitopes. These results represent an important advance in our understanding of part of blood-stage immunity to P. vivax and some of the specific targets for vaccine-elicited antibody protection.

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Identification of highly-protective combinations of Plasmodium vivax recombinant proteins for vaccine development

eLife ◽

10.7554/elife.28673 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 22

Author(s):

Camila Tenorio França ◽

Michael T White ◽

Wen-Qiang He ◽

Jessica B Hostetler ◽

Jessica Brewster ◽

...

Keyword(s):

Vaccine Development ◽

Protective Efficacy ◽

Functional Characterization ◽

Multiple Antigen ◽

Prospective Risk ◽

Antibody Levels ◽

First Time ◽

Papua New Guinean ◽

Antigenic Targets ◽

Annealing Algorithms

The study of antigenic targets of naturally-acquired immunity is essential to identify and prioritize antigens for further functional characterization. We measured total IgG antibodies to 38 P. vivax antigens, investigating their relationship with prospective risk of malaria in a cohort of 1–3 years old Papua New Guinean children. Using simulated annealing algorithms, the potential protective efficacy of antibodies to multiple antigen-combinations, and the antibody thresholds associated with protection were investigated for the first time. High antibody levels to multiple known and newly identified proteins were strongly associated with protection (IRR 0.44–0.74, p<0.001–0.041). Among five-antigen combinations with the strongest protective effect (>90%), EBP, DBPII, RBP1a, CyRPA, and PVX_081550 were most frequently identified; several of them requiring very low antibody levels to show a protective association. These data identify individual antigens that should be prioritized for further functional testing and establish a clear path to testing a multicomponent P. vivax vaccine.

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The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples

Pathogens ◽

10.3390/pathogens10081050 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1050

Author(s):

Stefan Magez ◽

Zeng Li ◽

Hang Thi Thu Nguyen ◽

Joar Esteban Pinto Torres ◽

Pieter Van Wielendaele ◽

...

Keyword(s):

Vaccine Development ◽

Surface Glycoprotein ◽

Humoral Immune ◽

Good Target ◽

Natural Hosts ◽

History Of ◽

Potential Vaccine ◽

Single Field ◽

Vaccine Approach ◽

Zoonotic Parasites

Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

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Bridging the Gaps in the Vaccine Development: Avant-Garde Vaccine Approach with Secreted Heat Shock Protein gp96-Ig

Heat Shock Proteins in the Immune System ◽

10.1007/978-3-319-69042-1_5 ◽

2018 ◽

pp. 75-95

Author(s):

Natasa Strbo

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Vaccine Development ◽

Avant Garde ◽

Heat Shock Protein Gp96 ◽

Vaccine Approach

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Strain-Specific Duffy Binding Protein Antibodies Correlate with Protection against Infection with Homologous Compared to Heterologous Plasmodium vivax Strains in Papua New Guinean Children

Infection and Immunity ◽

10.1128/iai.00158-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 4009-4017 ◽

Cited By ~ 56

Author(s):

Jennifer L. Cole-Tobian ◽

Pascal Michon ◽

Moses Biasor ◽

Jack S. Richards ◽

James G. Beeson ◽

...

Keyword(s):

Plasmodium Vivax ◽

Cox Regression ◽

Binding Protein ◽

Blood Stage ◽

Incidence Density ◽

High Antibody ◽

Duffy Binding Protein ◽

Specific Immunity ◽

Antibody Levels ◽

Papua New Guinean

ABSTRACT Individuals repeatedly infected with malaria acquire protection from infection and disease; immunity is thought to be primarily antibody-mediated and directed to blood-stage infection. Merozoite surface proteins involved in the invasion of host erythrocytes are likely targets of protective antibodies. We hypothesized that Papua New Guinean children (n = 206) who acquire high antibody levels to two Plasmodium vivax merozoite proteins, Duffy binding protein region II (PvDBPII) and the 19-kDa C-terminal region of P. vivax merozoite surface protein 1 (PvMSP119), would have a delay in the time to reinfection following treatment to clear all blood-stage malaria infections. Ninety-four percent of the children were reinfected with P. vivax during biweekly follow-ups for 6 months. Since PvDBPII is polymorphic, we examined whether individuals acquired strain-specific immunity to PvDBPII. Children with high antibody levels to a prevalent PvDBPII allele (O) were associated with a delay in the time to reinfection with the same variant of P. vivax by 25% compared to parasites expressing other PvDBPII alleles (age-adjusted hazard ratio, 0.75 [95% confidence interval, 0.56 to 1.00 by Cox regression]) and 39% lower incidence density parasitemia (P = 0.01). Two other prevalent alleles (AH and P) showed a similar trend of 16% and 18% protection, respectively, against parasites with the same PvDBPII allele and reduced incidence density parasitemia. Antibodies directed to PvDBPII PNG-P and -O were both associated with a 21 to 26% reduction in the risk of P. vivax infections with higher levels of parasitemia (>150 parasites/μl), respectively. There was no association with high antibody levels to PvMSP119 and a delay in the time to P. vivax reinfection. Thus, anti-PvDBPII antibodies are associated with strain-specific immunity to P. vivax and support the use of PvDBPII for a vaccine against P. vivax.

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