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1.  Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 among Plasmodium vivax Korean isolates 
Malaria Journal  2012;11:206.
The carboxy-terminal 42 kDa region of Plasmodium vivax merozoite surface protein-1 (PvMSP-142) is a leading candidate antigen for blood stage vaccine development. However, this region has been observed to be highly polymorphic among filed isolates of P. vivax. Therefore it is important to analyse the existing diversity of this antigen in the field isolates of P. vivax. In this study, the genetic diversity and natural selection in PvMSP-142 among P. vivax Korean isolates were analysed.
A total of 149 P. vivax-infected blood samples collected from patients in Korea were used. The region flanking PvMSP-142 was amplified by PCR, cloned into Escherichia coli, and then sequenced. The polymorphic characteristic and natural selection of PvMSP-142 were analysed using the DNASTAR, MEGA4 and DnaSP programs.
A total of 11 distinct haplotypes of PvMSP-142 with 40 amino acid changes, as compared to the reference Sal I sequence, were identified in the Korean P. vivax isolates. Most of the mutations were concentrated in the 33 kDa fragment (PvMSP-133), but a novel mutation was found in the 19 kDa fragment (PvMSP-119). PvMSP-142 of Korean isolates appeared to be under balancing selection. Recombination may also play a role in the resulting genetic diversity of PvMSP-142.
PvMSP-142 of Korean P. vivax isolates displayed allelic polymorphisms caused by mutation, recombination and balancing selection. These results will be useful for understanding the nature of the P. vivax population in Korea and for development of a PvMSP-142 based vaccine against P. vivax.
PMCID: PMC3487983  PMID: 22709605
Plasmodium vivax; Merozoite surface protein-1 C-terminal 42 kDa fragment; Genetic diversity; Natural selection; Korea
2.  Polymorphic patterns of the merozoite surface protein-3β in Korean isolates of Plasmodium vivax 
Malaria Journal  2014;13:104.
The merozoite surface protein-3β of Plasmodium vivax (PvMSP-3β) is one of the candidate antigens for blood stage malaria vaccine development. The polymorphisms in PvMSP-3β have been reported in certain P. vivax isolates. However, the diversity of PvMSP-3β throughout its global distribution has not been well understood. In this study, the genetic diversity and the effects of natural selection in PvMSP-3β among P. vivax Korean isolates were analysed.
Blood samples were collected from 95 patients with vivax malaria in Korea. The region flanking full-length PvMSP-3β was amplified by polymerase chain reaction and cloned into a TA cloning vector. The PvMSP-3β sequence of each isolate was determined and the polymorphic characteristics and effects of natural selection were analysed using the DNASTAR, MEGA4, and DnaSP programs.
Five different subtypes of PvMSP-3β were identified based on single nucleotide polymorphisms (SNPs), insertions, and deletions. Although a high level of sequence diversity was observed in the PvMSP-3β gene, the coiled-coil tertiary structure of the PvMSP-3β protein was well conserved in all of the sequences. The PvMSP-3β of Korean isolates is under natural selection. DNA polymerase slippage and intragenic recombination likely contributed to PvMSP-3β diversity in Korean P. vivax isolates.
The PvMSP-3β of Korean P. vivax isolates displayed polymorphisms, with SNPs, insertions and deletions scattered throughout of the gene. These results of parasite heterogeneity are relevant to the development of a PvMSP-3β based vaccine against P. vivax and the implementation of malaria control programmes in Korea.
PMCID: PMC3995521  PMID: 24635878
Plasmodium vivax; Merozoite surface protein-3β; Genetic polymorphism; Natural selection; Korea
3.  Distribution of Antibodies Specific to the 19-kDa and 33-kDa Fragments of Plasmodium vivax Merozoite Surface Protein 1 in Two Pathogenic Strains Infecting Korean Vivax Malaria Patients 
Plasmodium vivax merozoite surface protein 1 (PvMSP1) is the most intensively studied malaria vaccine candidate. Although high antibody response-inducing two C-terminal fragments of PvMSP1 (PvMSP1-19 and PvMSP1-42) are currently being developed as candidate malaria vaccine antigens, their high genetic diversity in various isolates is a major hurdle. The sequence polymorphism of PvMSP1 has been investigated; however, the humoral immune responses induced by different portions of this protein have not been evaluated in Korea.
Two fragments of PvMSP1 were selected for this study: (1) PvMSP1-19, which is genetically conserved; and (2) PvMSP1-33, which corresponds to a variable portion. For the latter, two representative strains, Sal 1 and Belem, were included. Thus, three recombinant proteins, PvMSP1-19, PvMSP1-33 Sal 1, and PvMSP1-33 Belem, were produced in Escherichia coli and then tested by enzyme-linked immunosorbent assays using sera from 221 patients with vivax malaria.
Of the 221 samples, 198, 142, and 106 samples were seropositive for PvMSP1-19, PvMSP1-33 Sal 1, and PvMSP1-33 Belem, respectively. Although 100 samples were simultaneously seropositive for antibodies specific to all the recombinant proteins, 39 and six samples were respectively seropositive for antibodies specific to MSP1-33 Sal 1 and MSP1-33 Belem. Antibodies specific to PvMSP1-19 were the most prevalent.
Monitoring seroprevalence is essential for the selection of promising vaccine candidates as most of the antigenic proteins in P. vivax are highly polymorphic.
PMCID: PMC5014746  PMID: 27635370
merozoite surface protein 1; Plasmodium vivax; seroprevalence
4.  Genetic Diversity and Natural Selection in 42 kDa Region of Plasmodium vivax Merozoite Surface Protein-1 from China-Myanmar Endemic Border 
Plasmodium vivax merozoite surface protein-1 (PvMSP1) gene codes for a major malaria vaccine candidate antigen. However, its polymorphic nature represents an obstacle to the design of a protective vaccine. In this study, we analyzed the genetic polymorphism and natural selection of the C-terminal 42 kDa fragment within PvMSP1 gene (Pv MSP142) from 77 P. vivax isolates, collected from imported cases of China-Myanmar border (CMB) areas in Yunnan province and the inland cases from Anhui, Yunnan, and Zhejiang province in China during 2009–2012. Totally, 41 haplotypes were identified and 30 of them were new haplotypes. The differences between the rates of non-synonymous and synonymous mutations suggest that PvMSP142 has evolved under natural selection, and a high selective pressure preferentially acted on regions identified of PvMSP133. Our results also demonstrated that PvMSP142 of P. vivax isolates collected on China-Myanmar border areas display higher genetic polymorphisms than those collected from inland of China. Such results have significant implications for understanding the dynamic of the P. vivax population and may be useful information towards China malaria elimination campaign strategies.
PMCID: PMC5678462  PMID: 29103262
Plasmodium vivax; merozoite surface protein-1; genetic polymorphism; natural selection; Myanmar; China
5.  The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax 
Infection and Immunity  2013;81(5):1585-1595.
Merozoite surface protein 1 of Plasmodium vivax (PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate for P. vivax. The paralog of PvMSP1, named P. vivax merozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera from P. vivax-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. An in vitro cytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibited in vitro binding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in the P. vivax merozoite and is a potential vaccine candidate against P. vivax.
PMCID: PMC3648005  PMID: 23460511
6.  Purification, Characterization, and Immunogenicity of a Disulfide Cross-Linked Plasmodium vivax Vaccine Candidate Antigen, Merozoite Surface Protein 1, Expressed in Escherichia coli 
Infection and Immunity  2001;69(9):5464-5470.
The Plasmodium vivax merozoite surface protein 1 (MSP-1) 42-kDa fragment (PvMSP-1 p42) is a promising vaccine candidate antigen against the blood stage of the malarial parasite. We have developed a process for the production of this vaccine target, keeping in mind its use in human volunteers. A novel strain, Origami(DE3), of Escherichia coli with mutations in the glutathione and thioredoxin reductase genes yielded 60% more soluble PvMSP-1 p42 than the conventional E. coli BL21(DE3) strain. Recombinant PvMSP-1 p42 was purified to ≥99% purity with a rapid two-step protocol designed for easy scaling up. The final product had a low endotoxin content and was stable in its lyophilized form. PvMSP-1 p42 was found to have the predicted primary and tertiary structures and consisted of a single conformer containing one free cysteine, as predicted. The product was recognized by conformational monoclonal antibodies against P. vivax MSP-1. Immunogenicity studies of PvMSP-1 p42 were carried out with two strains of mice and the adjuvants Montanide ISA51 and Montanide ISA720. Both formulations were found to induce high levels of immunoglobulin G1 (IgG1), IgG2b, and IgG2a antibodies along with low levels of IgG3. Lymphocytes from animals in all the PvMSP-1 p42-immunized groups showed proliferative responses upon stimulation with PvMSP-1 p42; the cytokines interleukin 2 (IL-2), gamma interferon, IL-4, and IL-10 were detected in the culture supernatants. These results indicate that PvMSP-1 p42 in combination with both of the adjuvants elicited cellular and humoral responses in mice.
PMCID: PMC98658  PMID: 11500418
7.  Naturally Acquired Immune Responses to P. vivax Merozoite Surface Protein 3α and Merozoite Surface Protein 9 Are Associated with Reduced Risk of P. vivax Malaria in Young Papua New Guinean Children 
Plasmodium vivax is the most geographically widespread human malaria parasite. Cohort studies in Papua New Guinea have identified a rapid onset of immunity against vivax-malaria in children living in highly endemic areas. Although numerous P. vivax merozoite antigens are targets of naturally acquired antibodies, the role of many of these antibodies in protective immunity is yet unknown.
Methodology/Principal Findings
In a cohort of children aged 1–3 years, antibodies to different regions of Merozoite Surface Protein 3α (PvMSP3α) and Merozoite Surface Protein 9 (PvMSP9) were measured and related to prospective risk of P. vivax malaria during 16 months of active follow-up. Overall, there was a low prevalence of antibodies to PvMSP3α and PvMSP9 proteins (9–65%). Antibodies to the PvMSP3α N-terminal, Block I and Block II regions increased significantly with age while antibodies to the PvMSP3α Block I and PvMSP9 N-terminal regions were positively associated with concurrent P. vivax infection. Independent of exposure (defined as the number of genetically distinct blood-stage infection acquired over time (molFOB)) and age, antibodies specific to both PvMSP3α Block II (adjusted incidence ratio (aIRR) = 0.59, p = 0.011) and PvMSP9 N-terminus (aIRR = 0.68, p = 0.035) were associated with protection against clinical P. vivax malaria. This protection was most pronounced against high-density infections. For PvMSP3α Block II, the effect was stronger with higher levels of antibodies.
These results indicate that PvMSP3α Block II and PvMSP9 N-terminus should be further investigated for their potential as P. vivax vaccine antigens. Controlling for molFOB assures that the observed associations are not confounded by individual differences in exposure.
Author Summary
Plasmodium vivax is the most geographically widespread human malaria parasite. In highly endemic areas such as Papua New Guinea, a very rapid onset of immunity against vivax-malaria is observed. Although it is known that numerous P. vivax merozoite antigens are targets of naturally acquired antibodies, the role of many of these antibodies in protective immunity is yet unknown. In a cohort of 183 children aged 1–3 years, we now show that the presence of antibodies to Merozoite Surface Protein 3α (PvMSP3α) and Merozoite Surface Protein 9 (PvMSP9) are associated with a significant reduction in the burden P. vivax malaria. Antibodies increased with age and in the presence of concurrent P. vivax infections. After adjusting for both age and individual differences in exposure, the strongest reductions in risk were seen in children with antibodies to PvMSP3α Block II (41% reduction, p = 0.001) and PvMSP9 N-terminal region. (32% reduction, p = 0.035). These results indicate that PvMSP3α Block II and PvMSP9 N-terminus should be further investigated for their potential as P. vivax vaccine antigens.
PMCID: PMC3828159  PMID: 24244763
8.  Comparison of Immunogenicities of Recombinant Plasmodium vivax Merozoite Surface Protein 1 19- and 42-Kilodalton Fragments Expressed in Escherichia coli  
Infection and Immunity  2004;72(10):5775-5782.
The 42- and 19-kDa C-terminal fragments of merozoite surface protein 1 (MSP-142 and MSP-119, respectively) are both promising blood-stage vaccine candidate antigens. At present, it is not clear which of the two antigens will be more suitable for inclusion in a cocktail malaria vaccine. In the present study, we expressed the two C-terminal fragments of Plasmodium vivax MSP-1 (PvMSP-1) in an Escherichia coli expression system and purified them by using a rapid two-step protocol. Both of the products were recognized by monoclonal antibodies against PvMSP-1 as well as by immune sera from several individuals exposed to P. vivax. We analyzed and compared the immunological responses to recombinant PvMSP-119 and PvMSP-142 in mice by using six different adjuvant formulations. Moderate to high antibody responses were observed with both of the antigens in different adjuvant formulations. Surprisingly, alum, which is generally considered to be a poor adjuvant for recombinant malaria antigens, was found to be as good an adjuvant as Montanide ISA 720, ASO2A, and other adjuvant formulations. Most adjuvant formulations induced high levels of immunoglobulin G1 (IgG1), followed by IgG3 and IgG2. Lymphocytes from animals in the PvMSP-142- and PvMSP-119-immunized groups showed proliferative responses upon stimulation with the respective antigens, and high levels of interleukin-4 (IL-4), IL-5, and gamma interferon were detected in the culture supernatants. Immunodepletion studies with sera from mice immunized with these two antigens showed that while immunization with PvMSP-142 does produce a PvMSP-119-specific response, a substantial portion is also focused on structures in PvMSP-142 not represented by the epidermal growth factor-like domains of PvMSP-119. These findings may have implications for the design of MSP-1-based vaccine constructs.
PMCID: PMC517592  PMID: 15385477
9.  High-Level Expression of Immunogenic Recombinant Plasmodium vivax Merozoite Surface Protein (Pvmsp-142 kDa) in pGEX 6P1 Vector 
Detection of Plasmodium vivax specific antibodies with serological tests could be a valuable tool for epidemiological researches. Whereas P. vivax cannot be simply obtained in vitro, serological tests using total or semi-purified antigens are infrequently used. Given this restriction, the present study investigated whether recombinant P. vivax merozoite surface protein 1 (PvMSP-1 42 kDa) could be useful in detection of antibodies from the serums of a P. vivax infected person using serological tests.
Parasite DNA was extracted from blood sample of an Iranian P. vivax-infected patient. The region of PvMSP-142 kDa was amplified by PCR then cloned into pTZ57R/T vector and sequenced. The insert was sub cloned into pGEX 6P1 expression vector. Afterwards, it was transformed into E. coli BL21 and cultured massively. Sub cloning of gene was confirmed by PCR and enzyme digestion and sequencing finally. Production of recombinant protein was confirmed by SDS-PAGE. Western blot was performed by human sera to appraisal binding ability to the IgG antibodies of P. vivax infected patients. Recombinant protein was purified and estimated by Bradford assay.
The specialty values of the Western blot determined with 10 sera from naturally infected individuals, 10 sera from healthy individuals and 7 sera from individuals with other infectious diseases.
For the Iranian population, using a Western blot assay for MSP-142 recombinant protein can be used as the foundation for promotion of serological assay for the detection of P. vivax malaria such as ELISA.
PMCID: PMC4450018  PMID: 26060780
Plasmodium vivax; Recombinant PvMSP-142 kDa; Expression vector; Iran
10.  Naturally acquired humoral and cellular immune responses to Plasmodium vivax merozoite surface protein 8 in patients with P. vivax infection 
Malaria Journal  2017;16:211.
Thirty-one glycosylphosphatidylinositol (GPI)-anchored proteins of Plasmodium vivax, merozoite surface protein 1 (MSP1), MSP1 paralogue, MSP4, MSP5, MSP8, and MSP10 have been reported from homologs of Plasmodium falciparum by gene annotation with bioinformatics tools. These GPI-anchored proteins contain two epidermal growth factor (EGF)-like domains at its C-terminus. Here, P. vivax merozoite surface protein 8 (PvMSP8) are considered as potential targets of protective immunity.
Recombinant PvMSP8 (rPvMSP8) was expressed, purified, and used for the assessment of humoral and cellular immune responses in P. vivax-infected patients and immune mice. Moreover, the target epitope of ant-PvMSP8 antibodies and subcellular localization of PvMSP8 was also determined.
The rPvMSP8 was successfully expressed and purified as soluble form as ~55 kDa. PvMSP8 was localized to the outer circle of pigments associated with the food vacuole. The rPvMSP8 protein had a high antigenicity (73.2% in sensitivity and 96.2% in specificity) in patients infected with P. vivax. IgG2 antibody subtype was the predominantly responses to this antigen. Antibody response to PvMSP8 increased up to day 7 and after that slightly decreased within a month. The longevity of anti-PvMSP8 antibody was stably sustained up to 12-year recovery patient samples. Most anti-PvMSP8 antibodies recognized two epitopes that were located outside the C-terminal EGF-like domain. The cellular immune response in P. vivax-exposed individuals produced high levels of IFN-γ and IL-10 upon PvMSP8 antigen stimulation in vitro.
All data in this study suggest that PvMSP8 antigen has a potential to induce both humoral and cellular immune responses in patients with P. vivax infection. The subcellular localization of PvMSP8 confirmed that it was associated with the parasite food vacuole in blood-stage parasites. A further characterization of this protein will be useful for blood stage P. vivax vaccine development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-017-1837-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5440977
Plasmodium vivax; Merozoite surface protein 8; Immunogenicity; Food vacuole
11.  Genetic diversity of Plasmodium Vivax revealed by the merozoite surface protein-1 icb5-6 fragment 
Plasmodium vivax remains a potential cause of morbidity and mortality for people living in its endemic areas. Understanding the genetic diversity of P. vivax from different regions is valuable for studying population dynamics and tracing the origins of parasites. The PvMSP-1 gene is highly polymorphic and has been used as a marker in many P. vivax population studies. The aim of this study was to investigate the genetic diversity of the PvMSP-1 gene icb5-6 fragment and to provide more genetic polymorphism data for further studies on P. vivax population structure and tracking of the origin of clinical cases.
Nested PCR and sequencing of the PvMSP-1 icb5-6 marker were performed to obtain the nucleotide sequences of 95 P. vivax isolates collected from Zhejiang province, China. To investigate the genetic diversity of PvMSP-1, the 95 nucleotide sequences of the PvMSP-1 icb5-6 fragment were genotyped and analyzed using DnaSP v5, MEGA software.
The 95 P. vivax isolates collected from Zhejiang province were either indigenous cases or imported cases from different regions around the world. A total of 95 sequences ranging from 390 to 460 bp were obtained. The 95 sequences were genotyped into four allele-types (Sal I, Belem, R-III and R-IV) and 17 unique haplotypes. R-III and Sal I were the predominant allele-types. The haplotype diversity (Hd) and nucleotide diversity (Pi) were estimated to be 0.729 and 0.062, indicating that the PvMSP-1 icb5-6 fragment had the highest level of polymorphism due to frequent recombination processes and single nucleotide polymorphism. The values of dN/dS and Tajima’s D both suggested neutral selection for the PvMSP-1icb5-6 fragment. In addition, a rare recombinant style of R-IV type was identified.
This study presented high genetic diversity in the PvMSP-1 marker among P. vivax strains from around the world. The genetic data is valuable for expanding the polymorphism information on P. vivax, which could be helpful for further study on population dynamics and tracking the origin of P. vivax.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-017-0302-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5458480  PMID: 28578709
Plasmodium vivax; PvMSP-1; Genetic diversity; Malaria
12.  The Plasmodium vivax Merozoite Surface Protein 3β Sequence Reveals Contrasting Parasite Populations in Southern and Northwestern Thailand 
Malaria control efforts have a significant impact on the epidemiology and parasite population dynamics. In countries aiming for malaria elimination, malaria transmission may be restricted to limited transmission hot spots, where parasite populations may be isolated from each other and experience different selection forces. Here we aim to examine the Plasmodium vivax population divergence in geographically isolated transmission zones in Thailand.
We employed the P. vivax merozoite surface protein 3β (PvMSP3β) as a molecular marker for characterizing P. vivax populations based on the extensive diversity of this gene in Southeast Asian parasite populations. To examine two parasite populations with different transmission levels in Thailand, we obtained 45 P. vivax isolates from Tak Province, northwestern Thailand, where the annual parasite incidence (API) was more than 2%, and 28 isolates from Yala and Narathiwat Provinces, southern Thailand, where the API was less than 0.02%. We sequenced the PvMSP3β gene and examined its genetic diversity and molecular evolution between the parasite populations.
Principal Findings
Of 58 isolates containing single PvMSP3β alleles, 31 sequence types were identified. The overall haplotype diversity was 0.77±0.06 and nucleotide diversity 0.0877±0.0054. The northwestern vivax malaria population exhibited extensive haplotype diversity (HD) of PvMSP3β (HD = 1.0). In contrast, the southern parasite population displayed a single PvMSP3β allele (HD = 0), suggesting a clonal population expansion. This result revealed that the extent of allelic diversity in P. vivax populations in Thailand varies among endemic areas.
Malaria parasite populations in a given region may vary significantly in genetic diversity, which may be the result of control and influenced by the magnitude of malaria transmission intensity. This is an issue that should be taken into account for the implementation of P. vivax control measures such as drug policy and vaccine development.
Author Summary
With intensified malaria control in endemic countries, there have been dramatic changes of malaria epidemiology. One of such changes is the increased proportion of Plasmodium vivax malaria, a demonstration of resilience of this parasite to control efforts. In Thailand, malaria has been largely eliminated from the central plain, and transmission is concentrated in isolated international border regions. This study aimed to examine whether the changing malaria epidemiology was reflected in the population dynamics and genetic diversity of the isolated parasite populations. We collected parasite samples from two regions in Thailand with drastically different endemicity settings and used a polymorphic genetic marker (Plasmodium vivax merozoite surface protein 3β – pvmsp3β) as an indicator of genetic diversity of the populations. Analysis of the pvmsp3β sequences revealed high genetic diversity of parasites from western Thailand, and suggested the suitability of this gene as a molecular marker to infer parasite genetic diversity. Comparing the pvmsp3β sequences, we further discovered extreme divergence in genetic diversity between the southern and northwestern Thai P. vivax populations. Our study offers important insights into malaria epidemiology and provides the needed knowledge for designing novel control tools in the malaria elimination campaigns.
PMCID: PMC4238993  PMID: 25412166
13.  Differing Patterns of Selection and Geospatial Genetic Diversity within Two Leading Plasmodium vivax Candidate Vaccine Antigens 
Although Plasmodium vivax is a leading cause of malaria around the world, only a handful of vivax antigens are being studied for vaccine development. Here, we investigated genetic signatures of selection and geospatial genetic diversity of two leading vivax vaccine antigens – Plasmodium vivax merozoite surface protein 1 (pvmsp-1) and Plasmodium vivax circumsporozoite protein (pvcsp). Using scalable next-generation sequencing, we deep-sequenced amplicons of the 42 kDa region of pvmsp-1 (n = 44) and the complete gene of pvcsp (n = 47) from Cambodian isolates. These sequences were then compared with global parasite populations obtained from GenBank. Using a combination of statistical and phylogenetic methods to assess for selection and population structure, we found strong evidence of balancing selection in the 42 kDa region of pvmsp-1, which varied significantly over the length of the gene, consistent with immune-mediated selection. In pvcsp, the highly variable central repeat region also showed patterns consistent with immune selection, which were lacking outside the repeat. The patterns of selection seen in both genes differed from their P. falciparum orthologs. In addition, we found that, similar to merozoite antigens from P. falciparum malaria, genetic diversity of pvmsp-1 sequences showed no geographic clustering, while the non-merozoite antigen, pvcsp, showed strong geographic clustering. These findings suggest that while immune selection may act on both vivax vaccine candidate antigens, the geographic distribution of genetic variability differs greatly between these two genes. The selective forces driving this diversification could lead to antigen escape and vaccine failure. Better understanding the geographic distribution of genetic variability in vaccine candidate antigens will be key to designing and implementing efficacious vaccines.
Author Summary
Plasmodium vivax causes tens of millions of malaria cases each year. Although some vaccines against P. vivax are being developed, little is known about the geospatial genetic diversity and selective constraints of the parasite surface antigens that these vaccines target. In order to create vaccines that are both efficacious and useful in diverse regions of the world, the strain diversity of these potential vaccine targets must be well understood. Specifically, we must understand whether and how the human immune system develops immunity against these antigens as well as understanding whether these antigens are similar in geographically diverse parasite populations. Here, using next-generation sequencing and population-genetic analyses, we found evidence of likely immune selection in specific regions of two leading vivax vaccine candidate antigens, PvMSP-1 and PvCSP. At the pvmsp-1 locus, we also found more genetic variability within populations than between populations, with some DNA sequences from geographically diverse populations being highly similar. In contrast, pvcsp sequences from geographically diverse populations are very distinct from one another, with specific sequence patterns occurring in certain geographic regions. Our findings provide new insights into the geographic genetic diversity of these two antigens and can help inform the development of effective P. vivax vaccines.
PMCID: PMC3990511  PMID: 24743266
14.  Antigenic Polymorphism and Naturally Acquired Antibodies to Plasmodium vivax Merozoite Surface Protein 1 in Rural Amazonians▿ †  
Clinical and Vaccine Immunology : CVI  2007;14(10):1249-1259.
Merozoite surface protein 1 of Plasmodium vivax (PvMSP-1), a major target for malaria vaccine development, contains six highly polymorphic domains interspersed with conserved sequences. Although there is evidence that the sequence divergence in PvMSP-1 has been maintained over 5 million years by balanced selection exerted by the host's acquired immunity, the variant specificity of naturally acquired antibodies to PvMSP-1 remains poorly investigated. Here, we show that 15 recombinant proteins corresponding to PvMSP-1 variants commonly found in local parasites were poorly recognized by 376 noninfected subjects aged 5 to 90 years exposed to malaria in rural Amazonia; less than one-third of them had detectable immunoglobulin G (IgG) antibodies to at least one variant of blocks 2, 6, and 10 that were expressed, although 54.3% recognized the invariant 19-kDa C-terminal domain PvMSP-119. Although the proportion of responders to PvMSP-1 variants increased substantially during subsequent acute P. vivax infections, the specificity of IgG antibodies did not necessarily match the PvMSP-1 variant(s) found in infecting parasites. We discuss the relative contribution of antigenic polymorphism, poor immunogenicity, and original antigenic sin (the skew in the specificity of antibodies elicited by exposure to new antigenic variants due to preexisting variant-specific responses) to the observed patterns of antibody recognition of PvMSP-1. We suggest that antibody responses to the repertoire of variable domains of PvMSP-1 to which subjects are continuously exposed are elicited only after several repeated infections and may require frequent boosting, with clear implications for the development of PvMSP-1-based subunit vaccines.
PMCID: PMC2168105  PMID: 17699838
15.  Plasmodium vivax Merozoite Surface Protein-3 (PvMSP3): Expression of an 11 Member Multigene Family in Blood-Stage Parasites 
PLoS ONE  2013;8(5):e63888.
Three members of the Plasmodium vivax merozoite surface protein-3 (PvMSP3) family (PvMSP3-α, PvMSP3-β and PvMSP3-γ) were initially characterized and later shown to be part of a larger highly diverse family, encoded by a cluster of genes arranged head-to-tail in chromosome 10. PvMSP3-α and PvMSP3-β have become genetic markers in epidemiological studies, and are being evaluated as vaccine candidates. This research investigates the gene and protein expression of the entire family and pertinent implications.
Methodology/Principal Findings
A 60 kb multigene locus from chromosome 10 in P. vivax (Salvador 1 strain) was studied to classify the number of pvmsp3 genes present, and compare their transcription, translation and protein localization patterns during blood-stage development. Eleven pvmsp3 paralogs encode an N-terminal NLRNG signature motif, a central domain containing repeated variable heptad sequences, and conserved hydrophilic C-terminal features. One additional ORF in the locus lacks these features and was excluded as a member of the family. Transcripts representing all eleven pvmsp3 genes were detected in trophozoite- and schizont-stage RNA. Quantitative immunoblots using schizont-stage extracts and antibodies specific for each PvMSP3 protein demonstrated that all but PvMSP3.11 could be detected. Homologs were also detected by immunoblot in the closely related simian species, P. cynomolgi and P. knowlesi. Immunofluorescence assays confirmed that eight of the PvMSP3s are present in mature schizonts. Uniquely, PvMSP3.7 was expressed exclusively at the apical end of merozoites.
Specific proteins were detected representing the expression of 10 out of 11 genes confirmed as members of the pvmsp3 family. Eight PvMSP3s were visualized surrounding merozoites. In contrast, PvMSP3.7 was detected at the apical end of the merozoites. Pvmsp3.11 transcripts were present, though no corresponding protein was detected. PvMSP3 functions remain unknown. The ten expressed PvMSP3s are predicted to have unique and complementary functions in merozoite biology.
PMCID: PMC3662707  PMID: 23717506
16.  Inter-allelic recombination in the Plasmodium vivax merozoite surface protein 1 gene among Indian and Colombian isolates 
Malaria Journal  2004;3:4.
A major concern in malaria vaccine development is the polymorphism observed among different Plasmodium isolates in different geographical areas across the globe. The merozoite surface protein 1 (MSP-1) is a leading vaccine candidate antigen against asexual blood stages of malaria parasite. To date, little is known about the extent of sequence variation in the Plasmodium vivax MSP-1 gene (Pvmsp-1) among Indian isolates. Since P. vivax accounts for >50% of malaria cases in India and in Colombia, it is essential to know the Pvmsp-1 gene variability in these two countries to sustain it as a vaccine candidate. The extent of polymorphism in Pvmsp-1 gene among Indian and Colombian isolates is described.
The sequence variation in the region encompassing the inter-species conserved blocks (ICBs) five and six of Pvmsp-1 gene was examined. PCR was carried out to amplify the polymorphic region of Pvmsp-1 and the PCR products from twenty (nine Indian and 11 Colombian) isolates were sequenced and aligned with Belem and Salvador-1 sequences.
Results revealed three distinct types of sequences among these isolates, namely, Salvador-like, Belem-like and a third type sequence which was generated due to interallelic recombination between Salvador-like sequences and Belem-like sequences. Existence of the third type in majority (44%) showed that allelic recombinations play an important role in PvMSP1 diversity in natural parasite population. Micro-heterogeneity was also seen in a few of these isolates due to nucleotide substitutions, insertions as well as deletions.
Intergenic recombination in the Pvmsp-1 gene was found and suggest that this is the main cause for genetic diversity of the Pvmsp-1 gene.
PMCID: PMC385245  PMID: 15003129
17.  Cellular and humoral immune responses against the Plasmodium vivax MSP-119 malaria vaccine candidate in individuals living in an endemic area in north-eastern Amazon region of Brazil 
Malaria Journal  2013;12:326.
Plasmodium vivax merozoite surface protein-1 (MSP-1) is an antigen considered to be one of the leading malaria vaccine candidates. PvMSP-1 is highly immunogenic and evidences suggest that it is target for protective immunity against asexual blood stages of malaria parasites. Thus, this study aims to evaluate the acquired cellular and antibody immune responses against PvMSP-1 in individuals naturally exposed to malaria infections in a malaria-endemic area in the north-eastern Amazon region of Brazil.
The study was carried out in Paragominas, Pará State, in the Brazilian Amazon. Blood samples were collected from 35 individuals with uncomplicated malaria. Peripheral blood mononuclear cells were isolated and the cellular proliferation and activation was analysed in presence of 19 kDa fragment of MSP-1 (PvMSP-119) and Plasmodium falciparum PSS1 crude antigen. Antibodies IgE, IgM, IgG and IgG subclass and the levels of TNF, IFN-γ and IL-10 were measured by enzyme-linked immunosorbent assay.
The prevalence of activated CD4+ was greater than CD8+ T cells, in both ex-vivo and in 96 h culture in presence of PvMSP-119 and PSS1 antigen. A low proliferative response against PvMSP-119 and PSS1 crude antigen after 96 h culture was observed. High plasmatic levels of IFN-γ and IL-10 as well as lower TNF levels were also detected in malaria patients. However, in the 96 h supernatant culture, the dynamics of cytokine responses differed from those depicted on plasma assays; in presence of PvMSP-119 stimulus, higher levels of TNF were noted in supernatant 96 h culture of malaria patient’s cells while low levels of IFN-γ and IL-10 were verified. High frequency of malaria patients presenting antibodies against PvMSP-119 was evidenced, regardless class or IgG subclass.PvMSP-119-induced antibodies were predominantly on non-cytophilic subclasses.
The results presented here shows that PvMSP-119 was able to induce a high cellular activation, leading to production of TNF and emphasizes the high immunogenicity of PvMSP-119 in naturally exposed individuals and, therefore, its potential as a malaria vaccine candidate.
PMCID: PMC3850502  PMID: 24041406
Malaria; Plasmodium vivax; MSP-119; Cellular response; Antibodies
18.  Heterogeneous genetic diversity pattern in Plasmodium vivax genes encoding merozoite surface proteins (MSP) -7E, −7F and -7L 
Malaria Journal  2014;13:495.
The msp-7 gene has become differentially expanded in the Plasmodium genus; Plasmodium vivax has the highest copy number of this gene, several of which encode antigenic proteins in merozoites.
DNA sequences from thirty-six Colombian clinical isolates from P. vivax (pv) msp-7E, −7F and -7L genes were analysed for characterizing and studying the genetic diversity of these pvmsp-7 members which are expressed during the intra-erythrocyte stage; natural selection signals producing the variation pattern so observed were evaluated.
The pvmsp-7E gene was highly polymorphic compared to pvmsp-7F and pvmsp-7L which were seen to have limited genetic diversity; pvmsp-7E polymorphism was seen to have been maintained by different types of positive selection. Even though these copies seemed to be species-specific duplications, a search in the Plasmodium cynomolgi genome (P. vivax sister taxon) showed that both species shared the whole msp-7 repertoire. This led to exploring the long-term effect of natural selection by comparing the orthologous sequences which led to finding signatures for lineage-specific positive selection.
The results confirmed that the P. vivax msp-7 family has a heterogeneous genetic diversity pattern; some members are highly conserved whilst others are highly diverse. The results suggested that the 3′-end of these genes encode MSP-7 proteins’ functional region whilst the central region of pvmsp-7E has evolved rapidly. The lineage-specific positive selection signals found suggested that mutations occurring in msp-7s genes during host switch may have succeeded in adapting the ancestral P. vivax parasite population to humans.
Electronic supplementary material
The online version of this article (doi:10.1186/1475-2875-13-495) contains supplementary material, which is available to authorized users.
PMCID: PMC4300842  PMID: 25496322
Plasmodium vivax; msp-7; Genetic diversity; Natural selection; Selective sweep
19.  Antigenicity and Immunogenicity of Plasmodium vivax Merozoite Surface Protein-3 
PLoS ONE  2013;8(2):e56061.
A recent clinical trial in African children demonstrated the potential utility of merozoite surface protein (MSP)-3 as a vaccine against Plasmodium falciparum malaria. The present study evaluated the use of Plasmodium vivax MSP-3 (PvMSP-3) as a target antigen in vaccine formulations against malaria caused by P. vivax. Recombinant proteins representing MSP-3α and MSP-3β of P. vivax were expressed as soluble histidine-tagged bacterial fusions. Antigenicity during natural infection was evaluated by detecting specific antibodies using sera from individuals living in endemic areas of Brazil. A large proportion of infected individuals presented IgG antibodies to PvMSP-3α (68.2%) and at least 1 recombinant protein representing PvMSP-3β (79.1%). In spite of the large responder frequency, reactivity to both antigens was significantly lower than was observed for the immunodominant epitope present on the 19-kDa C-terminal region of PvMSP-1. Immunogenicity of the recombinant proteins was studied in mice in the absence or presence of different adjuvant formulations. PvMSP-3β, but not PvMSP-3α, induced a TLR4-independent humoral immune response in the absence of any adjuvant formulation. The immunogenicity of the recombinant antigens were also tested in formulations containing different adjuvants (Alum, Salmonella enterica flagellin, CpG, Quil A,TiterMax® and incomplete Freunds adjuvant) and combinations of two adjuvants (Alum plus flagellin, and CpG plus flagellin). Recombinant PvMSP-3α and PvMSP-3β elicited higher antibody titers capable of recognizing P. vivax-infected erythrocytes harvested from malaria patients. Our results confirm that P. vivax MSP-3 antigens are immunogenic during natural infection, and the corresponding recombinant proteins may be useful in elucidating their vaccine potential.
PMCID: PMC3573074  PMID: 23457498
20.  Naturally-acquired cellular immune response against Plasmodium vivax merozoite surface protein-1 paralog antigen 
Malaria Journal  2015;14:159.
Plasmodium vivax merozoite surface protein-1 paralog (PvMSP1P) is a glycosylphosphatidylinositol-anchored protein expressed on the merozoite surface. This molecule is a target of natural immunity, as high anti-MSP1P-19 antibody levels were detected during P. vivax infection and the antibody inhibited PvMSP1P-erythrocyte binding. Recombinant PvMSP1P antigen results in production of a significant Th1 cytokine response in immunized mice. The present study was performed to characterize natural cellular immunity against PvMSP1P-19 and PvDBP region II in acute and recovery P. vivax infection.
Peripheral blood mononuclear cells (PBMCs) from acute and recovery P. vivax infection were obtained for lymphocyte proliferation assay upon PvMSP1P-19 and PvDBP region II antigen stimulation. The culture supernatant was examined for the presence of the cytokines IL-2, TNF, IFN-γ and IL-10 by enzyme-linked immunosorbent assay (ELISA). To determine whether Th1 or Th2 have a memory response against PvMSP1P-19 and PvDBPII protein antigen, PBMCs from subjects who had recovered from P. vivax infection 8–10 weeks prior to the study were obtained for lymphocyte proliferation assay. Cytokine-producing cells were analysed by flow cytometry.
IL-2 was detected at high levels in lymphocyte cultures from acutely infected P. vivax patients upon PvMSP1P-19 stimulation. Analysis of the Th1 or Th2 memory response in PBMC cultures from subjects who had recovered from P. vivax infection showed significantly elevated levels of PvMSP1P-19 and PvDBPII-specific IFN-γ-producing cells (P  <  0.05). Interestingly, the response of IFN-γ-producing cells in PvMSP1P stimulation was fourfold greater in recovered subjects than that in acute-infection patients. CD4+ T cells were the major cell phenotype involved in the response to PvMSP1P-19 and PvDBPII antigen.
PvMSP1P-19 strongly induces a specific cellular immune response for protection against P. vivax compared with PvDBPII as the antigen induces activation of IFN-γ-producing effector cells following natural P. vivax exposure. Upon stimulation, PvMSP1P-19 has the potential to activate the recall response of Th1 effector memory cells that play a role in killing the parasite.
PMCID: PMC4403936  PMID: 25889175
Plasmodium vivax; PvMSP1P; Cellular immune response; Patients; Infection
21.  Molecular Evolution of PvMSP3α Block II in Plasmodium vivax from Diverse Geographic Origins 
PLoS ONE  2015;10(8):e0135396.
Block II of Plasmodium vivax merozoite surface protein 3α (PvMSP3α) is conserved and has been proposed as a potential candidate for a malaria vaccine. The present study aimed to compare sequence diversity in PvMSP3a block II at a local microgeographic scale in a village as well as from larger geographic regions (countries and worldwide). Blood samples were collected from asymptomatic carriers of P. vivax in a village at the western border of Thailand and PvMSP3α was amplified and sequenced. For population genetic analysis, 237 PvMSP3α block II sequences from eleven P. vivax endemic countries were analyzed. PvMSP3α sequences from 20 village-level samples revealed two length variant types with one type containing a large deletion in block I. In contrast, block II was relatively conserved; especially, some non-synonymous mutations were extensively shared among 11 parasite populations. However, the majority of the low-frequency synonymous variations were population specific. The conserved pattern of nucleotide diversity in block II sequences was probably due to functional/structural constraints, which were further supported by the tests of neutrality. Notably, a small region in block II that encodes a predicted B cell epitope was highly polymorphic and showed signs of balancing selection, signifying that this region might be influenced by the immune selection and may serve as a starting point for designing multi-antigen/stage epitope based vaccines against this parasite.
PMCID: PMC4534382  PMID: 26266539
22.  Genetic diversity of Plasmodium vivax population before elimination of malaria in Hainan Province, China 
Malaria Journal  2015;14:78.
Hainan Province is one of the most severe endemic regions with high transmission of Plasmodium falciparum and Plasmodium vivax in China. However, the incidence of P. falciparum and P. vivax has dropped dramatically since 2007 and a national elimination malaria programme (NEMP) was launched after 2010. To better understand the genetic information on P. vivax population before elimination of malaria in Hainan Province, the extent of genetic diversity of P. vivax isolates in Hainan Province was investigated using four polymorphic genetic markers, including P. vivax merozoite surface proteins 1, 3α, and 3β (pvmsp-1, pvmsp-3α, and pvmsp-3β) and circumsporozoite protein (pvcsp).
Isolates of P. vivax (n = 27) from Hainan Province were collected from 2009 to 2010 and pvmsp-1 and pvcsp were analysed by DNA sequencing, respectively. Using polymerase chain reaction-restriction fragment length polymorphism were analysed in pvmsp-3α, and pvmsp-3β.
The DNA sequencing analysis on pvmsp1 revealed that there were three allele types: Salvador-1 (Sal-1), Belem and recombinant (R) types. Among them, Sal-1 type was a dominant strain with eight variant subtypes (88.9%), whereas R- (3.7%) and Belem-type strains (7.4%) had one variant subtypes, respectively. All the isolates carried pvcsp with VK210 type accounting for 85.2% (23/27 isolates) and VK247 type accounting for 14.8% (4/27). Only type A and type B alleles were successfully amplified in pvmsp-3α gene, and a high level of polymorphism was observed in pvmsp-3α. Considering pvmsp-3β gene, type A was the predominant type in 17 isolates (63%), whereas type B was dominant in only ten isolates (37%).
The present data indicate that there was high degree of genetic diversity among P. vivax population in Hainan Province of China during the pre-elimination stage of malaria, with 26 unique haplotypes observed among 27 samples.
PMCID: PMC4354742  PMID: 25888891
Plasmodium vivax; pvmsp-1; pvcsp; pvmsp-3α; pvmsp-3β; Hainan province; Elimination malaria; China
23.  B cell epitope mapping and characterization of naturally acquired antibodies to the Plasmodium vivax Merozoite Surface Protein-3α (PvMSP-3α) in malaria exposed individuals from Brazilian Amazon 
Vaccine  2011;29(9):1801-1811.
The Plasmodium vivax Merozoite Surface Protein-3α (PvMSP-3α) is considered as a potential vaccine candidates. However, the detailed investigations of the type of immune responses induced in naturally exposed populations are necessary. Therefore, we aim to characterize the naturally induced antibody to PvMSP-3α in 282 individuals with different levels of exposure to malaria infections residents in Brazilian Amazon. PvMSP3 specific antibodies (IgA, IgG and IgG subclass) to five recombinant proteins and the epitope mapping by Spot-synthesis technique to full-protein sequence of amino acids (15aa sequence with overlapping sequence of 9aa) were performed. Our results indicates that PvMSP3 is highly immunogenic in naturally exposed populations, where 78% of studied individuals present IgG immune response against the full-length recombinant protein (PVMSP3-FL) and IgG subclass profile was similar to all five recombinant proteins studied with a high predominance of IgG1 and IgG3. We also observe that IgG and subclass levels against PvMSP3 are associated with malaria exposure. The PvMSP3 epitope mapping by spot-synthesis shows a natural recognition of at least 15 antigenic determinants, located mainly in the two blocks of repeats, confirming the high immunogenicity of this region. In conclusion, PvMSP-3α is immunogenic in naturally exposed individuals to malaria infections and that antibodies to PvMSP3 are induced to several B cell epitopes. The presence of PvMSP3 cytophilic antibodies (IgG1 and IgG3), suggest that this mechanisms could also occur in P. vivax.
PMCID: PMC3065243  PMID: 21215342
Plasmodium vivax; Merozoite Surface Protein; B cell epitope; vaccine; malaria; immunity
24.  In silico Identification and Validation of a Linear and Naturally Immunogenic B-Cell Epitope of the Plasmodium vivax Malaria Vaccine Candidate Merozoite Surface Protein-9 
PLoS ONE  2016;11(1):e0146951.
Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and experimentally confirmed the potential of PvMSP9E795-A808 as an immunogenic linear B cell epitope within the P. vivax malaria vaccine candidate PvMSP9 and support its inclusion in future subunit vaccines.
PMCID: PMC4720479  PMID: 26788998
25.  A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119 
Scientific Reports  2016;6:34527.
The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate.
PMCID: PMC5052570  PMID: 27708348

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