ArticlePDF Available

Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children

Authors:
Daniel Dodoo at Noguchi Memorial Institute for Medical Research
Daniel Dodoo
Anastasia Aikins
Anastasia Aikins
Anastasia Aikins
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Kwadwo Asamoah Kusi at Noguchi Memorial Institute for Medical Research
Kwadwo Asamoah Kusi
Helena Lamptey at Noguchi Memorial Institute for Medical Research
Helena Lamptey
Show all 11 authorsHide
Download full-text PDFDownload full-text PDF
Read full-text
Download citation

Abstract and Figures

Antigen-specific antibody-mediated immune responses play an important role in natural protection against clinical malaria, but conflicting estimates of this association have emerged from immuno-epidemiological studies in different geographical settings. This study was aimed at assessing in a standardized manner the relationship between the antibody responses to four malaria vaccine candidate antigens and protection from clinical malaria, in a cohort of Ghanaian children. Standardized ELISA protocols were used to measure isotype and IgG subclass levels to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1-19 (MSP119), Merozoite Surface Protein 3 (MSP3) and Glutamate Rich Protein (GLURP) antigens in plasma samples from 352 Ghanaian children, aged three to 10 years with subsequent malaria surveillance for nine months. This is one of a series of studies in different epidemiological settings using the same standardized ELISA protocols to permit comparisons of results from different laboratories. The incidence rate of malaria was 0.35 episodes per child per year. Isotype and IgG subclasses for all antigens investigated increased with age, while the risk of malaria decreased with age. After adjusting for age, higher levels of IgG to GLURP, MSP119, MSP3 and IgM to MSP119, MSP3 and AMA1 were associated with decreased malaria incidence. Of the IgG subclasses, only IgG1 to MSP119 was associated with reduced incidence of clinical malaria. A previous study in the same location failed to find an association of antibodies to MSP119 with clinical malaria. The disagreement may be due to differences in reagents, ELISA and analytical procedures used in the two studies. When IgG, IgM and IgG subclass levels for all four antigens were included in a combined model, only IgG1 [(0.80 (0.67-0.97), p = 0.018)] and IgM [(0.48 (0.32-0.72), p < 0.001)] to MSP119 were independently associated with protection from malaria. Using standardized procedures, the study has confirmed the importance of antibodies to MSP119 in reducing the risk of clinical malaria in Ghanaian children, thus substantiating its potential as a malaria vaccine candidate.
Figures - uploaded by Kwadwo Asamoah Kusi
Author content
All figure content in this area was uploaded by Kwadwo Asamoah Kusi
Content may be subject to copyright.
1475-2875-7-1
42.pdf
Content uploaded by Kwadwo Asamoah Kusi
Author content
All content in this area was uploaded by Kwadwo Asamoah Kusi
Content may be subject to copyright.
Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian childr
en.pdf
Available via license: CC BY 2.0
Content may be subject to copyright.
A preview of the PDF is not available
... Malaria elicits a non-sterile immunity in age and exposure-dependent manner, first against severe malaria and later against uncomplicated malaria after repeated infections (7). This semi-immunity holds in check the asexual growth of the parasite and is believed to be mediated by antibodies, especially cytophilic immunoglobulin (Ig) G1 and IgG3 (8)(9)(10)(11). These antimalarial antibodies act independently to block merozoites' invasion of erythrocytes and, in conjunction with blood leukocytes, to retard parasite growth (12)(13)(14), as evidenced in parasite growth inhibition and antibody-dependent cell inhibition assays (12,14). ...
... One of such molecules is GMZ2, a glutamate-rich protein fusion protein and the merozoite surface protein 3 of Pf merozoite (15). IgG, particularly the IgG1 and IgG3 subclasses, directed against the individual components of this protein, are associated with reduced incidence of clinical malaria in populations naturally exposed to malaria (8)(9)(10)16). ...
... However, the details of the study site, sample collection, and diagnosis are described elsewhere (17). Total IgG and its subclasses (IgG1, IgG2, IgG3, and IgG4) against GMZ2 were quantified in plasma from children using the Afro Immuno Assay (AIA) ELISA protocol with slight modifications (9,10). Briefly, the GMZ2 antigen (Kindly provided by Michael Theisen), diluted in 1X phosphate-buffered saline (PBS) was adsorbed on the bottom and inner surfaces of the wells of 96-well microtiter ELISA plates (Maxisorp Nunc, Denmark) at 500 ng/mL and 100 mL/well. ...
Humoral antimalaria immune response in Nigerian children exposed to helminth and malaria parasites
Article
Full-text available
  • Sep 2022
Background Malaria and helminthic parasites are endemic in tropical countries, and co-infections might influence host-parasite interactions. In this community-based cross-sectional study, the effect that the presence of soil-transmitted helminths (STH) (Hookworm, Hymenolepis nana) and Schistosoma haematobium infections could have on the immunoglobulin (Ig) candidate protein of the malaria vaccine GMZ2 levels was evaluated. Methods Blood, stool, and urine samples were collected from 5-15-year-old children to diagnose P. falciparum (Pf), STH, and Schistosoma haematobium, respectively. Identification and quantification of the parasite load of STH and S. haematobium were achieved by light microscopy. A polymerase chain reaction was carried out to detect submicroscopic infections of P. falciparum. Plasma levels of GMZ2 specific IgG and its subclasses were quantified by ELISA. Results The median level of total IgG in individuals with co-infection with Pf/H. nana was significantly lower in the mono-infected group with Pf (p = 0.0121) or study participants without infection (p=0.0217). Similarly, the median level of IgG1 was statistically lower in Pf/H. nana group compared to Pf-group (p=0.0137). Equally, the Pf/H. nana infected individuals posted a lower level of IgG1 compared to Pf-group (p=0.0137) and IgG4 compared to the Pf-group (p=0.0144). Spearman rank correlation analyses indicated positive relationships between the densities of H. nana (ρ=0.25, p=0.015) and S. haematobium (ρ=0.36, p<0.0001). Conclusions Hookworm and H. nana infections are associated with reduced GMZ2 specific IgG levels. This study shows the possible manipulation of immune responses by helminths for their survival and transmission, which may have serious implications for vaccine development and deployment in helminth-endemic regions.
View
... Our data suggest that despite the extensive serological diversity we observed in this study, only a handful of variants may be sufficient to induce effective immunity when both isotypes are considered. Thus, an analysis incorporating both isotypes appears to be more instructive than those that focus on either isotype alone (55,(64)(65)(66)(67). ...
... IgM antibodies against ARMA were associated with protection and mirrored those against IgG (6,8,74). Similarly, IgM responses to the whole merozoite and few other antigens, such as MSP1, MSP3 and AMA1 have been associated with protection from malaria in other studies (64,66). Although we did not assess whether the IgM antibodies detected in our study were functional, anti-merozoite IgM has been shown to induce complement activity (66). ...
Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target
Article
Full-text available
  • Apr 2023
Introduction Detailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken. Methods Here, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP. Results We found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima’s D = -2.57; Fu and Li’s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria. Discussion Our systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.
View
... To assess the impact of these haemoglobinopathies on naturally acquired immunity, we measured antibody levels to several recombinant P. falciparum antigens spanning the various life cycle stages. The selected antigens have been associated with protection against malaria and are potential vaccine candidates (62)(63)(64). Here, we found higher IgG levels against PfCSP and lower to IT4VAR60 in HbAS individuals than in HbAA and HbAC. ...
... The higher antibody responses observed to some malaria antigens measured (non-PfEMP1 antigens) in our study among the HbAS, HbAC compared to the wild type, and the homozygous a-thalassaemia agrees with previous studies, which found higher antibody responses among individuals with various Hb variants and these have been associated with clinical protection from malaria (31,33,65). This finding could also be associated with the higher asymptomatic infection rate in haemoglobinopathy individuals, as chronic parasitaemia could boost antibody responses (46,63,66,67). Studies have proposed that HbAS and HbAC have similar mechanisms of conferring protection through impaired cytoadhesion, which enhances the acquisition of protective IgG responses to clear parasites (31,68). ...
Impact of haemoglobinopathies on asymptomatic Plasmodium falciparum infection and naturally acquired immunity among children in Northern Ghana
Article
Full-text available
  • Apr 2023
Background: The protective effect of certain haemoglobinopathies, such as HbS, HbC, and a-thalassaemia, against severe malaria has long been established; however, there is only limited and equivocal evidence regarding their impact on asymptomatic parasitaemia. Here, we investigated the effect of HbS, HbC, and a-thalassaemia on asymptomatic P. falciparum parasitaemia and acquired immunity among children in Northern Ghana. Materials and methods: A cross-sectional study was conducted among 1,017 healthy children (1-17 years) in 13 malaria-endemic communities in Northern Ghana. The children were screened for structural Hb phenotypes using SickleSCAN, for P. falciparum infection using anti-HRP2 malaria RDT and subsequently confirmed by capillary electrophoresis and PCR, respectively. a-thalassaemia genotyping was done using PCR. Levels of IgG specific for six recombinant malaria antigens (PfCSP, GLURP, MSP3, Pfs230, HB3VAR06, and IT4VAR60) and crude asexual blood-stage antigens were evaluated by ELISA. Results: 266 out of the 1,017 participants had either HbAC (18%) or HbAS (8.4%), whereas 35% had a-thalassaemia. Twenty-five percent and 6% HbAC individuals co-inherited heterozygous and homozygous a-thalassaemia respectively. Similarly, 25% and 10.5% of HbAS co-inherited heterozygous and homozygous a-thalassaemia. Asymptomatic parasitaemia rates were 23%, 24%, and 19% in those with HbAA, HbAC and HbAS, respectively. The overall parasite carriage rates in heterozygous (21%) and homozygous a-thalassaemia (25%) individuals were similar to that of individuals without a-thalassaemia (23%). P. falciparum Frontiers in Hematology parasite carriage risk was about three times higher among homozygous a-thalassaemia individuals with HbAC (OR = 2.97; 95% CI 0.83-10.62) and heterozygous carriers with HbAS variants (OR = 2.86; 95% CI 0.85-9.60) compared to the wildtype. In HbAS individuals, IgG levels to IT4VAR60 and HB3VAR06 were significantly lower, whereas anti-CSP levels were higher than in HbAA and HbAC. Conclusions: Co-inheritance of HbAS and HbAC with a-thalassaemia increased the risk of asymptomatic parasitaemia, an indication of a negative epistatic effect between these Hb variants. Antibody levels against non-PfEMP1 antigens were slightly higher among HbAS children, but quite similar in all study groups, indicating differences in parasite exposure.
View
... The low acquisition of gametocyte targeting antibodies is likely due to the very low antigen exposure to gametocytes, with only one child with detectable gametocytes by blood smear at time of sampling. For the blood-stage antigen MSP2, IgG1 was the predominant subclass in young children but switched to predominantly IgG3 with increasing age, consistent with the previous publications [37][38][39][40][41] . In contrast, IgG1 was the predominant subclass for AMA1 across all ages. ...
... Malaria naïve cohort. PBMCs were collected from a healthy malaria-naive cohort of children (n = 13, median age 8 IQR [3][4][5][6][7][8][9][10][11][12][13], 38% female) and adults (n = 14, median age 39.5 IQR [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43], 43% female) from a clinic of hospital outpatients. Volunteers were assessed by an on-site immunologist, where they were confirmed immunologically healthy and malaria-naïve. ...
Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children
Article
Full-text available
  • Jul 2022
T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria. Despite being key drivers of protective antibodies against malaria, little is known regarding the host and parasite factors that influence CD4 T-follicular helper cell and antibody development. Authors utilise samples from a study of children living in an area of high malaria transmission in Uganda, to characterize Tfh cells and functional antibodies to multiple parasites stages.
View
... Indeed, IgG3 and IgG4 against GLURP were associated with a reduced risk of clinical malaria by Nebie et al. [38] while only IgG2 and IgG4 against GLURP-R2 were significantly related to a reduced risk of malaria (19.8) in other studies [39][40][41][42]. In a longitudinal cohort study conducted in Ghana, all the GLURP-R0-specific antibodies except IgG2 were associated with an increased OP [16]. ...
Naturally acquired antibodies from Beninese infants promote Plasmodium falciparum merozoite-phagocytosis by human blood leukocytes: implications for control of asymptomatic malaria infections
Article
Full-text available
  • Nov 2022
  • MALARIA J
Background Immunoglobulin G (IgG) antibodies are thought to play important roles in the protection against Plasmodium falciparum ( P. falciparum ) malaria. A longitudinal cohort study performed in the Southern part of Benin, identified a group of infants who were able to control asymptomatic malaria infections (CAIG). Methods IgG antibodies against distinct merozoite antigens were quantified in plasma from Beninese infants. Functionality of these antibodies was assessed by the merozoite-phagocytosis assay using THP-1 cells and primary neutrophils as effector cells. Gm allotypes were determined by a serological method of haemagglutination inhibition. Results Purified IgG from infants in CAIG promoted higher levels of merozoite-phagocytosis than did IgG from children who were unable to control asymptomatic infections (Ologit multivariate regression model, Coef. = 0.06, 95% CI 0.02;0.10, P = 0.002). High level of merozoite-phagocytosis activity was significantly associated with high levels of IgG against AMA1 (Coef. = 1.76, 95% CI 0.39;3.14, P = 0.012) and GLURP-R2 (Coef. = 12.24, 95% CI 1.35;23.12, P = 0.028). Moreover, infants of the G3m5,6,10,11,13,14,24 phenotype showed higher merozoite-phagocytosis activity (Generalized linear model multivariate regression, Coef. = 7.46, 95% CI 0.31;14.61, P = 0.041) than those presenting other G3m phenotypes. Conclusion The results of the present study confirm the importance of antibodies to merozoite surface antigens in the control of asymptomatic malaria infection in Beninese infants. The study also demonstrated that G3m phenotypes impact the functional activity of IgG. This last point could have a considerable impact in the research of candidate vaccines against malaria parasites or other pathogens.
View
... This finding is in concordance with Abbas et al. who also observed a significant elevation in IgG1 and IgG2a levels in the lung tissue and suppressed eisonophils count in the blood using the mice model (Abbas et al., 2005). This inverse correlation between parasitemia and IgG levels corroborates with a study which reveals that serum antibodies, particularly, that is, TNF-alpha production (Couper et al., 2005;Dodoo et al., 2008;Kivity et al., 2010). This present research is also in concordance with a study by Biswas et al. which revealed that the production of TNFα and interleukin was induced during Plasmodium falciparum infection by the monocytes but was inhibited in the presence of serum IgM antibodies (Biswas et al., 2001). ...
Effect of black seeds (Nigella sativa) on inflammatory and immunomodulatory markers in Plasmodium berghei‐infected mice
Article
Full-text available
Nigella sativa, a core dietary supplement and food additive in folklore is one of the most broadly studied seed plants in the global nutraceutical sector. Malaria infection impairs the ability of principal cells of the immune system to trigger an efficient inflammatory and immune response. Ninety‐six mice, weighing 20–25 g, were grouped into 12 consisting of 8 animals each. The mice were infected with standard inoculum of the strain NK65 Plasmodium berghei (chloroquine sensitive) and the percentage parasitemia suppression were evaluated. The individual effect of black seed supplemented diet and its combinatory effect with chloroquine (CQ) were investigated on reactive oxygen species (ROS), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione‐S‐transferase (GST), serum immunoglobulins (IgG and IgM), and the hematological parameters (hemoglobin, packed cell volume, and red blood cell count) in P. berghei infected mice. The inflammatory cytokines, tumor necrosis factor (TNF‐α), interleukin (IL‐6 and IL‐10), as well as IgG and IgM were assayed in the serum. The mice temperature and behavioral changes were observed. Infected mice treated with the dietary supplementation of black seed with a percentage inclusion (2.5%, 5%, 10%) showed significantly decreased parasitemia and ROS levels (p < 0.05) compared with the untreated mice. The result demonstrated a significant suppression in the pro‐inflammatory cytokines (TNF‐α, IL‐6) levels and a notable elevation in the anti‐inflammatory cytokine (IL‐10), antioxidant markers as well as the immunoglobulin levels of the P. berghei‐infected mice treated with black seed. The study revealed that black seed enhanced host antioxidant status, modulated inflammatory and immune response by regulating some inflammatory cytokines and immunomodulatory mediators. Practical applications Black seed (Nigella sativa) has been a dietary supplement and natural remedy for many centuries. Inflammatory and immune diseases are the most notable cause of mortality in the world and more than 50% of deaths have been attributed to it. However, there is paucity of information on the effect of N. sativa on anti‐inflammatory and immunomodulatory ability during malaria infection. The result suggests that N. sativa produced antioxidant, anti‐inflammatory, and immunomodulatory effect in Plasmodium berghei‐infected mice via the participation of glutathione antioxidant system, serum antibodies, and some inflammatory cytokines.
View
... This implies that IgM primarily determines the magnitude of protection by specific antibodies to malaria pathogens. In addition, Dodoo et al. (62) reported IgM to confer protection and reduce incidence of malaria in African children. The levels of total IgG particularly reacting to glutamate rich protein (GLURP) of the parasite antigenic surface have been reported to be strongly associated with reduced malaria incidence in Africa (63). ...
Nutrient Deficiencies and Potential Alteration in Plasma Levels of Naturally Acquired Malaria-Specific Antibody Responses in Tanzanian Children
Article
Full-text available
  • Jun 2022
Immunoglobulin G (IgG) subclasses have been suggested to confer naturally acquired immunity to Plasmodium falciparum malaria. Cytophilic IgG1 and IgG3 with their potential for opsonization, phagocytosis, and antibody-dependent cellular inhibition in association with monocytes have been suggested to have a critical role in malaria. The potential for production of antibodies is influenced by micronutrient status. This study aimed at exploring the effect of micronutrients, particularly zinc status, on the profiles of IgG subclasses in 304 Tanzanian children aged ≤ 5 years. An enzyme-linked immunosorbent assay was performed using whole asexual blood stage malaria antigens to determine plasma malaria-specific antibody titers. This baseline cross-sectional study was done from 2005 – 2010 prior to the larger randomized control trial of the Micronutrient and Child Health (MACH) Study. Plasma concentrations of zinc and magnesium were measured by inductively coupled plasma atomic emission spectrometry and results correlated with plasma IgG subclass levels. The findings reveal zinc deficiency to possibly influence the production of IgM, total IgG, and several IgG subclasses in a malaria status-dependent manner. Among IgG subclasses, IgG3 and partly IgG2 displayed a remarkable association with zinc deficiency, particularly IgG3 which was predominant in children with malaria. Nevertheless, zinc, magnesium, and malaria status did not influence the association between IgG3 and IgG4. The study leads to the conclusion that, under conditions of micronutrient deficiency and malaria status, an imbalance in IgG subclass production may occur leading to predominantly higher levels of IgG3 and IgG2 that may not confer sufficient protection from infection. The profile of both cytophilic and non-cytophilic IgG subclasses has been shown to be variably influenced by zinc status; the effects vary with age at least in under-fives. These results provide insight for inclusion of micronutrients, particularly precise amounts of zinc, in future malaria interventional programs in endemic areas.
View
Identification and serological responses to a novel Plasmodium vivax merozoite surface protein 1 (PvMSP-1) derived synthetic peptide: a putative biomarker for malaria exposure
Article
Full-text available
  • Jun 2024
Background The integration of diagnostic methods holds promise for advancing the surveillance of malaria transmission in both endemic and non-endemic regions. Serological assays emerge as valuable tools to identify and delimit malaria transmission, serving as a complementary method to rapid diagnostic tests (RDT) and thick smear microscopy. Here, we evaluate the potential of antibodies directed against peptides encompassing the entire amino acid sequence of the Pv MSP-1 Sal-I strain as viable serological biomarkers for P. vivax exposure. Methods We screened peptides encompassing the complete amino acid sequence of the Plasmodium vivax Merozoite Surface Protein 1 ( Pv MSP-1) Sal-I strain as potential biomarkers for P. vivax exposure. Here, immunodominant peptides specifically recognized by antibodies from individuals infected with P. vivax were identified using the SPOT-synthesis technique followed by immunoblotting. Two 15-mer peptides were selected based on their higher and specific reactivity in immunoblotting assays. Subsequently, peptides p70 and p314 were synthesized in soluble form using SPPS (Solid Phase Peptide Synthesis) and tested by ELISA (IgG, and subclasses). Results This study unveils the presence of IgG antibodies against the peptide p314 in most P. vivax -infected individuals from the Brazilian Amazon region. In silico B-cell epitope prediction further supports the utilization of p314 as a potential biomarker for evaluating malaria transmission, strengthened by its amino acid sequence being part of a conserved block of Pv MSP-1. Indeed, compared to patients infected with P. falciparum and uninfected individuals never exposed to malaria, P. vivax -infected patients have a notably higher recognition of p314 by IgG1 and IgG3.
View
Antibody response to malaria vaccine candidates in pregnant women with Plasmodium falciparum and Schistosoma haematobium infections
Article
  • Apr 2024
  • PARASITE IMMUNOL
Malaria in pregnancy has severe consequences for the mother and foetus. Antibody response to specific malaria vaccine candidates (MVC) has been associated with a decreased risk of clinical malaria and its outcomes. We studied Plasmodium falciparum ( Pf ) and Schistosoma haematobium ( Sh ) infections and factors that could influence antibody responses to MVC in pregnant women. A total of 337 pregnant women receiving antenatal care (ANC) and 139 for delivery participated in this study. Pf infection was detected by qPCR and Sh infection using urine filtration method. Antibody levels against CSP, AMA‐1, GLURP‐R0, VAR2CSA and Pfs48/45 MVC were quantified by ELISA. Multivariable linear regression models identified factors associated with the modulation of antibody responses. The prevalence of Pf and Sh infections was 27% and 4% at ANC and 7% and 4% at delivery. Pf infection, residing in Adidome and multigravidae were positively associated with specific IgG response to CSP, AMA‐1, GLURP‐R0 and VAR2CSA. ITN use and IPTp were negatively associated with specific IgG response to GLURP‐R0 and Pfs48/45. There was no association between Sh infection and antibody response to MVC at ANC or delivery. Pf infections in pregnant women were positively associated with antibody response to CSP, GLURP‐R0 and AMA‐1. Antibody response to GLURP‐R0 and Pfs48/45 was low for IPTp and ITN users. This could indicate a lower exposure to Pf infection and low malaria prevalence observed at delivery.
View
Meta-Analysis of Human Antibodies Against Plasmodium falciparum Variable Surface and Merozoite Stage Antigens
Article
Full-text available
  • Jun 2022
Concerted efforts to fight malaria have caused significant reductions in global malaria cases and mortality. Sustaining this will be critical to avoid rebound and outbreaks of seasonal malaria. Identifying predictive attributes that define clinical malaria will be key to guide development of second-generation tools to fight malaria. Broadly reactive antibodies against variable surface antigens that are expressed on the surface of infected erythrocytes and merozoites stage antigens are targets of naturally acquired immunity and prime candidates for anti-malaria therapeutics and vaccines. However, predicting the relationship between the antigen-specific antibodies and protection from clinical malaria remains unresolved. Here, we used new datasets and multiple approaches combined with re-analysis of our previous data to assess the multi-dimensional and complex relationship between antibody responses and clinical malaria outcomes. We observed 22 antigens (17 PfEMP1 domains, 3 RIFIN family members, merozoite surface protein 3 (PF3D7_1035400), and merozoites-associated armadillo repeats protein (PF3D7_1035900) that were selected across three different clinical malaria definitions (1,000/2,500/5,000 parasites/µl plus fever). In addition, Principal Components Analysis (PCA) indicated that the first three components (Dim1, Dim2 and Dim3 with eigenvalues of 306, 48, and 29, respectively) accounted for 66.1% of the total variations seen. Specifically, the Dim1, Dim2 and Dim3 explained 52.8%, 8.2% and 5% of variability, respectively. We further observed a significant relationship between the first component scores and age with antibodies to PfEMP1 domains being the key contributing variables. This is consistent with a recent proposal suggesting that there is an ordered acquisition of antibodies targeting PfEMP1 proteins. Thus, although limited, and further work on the significance of the selected antigens will be required, these approaches may provide insights for identification of drivers of naturally acquired protective immunity as well as guide development of additional tools for malaria elimination and eradication.
View
Malaria-related beliefs and behaviour in southern Ghana: implications for treatment, prevention and control
Article
Full-text available
A research infrastructure was established in two ecological zones in southern Ghana to study the variables of malaria transmission and provide information to support the country's Malaria Action Plan (MAP) launched in 1992. Residents' beliefs and practices about causes, recognition, treatment and prevention of malaria were explored in two ecological zones in southern Ghana using epidemiological and social research methods. In both communities females constituted more than 80% of caretakers of children 1-9 years and the illiteracy rate was high. Fever and malaria, which are locally called Asra or Atridi, were found to represent the same thing and are used interchangeably. Caretakers were well informed about the major symptoms of malaria, which correspond to the current clinical case definition of malaria. Knowledge about malaria transmission is, however, shrouded in many misconceptions. Though the human dwellings in the study communities conferred no real protection against mosquitoes, bednet usage was low while residents combatted the nuisance of mosquitoes with insecticide sprays, burning of coils and herbs, which they largely considered as temporary measures. Home treatment of malaria combining herbs and over-the-counter drugs and inadequate doses of chloroquine was widespread. There i s a need for a strong educational component to be incorporated into the MAP to correct misconceptions about malaria transmission, appropriate treatment and protection of households. Malaria control policies should recognize the role of home treatment and drug shops in the management of malaria and incorporate them into existing control strategies.
View
Polymorphism of the Fcγ receptor IIA and malaria morbidity
Article
Full-text available
  • Jul 2005
  • J Mol Genet Med
Fc receptors (FcRs) are expressed on the surface of all types of cells of the immune system. They bind the Fc portion of immunoglobulin (Ig), thereby bridging specific antigen recognition by antibodies with cellular effector mechanisms. FcgammaRIIA, one of the three receptors for human IgG, is a low-affinity receptor for monomeric IgG, but binds IgG immune complexes efficiently. FcgammaRIIA is believed to play a major role in eliciting monocyte- and macrophage-mediated effector responses against blood-stage malaria parasites. A G --> A single nucleotide polymorphism, which causes an arginine (R) to be replaced with histidine (H) at position 131, defines two allotypes which difer in their avidity for complexed human IgG(2) and IgG(3). Because FcgammaRIIA-H131 is the only FcgammaR allotype which interacts efficiently with human IgG(2,) this polymorphism may determine whether parasite-specific IgG(2) may or may not elicit cooperation with cellular imune responses during blood-stage malaria infection. Here, we review data from four published case-control studies describing associations between FcgammaRIIA R/H131 polymorphism and malaria-related outcomes and discuss possible reasons for some incongruities found in these available results.
View
Merozoite surface protein-3: a malaria protein inducing antibodies that promote Plasmodium falciparum killing by cooperation with blood monocytes
Article
  • Sep 1994
We have previously found that the acquired protection against malaria implicates a mechanism of defense that relies on the cooperation between cytophilic antibodies and monocytes. Accordingly, an assay of antibody-dependent cellular inhibition (ADCI) of parasite growth was used as a means of selecting for molecules capable of inducing protective immunity to malaria. This allowed us to identify in the sera of clinically protected subjects an antibody specificity that promotes parasite killing mediated by monocytes. This antibody is directed to a novel merozoite surface protein (MSP-3) of a molecular mass of 48 kD. Purified IgG from protected subjects are effective in ADCI and those directed against MSP-3 are predominantly cytophilic. In contrast, in nonprotected individuals, whose antibodies are not effective in ADCI, anti-MSP-3 antibodies are mostly noncytophilic. A region in MSP-3 targetted by antibodies effective in the ADCI assay was identified and its sequence was determined; it contains an epitope not defined by a repetitive structure and does not appear to be polymorphic. Antibodies raised in mice against a peptide containing this epitope, as well as human antibodies immunopurified on this peptide, elicit a strong inhibition of Plasmodium falciparum growth in ADCI assay, whereas control antibodies, directed to peptides from other molecules, do not. The correlation between isotypes of antibodies produced against the 48- kD epitopes, clinical protection, and the ability of specific anti-MSP- 3 antibodies to block the parasite schizogony in the ADCI assay suggests that this molecule is involved in eliciting protective mechanisms.
View
Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages
Article
  • Aug 1995
The relevance of the antibody-dependent cellular inhibition (ADCI) of Plasmodium falciparum to clinical protection has been previously established by in vitro studies of material obtained during passive transfer of protection by immunoglobulin G in humans. We here report further in vitro investigations aimed at elucidating the mechanisms underlying this ADCI effect. Results obtained so far suggest that (a) merozoite uptake by monocytes (MN) as well as by polymorphonuclear cells has little influence on the course of parasitemia; (b) the ADCI effect is mediated by a soluble factor released by MN; (c) this or these factors are able to block the division of surrounding intraerythrocytic parasites at the one nucleus stage; (d) the critical triggering antigen(s) targeted by effective Abs would appear to be associated with the surface of merozoites, as opposed to that of infected red blood cells; (e) the MN receptor for Abs effective in ADCI is apparently Fc gamma RII, and not RI; (f) MN function is up- and down-regulated by interferon-gamma and interleukin 4, respectively; and (g) of several potential mediators released by MN, only tumor necrosis factor (TNF) proved of relevance. The involvement of TNF in defense may explain the recently described increased frequency of the TNF-2 high-expression promoter in individuals living in endemic regions despite its compromising role in severe malaria.
View
Primary structure and localization of a conserved immunogenicPlasmodium falciparum glutamate rich protein (GLURP) expressed in both the preerythrocytic and erythrocytic stages of the vertebrate life cycle
Article
  • Dec 1991
  • MOL BIOCHEM PARASIT
A gene coding for a 220-kDa glutamate rich protein (GLURP), an exoantigen ofPlasmodium falciparum, was isolated and its nucleotide sequence was determined. The deduced amino acid sequence contains 2 repeat regions. The sequence of one of these was shown to be conserved among geographically dispersed isolates, and a fusion protein containing that sequence was able to stimulate B- and T-cells. Antibodies against GLURP stained erythrocytic stages of the parasite as well as the hepatic stage as detected by electron microscopy.
View
Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum1
Article
  • May 2001
Merozoite surface protein 1 (MSP-1) is a precursor to major antigens on the surface of Plasmodium spp. merozoites, which are involved in erythrocyte binding and invasion. MSP-1 is initially processed into smaller fragments; and at the time of erythrocyte invasion one of these of 42 kDa (MSP-142) is subjected to a second processing, producing 33 kDa and 19 kDa fragments (MSP-133 and MSP-119). Certain MSP-1-specific monoclonal antibodies (mAbs) react with conformational epitopes contained within the two epidermal growth factor domains that comprise MSP-119, and are classified as either inhibitory (inhibit processing of MSP-142 and erythrocyte invasion), blocking (block the binding and function of the inhibitory mAb), or neutral (neither inhibitory nor blocking). We have mapped the epitopes for inhibitory mAbs 12.8 and 12.10, and blocking mAbs such as 1E1 and 7.5 by using site-directed mutagenesis to change specific amino acid residues in MSP-119 and abolish antibody binding, and by using PEPSCAN to measure the reaction of the antibodies with every octapeptide within MSP-142. Twenty-six individual amino acid residue changes were made and the effect of each on the binding of mAbs was assessed by Western blotting and BIAcore analysis. Individual changes had either no effect, or reduced, or completely abolished the binding of individual mAbs. No two antibodies had an identical pattern of reactivity with the modified proteins. Using PEPSCAN each mAb reacted with a number of octapeptides, most of which were derived from within the first epidermal growth factor domain, although 1E1 also reacted with peptides spanning the processing site. When the single amino acid changes and the reactive peptides were mapped onto the three-dimensional structure of MSP-119, it was apparent that the epitopes for the mAbs could be defined more fully by using a combination of both mutagenesis and PEPSCAN than by either method alone, and differences in the fine specificity of binding for all the different antibodies could be distinguished. The incorporation of several specific amino acid changes enabled the design of proteins that bound inhibitory but not blocking antibodies. These may be suitable for the development of MSP-1-based vaccines against malaria.
View
Secondary processing of the Plasmodium falciparum merozoite surface protein-1 (MSP1) by a calcium-dependent membrane-bound serine protease: shedding of MSP133 as a noncovalently associated complex with other fragments of the MSP1
Article
  • Mar 1992
  • MOL BIOCHEM PARASIT
Merozoites of the malaria parasite Plasmodium falciparum possess on their surface proteolytically processed fragments of the merozoite surface protein-1 (MSP1). Secondary processing of one of these fragments, MSP142, always occurs prior to, or at the point of successful erythrocyte reinvasion. It is shown that a product of this secondary processing, MSP133, is shed in the form of a noncovalently-associated complex with a number of other proteins, including the MSP1-derived species MSP138 and MSP183. Secondary processing of MSP142, is inhibited by the chelating agents ethylenediaminetetraacetic acid (EDTA) and ethyleneglycol-bis-(β-aminoethyl ether)-tetraacetic acid (EGTA), and this inhibition is reversible by addition of excess calcium. Secondary processing occurs in preparations of washed, disrupted merozoites, and is inhibited by the protease inhibitors phenylmethylsulphonyl fluoride (PMSF) and diisopropyl fluorophosphate (DFP), indicating that the protease responsible is a membrane-associated serine protease.
View
Natural antibody response to Plasmodium falciparum Exp-1, MSP-3 and GLURP long synthetic peptides and association with protection
Article
  • Jun 2004
A longitudinal study was undertaken in Burkina Faso among 293 children aged 6 months to 9 years in order to determine the correlation between an antibody response to several individual malarial antigens and malarial infection. It was found that the presence of a positive antibody response at the beginning of the rainy season to three long synthetic peptides corresponding to Plasmodium falciparum Exp-1 101-162, MSP-3 154-249 and GLURP 801-920 but not to CSP 274-375 correlated with a statistically significant decrease in malarial infection during the ongoing transmission season. The simultaneous presence of an antibody response to more than one antigen is indicative of a lower frequency of malarial infection. This gives scientific credibility to the notion that a successful malaria vaccine should contain multiple antigens.
View
Functional conservation of the malaria vaccine antigen MSP-1
Article
  • Jan 2000
The C-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP-119) is at present a leading malaria vaccine candidate. Antibodies against the epidermal growth factor-like domains of MSP-1 19are associated with immunity to P. falciparum and active immunization with recombinant forms of the molecule protect against malaria challenge in various experimental systems. These findings, with the knowledge that epidermal growth factor-like domains in other molecules have essential binding functions, indicate the importance of this protein in merozoite invasion of red blood cells. Despite extensive molecular epidemiological investigations, only limited sequence polymorphism has been identified in P. falciparum MSP-119 (refs. 9-11). This indicates its sequence is functionally constrained, and is used in support of the use of MSP-119 as a vaccine. Here, we have successfully complemented the function of most of P. falciparum MSP-119 with the corresponding but highly divergent sequence from the rodent parasite P. chabaudi. The results indicate that the role of MSP-119 in red blood cell invasion is conserved across distantly related Plasmodium species and show that the sequence of P. falciparum MSP-119 is not constrained by function.
View
A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kilodalton domain of Plasmodium falciparum in pregnant women and infants: Associations with febrile illness, parasitemia, and anemia
Article
  • Feb 1998
This study was aimed at delineating characteristics of naturally acquired immunity against the merozoite surface antigen-1 (MSP-1) of Plasmodium falciparum, a candidate malaria vaccine antigen. A case/control study was performed on 75 case/control pairs of infants with febrile illness at the time of the first detected infection indicating a clinical case. The presence and level of antibodies at one month prior to the first infection and at the time of the first infection in the afebrile group was significantly higher than in the febrile group. Decreased parasite density and decreased infection-related loss of hemoglobin was seen in infants with anti-MSP-1(19kD) IgG antibodies. In addition, mothers who were positive for the presence of these antibodies conferred protection against placental infection and infection in their infants. In this study, development of anti-MSP-1(19kD) antibody responses in 24 infants were studied longitudinally using monthly serum samples collected from birth until approximately one year of age. In addition, umbilical cord blood sera and respective mothers' sera were analyzed. Longitudinal studies of antibody responses revealed several short-lived IgG and IgM peaks throughout an infant's first year that correlated with detection of parasitemia. The protection against parasitemia and febrile illness was observed in infants when anti-MSP-1(19kD) antibodies were present; when infants were negative for IgG, they had a 10-times greater risk of becoming parasitemic. These data from a longitudinal and prospective study of malaria suggest a protective role for anti-MSP-1(19kD) antibodies in infants and pregnant women.
View