Acquired Antibodies to Merozoite Antigens in Children from Uganda with Uncomplicated or Severe Plasmodium falciparum Malaria

ABSTRACTMalaria can present itself as an uncomplicated or severe disease. We have here studied the quantity and quality of antibody responses against merozoite antigens, as well as multiplicity of infection (MOI), in children from Uganda. We found higher levels of IgG antibodies toward erythrocyte-binding antigen EBA181, MSP2 ofPlasmodium falciparum3D7 and FC27 (MSP2-3D7/FC27), and apical membrane antigen 1 (AMA1) in patients with uncomplicated malaria by enzyme-linked immunosorbent assay (ELISA) but no differences against EBA140, EBA175, MSP1, and reticulocyte-binding protein homologues Rh2 and Rh4 or for IgM against MSP2-3D7/FC27.Patients with uncomplicated malaria were also shown to have higher antibody affinities for AMA1 by surface plasmon resonance (SPR). Decreased invasion of two clinicalP. falciparumisolates in the presence of patient plasma correlated with lower initial parasitemia in the patients, in contrast to comparisons of parasitemia to ELISA values or antibody affinities, which did not show any correlations. Analysis of the heterogeneity of the infections revealed a higher MOI in patients with uncomplicated disease, with theP. falciparumK1 MSP1 (MSP1-K1) and MSP2-3D7 being the most discriminative allelic markers. Higher MOIs also correlated positively with higher antibody levels in several of the ELISAs. In conclusion, certain antibody responses and MOIs were associated with differences between uncomplicated and severe malaria. When different assays were combined, some antibodies, like those against AMA1, seemed particularly discriminative. However, only decreased invasion correlated with initial parasitemia in the patient, signaling the importance of functional assays in understanding development of immunity against malaria and in evaluating vaccine candidates.

Download Full-text

Plasmodium falciparum Malaria in the Peruvian Amazon, a Region of Low Transmission, Is Associated with Immunologic Memory

Infection and Immunity ◽

10.1128/iai.05961-11 ◽

2012 ◽

Vol 80 (4) ◽

pp. 1583-1592 ◽

Cited By ~ 43

Author(s):

Eva H. Clark ◽

Claudia J. Silva ◽

Greta E. Weiss ◽

Shanping Li ◽

Carlos Padilla ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Surface Protein ◽

Plasmodium Falciparum Malaria ◽

Merozoite Surface Protein ◽

Content Type ◽

Low Transmission ◽

Apical Membrane Antigen 1 ◽

Specific Memory ◽

Erythrocyte Binding ◽

Transmission Region

ABSTRACTThe development of clinical immunity toPlasmodium falciparummalaria is thought to require years of parasite exposure, a delay often attributed to difficulties in developing protective antibody levels. In this study, we evaluated severalP. falciparumvaccine candidate antigens, including apical membrane antigen 1 (AMA-1), circumsporozoite protein (CSP), erythrocyte binding antigen 175 (EBA-175), and the 19-kDa region of merozoite surface protein 1 (MSP119). After observing a more robust antibody response to MSP119, we evaluated the magnitude and longevity of IgG responses specific to this antigen in Peruvian adults and children before, during, and afterP. falciparuminfection. In this low-transmission region, even one reported prior infection was sufficient to produce a positive anti-MSP119IgG response for >5 months in the absence of reinfection. We also observed an expansion of the total plasmablast (CD19+CD27+CD38high) population in the majority of individuals shortly after infection and detected MSP1-specific memory B cells in a subset of individuals at various postinfection time points. This evidence supports our hypothesis that effective antimalaria humoral immunity can develop in low-transmission regions.

Download Full-text

Allele Specificity of Naturally Acquired Antibody Responses against Plasmodium falciparum Apical Membrane Antigen 1

Infection and Immunity ◽

10.1128/iai.73.1.422-430.2005 ◽

2005 ◽

Vol 73 (1) ◽

pp. 422-430 ◽

Cited By ~ 52

Author(s):

Alfred Cortés ◽

Mata Mellombo ◽

Rosella Masciantonio ◽

Vince J. Murphy ◽

John C. Reeder ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Apical Membrane ◽

Age Groups ◽

Antibody Responses ◽

Allelic Form ◽

Apical Membrane Antigen 1 ◽

Apical Membrane Antigen ◽

Younger Age ◽

Merozoite Antigens ◽

Allele Specificity

ABSTRACT Antibody responses against proteins located on the surface or in the apical organelles of merozoites are presumed to be important components of naturally acquired protective immune responses against the malaria parasite Plasmodium falciparum. However, many merozoite antigens are highly polymorphic, and antibodies induced against one particular allelic form might not be effective in controlling growth of parasites expressing alternative forms. The apical membrane antigen 1 (AMA1) is a polymorphic merozoite protein that is a target of naturally acquired invasion-inhibitory antibodies and is a leading asexual-stage vaccine candidate. We characterized the antibody responses against AMA1 in 262 individuals from Papua New Guinea exposed to malaria by using different allelic forms of the full AMA1 ectodomain and some individual subdomains. The majority of individuals had very high levels of antibodies against AMA1. The prevalence and titer of these antibodies increased with age. Although antibodies against conserved regions of the molecule were predominant in the majority of individuals, most plasma samples also contained antibodies directed against polymorphic regions of the antigen. In a few individuals, predominantly from younger age groups, the majority of antibodies against AMA1 were directed against polymorphic epitopes. The D10 allelic form of AMA1 apparently contains most if not all of the epitopes present in the other allelic forms tested, which might argue for its inclusion in future AMA1-based vaccines to be tested. Some important epitopes in AMA1 involved residues located in domain II or III but depended on more than one domain.

Download Full-text

Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-Resistant Plasmodium falciparum in Gambian Children

Infection and Immunity ◽

10.1128/iai.74.5.2887-2893.2006 ◽

2006 ◽

Vol 74 (5) ◽

pp. 2887-2893 ◽

Cited By ~ 10

Author(s):

Margaret Pinder ◽

Colin J. Sutherland ◽

Fatoumatta Sisay-Joof ◽

Jamila Ismaili ◽

Matthew B. B. McCall ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Immunoglobulin G ◽

Surface Protein ◽

Merozoite Surface Protein ◽

Clinical Malaria ◽

Enzyme Linked Immunosorbent Assay ◽

Plasma Samples ◽

Apical Membrane Antigen 1 ◽

Merozoite Antigens ◽

Functional Immunity

ABSTRACT We examined the hypothesis that recovery from uncomplicated malaria in patients carrying drug-resistant Plasmodium falciparum is a measure of acquired functional immunity and may therefore be associated with humoral responses to candidate vaccine antigens. Gambian children with malaria were treated with chloroquine in 28-day trials, and recovery was defined primarily as the absence of severe clinical malaria at any time and absence of parasitemia with fever after 3 days. Plasma samples from these children were assayed by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) to recombinant merozoite antigens: apical membrane antigen 1 (AMA-1) and the 19-kDa C-terminal region of merozoite surface protein 1 (MSP-119), including antigenic variants of MSP-119 with double and triple substitutions. Antigen-specific IgG was more frequent in children who recovered, particularly that for MSP-119 (age-adjusted odds ratios: 0.32 [95% confidence interval, 0.05, 1.87; P = 0.168] for AMA-1, 0.19 [0.03, 1.11; P = 0.019] for recombinant MSP-119, 0.24 [0.04, 1.31; P = 0.032] for the recombinant MSP-119 double variant, and 0.18 [0.03, 0.97; P = 0.013] for the triple variant). IgG titers to MSP-119 and to the triple variant were higher in plasma samples taken 7 days after chloroquine treatment from children who carried resistant parasites but recovered and remained parasite free. Moreover, in children who were parasitemic on day 14 or day 28, there was an age-independent relationship between parasite density and IgG to both MSP-119 and the triple variant (coefficients of −0.550 and −0.590 and P values of 0.002 and 0.001, respectively). The results validate the use of this approach to identify antigens that are associated with protection from malaria.

Download Full-text

Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children

Infection and Immunity ◽

10.1128/iai.01120-15 ◽

2016 ◽

Vol 84 (4) ◽

pp. 950-963 ◽

Cited By ~ 28

Author(s):

Linda M. Murungi ◽

Klara Sondén ◽

David Llewellyn ◽

Josea Rono ◽

Fatuma Guleid ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Rank Correlation ◽

Plasmodium Falciparum Malaria ◽

Cell Surface Antigens ◽

Immunological Parameters ◽

Content Type ◽

Merozoite Antigens ◽

Life Threatening ◽

Matched Case ◽

Functional Mechanisms

Severe malaria (SM) is a life-threatening complication of infection withPlasmodium falciparum. Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and have rarely been undertaken. We investigated the merozoite targets and antibody-mediated mechanisms associated with protection against SM in Kenyan children aged 0 to 2 years. We designed a unique prospective matched case-control study of well-characterized SM clinical phenotypes nested within a longitudinal birth cohort of children (n= 5,949) monitored over the first 2 years of life. We quantified immunological parameters in sera collected before the SM event in cases and their individually matched controls to evaluate the prospective odds of developing SM in the first 2 years of life. Anti-AMA1 antibodies were associated with a significant reduction in the odds of developing SM (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.15 to 0.90;P= 0.029) after adjustment for responses to all other merozoite antigens tested, while those against MSP-2, MSP-3,Plasmodium falciparumRh2 [PfRh2], MSP-119, and the infected red blood cell surface antigens were not. The combined ability of total IgG to inhibit parasite growth and mediate the release of reactive oxygen species from neutrophils was associated with a marked reduction in the odds of developing SM (OR = 0.07; 95% CI = 0.006 to 0.82;P= 0.03). Assays of these two functional mechanisms were poorly correlated (Spearman rank correlation coefficient [rs] = 0.12;P= 0.07). Our data provide epidemiological evidence that multiple antibody-dependent mechanisms contribute to protective immunity via distinct targets whose identification could accelerate the development of vaccines to protect against SM.

Download Full-text

Faculty Opinions recommendation of IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.722032138.793500843 ◽

2014 ◽

Author(s):

James Beeson

Keyword(s):

Plasmodium Falciparum ◽

Half Life ◽

Antibody Responses ◽

Igg Antibody ◽

Short Half Life ◽

Merozoite Antigens

Download Full-text

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

Malaria Journal ◽

10.1186/s12936-021-03760-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Youssouf Diarra ◽

Oumar Koné ◽

Lansana Sangaré ◽

Lassina Doumbia ◽

Dade Bouye Ben Haidara ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Uncomplicated Malaria ◽

Artemisinin Resistance ◽

National Malaria Control Programme ◽

Plasmodium Falciparum Malaria ◽

Control Programme ◽

Malaria Control Programme ◽

Pre Treatment ◽

Better Than

Abstract Background The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali. Methods Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000–200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing. Results A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5–88.4%) in the AL arm and 93.1% (95% CI 89.7–96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0–95.9%) in the AL arm and 97.1% (93.6–100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common. Conclusions The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali.

Download Full-text

Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

Infection and Immunity ◽

10.1128/iai.01924-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3775-3782 ◽

Cited By ~ 6

Author(s):

Lyticia A. Ochola ◽

Cyrus Ayieko ◽

Lily Kisia ◽

Ng'wena G. Magak ◽

Estela Shabani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Disease ◽

Clinical Malaria ◽

Necrosis Factor Alpha ◽

Content Type ◽

Highland Area ◽

Cytokine Responses ◽

Increased Risk ◽

Tnf Α ◽

Ifn Γ

ABSTRACTIndividuals naturally exposed toPlasmodium falciparumlose clinical immunity after a prolonged lack of exposure.P. falciparumantigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity ofP. falciparumantigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinicalP. falciparummalaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document thatP. falciparumantigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence ofP. falciparumexposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack ofP. falciparumexposure.

Download Full-text

TNFα*2 marks high risk of severe disease during Plasmodium falciparum malaria and other infections in Sri Lankans

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.1999.00804.x ◽

1999 ◽

Vol 115 (2) ◽

pp. 350-355 ◽

Cited By ~ 54

Author(s):

J. WATTAVIDANAGE ◽

R. CARTER ◽

K. L. R. L. PERERA ◽

A. MUNASINGHA ◽

S. BANDARA ◽

...

Keyword(s):

Plasmodium Falciparum ◽

High Risk ◽

Falciparum Malaria ◽

Severe Disease ◽

Plasmodium Falciparum Malaria

Download Full-text

Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

Infection and Immunity ◽

10.1128/iai.00970-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 152-164 ◽

Cited By ~ 54

Author(s):

K. Sony Reddy ◽

Alok K. Pandey ◽

Hina Singh ◽

Tajali Sahar ◽

Amlabu Emmanuel ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Neutralizing Antibodies ◽

Malaria Vaccine ◽

Expression System ◽

Full Length ◽

Blood Stage ◽

Parasite Protein ◽

Content Type ◽

Erythrocyte Binding ◽

Blood Stage Malaria

ABSTRACTPlasmodium falciparumreticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number ofP. falciparumstrains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 inEscherichia colithat exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number ofP. falciparumstrains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.P. falciparumhas the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwideP. falciparumstrains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

Download Full-text