Epitope-Specific Antibody Responses to a Plasmodium falciparum Subunit Vaccine Target in a Malaria-Endemic Population.
Ontology highlight
ABSTRACT:
SUBMITTER: Friedman-Klabanoff DJ
PROVIDER: S-EPMC8176638 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundPlasmodium falciparum causes the majority of malaria cases worldwide and children in sub-Saharan Africa are the most vulnerable group affected. Non-sterile clinical immunity that protects from symptoms develops slowly and is relatively short-lived. Moreover, current malaria vaccine candidates fail to induce durable high-level protection in endemic settings, possibly due to the immunomodulatory effects of the malaria parasite itself. Because dendritic cells play a crucial role in initiating immune responses, the aim of this study was to better understand the impact of cumulative malaria exposure as well as concurrent P. falciparum infection on dendritic cell phenotype and function.MethodsIn this cross-sectional study, the phenotype and function of dendritic cells freshly isolated from peripheral blood samples of Malian adults with a lifelong history of malaria exposure who were either uninfected (n = 27) or asymptomatically infected with P. falciparum (n = 8) was assessed. Additionally, plasma cytokine and chemokine levels were measured in these adults and in Malian children (n = 19) with acute symptomatic malaria.ResultsWith the exception of lower plasmacytoid dendritic cell frequencies in asymptomatically infected Malian adults, peripheral blood dendritic cell subset frequencies and HLA-DR surface expression did not differ by infection status. Peripheral blood myeloid dendritic cells of uninfected Malian adults responded to in vitro stimulation with P. falciparum blood-stage parasites by up-regulating the costimulatory molecules HLA-DR, CD80, CD86 and CD40 and secreting IL-10, CXCL9 and CXCL10. In contrast, myeloid dendritic cells of asymptomatically infected Malian adults exhibited no significant responses above the uninfected red blood cell control. IL-10 and CXCL9 plasma levels were elevated in both asymptomatic adults and children with acute malaria.ConclusionsThe findings of this study indicate that myeloid dendritic cells of uninfected adults with a lifelong history of malaria exposure are able to up-regulate co-stimulatory molecules and produce cytokines. Whether mDCs of malaria-exposed individuals are efficient antigen-presenting cells capable of mounting an appropriate immune response remains to be determined. The data also highlights IL-10 and CXCL9 as important factors in both asymptomatic and acute malaria and add to the understanding of asymptomatic P. falciparum infections in malaria-endemic areas.
| S-EPMC7787131 | biostudies-literature
Project description:Apical Membrane Antigen 1 (AMA1) of Plasmodium falciparum merozoites is a leading blood-stage malaria vaccine candidate. Protection of Aotus monkeys after vaccination with AMA1 correlates with antibody responses.A randomized, controlled, double-blind phase 1 clinical trial was conducted in 54 healthy Malian adults living in an area of intense seasonal malaria transmission to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of yeast-expressed recombinant proteins based on sequences from the FVO and 3D7 clones of P. falciparum, adsorbed on Alhydrogel. The control vaccine was the hepatitis B vaccine (Recombivax). Participants were enrolled into 1 of 3 dose cohorts (n = 18 per cohort) and randomized 2:1 to receive either AMA1-C1 or Recombivax. Participants in the first, second, and third cohorts randomized to receive AMA1-C1 were vaccinated with 5, 20 and 80 microg of AMA1-C1, respectively. Vaccinations were administered on days 0, 28, and 360, and participants were followed until 6 months after the final vaccination. AMA1-C1 was well tolerated; no vaccine-related severe or serious adverse events were observed. AMA1 antibody responses to the 80 microg dose increased rapidly from baseline levels by days 14 and 28 after the first vaccination and continued to increase after the second vaccination. After a peak 14 days following the second vaccination, antibody levels decreased to baseline levels one year later at the time of the third vaccination that induced little or no increase in antibody levels.Although the AMA1-C1 vaccine candidate was well-tolerated and induced antibody responses to both vaccine and non-vaccine alleles, the antibody response after a third dose given at one year was lower than the response to the initial vaccinations. Additionally, post-vaccination increases in anti-AMA1 antibody levels were not associated with significant changes in in vitro growth inhibition of P. falciparum.ClinicalTrials.gov NCT00343005.
| S-EPMC2013939 | biostudies-literature
Project description:BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection. CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center's Advanced Medical Development Program.
| S-EPMC5214067 | biostudies-literature
Project description:Antibodies constitute a critical component of the naturally acquired immunity that develops following frequent exposure to malaria. However, specific antibody titres have been reported to decline rapidly in the absence of reinfection, supporting the widely perceived notion that malaria infections fail to induce durable immunological memory responses. Currently, direct evidence for the presence or absence of immune memory to malaria is limited. In this study, we analysed the longevity of both antibody and B cell memory responses to malaria antigens among individuals who were living in an area of extremely low malaria transmission in northern Thailand, and who were known either to be malaria naïve or to have had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. We found that exposure to malaria results in the generation of relatively avid antigen-specific antibodies and the establishment of populations of antigen-specific memory B cells in a significant proportion of malaria-exposed individuals. Both antibody and memory B cell responses to malaria antigens were stably maintained over time in the absence of reinfection. In a number of cases where antigen-specific antibodies were not detected in plasma, stable frequencies of antigen-specific memory B cells were nonetheless observed, suggesting that circulating memory B cells may be maintained independently of long-lived plasma cells. We conclude that infrequent malaria infections are capable of inducing long-lived antibody and memory B cell responses.
| S-EPMC2824751 | biostudies-literature
Project description:In our aim to eliminate malaria, more sensitive tools to detect residual transmission are quickly becoming essential. Antimalarial antibody responses persist in the blood after a malaria infection and provide a wider window to detect exposure to infection compared to parasite detection metrics. Here, we aimed to select antibody responses associated with recent and cumulative exposure to malaria using cross-sectional survey data from Haiti, an elimination setting. Using a multiplex bead assay, we generated data for antibody responses (immunoglobulin G) to 23 Plasmodium falciparum targets in 29,481 participants across three surveys. This included one community-based survey in which participants were enrolled during household visits and two sentinel group surveys in which participants were enrolled at schools and health facilities. First, we correlated continuous antibody responses with age (Spearman) to determine which showed strong age-related associations indicating accumulation over time with limited loss. AMA-1 and MSP-119 antibody levels showed the strongest correlation with age (0.47 and 0.43, p < 0.001) in the community-based survey, which was most representative of the underlying age structure of the population, thus seropositivity to either of these antibodies was considered representative of cumulative exposure to malaria. Next, in the absence of a gold standard for recent exposure, we included antibody responses to the remaining targets to predict highly sensitive rapid diagnostic test (hsRDT) status using receiver operating characteristic curves. For this, only data from the survey with the highest hsRDT prevalence was used (7.2%; 348/4,849). The performance of the top two antigens in the training dataset (two-thirds of the dataset; n = 3,204)-Etramp 5 ag 1 and GLURP-R0 (area-under-the-curve, AUC, 0.892 and 0.825, respectively)-was confirmed in the test dataset (remaining one-third of the dataset; n = 1,652, AUC 0.903 and 0.848, respectively). As no further improvement was seen by combining seropositivity to GLURP-R0 and Etramp 5 ag 1 (p = 0.266), seropositivity to Etramp 5 ag 1 alone was selected as representative of current or recent exposure to malaria. The validation of antibody responses associated with these exposure histories simplifies analyses and interpretation of antibody data and facilitates the application of results to evaluate programs.
| S-EPMC7243477 | biostudies-literature
Project description:The magnitude of antibody responses varies across the individual proteins that constitute any given microorganism, both in the context of natural infection and vaccination with attenuated or inactivated pathogens. The protein-specific factors underlying this variability are poorly understood. In 267 individuals exposed to intense seasonal malaria, we examined the relationship between immunoglobulin G (IgG) responses to 861 Plasmodium falciparum proteins and specific features of these proteins, including their subcellular location, relative abundance, degree of polymorphism, and whether they are predicted to have human orthologs. We found that IgG reactivity was significantly higher to extracellular and plasma membrane proteins and also correlated positively with both protein abundance and degree of protein polymorphism. Conversely, IgG reactivity was significantly lower to proteins predicted to have human orthologs. These findings provide insight into protein-specific factors that are associated with variability in the magnitude of antibody responses to natural P. falciparum infection-data that could inform vaccine strategies to optimize antibody-mediated immunity as well as the selection of antigens for sero-diagnostic purposes.
| S-EPMC5928716 | biostudies-literature
Project description:BACKGROUND: Genetic evidence for diversifying selection identified the Merozoite Surface Protein1 block2 (PfMSP1 block2) as a putative target of protective immunity against Plasmodium falciparum. The locus displays three family types and one recombinant type, each with multiple allelic forms differing by single nucleotide polymorphism as well as sequence, copy number and arrangement variation of three amino acid repeats. The family-specific antibody responses observed in endemic settings support immune selection operating at the family level. However, the factors contributing to the large intra-family allelic diversity remain unclear. To address this question, population allelic polymorphism and sequence variant-specific antibody responses were studied in a single Senegalese rural community where malaria transmission is intense and perennial. RESULTS: Family distribution showed no significant temporal fluctuation over the 10 y period surveyed. Sequencing of 358 PCR fragments identified 126 distinct alleles, including numerous novel alleles in each family and multiple novel alleles of recombinant types. The parasite population consisted in a large number of low frequency alleles, alongside one high-frequency and three intermediate frequency alleles. Population diversity tests supported positive selection at the family level, but showed no significant departure from neutrality when considering intra-family allelic sequence diversity and all families combined. Seroprevalence, analysed using biotinylated peptides displaying numerous sequence variants, was moderate and increased with age. Reactivity profiles were individual-specific, mapped to the family-specific flanking regions and to repeat sequences shared by numerous allelic forms within a family type. Seroreactivity to K1-, Mad20- and R033 families correlated with the relative family genotype distribution within the village. Antibody specificity remained unchanged with cumulated exposure to an increasingly large number of alleles. CONCLUSION: The Pfmsp1 block2 locus presents a very large population sequence diversity. The lack of stable acquisition of novel antibody specificities despite exposure to novel allelic forms is reminiscent of clonal imprinting. The locus appears under antibody-mediated diversifying selection in a variable environment that maintains a balance between the various family types without selecting for sequence variant allelic forms. There is no evidence of positive selection for intra-family sequence diversity, consistent with the observed characteristics of the antibody response.
| S-EPMC2770483 | biostudies-literature
Project description:Endemic Burkitt lymphoma (eBL) is linked to Plasmodium falciparum (Pf) infection geographically, but evidence from individual-level studies is limited. We investigated this issue among 354 childhood eBL cases and 384 age-, sex-, and location-matched controls enrolled in Ghana from 1965 to 1994. Immunoglobulin G1 (IgG1) and immunoglobulin G3 (IgG3) antibodies to antigens diagnostic of recent infection Pf histidine-rich protein-II (HRP-II) and 6NANP, Pf-vaccine candidates SE36 and 42-kDa region of the 3D7 Pf merozoite surface protein-1 (MSP-1), and tetanus toxoid were measured by indirect enzyme-linked immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) for association with eBL were estimated using unconditional logistic regression. After adjustments, eBL was positively associated with HRP-IIIgG3 seropositivity (adjusted OR: 1.60; 95% CI 1.08-2.36) and inversely associated with SE36IgG1 seropositivity (adjusted OR: 0.37; 95% CI 0.21-0.64) and with tetanus toxoidIgG3 levels equal or higher than the mean (adjusted OR: 0.46; 95% CI 0.32-0.66). Anti-MSP-1IgG3 and anti-6NANPIgG3 were indeterminate. eBL risk was potentially 21 times higher (95% CI 5.8-74) in HRP-IIIgG3-seropositive and SE36IgG1-seronegative responders compared with HRP-IIIgG3-seronegative and SE36IgG1-seropositive responders. Our results suggest that recent malaria may be associated with risk of eBL but long-term infection may be protective.
| S-EPMC3731925 | biostudies-literature
Project description:BackgroundThe primary antibody (Ab) response to Plasmodium falciparum is a critical step in developing immunity to malaria. Information on the initial Ab responses of babies in malaria-endemic areas is incomplete, in part, because babies receive maternal IgG via transplacental-transfer and usually become infected before maternal IgG wanes. The study aimed to identify the primary IgM and IgG Ab responses to malarial antigens in Cameroonian babies.MethodsInfants (n = 70) living in a high malaria transmission area were followed from birth throughout the first year of life (mean 341 ± 42 days, an average of 8.5 time points per infant). Malaria infection was assessed by microscopy and PCR, and IgM and IgG antibodies (Abs) were measured using a multiplex immunoassay to AMA1, EBA-175, MSP1-42, MSP2, MSP3, RESA, LSA1, and CSP.ResultsThe half-life of maternal IgG varied among the antigens, ranging from 0.7 to 2.5 months. The first infection of 41% of the babies was sub-microscopic and only 11 to 44% of the babies produced IgM to the above antigens; however, when the first infection was detected by microscopy, 59-82% of the infants made IgM Abs to the antigens. Infants were able to produce IgM even when maternal IgG was present, suggesting maternal Abs did not suppress the baby's initial Ab response. Using longitudinal regression models that incorporated time-varying covariates, infants were found to produce IgG Ab to only AMA-1 when the first infection was sub-microscopic, but they produced IgG Abs to MSP1-42 (3D7, FVO), AMA1 (3D7, FVO) MSP2-FC27, MSP3, RESA, and LSA1, but not MSP 2-3D7, EBA-175, and CSP during their first slide-positive infection. Notably, the primary and secondary IgG responses were short-lived with little evidence of boosting.ConclusionsThe primary Ab response of babies who had maternal IgG was similar to that reported for primary infections in malaria-naïve adults.
| S-EPMC9675181 | biostudies-literature
Project description:In general, malaria immunity has been suggested to be species specific with very little, if any, known cross-reactivity between Plasmodium vivax and P. falciparum, both of which are responsible for >90% of human malaria, and co-endemic in many countries. It is therefore believed that species-specific immunity may be needed to target different species of Plasmodium. Pfs48/45 and Pvs48/45 are well established targets in the sexual stages of the malaria parasites, and are being pursued for the development of transmission blocking vaccines. Comparison of their sequences reveals 61% and 55% identity at the DNA and protein level, respectively raising the possibility that these two target antigens might share cross-reacting epitopes. Having succeeded in expressing recombinant Pfs48/45 and Pvs48/45 proteins, we hypothesized that these proteins will not only exhibit immunological cross-reactivity but also cross-boost immune responses. Mice were immunized with purified recombinant proteins using CFA, Montanide ISA-51 and alum as adjuvants, and the sera were analyzed by ELISA, Western blotting and indirect fixed and live IFA to address the hypothesis. Our studies revealed that Pvs48/45-immune sera showed strong cross-reactivity to full length Pfs48/45 protein, and the majority of this cross reactivity was in the amino-terminal and carboxyl-terminal sub-fragments of Pfs48/45. In cross-boosting experiments Pfs48/45 and Pvs48/45 antigens were able to cross-boost each other in mouse immunization studies. Additionally we also noticed an effect of adjuvants in the overall magnitude of observed cross-reactivity. These studies may have significant implications for immunity targeting transmission of both the species of malaria parasites.
| S-EPMC4954667 | biostudies-literature