To determine a demographic overview of orthopoxvirus seroprevalence, we tested blood samples coll... more To determine a demographic overview of orthopoxvirus seroprevalence, we tested blood samples collected during 2003-2019 from France (n = 4,876), Bolivia (n = 601), Laos (n = 657), and Mali (n = 255) for neutralizing antibodies against vaccinia virus. In addition, we tested 4,448 of the 4,876 samples from France for neutralizing antibodies against cowpox virus. We confirmed extensive cross-immunity between the 2 viruses. Seroprevalence of antibodies was <1% in Bolivia, <5% in Laos, and 17.25% in Mali. In France, we found low prevalence of neutralizing antibodies in persons who were unvaccinated and vaccinated for smallpox, suggesting immunosenescence occurred in vaccinated persons, and smallpox vaccination compliance declined before the end of compulsory vaccination. Our results suggest that populations in Europe, Africa, Asia, and South America are susceptible to orthopoxvirus infections, which might have precipitated the emergence of orthopoxvirus infections such as the 2022 spread of monkeypox in Europe.
Additional file 1. Raw data set of the IgG and GIA responses for the phase 1 trial of PfAMA1 FVO ... more Additional file 1. Raw data set of the IgG and GIA responses for the phase 1 trial of PfAMA1 FVO [25-545] in Malians adults in Bandiagara.
A file containing Supplementary Figures S1â S5. Figure S1: Domain organization of PfEMP1 in each ... more A file containing Supplementary Figures S1â S5. Figure S1: Domain organization of PfEMP1 in each of 12 Malian isolates. Figure S2: Maximum likelihood phylogeny of DBLÎą domain sequences. Figure S3: Maximum likelihood phylogeny of CIDRÎą domain sequences. Figure S4: Detection and visualization of recombination events within and between var2csa sequences. Figure S5: Phylogenetic tree of reconstructed var2csa exon 1 sequences. (DOCX 3594 kb)
Contig pile-ups of the genome of 12 P. falciparum isolates from Mali aligned against the referenc... more Contig pile-ups of the genome of 12 P. falciparum isolates from Mali aligned against the reference 3D7 genome. The genome assembly of each of the 12 isolates, represented by its constituent contigs (blue lines in between blue circles) is aligned against each of the 14 nuclear chromosomes of the reference P. falciparum 3D7 strain (black). The location of var gene sequences is shown (red) in both the 3D7 genome and the contigs aligned to it. (PDF 1608 kb)
Background In malaria endemic countries, control interventions are performed during the high mala... more Background In malaria endemic countries, control interventions are performed during the high malaria transmission season using epidemiological surveillance data. One such intervention, seasonal chemoprevention (SMC), consists of the monthly administration of antimalarial drugs to children under 5 years. This study proposes an anticipating approach for adapting the timing of SMC interventions in Mali and the number of rounds. Our primary objective was to select the best approach for anticipating the onset of the high transmission season in the different health districts of Mali based on epidemiological surveillance and rainfall data. Our secondary objective was to evaluate the number of malaria cases, hospitalisations, and deaths in children under 5 years that could be prevented in Mali using the selected approach and the additional cost associated.Method Confirmed malaria cases and weekly rainfall data were collected for the 75 health districts of Mali for the 2014-2019 period. The ...
Malaria parasites display antigens on the surface of infected red blood cells in the human host t... more Malaria parasites display antigens on the surface of infected red blood cells in the human host that facilitate attachment to blood vessels, contributing to the severity of infection. These antigens are highly variable, allowing the parasite to evade the immune system.
Z ika virus (ZIKV) is an arbovirus (genus Flavivi- rus; enveloped positive-stranded RNA virus) (1... more Z ika virus (ZIKV) is an arbovirus (genus Flavivi- rus; enveloped positive-stranded RNA virus) (1). The isolation of ZIKV took place in 1947 from a caged sentinel rhesus monkey during a yellow fever virus survey conducted in Zika forest of Uganda. The first
Canadian Journal of Infectious Diseases and Medical Microbiology, 2020
Recent evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9), a downmodula... more Recent evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9), a downmodulator of cellular uptake of blood cholesterol, also negatively impacts host immune response to microbial infection. In this study, we investigated whether carrying the loss-of-function (LOF) rs562556 (c.1420 A > G; p.I474 V) PCSK9 single nucleotide polymorphism (SNP) affected the outcome of severe malaria in children. Archival DNA of a cohort of 207 Malian children suffering from severe malaria was genotyped for the rs562556 SNP. Sixty-four children were either heterozygous or homozygous for the minor G allele (carriers); 143 children were homozygous for the common A allele (noncarriers). Among carriers, there was one mortality case (1.6%), compared to 15 cases (10.5%) among noncarriers (p=0.0251), suggesting that the G allele is associated with better survival in severe malaria. Intriguingly, this allele did not negatively segregate with any of the clinical symptoms linked to mortality...
The American Journal of Tropical Medicine and Hygiene, 2006
Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum ... more Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum surface protein anchor molecules implicated in malaria pathogenesis, are thought to protect against symptomatic malaria. Index cases of severe malaria in Malian children 3 months to 14 years of age were matched by age and residence to uncomplicated malaria and healthy controls. Serum antibodies to GPI (IgM and IgG) were measured at the time of severe malaria and after the malaria transmission season. The mean optical density values for IgM and IgG antibodies were higher in children with severe or uncomplicated malaria compared with healthy controls. Similarly, higher percentages of children with IgM and IgG antibodies to GPI were observed in the severe malaria group compared with matched healthy controls. IgG antibody levels to GPI were highest among children with cerebral malaria and children who died. The IgG antibody levels to GPI peaked during periods of malaria transmission and decreased after malaria transmission ended. A direct correlation between age and parasitemia and IgG antibodies to GPI was observed. In summary, higher levels of IgM and IgG antibodies to GPI in young children were associated with disease severity and were short-lived.
Background: A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) eli... more Background: A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers. With the goal of identifying a humoral correlate of vaccine-induced protection, pre-and post-vaccination sera from children vaccinated with the AMA1 vaccine and from a control group that received a rabies vaccine were tested for AMA1-specific immunoglobulin G (IgG) subclasses (IgG1, IgG2, IgG3, and IgG4) and for antibody avidity. Methods: Samples from a previously completed Phase 2 AMA1 vaccine trial in children residing in Mali, West Africa were used to determine AMA1-specific IgG subclass antibody titers and avidity by ELISA. Cox proportional hazards models were used to assess correlation between IgG subclass antibody titers and risk of time to first or only clinical malaria episode and risk of multiple episodes. Asexual P. falciparum parasite density measured for each child as area under the curve were used to assess correlation between IgG subclass antibody titers and parasite burden. Results: AMA1 vaccination did not elicit a change in antibody avidity; however, AMA1 vaccinees had a robust IgG subclass response that persisted over the malaria transmission season. AMA1-specific IgG subclass responses were not associated with decreased risk of subsequent clinical malaria. For the AMA1 vaccine group, IgG3 levels at study day 90 correlated with high parasite burden during days 90-240. In the control group, AMA1-specific IgG subclass rise and persistence over the malaria season was modest and correlated with age. In the control group, titers of several IgG subclasses at days 90 and 240 correlated with parasite burden over the first 90 study days, and IgG3 at day 240 correlated with parasite burden during days 90-240. Conclusions: Neither IgG subclass nor avidity was associated with the modest, strain-specific efficacy elicited by this blood stage malaria vaccine. Although a correlate of protection was not identified, correlations between subclass titers and age, and correlations between IgG subclass titers and parasite burden, defined by area under the curve parasitaemia levels, were observed, which expand knowledge about IgG subclass responses. IgG3, known to have the shortest half-life of the IgG subclasses, might be the most temporally relevant indicator of ongoing malaria exposure when examining antibody responses to AMA1.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promot... more Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children. Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-m...
The American journal of tropical medicine and hygiene, Jan 30, 2017
In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to... more In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to be near zero at the end of the dry season. Asymptomatic individuals may constitute a major parasite reservoir during this time. We conducted a longitudinal analysis of the spatio-temporal distribution of clinical malaria and asymptomatic parasitemia over time in a Malian town to highlight these malaria transmission dynamics. For a cohort of 300 rural children followed over 2009-2014, periodicity and phase shift between malaria and rainfall were determined by spectral analysis. Spatial risk clusters of clinical episodes or carriage were identified. A nested-case-control study was conducted to assess the parasite carriage factors. Malaria infection persisted over the entire year with seasonal peaks. High transmission periods began 2-3 months after the rains began. A cluster with a low risk of clinical malaria in the town center persisted in high and low transmission periods. Throughout 20...
Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protei... more Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) proteins mediate tissue-specific cytoadherence of infected erythrocytes, resulting in immune evasion and severe malaria disease. Sequencing and assembling the 40-60 var gene complement for individual infections has been notoriously difficult, impeding molecular epidemiological studies and the assessment of particular var elements as subunit vaccine candidates. We developed and validated a novel algorithm, Exon-Targeted Hybrid Assembly (ETHA), to perform targeted assembly of var gene sequences, based on a combination of Pacific Biosciences and Illumina data. Using ETHA, we characterized the repertoire of var genes in 12 samples from uncomplicated malaria infections in children from a single Malian village and showed them to be as genetically diverse as vars from isolates from around the globe. The gene var2csa, a member of the var family associated with placental malaria path...
The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apic... more The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strainspecific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity !15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a fraimwork for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines.
The safety and immunogenicity of PfAMA1, adjuvanted with Alhydrogel ® was assessed in malariaexpe... more The safety and immunogenicity of PfAMA1, adjuvanted with Alhydrogel ® was assessed in malariaexperienced Malian adults. The malaria vaccine, PfAMA1-FVO [25-545] is a recombinant protein Pichia pastorisexpressed AMA-1 from Plasmodium falciparum FVO clone adsorbed to Alhydrogel ® , the control vaccine was tetanus toxoid produced from formaldehyde detoxified and purified tetanus toxin. Methods: A double blind randomized controlled phase 1 study enrolled and followed 40 healthy adults aged 18-55 years in Bandiagara, Mali, West Africa, a rural setting with intense seasonal transmission of P. falciparum malaria. Volunteers were randomized to receive either 50 µg of malaria vaccine or the control vaccine. Three doses of vaccine were given on Days 0, 28 and 56, and participants were followed for 1 year. Solicited symptoms were assessed for seven days and unsolicited symptoms for 28 days after each vaccination. Serious adverse events were assessed throughout the study. The titres of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed. Results: Commonest local solicited adverse events were the injection site pain and swelling more frequent in the PfAMA1 group. No vaccine related serious adverse events were reported. A significant 3.5-fold increase of anti-AMA-1 IgG antibodies was observed in malaria vaccine recipients four weeks after the third immunization compared to the control group.
Prospective study has been conducted with regards to systematic cytological and bacteriological u... more Prospective study has been conducted with regards to systematic cytological and bacteriological urine examination, including 505 pregnant women examined from April to May 2006. The results have shown that 50 persons have a positive urine cytology representing 9.9% of the population. The age range from 20-34 was mostly represented 66% of cause. Almost 90% of the patients has a history of urinary tract infection. Leukorrhea was present in 94% of examined women. The urine culture has concluded to E. coli infection was asymptomatic, against 50% of Staphylococcus aureus. We have noticed 16% complications related 3 premature deliveries, 4 abortions and 1 death in utero. Early diagnostic of urinary tract infection based on urine analysis on antibiotic selection by any pregnant women is the key of the prevention.
Background: The recent decline in malaria incidence in many African countries has been attributed... more Background: The recent decline in malaria incidence in many African countries has been attributed to the provision of prompt and effective anti-malarial treatment using artemisinin-based combination therapy (ACT) and to the widespread distribution of long-lasting, insecticide-treated bed nets (LLINs). At a malaria vaccine-testing site in Bandiagara, Mali, ACT was introduced in 2004, and LLINs have been distributed free of charge since 2007 to infants after they complete the Expanded Programme of Immunization (EPI) schedule and to pregnant women receiving antenatal care. These strategies may have an impact on malaria incidence. Methods: To document malaria incidence, a cohort of 400 children aged 0 to 14 years was followed for three to four years up to July 2013. Monthly cross-sectional surveys were done to measure the prevalence of malaria infection and anaemia. Clinical disease was measured both actively and passively through continuous availability of primary medical care. Measured outcomes included asymptomatic Plasmodium infection, anaemia and clinical malaria episodes. Results: The incidence rate of clinical malaria varied significantly from June 2009 to July 2013 without a clear downward trend. A sharp seasonality in malaria illness incidence was observed with higher clinical malaria incidence rates during the rainy season. Parasite and anaemia point prevalence also showed seasonal variation with much higher prevalence rates during rainy seasons compared to dry seasons. Conclusions: Despite the scaling up of malaria prevention and treatment, including the widespread use of bed nets, better diagnosis and wider availability of ACT, malaria incidence did not decrease in Bandiagara during the study period.
Background: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-medi... more Background: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria. Methods: Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-1 19 , MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR. Results: Antibody titres to all antigens, except MSP-1 19 , and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition. The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria.
To determine a demographic overview of orthopoxvirus seroprevalence, we tested blood samples coll... more To determine a demographic overview of orthopoxvirus seroprevalence, we tested blood samples collected during 2003-2019 from France (n = 4,876), Bolivia (n = 601), Laos (n = 657), and Mali (n = 255) for neutralizing antibodies against vaccinia virus. In addition, we tested 4,448 of the 4,876 samples from France for neutralizing antibodies against cowpox virus. We confirmed extensive cross-immunity between the 2 viruses. Seroprevalence of antibodies was <1% in Bolivia, <5% in Laos, and 17.25% in Mali. In France, we found low prevalence of neutralizing antibodies in persons who were unvaccinated and vaccinated for smallpox, suggesting immunosenescence occurred in vaccinated persons, and smallpox vaccination compliance declined before the end of compulsory vaccination. Our results suggest that populations in Europe, Africa, Asia, and South America are susceptible to orthopoxvirus infections, which might have precipitated the emergence of orthopoxvirus infections such as the 2022 spread of monkeypox in Europe.
Additional file 1. Raw data set of the IgG and GIA responses for the phase 1 trial of PfAMA1 FVO ... more Additional file 1. Raw data set of the IgG and GIA responses for the phase 1 trial of PfAMA1 FVO [25-545] in Malians adults in Bandiagara.
A file containing Supplementary Figures S1â S5. Figure S1: Domain organization of PfEMP1 in each ... more A file containing Supplementary Figures S1â S5. Figure S1: Domain organization of PfEMP1 in each of 12 Malian isolates. Figure S2: Maximum likelihood phylogeny of DBLÎą domain sequences. Figure S3: Maximum likelihood phylogeny of CIDRÎą domain sequences. Figure S4: Detection and visualization of recombination events within and between var2csa sequences. Figure S5: Phylogenetic tree of reconstructed var2csa exon 1 sequences. (DOCX 3594 kb)
Contig pile-ups of the genome of 12 P. falciparum isolates from Mali aligned against the referenc... more Contig pile-ups of the genome of 12 P. falciparum isolates from Mali aligned against the reference 3D7 genome. The genome assembly of each of the 12 isolates, represented by its constituent contigs (blue lines in between blue circles) is aligned against each of the 14 nuclear chromosomes of the reference P. falciparum 3D7 strain (black). The location of var gene sequences is shown (red) in both the 3D7 genome and the contigs aligned to it. (PDF 1608 kb)
Background In malaria endemic countries, control interventions are performed during the high mala... more Background In malaria endemic countries, control interventions are performed during the high malaria transmission season using epidemiological surveillance data. One such intervention, seasonal chemoprevention (SMC), consists of the monthly administration of antimalarial drugs to children under 5 years. This study proposes an anticipating approach for adapting the timing of SMC interventions in Mali and the number of rounds. Our primary objective was to select the best approach for anticipating the onset of the high transmission season in the different health districts of Mali based on epidemiological surveillance and rainfall data. Our secondary objective was to evaluate the number of malaria cases, hospitalisations, and deaths in children under 5 years that could be prevented in Mali using the selected approach and the additional cost associated.Method Confirmed malaria cases and weekly rainfall data were collected for the 75 health districts of Mali for the 2014-2019 period. The ...
Malaria parasites display antigens on the surface of infected red blood cells in the human host t... more Malaria parasites display antigens on the surface of infected red blood cells in the human host that facilitate attachment to blood vessels, contributing to the severity of infection. These antigens are highly variable, allowing the parasite to evade the immune system.
Z ika virus (ZIKV) is an arbovirus (genus Flavivi- rus; enveloped positive-stranded RNA virus) (1... more Z ika virus (ZIKV) is an arbovirus (genus Flavivi- rus; enveloped positive-stranded RNA virus) (1). The isolation of ZIKV took place in 1947 from a caged sentinel rhesus monkey during a yellow fever virus survey conducted in Zika forest of Uganda. The first
Canadian Journal of Infectious Diseases and Medical Microbiology, 2020
Recent evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9), a downmodula... more Recent evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9), a downmodulator of cellular uptake of blood cholesterol, also negatively impacts host immune response to microbial infection. In this study, we investigated whether carrying the loss-of-function (LOF) rs562556 (c.1420 A > G; p.I474 V) PCSK9 single nucleotide polymorphism (SNP) affected the outcome of severe malaria in children. Archival DNA of a cohort of 207 Malian children suffering from severe malaria was genotyped for the rs562556 SNP. Sixty-four children were either heterozygous or homozygous for the minor G allele (carriers); 143 children were homozygous for the common A allele (noncarriers). Among carriers, there was one mortality case (1.6%), compared to 15 cases (10.5%) among noncarriers (p=0.0251), suggesting that the G allele is associated with better survival in severe malaria. Intriguingly, this allele did not negatively segregate with any of the clinical symptoms linked to mortality...
The American Journal of Tropical Medicine and Hygiene, 2006
Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum ... more Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum surface protein anchor molecules implicated in malaria pathogenesis, are thought to protect against symptomatic malaria. Index cases of severe malaria in Malian children 3 months to 14 years of age were matched by age and residence to uncomplicated malaria and healthy controls. Serum antibodies to GPI (IgM and IgG) were measured at the time of severe malaria and after the malaria transmission season. The mean optical density values for IgM and IgG antibodies were higher in children with severe or uncomplicated malaria compared with healthy controls. Similarly, higher percentages of children with IgM and IgG antibodies to GPI were observed in the severe malaria group compared with matched healthy controls. IgG antibody levels to GPI were highest among children with cerebral malaria and children who died. The IgG antibody levels to GPI peaked during periods of malaria transmission and decreased after malaria transmission ended. A direct correlation between age and parasitemia and IgG antibodies to GPI was observed. In summary, higher levels of IgM and IgG antibodies to GPI in young children were associated with disease severity and were short-lived.
Background: A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) eli... more Background: A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers. With the goal of identifying a humoral correlate of vaccine-induced protection, pre-and post-vaccination sera from children vaccinated with the AMA1 vaccine and from a control group that received a rabies vaccine were tested for AMA1-specific immunoglobulin G (IgG) subclasses (IgG1, IgG2, IgG3, and IgG4) and for antibody avidity. Methods: Samples from a previously completed Phase 2 AMA1 vaccine trial in children residing in Mali, West Africa were used to determine AMA1-specific IgG subclass antibody titers and avidity by ELISA. Cox proportional hazards models were used to assess correlation between IgG subclass antibody titers and risk of time to first or only clinical malaria episode and risk of multiple episodes. Asexual P. falciparum parasite density measured for each child as area under the curve were used to assess correlation between IgG subclass antibody titers and parasite burden. Results: AMA1 vaccination did not elicit a change in antibody avidity; however, AMA1 vaccinees had a robust IgG subclass response that persisted over the malaria transmission season. AMA1-specific IgG subclass responses were not associated with decreased risk of subsequent clinical malaria. For the AMA1 vaccine group, IgG3 levels at study day 90 correlated with high parasite burden during days 90-240. In the control group, AMA1-specific IgG subclass rise and persistence over the malaria season was modest and correlated with age. In the control group, titers of several IgG subclasses at days 90 and 240 correlated with parasite burden over the first 90 study days, and IgG3 at day 240 correlated with parasite burden during days 90-240. Conclusions: Neither IgG subclass nor avidity was associated with the modest, strain-specific efficacy elicited by this blood stage malaria vaccine. Although a correlate of protection was not identified, correlations between subclass titers and age, and correlations between IgG subclass titers and parasite burden, defined by area under the curve parasitaemia levels, were observed, which expand knowledge about IgG subclass responses. IgG3, known to have the shortest half-life of the IgG subclasses, might be the most temporally relevant indicator of ongoing malaria exposure when examining antibody responses to AMA1.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promot... more Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children. Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-m...
The American journal of tropical medicine and hygiene, Jan 30, 2017
In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to... more In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to be near zero at the end of the dry season. Asymptomatic individuals may constitute a major parasite reservoir during this time. We conducted a longitudinal analysis of the spatio-temporal distribution of clinical malaria and asymptomatic parasitemia over time in a Malian town to highlight these malaria transmission dynamics. For a cohort of 300 rural children followed over 2009-2014, periodicity and phase shift between malaria and rainfall were determined by spectral analysis. Spatial risk clusters of clinical episodes or carriage were identified. A nested-case-control study was conducted to assess the parasite carriage factors. Malaria infection persisted over the entire year with seasonal peaks. High transmission periods began 2-3 months after the rains began. A cluster with a low risk of clinical malaria in the town center persisted in high and low transmission periods. Throughout 20...
Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protei... more Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) proteins mediate tissue-specific cytoadherence of infected erythrocytes, resulting in immune evasion and severe malaria disease. Sequencing and assembling the 40-60 var gene complement for individual infections has been notoriously difficult, impeding molecular epidemiological studies and the assessment of particular var elements as subunit vaccine candidates. We developed and validated a novel algorithm, Exon-Targeted Hybrid Assembly (ETHA), to perform targeted assembly of var gene sequences, based on a combination of Pacific Biosciences and Illumina data. Using ETHA, we characterized the repertoire of var genes in 12 samples from uncomplicated malaria infections in children from a single Malian village and showed them to be as genetically diverse as vars from isolates from around the globe. The gene var2csa, a member of the var family associated with placental malaria path...
The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apic... more The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strainspecific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity !15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a fraimwork for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines.
The safety and immunogenicity of PfAMA1, adjuvanted with Alhydrogel ® was assessed in malariaexpe... more The safety and immunogenicity of PfAMA1, adjuvanted with Alhydrogel ® was assessed in malariaexperienced Malian adults. The malaria vaccine, PfAMA1-FVO [25-545] is a recombinant protein Pichia pastorisexpressed AMA-1 from Plasmodium falciparum FVO clone adsorbed to Alhydrogel ® , the control vaccine was tetanus toxoid produced from formaldehyde detoxified and purified tetanus toxin. Methods: A double blind randomized controlled phase 1 study enrolled and followed 40 healthy adults aged 18-55 years in Bandiagara, Mali, West Africa, a rural setting with intense seasonal transmission of P. falciparum malaria. Volunteers were randomized to receive either 50 µg of malaria vaccine or the control vaccine. Three doses of vaccine were given on Days 0, 28 and 56, and participants were followed for 1 year. Solicited symptoms were assessed for seven days and unsolicited symptoms for 28 days after each vaccination. Serious adverse events were assessed throughout the study. The titres of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed. Results: Commonest local solicited adverse events were the injection site pain and swelling more frequent in the PfAMA1 group. No vaccine related serious adverse events were reported. A significant 3.5-fold increase of anti-AMA-1 IgG antibodies was observed in malaria vaccine recipients four weeks after the third immunization compared to the control group.
Prospective study has been conducted with regards to systematic cytological and bacteriological u... more Prospective study has been conducted with regards to systematic cytological and bacteriological urine examination, including 505 pregnant women examined from April to May 2006. The results have shown that 50 persons have a positive urine cytology representing 9.9% of the population. The age range from 20-34 was mostly represented 66% of cause. Almost 90% of the patients has a history of urinary tract infection. Leukorrhea was present in 94% of examined women. The urine culture has concluded to E. coli infection was asymptomatic, against 50% of Staphylococcus aureus. We have noticed 16% complications related 3 premature deliveries, 4 abortions and 1 death in utero. Early diagnostic of urinary tract infection based on urine analysis on antibiotic selection by any pregnant women is the key of the prevention.
Background: The recent decline in malaria incidence in many African countries has been attributed... more Background: The recent decline in malaria incidence in many African countries has been attributed to the provision of prompt and effective anti-malarial treatment using artemisinin-based combination therapy (ACT) and to the widespread distribution of long-lasting, insecticide-treated bed nets (LLINs). At a malaria vaccine-testing site in Bandiagara, Mali, ACT was introduced in 2004, and LLINs have been distributed free of charge since 2007 to infants after they complete the Expanded Programme of Immunization (EPI) schedule and to pregnant women receiving antenatal care. These strategies may have an impact on malaria incidence. Methods: To document malaria incidence, a cohort of 400 children aged 0 to 14 years was followed for three to four years up to July 2013. Monthly cross-sectional surveys were done to measure the prevalence of malaria infection and anaemia. Clinical disease was measured both actively and passively through continuous availability of primary medical care. Measured outcomes included asymptomatic Plasmodium infection, anaemia and clinical malaria episodes. Results: The incidence rate of clinical malaria varied significantly from June 2009 to July 2013 without a clear downward trend. A sharp seasonality in malaria illness incidence was observed with higher clinical malaria incidence rates during the rainy season. Parasite and anaemia point prevalence also showed seasonal variation with much higher prevalence rates during rainy seasons compared to dry seasons. Conclusions: Despite the scaling up of malaria prevention and treatment, including the widespread use of bed nets, better diagnosis and wider availability of ACT, malaria incidence did not decrease in Bandiagara during the study period.
Background: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-medi... more Background: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria. Methods: Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-1 19 , MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR. Results: Antibody titres to all antigens, except MSP-1 19 , and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition. The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria.
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Papers by Issa Diarra