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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria is still a public health problem in Africa. Seasonal Malaria Chemoprevention (SMC) is an efficient control strategy recommended by WHO that targets children under five year old living in ...areas of seasonal malaria transmission. SMC uses the combination amodiaquine (AQ) – sulfadoxine-pyrimethamine (SP). However SP selects rapidly drug resistant parasites. And malaria burden may increase in older children where SMC is implemented. We initiated a pilot study to assess an alternative approach to SMC in older children in Mali.
A randomized open-label clinical trial was conducted to test the efficacy and safety of SMC using artesunate – amodiaquine in school aged children in Mali. Two hundred pupils aged 6–15 years old were enrolled and randomized into two arms of 100 each, to receive either artesunate–amodiaquine (ASAQ) monthly or no intervention. Both arms were followed and clinical malaria were diagnosed and treated with arthemeter-lumefanthrine as recommended by Mali National Malaria Control Program. ASAQ was administered 3 days under study team direct observation and during 4 consecutive months starting in October 2013. Follow up was continued until April 2014.
Overall, 20 cases of uncomplicated clinical malaria were encountered in the Control arm and three cases in the ASAQ arm, showing a protective efficacy of 85% 95% CI 80.1–89.9 against clinical malaria. Protective efficacy against malaria infection was 69.6% 95% CI 58.6–21.4. No effect on anemia was observed. ASAQ was well tolerated. Most common solicited adverse events were abdominal pain and headaches of mild intensity in respectively 64% and 44% of children that swallowed ASAQ.
ASAQ is effective and well tolerated as SMC targeting older children in a peri urban setting in Mali. Its administration at schools is a feasible and accepted strategy to deliver the intervention.
...seasonal RTS,S/AS01E vaccination might be useful to provide immunological cover to children who remain non-adherent to SMC. No reports of meningitis or higher incidences of death among girls were ...observed, both of which have been previously reported for RTS,S/AS01E phase 3 trials.8 The augmentation of vaccine efficacy by a drug regimen is very important for the field of vaccinology. Since there was no non-intervention control group, the nature of the interaction between the two interventions (additive or synergistic) could not be established. Alternatively, the quality of induced RTS,S/AS01E immunity might improve if blood-stage infection is kept under control by the SMC.9 Future surveillance studies are needed to establish whether children in the combination group are at an increased risk of malaria going forward compared with a control population that has acquired immunity via repeated P falciparum infections during this 5-year period.
Abstract
Circumsporozoite protein (CSP) coats the Plasmodium falciparum sporozoite surface and is a major malaria subunit vaccine target. We measured epitope-specific reactivity to field-derived CSP ...haplotypes in serum samples from Malian adults and children on a custom peptide microarray. Compared to children, adults showed greater antibody responses and responses to more variants in regions proximal to and within the central repeat region. Children acquired short-lived immunity to an epitope proximal to the central repeat region but not to the central repeat region itself. This approach has the potential to differentiate immunodominant from protective epitope-specific responses when combined with longitudinal infection data.
On a custom peptide microarray that measured naturally acquired, epitope-specific antibody reactivity to field-derived Plasmodium falciparum circumsporozoite protein haplotypes, Malian adult sera had immunoglobulin G (IgG) antibodies to the Region 1-NANP junction and children had short-lived IgG responses to the same region.
Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or "lacunae", in immunity to these Plasmodium falciparum antigens in children with severe malaria ...would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against
malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency ...has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of
infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of
infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion. Serologic responses to these antigens have been associated with protection from ...clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α "tag"). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. In this study, using sera from a malaria-endemic region, responses to DBL-α tags were compared to responses to the corresponding entire DBL-α domain (or "parent" domain) coupled with the succeeding cysteine-rich interdomain region (CIDR).
A protein microarray populated with DBL-α tags, the parent DBL-CIDR head structures, and downstream PfEMP1 protein fragments was probed with sera from Malian children (aged 1 to 6 years) and adults from the control arms of apical membrane antigen 1 (AMA1) vaccine clinical trials before and during a malaria transmission season. Serological responses to the DBL-α tag and the DBL-CIDR head structure were measured and compared in children and adults, and throughout the season.
Malian serologic responses to a PfEMP1's DBL-α tag region did not correlate with seasonal malaria exposure, or with responses to the parent DBL-CIDR head structure in either children or adults. Parent DBL-CIDR head structures were better indicators of malaria exposure.
Larger PfEMP1 domains may be better indicators of malaria exposure than short, variable PfEMP1 fragments such as DBL-α tags. PfEMP1 head structures that include conserved sequences appear particularly well suited for study as serologic predictors of malaria exposure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (
) gene, named
and
, ...occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between
and
and malaria phenotypes, and find they have opposing associations. The
polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the
polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between
and α
thalassaemia, with the protective association of
greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.
To prevent premature dismissal of promising vaccine programs, it is critical to determine if lack of efficacy in the field is due to allele specific-efficacy, rather than to the lack of ...immunogenicity of the candidate antigen. Here we use samples collected during a field trial of the AMA1-based FMP2.1/AS02A malaria vaccine, which incorporates the AMA1 variant encoded by the reference Plasmodium falciparum 3D7 strain, to assess the usefulness of epitope-based sieve analysis for the detection of vaccine-induced allele-specific immune responses.
The samples used are from volunteers who received the malaria vaccine FMP2.1/AS02A or a control (rabies vaccine), during a vaccine efficacy field trial, and who later developed malaria. In a previous study, P. falciparum DNA was extracted from all samples, and the ama1 locus amplified and sequenced. Here, a sieve analysis was used to measure T and B-cell escape, and difference in 3D7-like epitopes in the two treatment arms.
Overall, no difference was observed in mean amino acid distance to the 3D7 AMA1 variant between sequences from vaccinees and controls in B-cell epitopes. However, we found a significantly greater proportion of 3D7-like T-cell epitopes that map to the AMA1 cluster one loop (c1L) region in the control vs. the vaccinee group (p = 0.02), consistent with allele-specific vaccine efficacy. Interestingly, AMA1 epitopes in infections from vaccinees had higher mean IC50, and consequently lower binding affinity, than epitopes generated from the control group (p = 0.01), suggesting that vaccine-induced selection impacted the immunological profile of the strains that pass through the sieve imposed by the vaccine-induced protection. These findings are consistent with a vaccine-derived sieve effect on the c1L region of AMA1 and suggest that sieve analyses of malaria vaccine trial samples targeted to epitopes identified in silico can help identify protective malaria antigens that may be efficacious if combined in a multivalent vaccine.
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