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Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

ABSTRACT: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels.Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2.Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

SUBMITTER: Shelton JM

PROVIDER: S-EPMC4552443 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

Shelton Jennifer M G JM Corran Patrick P Risley Paul P Silva Nilupa N Hubbart Christina C Jeffreys Anna A Rowlands Kate K Craik Rachel R Cornelius Victoria V Hensmann Meike M Molloy Sile S Sepulveda Nuno N Clark Taane G TG Band Gavin G Clarke Geraldine M GM Spencer Christopher C A CC Kerasidou Angeliki A Campino Susana S Auburn Sarah S Tall Adama A Ly Alioune Badara AB Mercereau-Puijalon Odile O Sakuntabhai Anavaj A Djimdé Abdoulaye A Maiga Boubacar B Touré Ousmane O Doumbo Ogobara K OK Dolo Amagana A Troye-Blomberg Marita M Mangano Valentina D VD Verra Frederica F Modiano David D Bougouma Edith E Sirima Sodiomon B SB Ibrahim Muntaser M Hussain Ayman A Eid Nahid N Elzein Abier A Mohammed Hiba H Elhassan Ahmed A Elhassan Ibrahim I Williams Thomas N TN Ndila Carolyne C Macharia Alexander A Marsh Kevin K Manjurano Alphaxard A Reyburn Hugh H Lemnge Martha M Ishengoma Deus D Carter Richard R Karunaweera Nadira N Fernando Deepika D Dewasurendra Rajika R Drakeley Christopher J CJ Riley Eleanor M EM Kwiatkowski Dominic P DP Rockett Kirk A KA

Malaria journal 20150828

<h4>Background</h4>Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.<h4>Methods</h4>Sera, ...[more]

PMID: 26314886

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Project description:BackgroundAlthough vaccination of pregnant women against influenza is recommended, the vaccination rate remains low. We conducted a study to identify determinants of influenza vaccination uptake in pregnancy in order to identify strategies to improve seasonal influenza vaccination rates.MethodsProspective observational hospital-based study in the French hospital performing the highest number of deliveries, located in the city of Lille, among all women who had given birth during the 2014-2015 influenza season. Data were collected through a self-completed questionnaire and from medical files. The vaccination uptake was self-reported. Determinants of vaccination uptake were identified using logistic regression analysis.ResultsOf the 2045 women included in the study, 35.5% reported that they had been vaccinated against influenza during their pregnancy. The principal factors significantly associated with greater vaccination uptake were previous influenza vaccination (50.9% vs 20.2%, OR 4.1, 95% CI 3.1-5.5), nulliparity (41.0% vs 31.3%, OR 2.5, 95% CI 1.7-3.7), history of preterm delivery < 34 weeks (43.4% vs 30.3%, OR 2.3, 95% CI 1.1-4.9), the mother's perception that the frequency of vaccine complications for babies is very low (54.6% vs 20.6%, OR 1.1, 95% CI 0.5-2.2), the mother's good knowledge of influenza and its vaccine (61.7% vs 24.4%, OR 3.1, 95% CI 2.2-4.4), hospital-based prenatal care in their first trimester of pregnancy (55.0% vs 30.2%, OR 2.1, 95% CI 1.2-3.7), vaccination recommendations during pregnancy by a healthcare worker (47.0% vs 2.7%, OR 18.8, 95% CI 10.0-35.8), receipt of a vaccine reimbursement form (52.4% vs 18.6%, OR 2.0, 95% CI 1.5-2.7), and information from at least one healthcare worker about the vaccine (43.8% vs 19.1%, OR 1.8, 95% CI 1.3-2.6).ConclusionsOur findings suggest that in order to increase flu vaccination compliance among pregnant women, future public health programmes must ensure cost-free access to vaccination, and incorporate education about the risks of influenza and the efficacy/safety of vaccination and clear recommendations from healthcare professionals into routine antenatal care.

Project description:BackgroundNaturally acquired immunity can reduce parasitaemia and potentially influence anti-malarial treatment outcomes; however, evidence for this in the current literature provides conflicted results. The available evidence was synthesized to determine and quantify the association between host immunity and anti-malarial treatment failure.MethodsFour databases were searched to identify studies investigating malaria antibody levels in patients receiving anti-malarial treatment for symptomatic malaria with treatment failure recorded according to the World Health Organization classification. Odds ratios or hazard ratios were extracted or calculated to quantify the association between malarial antibody levels and treatment failure, and findings from different studies were visualized using forest plots.ResultsEight studies, including patients with falciparum malaria treated with mono- and combination therapy of artemisinin derivatives, sulfadoxine, pyrimethamine and chloroquine, were identified. Reported and calculated effect estimates varied greatly between studies, even those assessing the same antigens and treatments. An association between blood-stage IgG responses and treatment efficacy was observed. The greatest magnitudes of effect were observed for artemisinin [OR/HR (95% CI) range 0.02 (0.00, 0.45)-1.08 (0.57, 2.06)] and chloroquine [0.24 (0.04, 1.37)-0.32 (0.05, 1.96)] treatments, and larger magnitudes of effect were observed for variant surface antigen responses [0.02 (0.00, 0.45)-1.92 (0.94, 3.91)] when compared with merozoite specific responses [0.24 (0.04, 1.37)-2.83 (1.13, 7.09)].ConclusionsNaturally acquired malarial immunity is associated with reduced anti-malarial treatment failure in malaria endemic populations. Anti-malarial IgG effects treatment outcome differently for different anti-malarial drugs and antigen targets, and had the greatest impact during treatment with the current first-line treatments, the artemisinins. This has implications for the assessment of the therapeutic efficacy of anti-malarials, particularly in the context of emerging artemisinin resistance.

Project description:BACKGROUND:Community-acquired pneumonia (CAP) is a major cause of death worldwide and occurs with variable severity. There are few studies focused on the expression of soluble urokinase-type plasminogen activator receptor (suPAR) and syndecan-4 in patients with CAP. METHODS:A prospective, multi-centre study was conducted between January 2014 and December 2016. A total of 103 patients with severe CAP (SCAP), 149 patients with non-SCAP, and 30 healthy individuals were enrolled. Clinical data were recorded for all enrolled patients. Serum suPAR and syndecan-4 levels were determined by quantitative enzyme-linked immunosorbent assay. The t test and Mann-Whitney U test were used to compare between two groups; one-way analysis of variance and the Kruskal-Wallis test were used to compare multiple groups. Correlations were assessed using Pearson and Spearman tests. Area under the curve (AUCs), optimal threshold values, sensitivity, and specificity were calculated. Survival curves were constructed and compared by log-rank test. Regression analyses assessed the effect of multiple variables on 30-day survival. RESULTS:suPAR levels increased in all patients with CAP, especially in severe cases. Syndecan-4 levels decreased in patients with CAP, especially in non-survivors. suPAR and syndecan-4 levels were positively and negatively correlated with severity scores, respectively. suPAR exhibited high accuracy in predicting SCAP among patients with CAP with an AUC of 0.835 (p?<?0.001). In contrast, syndecan-4 exhibited poor diagnostic value for predicting SCAP (AUC 0.550, p?=?0.187). The AUC for predicting mortality in patients with SCAP was 0.772 and 0.744 for suPAR and syndecan-4, respectively; the respective prediction threshold values were 10.22 ng/mL and 6.68 ng/mL. Addition of both suPAR and syndecan-4 to the Pneumonia Severity Index significantly improved their prognostic accuracy, with an AUC of 0.885. Regression analysis showed that suPAR ?10.22 ng/mL and syndecan-4???6.68 ng/mL were reliable independent markers for prediction of 30-day survival. CONCLUSION:suPAR exhibits high accuracy for both diagnosis and prognosis of SCAP. Syndecan-4 can reliably predict mortality in patients with SCAP. Addition of both suPAR and syndecan-4 to a clinical scoring method could improve prognostic accuracy. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03093220 . Registered on 28 March 2017 (retrospectively registered).

Dataset Information

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

Publications

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

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