Repeat sequences in block 2 of Plasmodium falciparum merozoite surface protein 1 are targets of antibodies associated with protection from malaria

Human antibodies to the block 2 region of Plasmodium falciparum merozoite surface protein 1 (MSP1) are associated with a reduced prospective risk of clinical malaria. Block 2 is highly polymorphic, but all known alleles can be grouped into three major types. Two of these types (the K1-like and MAD20-like types) contain type-specific sequences (found in all alleles of a particular type) that flank polymorphic tripeptide repeats. These repeats contain both type-specific and subtype-specific sequences. To evaluate the antibody recognition of these parts of block 2, a new panel of six recombinant proteins was used (fused type-specific flanking sequences and two representative repeat sequences for each of the K1-like and MAD20-like types separately). Extensive testing of these antigens and full-length block 2 antigens showed that human serum immunoglobulin G antibodies induced by infection can recognize (i) type-specific epitopes in the repeats, (ii) subtype-specific epitopes in the repeats, or (iii) type-specific epitopes in flanking sequences. A large prospective study in The Gambia showed that antibodies to the repeats are strongly associated with protection from clinical malaria. The results are important for design of a vaccine to induce protective antibodies, and they address hypotheses about repeat sequences in malaria antigens.     

Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial

This double-blind, randomized, controlled study investigated the efficacy, safety and tolerability of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria among Gambian children. Combined use of artesunate and pyrimethamine-sulphadoxine was hypothesized to delay or prevent resistance, which proved to be effective in reducing childhood mortality in sub-Saharan Africa. A total of 600 children with acute uncomplicated Plasmodium falciparum malaria, 6 months to 10 years old, were randomly administered pyrimethamine-sulphadoxine (25 mg/500 mg) with placebo, 4 mg/kg body weight pyrimethamine-sulphadoxine plus 1 dose of artesunate, or pyrimethamine-sulphadoxine plus 4 mg/kg body weight artesunate for 3 days. Results indicate that combined treatment was well tolerated. On day 1, 178 of 381 children treated with artesunate were still parasitemic compared with 157 of 195 children in the pyrimethamine-sulphadoxine group. On the other hand, failure rates on day 14 were 3.1% in the pyrimethamine-sulphadoxine group and 3.7% in the 1-dose artesunate group and 1.6% in the 3-dose group. Insignificant differences were found among children administered 1-dose and 3-dose artesunate, and were found less likely to be gametocytemic after treatment. In conclusion, this study confirms the safety and efficacy of a combined treatment, which eventually results in lower gametocyte rates and lower transmission rates.     

A multimedia consent tool for research participants in the Gambia: a randomized controlled trial

ObjectiveTo assess the effectiveness of a multimedia informed consent tool for adults participating in a clinical trial in the Gambia.MethodsAdults eligible for inclusion in a malaria treatment trial (n = 311) were randomized to receive information needed for informed consent using either a multimedia tool (intervention arm) or a standard procedure (control arm). A computerized, audio questionnaire was used to assess participants’ comprehension of informed consent. This was done immediately after consent had been obtained (at day 0) and at subsequent follow-up visits (days 7, 14, 21 and 28). The acceptability and ease of use of the multimedia tool were assessed in focus groups.FindingsOn day 0, the median comprehension score in the intervention arm was 64% compared with 40% in the control arm (P = 0.042). The difference remained significant at all follow-up visits. Poorer comprehension was independently associated with female sex (odds ratio, OR: 0.29; 95% confidence interval, CI: 0.12–0.70) and residing in Jahaly rather than Basse province (OR: 0.33; 95% CI: 0.13–0.82). There was no significant independent association with educational level. The risk that a participant’s comprehension score would drop to half of the initial value was lower in the intervention arm (hazard ratio 0.22, 95% CI: 0.16–0.31). Overall, 70% (42/60) of focus group participants from the intervention arm found the multimedia tool clear and easy to understand.ConclusionA multimedia informed consent tool significantly improved comprehension and retention of consent information by research participants with low levels of literacy.     

The impact of childhood vaccines on bacterial carriage in the nasopharynx: a longitudinal study

Background

There is increasing evidence that childhood vaccines have effects that extend beyond their target disease. The objective of this study was to assess the effects of routine childhood vaccines on bacterial carriage in the nasopharynx.

Methods

A cohort of children from rural Gambia was recruited at birth and followed up for one year. Nasopharyngeal swabs were taken immediately after birth, every two weeks for the first six months and then every other month. The presence of bacteria in the nasopharynx (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus) was compared before and after the administration of DTP-Hib-HepB and measles-yellow fever vaccines.

Results

A total of 1,779 nasopharyngeal swabs were collected from 136 children for whom vaccination data were available. The prevalence of bacterial carriage was high: 82.2% S. pneumoniae, 30.6%, S.aureus, 27.8% H. influenzae. Carriage of H. influenzae (OR = 0.36; 95% CI: 0.13, 0.99) and S. pneumoniae (OR = 0.25; 95% CI: 0.07, 0.90) were significantly reduced after measles-yellow fever vaccination; while DTP-Hib-HepB had no effect on bacterial carriage.

Conclusions

Nasopharyngeal bacterial carriage is unaffected by DTP-Hib-HepB vaccination and reduced after measles-yellow fever vaccination.     

Mass drug administration with azithromycin for trachoma elimination and the population structure of Streptococcus pneumoniae in the nasopharynx

ObjectiveMass drug administration (MDA) with azithromycin for trachoma elimination reduces nasopharyngeal carriage of Streptococcus pneumoniae in the short term. We evaluated S. pneumoniae carried in the nasopharynx before and after a round of azithromycin MDA to determine whether MDA was associated with changes in pneumococcal population structure and resistance.MethodsWe analysed 514 pneumococcal whole genomes randomly selected from nasopharyngeal samples collected in two Gambian villages that received three annual rounds of MDA for trachoma elimination. The 514 samples represented 293 participants, of which 75% were children aged 0–9 years, isolated during three cross-sectional surveys (CSSs) conducted before the third round of MDA (CSS-1) and at 1 (CSS-2) and 6 (CSS-3) months after MDA. Bayesian Analysis of Population Structure (BAPS) was used to cluster related isolates by capturing variation in the core genome. Serotype and multilocus sequence type were inferred from the genotype. Antimicrobial resistance determinants were identified from assemblies, including known macrolide resistance genes.ResultsTwenty-seven BAPS clusters were assigned. These consisted of 81 sequence types (STs). Two BAPS clusters not observed in CSS-1 (n = 109) or CSS-2 (n = 69), increased in frequency in CSS-3 (n = 126); BAPS20 (8.73%, p 0.016) and BAPS22 (7.14%, p 0.032) but were not associated with antimicrobial resistance. Macrolide resistance within BAPS17 increased after treatment (CSS-1 n = 0/6, CSS-2/3 n = 5/5, p 0.002) and was carried on a mobile transposable element that also conferred resistance to tetracycline.DiscussionLimited changes in pneumococcal population structure were observed after the third round of MDA, suggesting treatment had little effect on the circulating lineages. An increase in macrolide resistance within one BAPS highlights the need for antimicrobial resistance surveillance in treated villages.     

Effect of age and vaccination with a pneumococcal conjugate vaccine on the density of pneumococcal nasopharyngeal carriage

Background.?This study evaluated the impact of age and pneumococcal vaccination on the density of pneumococcal nasopharyngeal carriage. Methods.?A cluster-randomized trial was conducted in rural Gambia. In 11 villages (the vaccine group), all residents received 7-valent pneumococcal conjugate vaccine (PCV-7), while in another 10 villages (the control group), only children <30 months old or born during the study period received PCV-7. Cross-sectional surveys (CSSs) were conducted to collect nasopharyngeal swabs before vaccination (baseline CSS) and 4, 12, and 22 months after vaccination. Pneumococcal density was defined using a semiquantitative classification (range, 1-4) among colonized individuals. An age-trend analysis of density was conducted using data from the baseline CSS. Mean pneumococcal density was compared in CSSs conducted before and after vaccination. Results.?Mean bacterial density among colonized individuals in the baseline CSS was 2.57 for vaccine-type (VT) and non-vaccine-type (NVT) pneumococci; it decreased with age (P?相似文献   

Pharmacokinetics of Transfer of Azithromycin into the Breast Milk of African Mothers

Azithromycin (AZI) is used for its antibiotic and antimalarial properties in pregnancy. Reported estimates of AZI breast milk transfer, based on concentrations in mostly single samples from small numbers of women, have suggested that infant intake is safe. To better characterize infant intake and the associated potential benefits and risks, AZI was measured by liquid chromatography-mass spectrometry in four breast milk samples taken over 28 days postpartum from each of 20 Gambian women given 2 g AZI during labor. A population pharmacokinetic model utilizing published parameters for AZI disposition in pregnancy, the present breast milk concentrations, and increasing/decreasing sigmoid maximum-effect (E_max) functions adequately described temporal changes in the milk/plasma ratio. The median estimated absolute and relative cumulative infant doses were 4.5 mg/kg of body weight (95% prediction interval, 0.6 to 7.0 mg/kg) and 15.7% (95% prediction interval, 2.0 to 27.8%) of the maternal dose, respectively; the latter exceeded the recommended 10% safety limit. Although some infants with bacterial infections may benefit from AZI in breast milk, there is a risk of hypertrophic pyloric stenosis with a worst-case number needed to harm of 60 based on the present and available epidemiologic data. (This study has been registered at ClinicalTrials.gov under registration no. NCT01800942.)     

Molecular epidemiology of human liver cancer: insights into etiology, pathogenesis and prevention from The Gambia, West Africa

Human liver cancer, primarily hepatocellular carcinoma (HCC), is both common and lethal. Notable variation in HCC incidence rates worldwide corresponds to the prevalence and pattern of the primary etiologic factors. In summary of decades of collaborative research centered in The Gambia, West Africa, this review explores the independent and combined effects of hepatitis B virus (HBV), hepatitis C virus (HCV) and dietary aflatoxin exposure in the etiology of HCC. Through population surveys, field trials and a series of HCC case-control studies, the patterns and natural history of HBV, HCV and aflatoxin exposures have been defined within this population. These investigations have paralleled and informed the development of molecular biomarkers of these etiologic agents and contributed to understanding the complex mechanisms involved in hepatocarcinogenesis. We discuss preventive approaches to reduce the global burden of HCC, emphasizing The Gambia Hepatitis Intervention Study, a countrywide randomized controlled trial designed to document the efficacy of HB vaccination in preventing HBV infections and HBV-related HCC. By recognizing the synergy of applying molecular techniques to population-based epidemiological studies, the portfolio of Gambian research projects presented provides a model for partnering etiologic and mechanistic investigations with applied research.