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1.  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.
doi:10.1186/s12982-014-0022-3
PMCID: PMC4312604  PMID: 25642277
Non-specific vaccine effects; Measles; DTP; Nasopharyngeal bacterial carriage
2.  Broad Adaptive Immune Responses to M. tuberculosis Antigens Precede TST Conversion in Tuberculosis Exposed Household Contacts in a TB-Endemic Setting 
PLoS ONE  2014;9(12):e116268.
Background
The identification of Mycobacterium-tuberculosis (Mtb) infected individuals remains a challenge due to an insufficient understanding of immune responses detected with the current diagnostic tests for latent tuberculosis i.e. the tuberculin skin test (TST) or IFN–γ release assays (IGRAs) and an inability to distinguish infection stages with current immunologic assays. Further classification based on markers other than IFN–γ may help to define markers of early Mtb infection.
Methods
We assessed the TST status of Mtb-exposed household contacts at baseline and at 6 months. Contacts were classified into those with initial positive TST (TST+); those with baseline negative TST but TST conversion at 6 months (TST converters, TSTC) and those with persistently negative TST (PTST−). We assessed their short- and long-term immune responses to PPD and ESAT–6/CFP–10 (EC) via IFN–γ ELISPOT and a multiplex cytokine array in relation to TST status and compared them to those of TB cases to identify immune profiles associated with a spectrum of infection stages.
Results
After 1 and 6 days stimulation with EC, 12 cytokines (IFN–γ, IL–2, IP–10, TNF–α, IL–13, IL–17, IL–10, GMCSF, MIP–1β, MCP–3, IL–2RA and IL–1A) were not different in TSTC compared to TST+ suggesting that robust adaptive Mtb-specific immune responses precede TST conversion. Stratifying contacts by baseline IFN–γ ELISPOT to EC in combination with TST results revealed that IP–10 and IL–17 were highest in the group of TST converters with positive baseline ELISPOT, suggesting they might be markers for recent infection.
Conclusion
We describe a detailed analysis of Mtb-specific biomarker profiles in exposed household contacts in a TB endemic area that provides insights into the dynamic immune responses to Mtb infection and may help to identify biomarkers for ‘at-risk’ populations beyond TST and IGRA.
doi:10.1371/journal.pone.0116268
PMCID: PMC4280211  PMID: 25549338
4.  Community-based scheduled screening and treatment of malaria in pregnancy for improved maternal and infant health in The Gambia, Burkina Faso and Benin: study protocol for a randomized controlled trial 
Trials  2014;15(1):340.
Background
In sub-Saharan Africa, malaria continues to cause over 10,000 maternal deaths and 75,000 to 200,000 infant deaths. Successful control of malaria in pregnancy could save lives of mothers and babies and is an essential part of antenatal care in endemic areas. The primary objective is to determine the protective efficacy of community-scheduled screening and treatment (CSST) using community health workers (CHW) against the primary outcome of prevalence of placental malaria. The secondary objectives are to determine the protective efficacy of CSST on maternal anaemia, maternal peripheral infection, low birth weight, selection of sulfadoxine-pyrimethamine (SP) resistance markers, and on antenatal clinic (ANC) attendance and coverage of intermittent preventive treatment during pregnancy (IPTp-SP).
Methods/design
This is a multi-centre cluster-randomised controlled trial involving three countries with varying malaria endemicity; low (The Gambia) versus high transmission (Burkina Faso and Benin), and varying degrees of SP resistance (high in Benin and moderate in Gambia and Burkina Faso). CHW and their related catchment population who are randomised into the intervention arm will receive specific training on community-based case management of malaria in pregnancy. All women in both study arms will be enrolled at their first ANC visits in their second trimester where they will receive their first dose of IPTp-SP. Thereafter, CHW in the intervention arm will perform scheduled monthly screening and treatment in the womens homes. At time of delivery, a placental biopsy will be collected from all women to determine placental malaria. At each contact point, filter paper and blood slides will be collected for detection of malaria infection and SP resistance markers.
Discussion
To reach successful global malaria control, there is an urgent need to access those at greatest risk of malaria infection. The project is designed to develop a low-cost intervention in pregnant women which will have an immediate impact on the malaria burden in resource-limited countries. This will be done by adding to the standard IPTp-SP delivered through the health facilities: an “extension” strategy to the communities in rural areas thus bringing health services closer to where women live.
Trial registration
Current Controlled Trials: ISRCTN37259296 (5 July 2013), and clinicaltrials.gov: NCT01941264 (10 September 2013).
doi:10.1186/1745-6215-15-340
PMCID: PMC4156609  PMID: 25169073
Malaria; Pregnancy; Community based treatment; Rapid diagnostic tests; Sulfadoxine-pyrimethamine; Sub-Saharan Africa; Artemether-lumefantrine
5.  Multimedia Informed Consent Tool for a Low Literacy African Research Population: Development and Pilot-Testing 
Background
International guidelines recommend the use of appropriate informed consent procedures in low literacy research settings because written information is not known to guarantee comprehension of study information.
Objectives
This study developed and evaluated a multimedia informed consent tool for people with low literacy in an area where a malaria treatment trial was being planned in The Gambia.
Methods
We developed the informed consent document of the malaria treatment trial into a multimedia tool integrating video, animations and audio narrations in three major Gambian languages. Acceptability and ease of use of the multimedia tool were assessed using quantitative and qualitative methods. In two separate visits, the participants’ comprehension of the study information was measured by using a validated digitised audio questionnaire.
Results
The majority of participants (70%) reported that the multimedia tool was clear and easy to understand. Participants had high scores on the domains of adverse events/risk, voluntary participation, study procedures while lowest scores were recorded on the question items on randomisation. The differences in mean scores for participants’ ‘recall’ and ‘understanding’ between first and second visits were statistically significant (F (1,41)=25.38, p<0.00001 and (F (1, 41) = 31.61, p<0.00001 respectively.
Conclusions
Our locally developed multimedia tool was acceptable and easy to administer among low literacy participants in The Gambia. It also proved to be effective in delivering and sustaining comprehension of study information across a diverse group of participants. Additional research is needed to compare the tool to the traditional consent interview, both in The Gambia and in other sub-Saharan settings.
doi:10.4172/2155-9627.1000178
PMCID: PMC4133653  PMID: 25133065
Informed consent; Video; Technology; Vulnerable population; Development; The Gambia
6.  Knowing who to trust: exploring the role of ‘ethical metadata’ in mediating risk of harm in collaborative genomics research in Africa 
BMC Medical Ethics  2014;15:62.
Background
The practice of making datasets publicly available for use by the wider scientific community has become firmly integrated in genomic science. One significant gap in literature around data sharing concerns how it impacts on scientists’ ability to preserve values and ethical standards that form an essential component of scientific collaborations. We conducted a qualitative sociological study examining the potential for harm to ethnic groups, and implications of such ethical concerns for data sharing. We focused our empirical work on the MalariaGEN Consortium, one of the first international collaborative genomics research projects in Africa.
Methods
We conducted a study in three MalariaGEN project sites in Kenya, the Gambia, and the United Kingdom. The study entailed analysis of project documents and 49 semi-structured interviews with fieldworkers, researchers and ethics committee members.
Results
Concerns about how best to address the potential for harm to ethnic groups in MalariaGEN crystallised in discussions about the development of a data sharing policy. Particularly concerning for researchers was how best to manage the sharing of genomic data outside of the original collaboration. Within MalariaGEN, genomic data is accompanied by information about the locations of sample collection, the limitations of consent and ethics approval, and the values and relations that accompanied sample collection. For interviewees, this information and context were of important ethical value in safeguarding against harmful uses of data, but is not customarily shared with secondary data users. This challenged the ability of primary researchers to protect against harmful uses of ‘their’ data.
Conclusion
We identified three protective mechanisms – trust, the existence of a shared morality, and detailed contextual understanding – which together might play an important role in preventing the use of genomic data in ways that could harm the ethnic groups included in the study. We suggest that the current practice of sharing of datasets as isolated objects rather than as embedded within a particular scientific culture, without regard for the normative context within which samples were collected, may cause ethical tensions to emerge that could have been prevented or addressed had the ‘ethical metadata’ that accompanies genomic data also been shared.
doi:10.1186/1472-6939-15-62
PMCID: PMC4146449  PMID: 25124199
Data sharing; Genomics; Africa; MalariaGEN; Ethnic stigmatisation; Secondary use; Ethics; Ethnic groups
7.  A comparative case control study of the determinants of clinical malaria in The Gambia 
Malaria Journal  2014;13(1):306.
Background
The massive deployment of life saving malaria interventions has not only resulted in a decline in disease burden but a change in the risk of infection and disease. The study reassesses the importance of known risk factors and reviews demographic and socio-economic determinants of malaria risk in the population.
Methods
This was a case-control study involving 150 children with test-confirmed malaria infection recruited from the outpatient clinics of three health facilities (cases) in the Greater Banjul area, The Gambia. One hundred and fifty controls, negative for malaria were matched on age, residence. Information was collected from respondents on the use of long lasting insecticidal nets, occupation, housing structure, knowledge of malaria and socio-demographic factors.
Results
The mean age of study participants was 6.8 (SD 3.3) years with 147 (49%) being males. Significant determinants of malaria risk were parent’s occupation: mother as trader (OR 0.18, 95% CI 0.04 - 0.73, p = 0.017), father as trader (OR 0.02, 95% CI 0.002- 0.193, p = 0.001), civil servants (OR 0.04, 95% CI 0.008- 0.257, p =0.001) or handyman (OR 0.03, 95% CI 0.005- 0.182, p < 0.001). Children sleeping in rooms with windowpanes had a 76% reduction in their odds of malaria (OR 0.24, 95%CI 0.07- 0.82, p = 0.022.
Conclusion
Household socio-economic status plays an important role in management of illnesses. The ability of mothers to engage in an occupation increases household resources to access healthcare and on time. The balance between the type of mother’s occupation and her time available to supervise the child is an interesting emerging issue that needs further investigation.
doi:10.1186/1475-2875-13-306
PMCID: PMC4248480  PMID: 25106080
Malaria; Risk; Socio-economic
8.  A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine 
BMC Medicine  2014;12:117.
Background
The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria.
Methods
Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.
Results
Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.
Conclusions
Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
doi:10.1186/s12916-014-0117-2
PMCID: PMC4227280  PMID: 25012228
Malaria; Vaccine; Circumsporozoite protein; Antibody; RTS,S; Phase 2 clinical trials; Mathematical model; Clinical immunity
9.  Digitised audio questionnaire for assessment of informed consent comprehension in a low-literacy African research population: development and psychometric evaluation 
BMJ Open  2014;4(6):e004817.
Objective
To develop and psychometrically evaluate an audio digitised tool for assessment of comprehension of informed consent among low-literacy Gambian research participants.
Setting
We conducted this study in the Gambia where a high illiteracy rate and absence of standardised writing formats of local languages pose major challenges for research participants to comprehend consent information. We developed a 34-item questionnaire to assess participants’ comprehension of key elements of informed consent. The questionnaire was face validated and content validated by experienced researchers. To bypass the challenge of a lack of standardised writing formats, we audiorecorded the questionnaire in three major Gambian languages: Mandinka, Wolof and Fula. The questionnaire was further developed into an audio computer-assisted interview format.
Participants
The digitised questionnaire was administered to 250 participants enrolled in two clinical trials in the urban and rural areas of the Gambia. One week after first administration, the questionnaire was readministered to half of the participants who were randomly selected. Participants were eligible if enrolled in the parent trials and could speak any of the three major Gambian languages.
Outcome measure
The primary outcome measure was reliability and validity of the questionnaire.
Results
Item reduction by factor analysis showed that 21 of the question items have strong factor loadings. These were retained along with five other items which were fundamental components of informed consent. The 26-item questionnaire has high internal consistency with a Cronbach's α of 0.73–0.79 and an intraclass correlation coefficient of 0.94 (95% CI 0.923 to 0.954). Hypotheses testing also showed that the questionnaire has a positive correlation with a similar questionnaire and discriminates between participants with and without education.
Conclusions
We have developed a reliable and valid measure of comprehension of informed consent information for the Gambian context, which might be easily adapted to similar settings. This is a major step towards engendering comprehension of informed consent information among low-literacy participants.
doi:10.1136/bmjopen-2014-004817
PMCID: PMC4078776  PMID: 24961716
Ethics (see Medical Ethics); Medical Ethics
10.  LOW-LEVEL MALARIA INFECTIONS DETECTED BY A SENSITIVE POLYMERASE CHAIN REACTION ASSAY AND USE OF THIS TECHNIQUE IN THE EVALUATION OF MALARIA VACCINES IN AN ENDEMIC AREA 
The feasibility of using a sensitive polymerase chain reaction (PCR) to evaluate malaria vaccines in small group sizes was tested in 102 adult Gambian volunteers who received either the malaria vaccine regimen FP9 ME-TRAP/MVA ME-TRAP or rabies vaccine. All volunteers received the antimalarial drugs primaquine and Lapdap plus artesunate to eliminate malaria parasites. Volunteers in a further group received an additional single treatment with sulfadoxine-pyrimethamine (SP) to prevent new infections. There was substantially lower T-cell immunogenicity than in previous trials with this vaccine regimen and no protection against infection in the malaria vaccine group. Using the primary endpoint of 20 parasites per mL, no difference was found in the prevalence of low-level infections in volunteers who received SP compared with those who did not, indicating that SP did not reduce the incidence of very low-density infection. However, SP markedly reduced the incidence of higher density infections. These findings support the feasibility and potential of this approach to screen pre-erythrocytic vaccines for efficacy against infection in small numbers of vaccinees in endemic areas.
PMCID: PMC3836239  PMID: 17360872
11.  Changes in Malaria Parasite Drug Resistance in an Endemic Population Over a 25-Year Period With Resulting Genomic Evidence of Selection 
The Journal of Infectious Diseases  2013;209(7):1126-1135.
Background. Analysis of genome-wide polymorphism in many organisms has potential to identify genes under recent selection. However, data on historical allele frequency changes are rarely available for direct confirmation.
Methods. We genotyped single nucleotide polymorphisms (SNPs) in 4 Plasmodium falciparum drug resistance genes in 668 archived parasite-positive blood samples of a Gambian population between 1984 and 2008. This covered a period before antimalarial resistance was detected locally, through subsequent failure of multiple drugs until introduction of artemisinin combination therapy. We separately performed genome-wide sequence analysis of 52 clinical isolates from 2008 to prospect for loci under recent directional selection.
Results. Resistance alleles increased from very low frequencies, peaking in 2000 for chloroquine resistance-associated crt and mdr1 genes and at the end of the survey period for dhfr and dhps genes respectively associated with pyrimethamine and sulfadoxine resistance. Temporal changes fit a model incorporating likely selection coefficients over the period. Three of the drug resistance loci were in the top 4 regions under strong selection implicated by the genome-wide analysis.
Conclusions. Genome-wide polymorphism analysis of an endemic population sample robustly identifies loci with detailed documentation of recent selection, demonstrating power to prospectively detect emerging drug resistance genes.
doi:10.1093/infdis/jit618
PMCID: PMC3952670  PMID: 24265439
resistance monitoring; population genetics; genomic surveillance; archival analysis; policy and practice
12.  Five-year safety and immunogenicity of GlaxoSmithKline’s candidate malaria vaccine RTS,S/AS02 following administration to semi-immune adult men living in a malaria-endemic region of The Gambia 
Human vaccines  2009;5(4):242-247.
RTS,S is a pre-erythrocytic malaria vaccine candidate antigen based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a novel Adjuvant System (AS02). The first field efficacy of RTS,S/AS02 against infection was demonstrated in a trial initiated in The Gambia in 1998. This paper presents the five-year safety and immunogenicity follow up of the 306 men who were enrolled in the original trial.
In the primary study men aged 18 to 45 years were randomized to receive either RTS,S/AS02 or rabies vaccine at 0, 1, 5 months followed by a booster dose at month 19. The subjects were observed for long term safety and immunogenicity continuously until month 58.
Of the 153 subjects in each group at enrollment, 80 (52%) subjects in the RTS,S/AS02 group and 83 (54%) subjects in the rabies group returned for the final long-term follow-up visit at month 58. The main reason for non-attendance at month 58 was migration (76% of all drop-outs). Nine subjects in the RTS,S/AS02 group and seven in the rabies group experienced serious adverse events (SAEs) over the 58 month surveillance period, of which seven had a fatal outcome (five RTS,S/AS02 and two rabies group). None of the SAEs with fatal outcome were attributed to the study vaccine. Anti-CS antibody persistence compared to control was observed for five years, although titres had waned from post-booster levels; similar responses in anti-HBs antibody persistence were observed in initially HBsAg seronegative subjects.
This study provides the first indication of the long-term safety and persistence of anti-CS and anti-HBs antibodies of the RTS,S vaccine candidate in combination with the novel AS02 Adjuvant System.
PMCID: PMC3787299  PMID: 19276646
malaria vaccine; RTS,S; five-year follow-up; long term persistence of anti-HBs; AS02 adjuvant system
13.  Nasopharyngeal Carriage of Pneumococci Four Years after Community-Wide Vaccination with PCV-7 in The Gambia: Long-Term Evaluation of a Cluster Randomized Trial 
PLoS ONE  2013;8(9):e72198.
Background
A village-randomized trial of a seven-valent pneumococcal-conjugate-vaccine (PCV-7) conducted in rural Gambia showed a decrease of vaccine-type (VT) and a non-significant increase in non-vaccine-type (NVT) nasopharyngeal carriage of pneumococci two years after vaccination. Here, we report findings four years after vaccination.
Methods
PCV-7 was given to all children below 30 months of age enrolled in the trial and to those born during its course in all study villages. Villages were randomized (older children and adults) to receive PCV-7 (wholly vaccinated villages) or serogroup-C-meningococcal-conjugate-vaccine (partly vaccinated villages). Cross-sectional surveys (CSS) to collect nasopharyngeal swabs were conducted before and at various intervals after vaccination. Sixteen of these randomized villages (8 wholly vaccinated and 8 partly vaccinated) participated in a CSS conducted four years after vaccination started.
Results
Four years after vaccination, the prevalence of VT pneumococcal carriage was slightly higher in partly than in wholly vaccinated villages [6.4% versus 3.9% (p = 0.120)] compared to 24.4% in the pre-vaccination CSS (p<0.001). Prevalence of NVT four years after vaccination was similar between study groups [32.7% versus 29.8% (p = 0.392), respectively] compared to 51.1% in the pre-vaccination CSS (p<0.001). Four years after vaccination started, lower prevalence of serotype 6A was detected in wholly vaccinated than in partly vaccinated villages (1.6% versus 3.5%, p = 0.093) whilst the prevalence of serotype 19A was similar between groups (2.9% versus 2.5%, p = 0.779). The most prevalent serotype 19A clone was ST 847. The most prevalent serotype 6A clone before vaccination was ST3324 whilst after vaccination ST913 and ST1737 predominated. Fourteen out of 26 STs detected among the serotype 6A isolates were new while no new 19A serotype ST was found.
Conclusions
The decline in prevalence of VT pneumococci seen shortly after PCV-7 vaccination was sustained four years later with only a small difference between study arms. No significant serotype replacement was detected.
Trial Registration
ClinicalTrials.gov ISRCTN51695599
doi:10.1371/journal.pone.0072198
PMCID: PMC3785494  PMID: 24086259
14.  Comparison of the Prevalence of Common Bacterial Pathogens in the Oropharynx and Nasopharynx of Gambian Infants 
PLoS ONE  2013;8(9):e75558.
Background
CRM- based pneumococcal conjugate vaccines generally have little impact on the overall prevalence of pneumococcal carriage because of serotype replacement. In contrast, protein vaccines could substantially reduce the overall prevalence of pneumococcal carriage with potential microbiological and clinical consequences. Therefore, trials of pneumococcal protein vaccines need to evaluate their impact on carriage of other potentially pathogenic bacteria in addition to the pneumococcus.
Methods
As a prelude to a trial of an investigational pneumococcal vaccine containing pneumococcal polysaccharide conjugates and pneumococcal proteins, the prevalence of carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella species and Staphylococcus aureus in the nasopharynx of 1030 Gambian infants (median age 35 weeks) was determined. An oropharyngeal swab was obtained at the same time from the first 371 infants enrolled. Standard microbiological techniques were used to evaluate the bacterial flora of the pharynx and to compare that found in the oropharynx and in the nasopharynx.
Results
The overall pneumococcal carriage rate was high. Isolation rates of S. pneumoniae and Moraxella species were significantly higher using nasopharyngeal rather than oropharyngeal swabs (76.1% [95% CI 73.4%,78.7%] vs. 21.3% [95% CI 17.2%,25.8%] and 48.9% [95% CI 45.8%, 52.0%] vs. 20.5% % [95% CI 16.5%,25.0%] respectively). In contrast, S. aureus and H. influenzae were isolated more frequently from oropharyngeal than from nasopharyngeal swabs (65.0% [95% CI 59.9%, 69.8%] vs. 33.6% [95% CI 30.7%, 36.5%] and 31.8% [95% CI 16.5%, 25.0%] vs. 22.4% [95% CI 19.9%, 25.1%] respectively). No group A β haemolytic streptococci were isolated.
Conclusion
Collection of an oropharyngeal swab in addition to a nasopharyngeal swab will provide little additional information on the impact of a novel pneumococcal vaccine on pneumococcal carriage but it might provide additional, valuable information on the impact of the vaccine on the overall microbiota of the pharynx.
doi:10.1371/journal.pone.0075558
PMCID: PMC3781055  PMID: 24086570
15.  Association between Ocular Bacterial Carriage and Follicular Trachoma Following Mass Azithromycin Distribution in The Gambia 
Background
Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindess, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs.
Methodology/Principal Findings
We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communitites. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32–81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03–4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53–14.5, p = 0.01).
Conclusions/Significance
Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration.
Author Summary
Trachoma, the world's leading infectious cause of blindness, is caused by ocular infection with the bacterium Chlamydia trachomatis. In low-prevalence settings and following mass treatment campaigns, clinically active follicular trachoma (TF) can be found in the absence of C. trachomatis infection. We carried out this study to investigate associations between ocular carriage of non-chlamydial pathogens and a clinical diagnosis of TF following a mass treatment campaign in The Gambia. We found that children who carried Streptococcus pneumoniae or Haemophilus influenza in their eyes were more likely to have been diagnosed with TF than children who did not carry these pathogens. In The Gambia, non-chlamydial pathogens may be inducing or exacerbating TF in the absence of C. trachomatis infection.
doi:10.1371/journal.pntd.0002347
PMCID: PMC3723595  PMID: 23936573
16.  Seroepidemiological and parasitological evaluation of the heterogeneity of malaria infection in the Gambia 
Malaria Journal  2013;12:222.
Background
As countries make progress in malaria control, transmission may be reduced to such an extent that few cases occur, and identification of the remaining foci of transmission may require a combination of surveillance tools. The study explored the usefulness of parasite prevalence, seroprevalence and model-estimated seroconversion rates for detecting local differences in malaria transmission in a West African country.
Methods
Age-stratified cross-sectional surveys were conducted during the wet season in 2008 and the following dry season in 2009 in The Gambia. In each season, 20 village communities were sampled from six diverse areas throughout the country. A total of 7,586 participants were surveyed, 51% (3,870) during the wet season. Parasites were detected by thick film slide microscopy, and anti-MSP1-19 antibodies were detected by ELISA using eluted dried blood from filter papers.
Results
Overall parasite prevalence was 12.4% in the wet season and 2.2% in the dry season, with village-specific parasite prevalence ranging from 1.4 to 45.9% in the wet season and from 0.0 to 13.2% in the dry season. Prevalence was highest in the eastern part of the country. Serological indices also varied between villages, indicating local heterogeneity in transmission, and there was a high correlation between wet and dry season estimates across the villages. The overall prevalence of anti-MSP119 antibodies was similar in the wet (19.5%) and in the dry (19.6%) seasons.
Conclusion
The study illustrates the utility of measuring both parasite prevalence and serological indices for monitoring local variation in malaria transmission, which are more informative than single measures as control intensifies and malaria declines. Measurements of seropositivity have the logistical advantage of being relative stable seasonally so that sampling at any time of year may be conducted.
doi:10.1186/1475-2875-12-222
PMCID: PMC3701490  PMID: 23815826
Evaluation; Microheterogeneity; Plasmodium falciparum; Parasite prevalence; Serology; The Gambia
18.  Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations 
PLoS Genetics  2013;9(5):e1003509.
Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP–based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.
Author Summary
Malaria kills nearly a million people every year, most of whom are young children in Africa. The risk of developing severe malaria is known to be affected by genetics, but so far only a handful of genetic risk factors for malaria have been identified. We studied over a million DNA variants in over 5,000 individuals with severe malaria from the Gambia, Malawi, and Kenya, and about 7,000 healthy individuals from the same countries. Because the populations of Africa are far more genetically diverse than those in Europe, it is necessary to use statistical models that can account for both broad differences between countries and subtler differences between ethnic groups within the same community. We identified known associations at the genes ABO (which affects blood type) and HBB (which causes sickle cell disease), and showed that the latter is heterogeneous across populations. We used these findings to guide the development of statistical tests for association that take this heterogeneity into account, by modelling differences in the strength and genomic location of effect across and within African populations.
doi:10.1371/journal.pgen.1003509
PMCID: PMC3662650  PMID: 23717212
19.  Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in Healthy Gambian and Kenyan Adults 
PLoS ONE  2013;8(3):e57726.
Background
Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI).
Methodology
We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.
Results
ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC).
Conclusions
ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.
Trial Registration
Pactr.org PACTR2010020001771828
Pactr.org PACTR201008000221638
ClinicalTrials.gov NCT01373879 NCT01373879
ClinicalTrials.gov NCT01379430 NCT01379430
doi:10.1371/journal.pone.0057726
PMCID: PMC3602521  PMID: 23526949
20.  Mortality Patterns and Site Heterogeneity of Severe Malaria in African Children 
PLoS ONE  2013;8(3):e58686.
Background
In this study we aimed to assess site heterogeneity of early, intermediate, and late mortality prediction in children with severe Plasmodium falciparum malaria in sub-Saharan Africa.
Methods
Medical records of 26,036 children admitted with severe Plasmodium falciparum malaria in six hospital research centers between December 2000 to May 2005 were analyzed. Demographic, clinical and laboratory data of children who died within 24 hours (early), between 24 and 47 hours (intermediate) and thereafter (48 hours or later, late mortality) were compared between groups and survivors.
Results
Overall mortality was 4·3% (N = 1,129). Median time to death varied across sites (P<0·001), ranging from 8h (3h–52h) in Lambaréné to 40h (10h–100h) in Kilifi. Fifty-eight percent of deaths occurred within 24 hours and intermediate and late mortality rate were 19% and 23%, respectively. Combining all sites, deep breathing, prostration and hypoglycemia were independent predictors for early, intermediate and late mortality (P<0·01). Site specific independent predictors for early death included prostration, coma and deep breathing at all sites (P<0·001). Site specific independent predictors for intermediate and late death largely varied between sites (P<0·001) and included between 1 and 7 different clinical and laboratory variables.
Conclusion
Site heterogeneity for mortality prediction is evident in African children with severe malaria. Prediction for early mortality has the highest consistency between sites.
doi:10.1371/journal.pone.0058686
PMCID: PMC3591404  PMID: 23505549
21.  Sahel, Savana, Riverine and Urban Malaria in West Africa: Similar Control Policies with Different Outcomes 
Acta Tropica  2011;121(3):166-174.
The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and are located within 750 km of each other. In addition, the National Malaria Control Programmes of these countries have virtually identical policies: 1] Artemisinin Combination Therapies (ACTs) for the treatment of symptomatic Plasmodium falciparum infection, 2] Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce the Entomololgic Inoculation Rate (EIR) and 3] Sulfadoxine-Pyrimethamine for the Intermittent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparum malaria and the status of malaria control vary markedly across the four sites with differences in the duration of the transmission season (from 4–5 to 10–11 months), the intensity of transmission (with EIRs from unmeasurably low to 4–5 per person per month), multiplicity of infection (from a mean of 1.0 to means of 2–5) and the status of malaria control (from areas which have virtually no control to areas that are at the threshold of malaria elimination). The most important priority is the need to obtain comparable data on the population-based prevalence, incidence and transmission of malaria before new candidate interventions or combinations of interventions are introduced for malaria control.
doi:10.1016/j.actatropica.2011.11.005
PMCID: PMC3294051  PMID: 22119584
Artemisinin combination therapies; Long-lasting insecticide treated bed nets: Entomologic inoculation rate; Intermittent preventive treatment of malaria during pregnancy; transmission intensity; multiplicity of infection
22.  Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data 
The Lancet Infectious Diseases  2013;13(4):319-327.
Summary
Background
The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data.
Methods
We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2–10 years (PrP2–10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02.
Findings
Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP2–10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2–10 20%) it was 41% (21 to 57), and at high transmission (PrP2–10 70%) the efficacy was 4% (−10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)—eg, at low transmission (PrP2–10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (−38 to 38) after 3 years.
Interpretation
Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination.
Funding
Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust.
doi:10.1016/S1473-3099(13)70005-7
PMCID: PMC3771416  PMID: 23454164
23.  Malaria in infants aged less than six months - is it an area of unmet medical need? 
Malaria Journal  2012;11:400.
Despite the protection provided by several factors, including maternal antibodies, the burden of malaria in young infants may be higher than previously thought. Infants with congenital or neonatal malaria may have a different clinical presentation than older children, and diagnosis may be confused with other neonatal diseases due to an overlap of clinical manifestations. In addition, there is little information on the use of artemisinin-based combination therapy in young infants. There is the need for a more accurate estimate of the parasite prevalence and the incidence of clinical malaria in infants under 6 months old, as well as a better characterization of risk factors, pharmacokinetic profiles, safety and efficacy of currently available anti-malarial treatments, in order to develop evidence-based treatment guidelines for this population.
doi:10.1186/1475-2875-11-400
PMCID: PMC3529680  PMID: 23198986
Malaria; Neonate; Congenital; Prevalence; Parasitaemia; Artemisinin-based combination therapy
24.  Indirect Effect of 7-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Newborns in Rural Gambia: A Randomised Controlled Trial 
PLoS ONE  2012;7(11):e49143.
Background
Gambian infants frequently acquire Streptococcus pneumoniae soon after birth. We investigated the indirect effect of 7-valent pneumococcal conjugate vaccine (PCV-7) on pneumococcal acquisition in newborn Gambian babies.
Methods
Twenty-one villages were randomised to receive PCV-7 to all subjects (11 vaccinated villages) or to infants aged 2–30 months (10 control villages). Other control villagers received Meningococcal C conjugate vaccine. From 328 babies born during the trial, nasopharyngeal swabs were collected after birth, then weekly until 8 weeks of age when they received their first dose of PCV-7. Pneumococcal carriage and acquisition rates were compared between the study arms and with a baseline study.
Results
57.4% of 2245 swabs were positive for S. pneumoniae. Overall carriage was similar in both arms. In vaccinated villages fewer infants carried pneumococci of vaccine serotypes (VT) (16.9% [31/184] vs. 37.5% [54/144], p<0.001) and more carried pneumococci of non-vaccine serotypes (NVT) (80.9% [149/184] vs. 75.7% [109/144], p = 0.246). Infants from vaccinated villages had a significantly lower acquisition rate of VT (HR 0.39 [0.26–0.58], p<0.001) and increased acquisition of NVT (HR 1.16 [0.87–1.56], p = 0.312). VT carriage (51.6% vs. 37.5%, p = 031 in control and 46.1% vs. 16.8%, p<0.001 in vaccinated villages) and acquisition rates (HR 0.68 [0.50–0.92], p = 0.013 in control villages and HR 0.31 [0.19–0.50], p<.001 in vaccinated villages) were significantly lower in both study arms than in the baseline study. NVT carriage (63.2% vs. 75.7%, p = 0.037 in control and 67.2% vs. 75.3%, p = 0.005 in vaccinated villages) and acquisition rates (HR 1.48 [1.06–2.06], p = 0.022) and (HR 1.52 [1.11–2.10], p = 0.010 respectively) were significantly higher.
Conclusion
PCV-7 significantly reduced carriage of VT pneumococci in unvaccinated infants. This indirect effect likely originated from both the child and adult vaccinated populations. Increased carriage of NVT pneumococci needs ongoing monitoring.
Trial Registration
ISRCTN Register 51695599
doi:10.1371/journal.pone.0049143
PMCID: PMC3504064  PMID: 23185303
25.  Clinical Features of Severe Malaria Associated with Death: A 13-Year Observational Study in The Gambia 
PLoS ONE  2012;7(9):e45645.
Background
Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management.
Methods
A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in The Gambia to identify sensitive and specific predictors of poor outcome in Gambian children with severe malaria between the ages 4 months to 14 years. We have measured the sensitivity and specificity of clinical features that predict death or development of neurological sequelae.
Findings
Impaired consciousness (odds ratio {OR} 4.4 [95% confidence interval {CI}, 2.7–7.3]), respiratory distress (OR 2.4 [95%CI, 1.7–3.2]), hypoglycemia (OR 1.7 [95%CI, 1.2–2.3]), jaundice (OR 1.9 [95%CI, 1.2–2.9]) and renal failure (OR 11.1 [95%CI, 3.3–36.5]) were independently associated with death in children with SM. The clinical features that showed the highest sensitivity and specificity to predict death were respiratory distress (area under the curve 0.63 [95%CI, 0.60–0.65]) and impaired consciousness (AUC 0.61[95%CI, 0.59–0.63]), which were comparable to the ability of hyperlactatemia (blood lactate>5 mM) to predict death (AUC 0.64 [95%CI, 0.55–0.72]). A Blantyre coma score (BCS) of 2 or less had a sensitivity of 74% and specificity of 67% to predict death (AUC 0.70 [95% C.I. 0.68–0.72]), and sensitivity and specificity of 74% and 69%, respectively to predict development of neurological sequelae (AUC 0.72 [95% CI, 0.67–0.76]).The specificity of this BCS threshold to identify children at risk of dying improved in children less than 3 years of age (AUC 0.74, [95% C.I 0.71–0.76]).
Conclusion
The BCS is a quantitative predictor of death. A BCS of 2 or less is the most sensitive and specific clinical feature to predict death or development of neurological sequelae in children with SM.
doi:10.1371/journal.pone.0045645
PMCID: PMC3460946  PMID: 23029157

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