[Show abstract][Hide abstract] ABSTRACT: Background:
Insecticide treated nets (ITNs) and indoor residual spraying (IRS) have been scaled up for malaria prevention in sub-Saharan Africa. However, there are few studies on the benefit of implementing IRS in areas with moderate to high coverage of ITNs. We evaluated the impact of an IRS program on malaria related outcomes in western Kenya, an area of intense perennial malaria transmission and moderate ITN coverage (55-65% use of any net the previous night).
The Kenya Division of Malaria Control, with support from the US President's Malaria Initiative, conducted IRS in one lowland endemic district with moderate coverage of ITNs. Surveys were conducted in the IRS district and a neighboring district before IRS, after one round of IRS in July-Sept 2008 and after a second round of IRS in April-May 2009. IRS was conducted with pyrethroid insecticides. At each survey, 30 clusters were selected for sampling and within each cluster, 12 compounds were randomly selected. The primary outcomes measured in all residents of selected compounds included malaria parasitemia, clinical malaria (P. falciparum infection plus history of fever) and anemia (Hb<8) of all residents in randomly selected compounds. At each survey round, individuals from the IRS district were matched to those from the non-IRS district using propensity scores and multivariate logistic regression models were constructed based on the matched dataset.
At baseline and after one round of IRS, there were no differences between the two districts in the prevalence of malaria parasitemia, clinical malaria or anemia. After two rounds of IRS, the prevalence of malaria parasitemia was 6.4% in the IRS district compared to 16.7% in the comparison district (OR = 0.36, 95% CI = 0.22-0.59, p<0.001). The prevalence of clinical malaria was also lower in the IRS district (1.8% vs. 4.9%, OR = 0.37, 95% CI = 0.20-0.68, p = 0.001). The prevalence of anemia was lower in the IRS district but only in children under 5 years of age (2.8% vs. 9.3%, OR = 0.30, 95% CI = 0.13-0.71, p = 0.006). Multivariate models incorporating both IRS and ITNs indicated that both had an impact on malaria parasitemia and clinical malaria but the independent effect of ITNs was reduced in the district that had received two rounds of IRS. There was no statistically significant independent effect of ITNs on the prevalence of anemia in any age group.
Both IRS and ITNs are effective tools for reducing malaria burden and when implemented in an area of moderate to high transmission with moderate ITN coverage, there may be an added benefit of IRS. The value of adding ITNs to IRS is less clear as their benefits may be masked by IRS. Additional monitoring of malaria control programs that implement ITNs and IRS concurrently is encouraged to better understand how to maximize the benefits of both interventions, particularly in the context of increasing pyrethroid resistance.
[Show abstract][Hide abstract] ABSTRACT: Background: An initial study of genetic diversity of Plasmodium falciparum in Asembo, western Kenya showed that the parasite maintained overall genetic stability 5 years after insecticide-treated bed net (ITN) introduction in 1997. This study investigates further the genetic diversity of P. falciparum 10 years after initial ITN introduction in the same study area and compares this with two other neighbouring areas, where ITNs were introduced in 1998 (Gem) and 2004 (Karemo).
Methods: From a cross-sectional survey conducted in 2007, 235 smear-positive blood samples collected from children ≤15-year-old in the original study area and two comparison areas were genotyped employing eight neutral microsatellites. Differences in multiple infections, allele frequency, parasite genetic diversity and parasite population structure between the three areas were assessed. Further, molecular data reported previously (1996 and 2001) were compared to the 2007 results in the original study area Asembo.
Results: Overall proportion of multiple infections (MA) declined with time in the original study area Asembo (from 95.9 %-2001 to 87.7 %-2007). In the neighbouring areas, MA was lower in the site where ITNs were introduced in 1998 (Gem 83.7 %) compared to where they were introduced in 2004 (Karemo 96.7 %) in 2007. Overall mean allele count (MAC ~ 2.65) and overall unbiased heterozygosity (He ~ 0.77) remained unchanged in 1996, 2001 and 2007 in Asembo and was the same level across the two neighbouring areas in 2007. Overall parasite population differentiation remained low over time and in the three areas at FST < 0.04. Both pairwise and multilocus linkage disequilibrium showed limited to no significant association between alleles in Asembo (1996, 2001 and 2007) and between three areas.
Conclusions: This study showed the P. falciparum high genetic diversity and parasite population resilience on samples collected 10 years apart and in different areas in western Kenya. The results highlight the need for long-term molecular monitoring after implementation and use of combined and intensive prevention and intervention measures in the region.
Keywords: Plasmodium falciparum, Population structure, Genetic diversity, ITNs, Transmission
[Show abstract][Hide abstract] ABSTRACT: Although it is well known that drug pressure selects for drug-resistant parasites, the role of transmission reduction by insecticide-treated bed nets (ITNs) on drug resistance remains unclear. In this study, the drug resistance profile of current and previous first-line anti-malarials in Kenya was assessed within the context of drug policy change and scale-up of ITNs. National first-line treatment changed from chloroquine (CQ) to sulphadoxine-pyrimethamine (SP) in 1998 and to artemether-lumefantrine (AL) in 2004. ITN use was scaled-up in the Asembo, Gem and Karemo areas of western Kenya in 1997, 1999 and 2006, respectively.
Smear-positive samples (N = 253) collected from a 2007 cross-sectional survey among children in Asembo, Gem and Karemo were genotyped for mutations in pfcrt and pfmdr1 (CQ), dhfr and dhps (SP), and at pfmdr-N86 and the gene copy number in pfmdr1 (lumefantrine). Results were compared among the three geographic areas in 2007 and to retrospective molecular data from children in Asembo in 2001.
In 2007, 69 and 85% of samples harboured the pfmdr1-86Y mutation and dhfr/dhps quintuple mutant, respectively, with no significant differences by study area. However, the prevalence of the pfcrt-76T mutation differed significantly among areas (p <0.02), between 76 and 94%, with the highest prevalence in Asembo. Several 2007 samples carried mutations at dhfr-164L, dhps-436A, or dhps-613T. From 2001 to 2007, there were significant increases in the pfcrt-76T mutation from 82 to 94% (p <0.03), dhfr/dhps quintuple mutant from 62 to 82% (p <0.03), and an increase in the septuple CQ and SP combined mutant haplotype, K 76 Y 86 I 51 R 59 N 108 G 437 E 540 , from 28 to 39%. The prevalence of the pfmdr1-86Y mutation remained unchanged. All samples were single copy for pfmdr1.
Molecular markers associated with lumefantrine resistance were not detected in 2007. More recent samples will be needed to detect any selective effects by AL. The prevalence of CQ and SP resistance markers increased from 2001 to 2007 in the absence of changes in transmission intensity. In 2007, only the prevalence of pfcrt-76T mutation differed among study areas of varying transmission intensity. Resistant parasites were most likely selected by sustained drug pressure from the continued use of CQ, SP, and mechanistically similar drugs, such as amodiaquine and cotrimoxazole. There was no clear evidence that differences in transmission intensity, as a result of ITN scale-up, influenced the prevalence of drug resistance molecular markers.
[Show abstract][Hide abstract] ABSTRACT: Background:
The artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce.
This was a prospective cohort study of women of child-bearing age carried out in 2011-2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used.
The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56-2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12-8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small.
ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.
[Show abstract][Hide abstract] ABSTRACT: Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. Methods We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. Results In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P = 0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P = 0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. Conclusions These Results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles.
Full-text · Article · Oct 2015 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.
Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.
RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity.
Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.
UK Medical Research Council.
[Show abstract][Hide abstract] ABSTRACT: Coverage of civil registration and vital statistics varies globally, with most deaths in Africa and Asia remaining either unregistered or registered without cause of death. One important constraint has been a lack of fit-for-purpose tools for registering deaths and assigning causes in situations where no doctor is involved. Verbal autopsy (interviewing care-givers and witnesses to deaths and interpreting their information into causes of death) is the only available solution. Automated interpretation of verbal autopsy data into cause of death information is essential for rapid, consistent and affordable processing.
Verbal autopsy archives covering 54 182 deaths from five African and Asian countries were sourced on the basis of their geographical, epidemiological and methodological diversity, with existing physician-coded causes of death attributed. These data were unified into the WHO 2012 verbal autopsy standard format, and processed using the InterVA-4 model. Cause-specific mortality fractions from InterVA-4 and physician codes were calculated for each of 60 WHO 2012 cause categories, by age group, sex and source. Results from the two approaches were assessed for concordance and ratios of fractions by cause category. As an alternative metric, the Wilcoxon matched-pairs signed ranks test with two one-sided tests for stochastic equivalence was used.
The overall concordance correlation coefficient between InterVA-4 and physician codes was 0.83 (95% CI 0.75 to 0.91) and this increased to 0.97 (95% CI 0.96 to 0.99) when HIV/AIDS and pulmonary TB deaths were combined into a single category. Over half (53%) of the cause category ratios between InterVA-4 and physician codes by source were not significantly different from unity at the 99% level, increasing to 62% by age group. Wilcoxon tests for stochastic equivalence also demonstrated equivalence.
These findings show strong concordance between InterVA-4 and physician-coded findings over this large and diverse data set. Although these analyses cannot prove that either approach constitutes absolute truth, there was high public health equivalence between the findings. Given the urgent need for adequate cause of death data from settings where deaths currently pass unregistered, and since the WHO 2012 verbal autopsy standard and InterVA-4 tools represent relatively simple, cheap and available methods for determining cause of death on a large scale, they should be used as current tools of choice to fill gaps in cause of death data.
Full-text · Article · Jun 2015 · Global journal of health science
[Show abstract][Hide abstract] ABSTRACT: Summary
Background The effi cacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have
been published previously. Herein, we report the fi nal results from the same trial, including the effi cacy of a booster dose.
Methods From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were
enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at fi rst
vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1,
and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at
month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were
followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection.
Serious adverse events (SAEs) were recorded. Analyses were by modifi ed intention to treat and per protocol. The
coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this fi nal
analysis, we present data for the effi cacy of the booster on the occurrence of malaria. Vaccine effi cacy (VE) against
clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction.
This trial is registered with ClinicalTrials.gov, number NCT00866619.
Findings 8922 children and 6537 young infants were included in the modifi ed intention-to-treat analyses. Children
were followed up for a median of 48 months (IQR 39–50) and young infants for 38 months (34–41) after dose 1. From
month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case defi nition in
children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8–40·5) and 7396 occurred
in the R3C group (28·3%, 23·3–32·9); compared with 171 children who experienced at least one episode of severe
malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%,
13·7 to 46·9) and 169 in the R3C group (1·1%, –23·0 to 20·5). In young infants, compared with 6170 episodes of
clinical malaria that met the primary case defi nition in the C3C group, 4993 episodes occurred in the R3R group (VE
25·9%, 95% CI 19·9–31·5) and 5444 occurred in the R3C group (18·3%, 11·7–24·4); and compared with 116 infants
who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode
of severe malaria in the R3R group (17·3%, 95% CI –9·4 to 37·5) and 104 in the R3C group (10·3%, –17·9 to 31·8).
In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387–2186) in the R3R group and
1363 per 1000 children (995–1797) in the R3C group. The numbers of cases averted per 1000 young infants were
983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was
balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the
R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01
booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children.
Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young
infants and children when administered with or without a booster dose. Effi cacy was enhanced by the administration of
a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria
control when used in combination with other eff ective control measures, especially in areas of high transmission.
[Show abstract][Hide abstract] ABSTRACT: Background:
Coverage of malaria in pregnancy interventions in sub-Saharan Africa is suboptimal. We undertook a systematic examination of the operational, socio-economic and cultural constraints to pregnant women's access to intermittent preventive treatment (IPTp), long-lasting insecticide-treated nets (LLINs) and case management in Kenya and Mali to provide empirical evidence for strategies to improve coverage.
Focus group discussions (FGDs) were held as part of a programme of research to explore the delivery, access and use of interventions to control malaria in pregnancy. FGDs were held with four sub-groups: non-pregnant women of child bearing age (aged 15-49 years), pregnant women or mothers of children aged <1 year, adolescent women, and men. Content analysis was used to develop themes and sub-themes from the data.
Women and men's perceptions of the benefits of antenatal care were generally positive; motivation among women consisted of maintaining a healthy pregnancy, disease prevention in mother and foetus, checking the position of the baby in preparation for delivery, and ensuring admission to a facility in case of complications. Barriers to accessing care related to the quality of the health provider-client interaction, perceived health provider skills and malpractice, drug availability, and cost of services. Pregnant women perceived themselves and their babies at particular risk from malaria, and valued diagnosis and treatment from a health professional, but cost of treatment at health facilities drove women to use herbal remedies or drugs bought from shops. Women lacked information on the safety, efficacy and side effects of antimalarial use in pregnancy.
Women in these settings appreciated the benefits of antenatal care and yet health services in both countries are losing women to follow-up due to factors that can be improved with greater political will. Antenatal services need to be patient-centred, free-of-charge or highly affordable and accountable to the women they serve.
[Show abstract][Hide abstract] ABSTRACT: Malaria is among the leading causes of mortality in the younger under-five group of children zero to four years of age. This study aims at describing the relationship between rainfall and temperature on under-five malaria or anaemia mortality in Kenya Medical Research Institute and United States Centers for Disease Control (KEMRI/CDC) Health and Demographic Surveillance System (HDSS). This study was conducted through the ongoing KEMRI and CDC collaboration. A general additive model with a Poisson link function was fit to model the weekly association of lagged cumulative rainfall and average temperature on malaria/anemia mortality in KEMRI/CDC HDSS for the period 2003 to 2008. A trend function was included in the model to control for time trends and seasonality not explained by weather fluctuations. 95% confidence intervals was presented with estimates. Malaria or anemia mortality was found to be associated with changes in temperature and rainfall in the KEMRI HDSS, with a delay up to 16 weeks. The empirical estimates of associations describe OPEN ACCESS Int. J. Environ. Res. Public Health 2015, 12 1984 established biological relationships well. This information, and particularly, the strength of the relationships over longer lead times can highlight the possibility of developing a predictive forecast with lead times up to 16 weeks in order to enhance preparedness to high transmission episodes.
Full-text · Article · Feb 2015 · International Journal of Environmental Research and Public Health
[Show abstract][Hide abstract] ABSTRACT: Continuous monitoring in health and demographic surveillance sites (HDSS) allows for collection of longitudinal demographic data, health related, and socio-economic indicators of the site population. We sought to use household survey data collected between 2002 and 2006 in the Kenya Medical Research Institute in collaboration with Centers for Disease Control and prevention (KEMRI/CDC) HDSS site in Asembo and Gem Western Kenya to estimate socio-economic status (SES) and assess changes of SES over time and space. Data on household assets and characteristics, mainly source of drinking water, cooking fuel, and occupation of household head was annually collected from 44,313 unique households during the study period. An SES index was calculated as a weighted average of assets using weights generated via Principal Component Analysis (PCA), Polychoric PCA, and Multiple Correspondence Analysis (MCA) methods applied to the pooled data. The index from the best method was used to rank households into SES quintiles and assess their transition over time across SES categories. Kriging was employed to produce SES maps at the start and the end of the study period. First component of PCA, Polychoric PCA, and MCA accounted for 13.7%, 31.8%, and 47.3%, respectively of the total variance of all variables. The gap between the poorest and the least poor increased from 1% at the start to 6% at the end of the study period. Spatial analysis revealed that the increase in least poor households was centered in the lower part of study area (Asembo) over time. No significant changes were observed in Gem. The HDSS sites can provide a platform to assess spatial–temporal changes in the SES status of the population. Evidence on how SES varied over time and space within the same geographical area may provide a useful tool to design interventions in health and other areas that have a close bearing to the SES of the population.
[Show abstract][Hide abstract] ABSTRACT: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.
From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619.
8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children.
RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.
GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.
[Show abstract][Hide abstract] ABSTRACT: Non-communicable diseases (NCDs) result in more deaths globally than other causes. Monitoring systems require strengthening to attribute the NCD burden and deaths in low and middle-income countries (LMICs). Data from health and demographic surveillance systems (HDSS) can contribute towards this goal.
Between 2003 and 2010, 15,228 deaths in adults aged 15 years (y) and older were identified retrospectively using the HDSS census and verbal autopsy in rural western Kenya, attributed into broad categories using InterVA-4 computer algorithms; 37% were ascribed to NCDs, 60% to communicable diseases (CDs), 3% to injuries, and <1% maternal causes. Median age at death for NCDs was 66y and 71y for females and males, respectively, with 43% (39% male, 48% female) of NCD deaths occurring prematurely among adults aged below 65y. NCD deaths were mainly attributed to cancers (35%) and cardio-vascular diseases (CVDs; 29%). The proportionate mortality from NCDs rose from 35% in 2003 to 45% in 2010 (χ2 linear trend 93.4; p<0.001). While overall annual mortality rates (MRs) for NCDs fell, cancer-specific MRs rose from 200 to 262 per 100,000 population, mainly due to increasing deaths in adults aged 65y and older, and to respiratory neoplasms in all age groups. The substantial fall in CD MRs resulted in similar MRs for CDs and NCDs among all adult females by 2010. NCD MRs for adults aged 15y to <65y fell from 409 to 183 per 100,000 among females and from 517 to 283 per 100,000 population among males. NCD MRs were higher among males than females aged both below, and at or above, 65y.
NCDs constitute a significant proportion of deaths in rural western Kenya. Evidence of the increasing contribution of NCDs to overall mortality supports international recommendations to introduce or enhance prevention, screening, diagnosis and treatment programmes in LMICs.
[Show abstract][Hide abstract] ABSTRACT: Monitoring local malaria transmission intensity is essential for planning evidence-based control strategies and evaluating their impact over time. Anti-malarial antibodies provide information on cumulative exposure and have proven useful, in areas where transmission has dropped to low sustained levels, for retrospectively reconstructing the timing and magnitude of transmission reduction. It is unclear whether serological markers are also informative in high transmission settings, where interventions may reduce transmission, but to a level where considerable exposure continues.
This study was conducted through ongoing KEMRI and CDC collaboration. Asembo, in Western Kenya, is an area where intense malaria transmission was drastically reduced during a 1997-1999 community-randomized, controlled insecticide-treated net (ITN) trial. Two approaches were taken to reconstruct malaria transmission history during the period from 1994 to 2009. First, point measurements were calculated for seroprevalence, mean antibody titre, and seroconversion rate (SCR) against three Plasmodium falciparum antigens (AMA-1, MSP-119, and CSP) at five time points for comparison against traditional malaria indices (parasite prevalence and entomological inoculation rate). Second, within individual post-ITN years, age-stratified seroprevalence data were analysed retrospectively for an abrupt drop in SCR by fitting alternative reversible catalytic conversion models that allowed for change in SCR.
Generally, point measurements of seroprevalence, antibody titres and SCR produced consistent patterns indicating that a gradual but substantial drop in malaria transmission (46-70%) occurred from 1994 to 2007, followed by a marginal increase beginning in 2008 or 2009. In particular, proportionate changes in seroprevalence and SCR point estimates (relative to 1994 baseline values) for AMA-1 and CSP, but not MSP-119, correlated closely with trends in parasite prevalence throughout the entire 15-year study period. However, retrospective analyses using datasets from 2007, 2008 and 2009 failed to detect any abrupt drop in transmission coinciding with the timing of the 1997-1999 ITN trial.
In this highly endemic area, serological markers were useful for generating accurate point estimates of malaria transmission intensity, but not for retrospective analysis of historical changes. Further investigation, including exploration of different malaria antigens and/or alternative models of population seroconversion, may yield serological tools that are more informative in high transmission settings.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Childhood mortality, particularly in the first 5 years of life, is a major global concern and the target of Millennium Development Goal 4. Although the majority of childhood deaths occur in Africa and Asia, these are also the regions where such deaths are least likely to be registered. The INDEPTH Network works to alleviate this problem by collating detailed individual data from defined Health and Demographic Surveillance sites. By registering deaths and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. OBJECTIVE: To present a description of cause-specific mortality rates and fractions over the first 15 years of life as documented by INDEPTH Network sites in sub-Saharan Africa and south-east Asia. DESIGN: All childhood deaths at INDEPTH sites are routinely registered and followed up with verbal autopsy (VA) interviews. For this study, VA archives were transformed into the WHO 2012 VA standard format and processed using the InterVA-4 model to assign cause of death. Routine surveillance data also provided person-time denominators for mortality rates. Cause-specific mortality rates and cause-specific mortality fractions are presented according to WHO 2012 VA cause groups for neonatal, infant, 1-4 year and 5-14 year age groups. RESULTS: A total of 28,751 childhood deaths were documented during 4,387,824 person-years over 18 sites. Infant mortality ranged from 11 to 78 per 1,000 live births, with under-5 mortality from 15 to 152 per 1,000 live births. Sites in Vietnam and Kenya accounted for the lowest and highest mortality rates reported. CONCLUSIONS: Many children continue to die from relatively preventable causes, particularly in areas with high rates of malaria and HIV/AIDS. Neonatal mortality persists at relatively high, and perhaps sometimes under-documented, rates. External causes of death are a significant childhood problem in some settings.
Full-text · Article · Oct 2014 · Global Health Action
[Show abstract][Hide abstract] ABSTRACT: Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies.
To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions.
From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992-2012, but two-thirds of the observations related to 2006-2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality.
Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level.
The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology.
Full-text · Article · Oct 2014 · Global Health Action
[Show abstract][Hide abstract] ABSTRACT: Background
Assessing the progress in achieving the United Nation's Millennium Development Goals in terms of population health requires consistent and reliable information on cause-specific mortality, which is often rare in resource-constrained countries. Health and demographic surveillance systems (HDSS) have largely used medical personnel to review and assign likely causes of death based on the information gathered from standardized verbal autopsy (VA) forms. However, this approach is expensive and time consuming, and it may lead to biased results based on the knowledge and experience of individual clinicians. We assessed the cause-specific mortality for children under 5 years old (under-5 deaths) in Siaya County, obtained from a computer-based probabilistic model (InterVA-4).
Successfully completed VA interviews for under-5 deaths conducted between January 2003 and December 2010 in the Kenya Medical Research Institute/US Centers for Disease Control and Prevention HDSS were extracted from the VA database and processed using the InterVA-4 (version 4.02) model for interpretation. Cause-specific mortality fractions were then generated from the causes of death produced by the model.
A total of 84.33% (6,621) childhood deaths had completed VA data during the study period. Children aged 1–4 years constituted 48.53% of all cases, and 42.50% were from infants. A single cause of death was assigned to 89.18% (5,940) of cases, 8.35% (556) of cases were assigned two causes, and 2.10% (140) were assigned ‘indeterminate’ as cause of death by the InterVA-4 model. Overall, malaria (28.20%) was the leading cause of death, followed by acute respiratory infection including pneumonia (25.10%), in under-5 children over the study period. But in the first 5 years of the study period, acute respiratory infection including pneumonia was the main cause of death, followed by malaria. Similar trends were also reported in infants (29 days–11 months) and children aged 1–4 years.
Under-5 cause-specific mortality obtained using the InterVA-4 model is consistent with existing knowledge on the burden of childhood diseases in rural western Kenya.
Full-text · Article · Oct 2014 · Global Health Action
[Show abstract][Hide abstract] ABSTRACT: Recent global malaria burden modeling efforts have produced significantly different estimates, particularly in adult malaria mortality. To measure malaria control progress, accurate malaria burden estimates across age groups are necessary. We determined age-specific malaria mortality rates in western Kenya to compare with recent global estimates. We collected data from 148,000 persons in a health and demographic surveillance system from 2003-2010. Standardized verbal autopsies were conducted for all deaths; probable cause of death was assigned using the InterVA-4 model. Annual malaria mortality rates per 1,000 person-years were generated by age group. Trends were analyzed using Poisson regression. From 2003-2010, in children <5 years the malaria mortality rate decreased from 13.2 to 3.7 per 1,000 person-years; the declines were greatest in the first three years of life. In children 5-14 years, the malaria mortality rate remained stable at 0.5 per 1,000 person-years. In persons ≥15 years, the malaria mortality rate decreased from 1.5 to 0.4 per 1,000 person-years. The malaria mortality rates in young children and persons aged ≥15 years decreased dramatically from 2003-2010 in western Kenya, but rates in older children have not declined. Sharp declines in some age groups likely reflect the national scale up of malaria control interventions and rapid expansion of HIV prevention services. These data highlight the importance of age-specific malaria mortality ascertainment and support current strategies to include all age groups in malaria control interventions.