[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. (Funded by the National Institutes of Health and others.).
New England Journal of Medicine 10/2015; 373(21). DOI:10.1056/NEJMoa1505819 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
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.
The Lancet Infectious Diseases 09/2015; DOI:10.1016/S1473-3099(15)00239-X · 22.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fever is a common clinical symptom in children attending hospital outpatient clinics in rural Tanzania, yet there is still a paucity of data on the burden of bloodstream bacterial infection among these patients.
The present study was conducted at Korogwe District Hospital in north-eastern Tanzania. Patients aged between 2 and 59 months with a history of fever or measured axillary temperature ≥37.5°C attending the outpatient clinic were screened for enrolment into the study. Blood culturing was performed using the BACTEC 9050® system. A biochemical analytical profile index and serological tests were used for identification and confirmation of bacterial isolates. In-vitro antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method. The identification of Plasmodium falciparum malaria was performed by microscopy with Giemsa stained blood films.
A total of 808 blood cultures were collected between January and October 2013. Bacterial growth was observed in 62/808 (7.7%) of the cultured samples. Pathogenic bacteria were identified in 26/808 (3.2%) cultures and the remaining 36/62 (58.1%) were classified as contaminants. Salmonella typhi was the predominant bacterial isolate detected in 17/26 (65.4%) patients of which 16/17 (94.1%) were from patients above 12 months of age. Streptococcus pneumoniae was the second leading bacterial isolate detected in 4/26 (15.4%) patients. A high proportion of S. typhi 11/17 (64.7%) was isolated during the rainy season. S. typhi isolates were susceptible to ciprofloxacin (n = 17/17, 100%) and ceftriaxone (n = 13/17, 76.5%) but resistant to chloramphenicol (n = 15/17, 88.2%). P. falciparum malaria was identified in 69/808 (8.5%) patients, none of whom had bacterial infection.
Bloodstream bacterial infection was not found to be a common cause of fever in outpatient children; and S. typhi was the predominant isolate. This study highlights the need for rational use of antimicrobial prescription in febrile paediatric outpatients presenting at healthcare facilities in rural Tanzania.
BMC Research Notes 07/2015; 8(1):289. DOI:10.1186/s13104-015-1178-9
[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.
The Lancet 04/2015; 385:1581. · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to determine the current prevalence of four P. falciparum candidate artemisinin resistance biomarkers L263E, E431K, A623E, and S769N in the pfatpase6 gene in a high transmission area in Tanzania in a retrospective cross sectional study using 154 archived samples collected from three previous malaria studies in 2010, 2011 and 2013. Mutations in pfatpase6 gene were detected in parasite DNA isolated from Dried Blood Spots by using PCR-RFLP. We observed overall allelic frequencies for L263E, E431K, A623E, and S769N to be 5.8% (9/154), 16.2% (25/154), 0.0% (0/154), and 3.9% (6/154). The L263E mutation was not detected in 2010 but occurred at 3.9% and 2.6% in 2011 and 2013 respectively. The L263E mutation showed a significant change of frequency between 2010 and 2011, but not between 2011 and 2013 (íµí± < 0.05). Frequency of E431K was highest of all without any clear trend whereas S769N increased from 2.2% in 2010 to 3.6% in 2011 and 5.1% in 2013. A623E mutation was not detected. The worrisome detection and the increase in the frequency of S769N and other mutations calls for urgent assessment of temporal changes of known artemisinin biomarkers in association with in vivo ACT efficacy.
Malaria Research and Treatment 01/2015; 2015(1):7. DOI:10.1155/2015/279028
[Show abstract][Hide abstract] ABSTRACT: Introduction
Although the burden of malaria in many parts of Tanzania has declined, the proportion of children with fever has not changed. This situation underscores the need to explore the possible causes of febrile episodes in patients presenting with symptoms at the Korogwe District Hospital (KDH).
A hospital based cross-sectional study was conducted at KDH, north-eastern Tanzania. Patients aged 2 to 59 months presenting at the outpatient department with an acute medical condition and fever (measured axillary temperature ≥37.5°C) were enrolled. Blood samples were examined for malaria parasites, human immunodeficiency virus (HIV) and bacterial infections. A urine culture was performed in selected cases to test for bacterial infection and a chest radiograph was requested if pneumonia was suspected. Diagnosis was based on both clinical and laboratory investigations.
A total of 867 patients with a median age of 15.1 months (Interquartile range 8.6–29.9) were enrolled from January 2013 to October 2013. Respiratory tract infections were the leading clinical diagnosis with 406/867 (46.8%) of patients diagnosed with upper respiratory tract infection and 130/867 (15.0%) with pneumonia. Gastroenteritis was diagnosed in 184/867 (21.2%) of patients. Malaria infection was confirmed in 72/867 (8.3%) of patients. Bacterial infection in blood and urine accounted for 26/808 (3.2%) infections in the former, and 66/373 (17.7%) infections in the latter. HIV infection was confirmed in 10/824 (1.2%) of patients. Respiratory tract infections and gastroenteritis were frequent in patients under 36 months of age (87.3% and 91.3% respectively). Co-infections were seen in 221/867 (25.5%) of patients. The cause of fever was not identified in 65/867 (7.5%) of these patients.
The different proportions of infections found among febrile children reflect the causes of fever in the study area. These findings indicate the need to optimise patient management by developing malaria and non-malaria febrile illnesses management protocols.
PLoS ONE 08/2014; 9(8):e104197. DOI:10.1371/journal.pone.0104197 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using samples collected during 2004-2008, we investigated the evolutionary origin of the A581G mutation by characterizing microsatellite diversity flanking Pfdhps triple-mutant (437G+540E+581G) alleles from 3 locations in eastern Africa and comparing it with double-mutant (437G+540E) alleles from the same area. In Ethiopia, both alleles derived from 1 lineage that was distinct from those in Uganda and Tanzania. Uganda and Tanzania triple mutants derived from the previously characterized southeastern Africa double-mutant lineage. The A581G mutation has occurred multiple times on local Pfdhps double-mutant backgrounds; however, a novel microsatellite allele incorporated into the Tanzania lineage since 2004 illustrates the local expansion of emergent triple-mutant lineages.
[Show abstract][Hide abstract] ABSTRACT: Abstract
Background:A malaria vaccine could be an important addition to current control strategies. We report the safety and
vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria
Methods and Findings:6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three
doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3
(per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p,0.01 across all sites). VE during the 20 mo after
vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and
all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%),
respectively (ITT). VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%],
ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Postvaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and
from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residualsp,0.001).
The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365
and from21 to 49, respectively; corresponding ranges among infants were210 to 1,402 and213 to 37, respectively (ITT).
Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in
the RTS,S/AS01 and control groups, respectively.
Conclusions:RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the
highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest
levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current
malaria control in Africa.
Trial registration:http://www.ClinicalTrials.gov NCT00866619
Please see later in the article for the Editors’ Summary
PLoS Medicine 07/2014; 11(7). DOI:10.1371/journal.pmed.1001685 · 14.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
BMC Medicine 07/2014; 12(1):117. DOI:10.1186/PREACCEPT-5212460251240508 · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS,S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated.
Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated.
Polyclonal anti-CS IgG preparations from RTS,S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation.
This study does not support the concept that anti-CS antibodies induced by the RTS,S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding.
[Show abstract][Hide abstract] ABSTRACT: Community perception in biomedical research remains critical in Africa with many participants being driven by different motives. The objective of this study was to explore the perceived motives for women or females guardians to volunteer for their children to participate in biomedical research and to explore experiences and challenges faced by Community Owned Resource Persons (CORPs) when mobilizing community members to participate in biomedical research.
This cross sectional study was conducted in Korogwe district, in north-eastern Tanzania. Qualitative methods combining random and purposive sampling techniques were used for data collection. A randomly selected sample using random table method from the existing list of households in the ward office was used to select participants for Focus Group Discussions (FGDs). A purposive sampling technique was used for In-Depth Interviews (IDIs) with CORPs. Thematic framework analysis was used to analyze the data.
Need for better health services, availability of qualified clinicians, and better access to services provided at the research points were reported as main motives for community members to participate in biomedical research. With regard to experience and challenges faced by CORPs, the main reasons for mothers and guardians not participating in biomedical research were linked to misconception of the malariometric surveys, negative perception of the validity and sensitivity of rapid diagnostic tests, fear of knowing Human Immunodeficiency Virus Infection (HIV) /Acquired Immune Deficiency Syndrome (HIV/AIDS) sero status, and lack of trust for the medical information provided by the CORPs. Challenges reported by CORPs included lack ofawareness of malariometric surveys among participants, time consumption in mobilization of the community, difficulties in identifying individual results, and family responsibilities.
This study has shown that majority of community members had positive perceptions of the about malariometric surveys services provided. The availability of free health services was the major determining factor for community members' participation in malariometric surveys. CORPs are instrumental in mobilizing community members participation during malariometric surveys, despite their experiences and the challenges they face.
BMC Public Health 04/2014; 14(1):385. DOI:10.1186/1471-2458-14-385 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008-October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birthweights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.
[Show abstract][Hide abstract] ABSTRACT: National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010.
The Lancet Global Health 07/2013; 1(1):e26-e36. DOI:10.1016/S2214-109X(13)70006-8 · 10.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.
[Show abstract][Hide abstract] ABSTRACT: Background
Studies conducted thus far have demonstrated that the malaria vaccine (RTS,S) has a promising safety profile. Within the context of planning for future vaccine trials and for the purpose of building on previous research that has been undertaken in sub-Saharan Africa with regard to community perceptions about clinical studies, this research aimed to explore the community perceptions on the secondary health benefits established by the malaria vaccine trials (RTS,S Phase 2 and Phase 3) at the Korogwe site in Tanzania.
An exploratory qualitative study design was used. Participants were recruited from the Korogwe site. Sampling techniques were purposive and random. A total of five focus group discussions and six in-depth interviews were conducted. Interview guides with open-ended questions were employed to collect data. Male and female parents whose infants participated and those whose infants did not participate in the trials, health workers and community leaders were interviewed. Thematic analysis framework was used to analyse the data.
The activities of a malaria vaccine project appeared to be well known to the community. Respondents had largely positive views towards the secondary health benefits which have been established by malaria vaccine trials. The project has led to a massive investment in health care infrastructure and an improvement in health care services across the study areas. The project was perceived by the community to have established major secondary health benefits. Misconceptions amongst respondents, especially with regard to blood samples, were also observed in this study.
Despite some misconceptions with regard to the conduct of malaria vaccine trials, especially on blood sampling, generally this study observed that most participants were positive about the secondary health benefits brought about by the malaria vaccine trials in Korogwe.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Pregnancy associated malaria is associated with decreased birth weight, but in-utero evaluation of fetal growth alterations is rarely performed. The objective of this study was to investigate malaria induced changes in fetal growth during the 3(rd) trimester using trans-abdominal ultrasound.
An observational study of 876 pregnant women (398 primi- and secundigravidae and 478 multigravidae) was conducted in Tanzania. Fetal growth was monitored with ultrasound and screening for malaria was performed regularly. Birth weight and fetal weight were converted to z-scores, and fetal growth evaluated as fetal weight gain from the 26th week of pregnancy.
Malaria infection only affected birth weight and fetal growth among primi- and secundigravid women. Forty-eight of the 398 primi- and secundigravid women had malaria during pregnancy causing a reduction in the newborns z-score of -0.50 (95% CI: -0.86, -0.13, P = 0.008, multiple linear regression). Fifty-eight percent (28/48) of the primi- and secundigravidae had malaria in the first half of pregnancy, but an effect on fetal growth was observed in the 3(rd) trimester with an OR of 4.89 for the fetal growth rate belonging to the lowest 25% in the population (95%CI: 2.03-11.79, P<0.001, multiple logistic regression). At an individual level, among the primi- and secundigravidae, 27% experienced alterations of fetal growth immediately after exposure but only for a short interval, 27% only late in pregnancy, 16.2% persistently from exposure until the end of pregnancy, and 29.7% had no alterations of fetal growth.
The effect of malaria infections was observed during the 3(rd) trimester, despite infections occurring much earlier in pregnancy, and different mechanisms might operate leading to different patterns of growth alterations. This study highlights the need for protection against malaria throughout pregnancy and the recognition that observed changes in fetal growth might be a consequence of an infection much earlier in pregnancy.
PLoS ONE 01/2013; 8(1):e53794. DOI:10.1371/journal.pone.0053794 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The ability of Plasmodium falciparum to undergo antigenic variation, by switching expression among protein variants encoded by multigene families, such as var, rif and stevor, is key to the survival of this parasite in the human host. The RIFIN protein family can be divided into A and B types based on the presence or absence of a 25 amino acid motif in the semi-conserved domain. A particular type B RIFIN, PF13_0006, has previously been shown to be strongly transcribed in the asexual and sexual stages of P. falciparum in vitro.
Antibodies to recombinant PF13_0006 RIFIN were used in immunofluorescence and confocal imaging of 3D7 parasites throughout the asexual reproduction and sexual development to examine the expression of PF13_0006. Furthermore, reactivity to recombinant PF13_0006 was measured in plasma samples collected from individuals from both East and West African endemic areas.
The PF13_0006 RIFIN variant appeared expressed by both released merozoites and gametes after emergence. 7.4% and 12.1% of individuals from East and West African endemic areas, respectively, carry plasma antibodies that recognize recombinant PF13_0006, where the antibody responses were more common among older children.
The stage specificity of PF13_0006 suggests that the diversity of RIFIN variants has evolved to provide multiple specialized functions in different stages of the parasite life cycle. These data also suggest that RIFIN variants antigenically similar to PF13_0006 occur in African parasite populations.