192 research outputs found
Randomized, Controlled Trial of the Long Term Safety, Immunogenicity and Efficacy of RTS,S/AS02(D) Malaria Vaccine in Infants Living in a Malaria-Endemic Region.
The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02(D) vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up. This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02(D) or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20. From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02(D) (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02(D) and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02(D) and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02(D) group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against multiple episodes of malaria disease was 14.4% (95% CI: -41.9 to 48.4, p = 0.545). The acceptable safety profile and good tolerability of RTS,S/AS02(D) in combination with EPI vaccines previously reported from month 0 to 9 was confirmed over a 20 month surveillance period in this infant population. Antibodies against both CS and HBsAg in the RTS,S/AS02(D) group remained significantly higher compared to control for the study duration. Over 18 months follow up, RTS,S/AS02(D) prevented approximately a quarter of malaria cases in the study population. CLINICAL TRIALS: Gov identifier: NCT00289185
Safety, Immunogenicity and Duration of Protection of the RTS,S/AS02D Malaria Vaccine: One Year Follow-Up of a Randomized Controlled Phase I/IIb Trial
The RTS,S/AS02(D) vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D) given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D) and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D), remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003).The RTS,S/AS02(D) malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028
Radiological findings in young children investigated for tuberculosis in Mozambique
INTRODUCTION: Chest radiography remains a critical tool for
diagnosing intrathoracic tuberculosis (TB) in young children who
are unable to expectorate. We describe the radiological findings
in children under 3 years of age investigated for TB in the
district of Manhica, southern Mozambique, an area with a high
prevalence of TB and HIV. METHODS: Digital antero-posterior and
lateral projections were performed and reviewed by two
independent readers, using a standardized template. Readers
included a local pediatrician and a pediatric radiologist
blinded to all clinical information. International consensus
case definitions for intra-thoracic TB in children were applied.
RESULTS: A total of 766 children were evaluated of whom 43
(5.6%) had TB. The most frequent lesion found in TB cases was
air space consolidation (65.1%), followed by suggestive hilar
lymphadenopathy (17.1%) and pleural effusion (7.0%). Air space
consolidation was significantly more common in TB cases than in
non-TB cases (odds ratio 8.9; 95% CI: 1.6-50.5), as were hilar
lymphadenopathy (OR 17.2; 95% CI: 5.7-52.1). The only case with
miliary infiltrates and 3 with pleural effusions occurred in
HIV-infected children. CONCLUSION: Frequent air space
consolidation complicates radiological distinction between TB
and bacterial pneumonia in young children, underscoring the need
for epidemiological contextualization and consideration of all
relevant signs and symptoms
Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data.
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
Prevalence and Risk Factors of Sexually Transmitted Infections and Cervical Neoplasia in Women from a Rural Area of Southern Mozambique
There is limited information on the prevalence of sexually transmitted infections and the prevalence of cervical neoplasia in rural sub-Saharan Africa. This study describes the prevalence and the etiology of STIs and the prevalence of cervical neoplasia among women in southern Mozambique.
An age-stratified cross-sectional study was performed where 262 women aged 14 to 61 years were recruited at the antenatal clinic (59%), the family-planning clinic (7%), and from the community (34%).
At least one active STI was diagnosed in 79% of women. Trichomonas vaginalis was present in 31% of all study participants. The prevalence of Neisseria gonorrhea and Chlamydia trachomatis were 14% and 8%, respectively, and Syphilis was diagnosed in 12% of women. HPV DNA was detected in 40% of women and cervical neoplasia was diagnosed in 12% of all women.
Risk factors associated with the presence of some of the STIs were being divorced or widowed, having more than one sexual partner and having the partner living in another area. A higher prevalence was observed in the reproductive age group and some of the STIs were more frequently diagnosed in pregnant women. STI control programs are a priority to reduce the STIs burden, including HIV and cervical neoplasia
Caretakers' perspectives of paediatric TB and implications for care-seeking behaviours in Southern Mozambique
Background: Tuberculosis (TB) remains an important public health concern, especially in poorly resourced settings. TB diagnosis is challenging, particularly for children, who are the most vulnerable to its′ impacts. Lack of knowledge and awareness of the disease compromises prompt diagnosis and treatment compliance. Objective: To gain insights regarding caretakers′ knowledge of the aetiology and prevention of paediatric TB in southern Mozambique, to describe their care-seeking behaviours and to assess the acceptability of diagnostic procedures. Methods: A total of 35 caretakers were interviewed, all of which had children with TB compatible symptoms. Eleven were caretakers of children diagnosed with TB at the health facility, 11 of children for whom TB was excluded as a diagnosis at the health facility and 13 of children with TB compatible symptoms identified in the community. The first two groups took part in a TB incidence study, while the third group did not. All underwent the same semi-structured interviews, the results of which were analysed and compared using content analysis. Results: Even when confronted with signs suggestive of TB, most caretakers never suspected it or misinterpreted the signs, even among caretakers with TB and TB contacts. There was limited knowledge of TB, except among those undergoing treatment. The transgression of social norms was often presented as an explanation for TB in parallel to medically sound causes. The use of traditional care for prevention is widespread, but it varied for treatment purposes. TB diagnostic procedures were considered painful but were unanimously tolerated. Conclusions and significance: Misconceptions of paediatric TB, associated complex care-seeking itineraries and negative feelings of the diagnostic procedures may result in delays, low adherence and lost to follow-up, which needs to be addressed by adequately framed health promotion approaches
Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
Background: Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S
confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary
immunization. Vaccine efficacy has some association with anti-CSP IgG; however, it is unclear how these antibodies
function, and how functional antibodies are induced and maintained over time. Recent studies identified antibodycomplement interactions as a potentially important immune mechanism against sporozoites. Here, we investigated
whether RTS,S vaccine-induced antibodies could function by interacting with complement.
Methods: Serum samples were selected from children in a phase IIb trial of RTS,S/AS02A conducted at two study
sites of high and low malaria transmission intensity in Manhiça, Mozambique. Samples following primary
immunization and 5-year post-immunization follow-up time points were included. Vaccine-induced antibodies were
characterized by isotype, subclass, and epitope specificity, and tested for the ability to fix and activate complement.
We additionally developed statistical methods to model the decay and determinants of functional antibodies after
vaccination.
Results: RTS,S vaccination induced anti-CSP antibodies that were mostly IgG1, with some IgG3, IgG2, and IgM.
Complement-fixing antibodies were effectively induced by vaccination, and targeted the central repeat and Cterminal regions of CSP. Higher levels of complement-fixing antibodies were associated with IgG that equally
recognized both the central repeat and C-terminal regions of CSP. Older age and higher malaria exposure were
significantly associated with a poorer induction of functional antibodies. There was a marked decay in functional
complement-fixing antibodies within months after vaccination, as well as decays in IgG subclasses and IgM.
Statistical modeling suggested the decay in complement-fixing antibodies was mostly attributed to the waning of
anti-CSP IgG1, and to a lesser extent IgG3. Conclusions: We demonstrate for the first time that RTS,S can induce complement-fixing antibodies in young
malaria-exposed children. The short-lived nature of functional responses mirrors the declining vaccine efficacy of
RTS,S over time. The negative influence of age and malaria exposure on functional antibodies has implications for
understanding vaccine efficacy in different settings. These findings provide insights into the mechanisms and
longevity of vaccine-induced immunity that will help inform the future development of highly efficacious and longlasting malaria vaccines
Varying efficacy of intermittent preventive treatment for malaria in infants in two similar trials: public health implications.
BACKGROUND\ud
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Intermittent preventive treatment (IPTi) with sulphadoxine-pyrimethamine (SP) in infants resulted in different estimates of clinical malaria protection in two trials that used the same protocol in Ifakara, Tanzania, and Manhiça, Mozambique. Understanding the reasons for the discrepant results will help to elucidate the action mechanism of this intervention, which is essential for rational policy formulation.\ud
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METHODS\ud
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A comparative analysis of two IPTi trials that used the same study design, follow-up, intervention, procedures and assessment of outcomes, in Tanzania and Mozambique was undertaken. Children were randomised to receive either SP or placebo administered 3 times alongside routine vaccinations delivered through the Expanded Program on Immunisation (EPI). Characteristics of the two areas and efficacy on clinical malaria after each dose were compared.\ud
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RESULTS\ud
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The most relevant difference was in ITN's use ; 68% in Ifakara and zero in Manhiça. In Ifakara, IPTi was associated with a 53% (95% CI 14.0; 74.1) reduction in the risk of clinical malaria between the second and the third dose; during the same period there was no significant effect in Manhiça. Similarly, protection against malaria episodes was maintained in Ifakara during 6 months after dose 3, but no effect of IPTi was observed in Manhiça.\ud
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CONCLUSION\ud
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The high ITN coverage in Ifakara is the most likely explanation for the difference in IPTi efficacy on clinical malaria. Combination of IPTi and ITNs may be the most cost-effective tool for malaria control currently available, and needs to be explored in current and future studies.\ud
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TRIAL REGISTRATION\ud
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Manhiça study registration number: NCT00209795Ifakara study registration number: NCT88523834
Incidence of Tuberculosis Among Young Children in Rural Mozambique
BACKGROUND: Tuberculosis (TB) contributes significantly to child
morbidity and mortality. This study aimed to estimate the
minimum community-based incidence rate of TB among children
<3 years of age in Southern Mozambique. METHODS: Between
October 2011 and October 2012, in the Manhica District Health
and Demographic Surveillance System, we enrolled prospectively
all presumptive TB cases younger than 3 years of age through
passive and active case finding. Participants included all
children who were either symptomatic or were close contacts of a
notified adult smear-positive pulmonary TB. Children were
clinically evaluated at baseline and follow-up visits.
Investigation for TB disease included chest radiography, HIV and
tuberculin skin testing as well as gastric aspirate and induced
sputum sampling, which were processed for smear, culture and
mycobacterial molecular identification. RESULTS: During the
study period, 13,764 children <3 years contributed to a total
of 9575 person-year. Out of the 789 presumptive TB cases
enrolled, 13 had TB culture confirmation and 32 were probable TB
cases. The minimum community-based incidence rate of TB
(confirmed plus probable cases) was 470 of 100,000 person-year
(95% confidence interval: 343-629 of 100,000). HIV co-infection
was present in 44% of the TB cases. CONCLUSION: These data
highlight the huge burden of pediatric TB. This study provides
one of the first prospective population-based incidence data of
childhood tuberculosis and adds valuable information to the
global effort of producing better estimates, a critical step to
inform public health policy
Malaria in rural Mozambique. Part II: children admitted to hospital
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