Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

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.).

Approaching the community about screening children for a multicentre malaria vaccine trial.

Community sensitisation, as a component of community engagement, plays an important role in strengthening the ethics of community-based trials in developing countries and is fundamental to trial success. However, few researchers have shared their community sensitisation strategies and experiences. We report on our perspective as researchers on the sensitisation activities undertaken for a phase II malaria vaccine trial in Kilifi District (Kenya) and Korogwe District (Tanzania), with the aim of informing and guiding the operational planning of future trials. We report wide variability in recruitment rates within both sites; a variability that occurred against a backdrop of similarity in overall approaches to sensitisation across the two sites but significant differences in community exposure to biomedical research. We present a range of potential factors contributing to these differences in recruitment rates, which we believe are worth considering in future community sensitisation plans. We conclude by arguing for carefully designed social science research around the implementation and impact of community sensitisation activities.

Prevalence, incidence and risk factors of epilepsy in older children in rural Kenya.

BACKGROUND: There is little data on the burden or causes of epilepsy in developing countries, particularly in children living in sub-Saharan Africa. METHODS: We conducted two surveys to estimate the prevalence, incidence and risk factors of epilepsy in children in a rural district of Kenya. All children born between 1991 and 1995 were screened with a questionnaire in 2001 and 2003, and those with a positive response were then assessed for epilepsy by a clinician. Active epilepsy was defined as two or more unprovoked seizures with one in the last year. RESULTS: In the first survey 10,218 children were identified from a census, of whom 110 had epilepsy. The adjusted prevalence estimates of lifetime and active epilepsy were 41/1000 (95% CI: 31-51) and 11/1000 (95% CI: 5-15), respectively. Overall two-thirds of children had either generalized tonic-clonic and/or secondary generalized seizures. A positive history of febrile seizures (OR=3.01; 95% CI: 1.50-6.01) and family history of epilepsy (OR=2.55; 95% CI: 1.19-5.46) were important risk factors for active epilepsy. After the second survey, 39 children from the same birth cohort with previously undiagnosed epilepsy were identified, thus the incidence rate of active epilepsy is 187 per 100,000 per year (95% CI: 133-256) in children aged 6-12 years. CONCLUSIONS: There is a considerable burden of epilepsy in older children living in this area of rural Kenya, with a family history of seizures and a history of febrile seizures identified as risk factors for developing epilepsy.

Evaluation of assessment instruments used on children presenting with altered level of consciousness.

OBJECTIVE: To compare current care with a proposed gold standard (formal coma scale use) for assessment of children presenting with altered consciousness. DESIGN: A prospective study. SETTING: Kenyatta National Hospital, Nairobi, Kenya. SUBJECTS: One hundred and seventy children consecutively admitted to the hospital. MAIN OUTCOME MEASURES: Proportion of children assessed using a formal coma scale (gold standard) while presenting with altered consciousness. RESULTS: Findings revealed that only 8% of children were assessed using the formal coma scale at admission. The level of neurological deficit was described using general and potentially misleading descriptive terms rather than formal coma scales. CONCLUSION: The use of a formal coma scale and relevant simple investigations were seldom used. The quality of care of children admitted to the hospital with altered consciousness standard would benefit from defining and implementing management guidelines (protocols).

Computerized tomography scan of the brain in a community study of neurological impairment in Kenya.

Neurological impairment is common in resource-poor countries, but its causes are not clear. Computerized tomography (CT) of the brain has been used to determine the cause of brain insults that may manifest as neurological impairments. The authors conducted a community survey in Kilifi of 10 218 children aged 6 to 9 years to detect neurological impairment. From this survey, 34 children were identified, of whom 16 had motor deficits, 11 complex partial seizures, 4 microcephaly or macrocephaly, and 3 severe developmental delay. These children were assessed with elicitation of history, physical examination, and CT scan of the brain. Sixteen (47%) of the scans showed abnormalities: cerebral atrophy (n = 9), schizencephaly (n = 3), periventricular leukomalacia (n = 2), porencephalic cyst (n = 1), and agenesis of the corpus callosum (n = 1). The minimum prevalence of abnormalities on the CT scan of the brain is 1.56 of 1000, and the prevalence of schizencephaly is 0.29 of 1000. Motor impairments were more likely to show abnormality than the other indications. CT abnormalities are common in children with neurological impairment in Kenya, but the appearances did not identify a major cause.

Prevalence and risk factors of neurological disability and impairment in children living in rural Kenya.

BACKGROUND: There is little data on the burden of neurological impairment (NI) in developing countries, particularly in children of Africa. METHODS: We conducted a survey of NI in children aged 6-9 years in a rural district of Kenya. First, we screened for neurological disability by administering the Ten Questions Questionnaire (TQQ) to parents/guardians of children in a defined population. In phase two, we performed a comprehensive clinical and psychological assessment on children who tested positive on TQQ and on a similar number of children who tested negative. RESULTS: A total of 10 218 children were screened, of whom 955 (9.3%) were positive on TQQ. Of these, 810 (84.8%) were assessed, and of those who tested negative 766 (8.3%) were assessed. The prevalence for moderate/severe NI was 61/1000 [95% confidence interval (95% CI) 48-74]. The most common domains affected were epilepsy (41/1000), cognition (31/1000), and hearing (14/1000). Motor (5/1000) and vision (2/1000) impairments were less common. Of the neurologically impaired children (n = 251), 56 (22%) had more than one impairment. Neonatal insults were found to have a significant association with moderate/severe NI in both the univariate [odds ratio (OR) = 1.70; 95% CI 1.12-2.47] and multivariate analyses (OR = 1.30; 95% CI 1.09-1.65). CONCLUSIONS: There is a considerable burden of moderate/severe NI in this area of rural Kenya, with epilepsy, cognition, and hearing being the most common domains affected. Neonatal insults were identified as an important risk factor.

Management of severe falciparum malaria.

Plasmodium falciparum is the most common cause of severe and life-threatening malaria. Falciparum malaria causes over one million deaths every year. In Africa, a vast majority of these deaths occur in children under five years of age. The presentation of severe malaria varies with age and geographical distribution. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. The management of severe malaria includes prompt administration of appropriate parenteral anti-malarial agents and early recognition and treatment of the complications. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure. In adults, renal failure and pulmonary oedema are more common causes of death. In contrast, concomitant bacterial infections occur more frequently in children and are associated with mortality in children. Admission to critical or intensive care units may help reduce the mortality, and the frequency and severity of sequelae related to severe malaria.

Validity and reliability of the 'Ten Questions' questionnaire for detecting moderate to severe neurological impairment in children aged 6-9 years in rural Kenya.

BACKGROUND: The 'Ten Questions' Questionnaire (TQQ) is used to detect severe neurological impairment in children living in resource-poor countries. Its usefulness has been established in Asia and the Caribbean, but there are a few published studies from Africa. We evaluated the TQQ as part of a larger study of neurological impairment in a rural community, on the coast of Kenya. METHODS: The study was conducted in two phases from June 2001 to May 2002; in phase one, a community household screening of 10,218 children aged 6-9 years using the TQQ was performed. Phase two involved a comprehensive clinical and psychological assessment of all children testing positive on the TQQ (n = 810) and an equivalent number of those testing negative (n = 766). Data were interpreted using the impairment-specific approach. RESULTS: Overall, the sensitivity rates for screening the different impairments were: cognitive (70.0%), motor (71.4%), epilepsy (100%), hearing (87.4%) and visual (77.8%). All the specificity rates were greater than 96%. However, the positive predictive values were low, and ranged from 11 to 33%. CONCLUSIONS: These results are similar to those from other continents and provide evidence that the TQQ can be used to compare the epidemiology of moderate/severe impairment in different parts of the world. Furthermore, the TQQ can be used to screen for moderately/severely impaired children in resource-poor countries; however, the low positive predictive values mean that other assessments are required for confirmation.