Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya.

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in 13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups. These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373).

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.).

In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya.

OBJECTIVES: To assess the efficacy of amodiaquine-artesunate in an area with high chloroquine resistance in western Kenya. METHODS: Twenty-eight day in-vivo efficacy trial of amodiaquine-artesunate in 103 children aged 6-59 months in western Kenya with smear-confirmed uncomplicated Plasmodium falciparum malaria. RESULTS: The 28-day uncorrected adequate clinical and parasitological response (ACPR) was 69.0%, with 15.5% Late Clinical Failure and 15.5% Late Parasitologic Failure rates. The PCR-corrected 28-day ACPR was 90.2%. Clinical risk factors for recurrent infection (recrudescences and reinfections) were lower axillary temperature at enrollment and low weight-for-age Z-score. The presence of single nucleotide polymorphisms pfcrt 76T and pfmdr1 86Y at baseline was associated with increased risk of recurrent infections, both reinfections and recrudescences. CONCLUSION: Although artemether-lumefantrine (Coartem) is the first line ACT in Kenya, amodiaquine-artesunate is registered as an option for treatment of uncomplicated P. falciparum and remains an effective alternative to Coartem in western Kenya. Continued amodiaquine monotherapy in the private sector may jeopardize the future use of amodiaquine-artesunate as an alternative artemisinin-based combination therapy.

The effect of health care worker training on the use of intermittent preventive treatment for malaria in pregnancy in rural western Kenya.

BACKGROUND: In 1998, Kenya adopted intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) for malaria prevention during pregnancy. We conducted a survey in 2002 among women who had recently delivered in the rural neighbouring areas Asembo and Gem and reported coverage of 19% of at least one dose and 7% of two or more doses of SP. Health care workers (HCW) in Asembo were retrained on IPTp in 2003. OBJECTIVES: To evaluate if IPTp coverage increased and if the training in Asembo led to better coverage than in Gem, and to identify barriers to the effective implementation of IPTp. METHODS: Community-based cross-sectional survey among a simple random sample of women who had recently delivered in April 2005, interviews with HCW of antenatal clinics (ANC) in Asembo and Gem. RESULTS: Of the 724 women interviewed, 626 (86.5%) attended the ANC once and 516 (71.3%) attended two or more times. Overall IPTp coverage was 41% for at least one dose, and 21% for at least two doses of SP. In Asembo, coverage increased from 19% in 2002 to 61% in 2005 for at least one dose and from 7% to 17% for two doses of SP. In Gem, coverage increased from 17% to 28% and 7% to 11%, respectively. Interviews of HCW in both Asembo and Gem revealed confusion about appropriate timing, and lack of direct observation of IPTp. CONCLUSION: Training of HCW and use of simplified IPTp messages may be a key strategy in achieving Roll Back Malaria targets for malaria prevention in pregnancy in Kenya.

Malaria control in Bungoma District, Kenya: a survey of home treatment of children with fever, bednet use and attendance at antenatal clinics.

OBJECTIVE: To lay the basis for planning an improved malaria control programme in Bungoma District, Kenya. METHODS: By means of a cluster sample household survey an investigation was conducted into the home management of febrile children, the use of bednets, and attendance at antenatal clinics. FINDINGS: Female carers provided information on 314 recently febrile children under 5 years of age, of whom 43% received care at a health facility, 47% received an antimalarial drug at home, and 25% received neither. Of the antimalarial treatments given at home, 91% were started by the second day of fever and 92% were with chloroquine, the nationally recommended antimalarial at the time. The recommended dosage of chloroquine to be administered over three days was 25 mg/kg but the median chloroquine tablet or syrup dosage given over the first three days of treatment was 15 mg/kg. The total dosages ranged from 2.5 mg/kg to 82 mg/kg, administered over one to five days. The dosages were lower when syrup was administered than when tablets were used. Only 5% of children under 5 years of age slept under a bednet. No bednets had been treated with insecticide since purchase. At least two antenatal visits were made by 91% of pregnant women. CONCLUSIONS: Carers are major and prompt providers of antimalarial treatment. Home treatment practices should be strengthened and endorsed when prompt treatment at a health facility is impossible. The administration of incorrect dosages, which proved common with chloroquine, may occur less frequently with sulfadoxine-pyrimethamine, as its dosage regimen is simpler. High levels of utilization of antenatal clinics afford the opportunity to achieve good coverage with presumptive intermittent malaria treatments during pregnancy, and to reach the goal of widespread bednet use by pregnant women and children by distributing nets during antenatal clinic visits.

Community health worker performance in the management of multiple childhood illnesses: Siaya District, Kenya, 1997-2001.

OBJECTIVES: To characterize community health worker (CHW) performance using an algorithm for managing common childhood illnesses in Siaya District, Kenya, we conducted CHW evaluations in 1998, 1999, and 2001. METHODS: Randomly selected CHWs were observed managing sick outpatient and inpatient children at a hospital, and their management was compared with that of an expert clinician who used the algorithm. RESULTS: One hundred, 108, and 114 CHWs participated in the evaluations in 1998, 1999, and 2001, respectively. The proportions of children treated "adequately" (with an antibiotic, antimalarial, oral rehydration solution, or referral, depending on the child's disease classifications) were 57.8%, 35.5%, and 38.9%, respectively, for children with a severe classification and 27.7%, 77.3%, and 74.3%, respectively, for children with a moderate (but not severe) classification. CHWs adequately treated 90.5% of malaria cases (the most commonly encountered classification). CHWs often made mistakes assessing symptoms, classifying illnesses, and prescribing correct doses of medications. CONCLUSIONS: Deficiencies were found in the management of sick children by CHWs, although care was not consistently poor. Key reasons for the deficiencies appear to be guideline complexity and inadequate clinical supervision; other possible causes are discussed.

Screening for Chlamydia trachomatis in an anonymous and confidential HIV counseling and testing site: feasibility and prevalence rates.

BACKGROUND: Chlamydia trachomatis is the most common bacterial sexually transmitted disease (STD) in the United States. The development of nucleic acid amplification tests for C trachomatis in urine specimens allows for screening outside traditional clinic settings. Persons visiting an HIV counseling and testing site may be at increased risk for STDs, including C trachomatis. GOAL: To measure the acceptance of C trachomatis urine screening and the prevalence of C trachomatis infection among clients at an HIV counseling and testing site. STUDY DESIGN: Site HIV counselors offered urine C trachomatis screening to clients, administered a questionnaire, and collected urine samples. RESULTS: Of 808 counseling and testing site clients approached for C trachomatis screening, 572 (71%) accepted. The most common reasons for declining screening were absence of symptoms (33%) and recent STD testing (32%). Men were more likely to accept urine screening than women (risk ratio, 1.31; 95% CI, 1.06-1.62), as were clients who practiced oral sex, had a history of STD, or who had never been screened for STD. Of 560 urine specimens processed, only 8 (1.43%; 95% CI, 0.66-2.91%) were infected with C trachomatis. CONCLUSIONS: Sites offering HIV testing and counseling are a feasible alternative to clinical settings for C trachomatis screening. Prevalence may be too low for screening to be cost effective unless higher-risk subpopulations can be identified.

Predictors of correct treatment of children with fever seen at outpatient health facilities in the Central African Republic.

To identify factors associated with improved performance of health care workers who treat ill children in developing countries, the authors analyzed a sample of consultations of children with malaria (defined as any fever) from a national health facility survey conducted in the Central African Republic from December 1995 to January 1996. Twenty-eight health care workers and 204 children were studied. A univariate analysis revealed the following significant predictors of correct treatment, as defined by the Central African malaria control program: high fever (odds ratio (OR) = 3.25, 95% confidence interval (CI): 1.47, 7.17); correct health care worker diagnosis (OR = 2.59, 95% CI: 1.39, 4.85); and the caregiver's reporting the child's fever to the health care worker (OR = 2.18, 95% CI: 1.32, 3.62). There was an unexpected inverse association between the presence of a fever treatment chart and correct treatment (OR = 0.19, 95% CI: 0.04, 0.91). Correct treatment was marginally associated with a longer consultation time (p value for trend = 0.058). Neither in-service training in the treatment of fever nor supervision was significantly associated with correct treatment. For child health programs to improve, targeted studies are needed to understand which factors, alone or in combination, improve health care worker performance.