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Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

ABSTRACT: The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations.374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7).FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs.Clinicaltrials.gov NCT00223990.

SUBMITTER: Ogutu BR

PROVIDER: S-EPMC2650803 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

Ogutu Bernhards R BR Apollo Odika J OJ McKinney Denise D Okoth Willis W Siangla Joram J Dubovsky Filip F Tucker Kathryn K Waitumbi John N JN Diggs Carter C Wittes Janet J Malkin Elissa E Leach Amanda A Soisson Lorraine A LA Milman Jessica B JB Otieno Lucas L Holland Carolyn A CA Polhemus Mark M Remich Shon A SA Ockenhouse Christian F CF Cohen Joe J Ballou W Ripley WR Martin Samuel K SK Angov Evelina E Stewart V Ann VA Lyon Jeffrey A JA Heppner D Gray DG Withers Mark R MR

PloS one 20090305 3

<h4>Objective</h4>The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.<h4>Methods</h4>A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field st ...[more]

PMID: 19262754

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Project description:BACKGROUND: Models of Plasmodium falciparum malaria epidemiology that provide realistic quantitative predictions of likely epidemiological outcomes of existing vector control strategies have the potential to assist in planning for the control and elimination of malaria. This work investigates the applicability of mathematical modelling of malaria transmission dynamics in Rachuonyo South, a district with low, unstable transmission in the highlands of western Kenya. METHODS: Individual-based stochastic simulation models of malaria in humans and a deterministic model of malaria in mosquitoes as part of the OpenMalaria platform were parameterized to create a scenario for the study area based on data from ongoing field studies and available literature. The scenario was simulated for a period of two years with a population of 10,000 individuals and validated against malaria survey data from Rachuonyo South. Simulations were repeated with multiple random seeds and an ensemble of 14 model variants to address stochasticity and model uncertainty. A one-dimensional sensitivity analysis was conducted to address parameter uncertainty. RESULTS: The scenario was able to reproduce the seasonal pattern of the entomological inoculation rate (EIR) and patent infections observed in an all-age cohort of individuals sampled monthly for one year. Using an EIR estimated from serology to parameterize the scenario resulted in a closer fit to parasite prevalence than an EIR estimated using entomological methods. The scenario parameterization was most sensitive to changes in the timing and effectiveness of indoor residual spraying (IRS) and the method used to detect P. falciparum in humans. It was less sensitive than expected to changes in vector biting behaviour and climatic patterns. CONCLUSIONS: The OpenMalaria model of P. falciparum transmission can be used to simulate the impact of different combinations of current and potential control interventions to help plan malaria control in this low transmission setting. In this setting and for these scenarios, results were highly sensitive to transmission, vector exophagy, exophily and susceptibility to IRS, and the detection method used for surveillance. The level of accuracy of the results will thus depend upon the precision of estimates for each. New methods for analysing and evaluating uncertainty in simulation results will enhance the usefulness of simulations for malaria control decision-making. Improved measurement tools and increased primary data collection will enhance model parameterization and epidemiological monitoring. Further research is needed on the relationship between malaria indices to identify the best way to quantify transmission in low transmission settings. Measuring EIR through mosquito collection may not be the optimal way to estimate transmission intensity in areas with low, unstable transmission.

Project description:BACKGROUND:Increasing pyrethroid resistance in malaria vectors has been reported in western Kenya where long lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the mainstays of vector control. To ensure the sustainability of insecticide-based malaria vector control, monitoring programs need to be implemented. This study was designed to investigate the extent and distribution of pyrethroid resistance in 4 Districts of western Kenya (Nyando, Rachuonyo, Bondo and Teso). All four Districts have received LLINs while Nyando and Rachuonyo Districts have had IRS campaigns for 3-5 years using pyrethroids. This study is part of a programme aimed at determining the impact of insecticide resistance on malaria epidemiology. METHODS:Three day old adult mosquitoes from larval samples collected in the field, were used for bioassays using the WHO tube bioassay, and mortality recorded 24 hours post exposure. Resistance level was assigned based on the 2013 WHO guidelines where populations with <90% mortality were considered resistant. Once exposed, samples were identified to species using PCR. RESULTS:An. arabiensis comprised at least 94% of all An. gambiae s.l. in Bondo, Rachuonyo and Nyando. Teso was a marked contrast case with 77% of all samples being An. gambiae s.s. Mortality to insecticides varied widely between clusters even in one District with mortality to deltamethrin ranging from 45-100%, while to permethrin the range was 30-100%. Mortality to deltamethrin in Teso District was?<?90% in 4 of 6 clusters tested in An arabiensis and <90% in An. gambiae s.s in 5 of 6 clusters tested. To permethrin, mortality ranged between 5.9-95%, with <90% mortality in 9 of 13 and 8 of 13 in An. arabiensis and An. gambiae s.s. respectively. Cluster specific mortality of An. arabiensis between permethin and deltamethrin were not correlated (Z?=?2.9505, P?=?0.2483). CONCLUSION:High levels of pyrethroid resistance were observed in western Kenya. This resistance does not seem to be associated with either species or location. Insecticide resistance can vary within small geographical areas and such heterogeneity may make it possible to evaluate the impact of resistance on malaria and mosquito parameters within similar eco-epidemiological zones.

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Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

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Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

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