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Abstracts 1001 303 surface. In order to test whether antibodies to PfMAS170 could block molecule in E. coli, structural complexity has continued to be a challenge merozoite invasion, growth of P. falciparum 3D7 parasite in the presence for further development of an effective vaccine. The goal of this study of anti-PfMAS170 antibody was tested. The anti-PfMAS170 antibody was to investigate Pfs48/45 using DNA vaccine platform. The rationale significantly inhibits the merozoite invasion to erythrocytes. Since anti- is to develop a TBV that is: (i) technically less challenging in comparison PfMAS170 antibodies inhibited merozoite invasion in vitro, we decided to to recombinant protein production, (ii) cost-effective, (iii) stable, and investigate whether PfMAS170 is exposed to the human immune system (iv) easy to manufacture. In addition, DNA vaccine platform allows a in P. falciparum-infected individuals. The sera from P. falciparum infected multivalent approach by combining several antigens. Our vaccine design individuals in Thailand reacted with the recombinant PfMAS170, indicating included codon optimization of DNA sequence for optimum expression, PfMAS170 is immunogenic in humans. Taken together, these results in-vivo electroporation for enhanced immunogenicity, mutations to block suggested that PfMAS170 plays important role in the merozoite invasion any N-linked glycosylation in the expressed protein, and a heterologous process. The C-terminal erythrocyte-binding domain is of interest for the prime-boost approach. Additionally, we evaluated a combination of DNA development of blood-stage malaria vaccine. vaccines encoding Pfs48/45 and Pfs25. All 7 putative N-linked glycosylation sites in Pfs48/45 were mutated (N to D or K) based on available sequences 999 of P48/45 orthlogs in various Plasmodium species. Rhesus macaques (N=4) were assigned to each of three groups and immunized (IM) with 3 DNA EVALUATING THE POTENTIAL IMPACT OF TRANSMISSION vaccine doses (2.5mg), using in vivo electroporation at 4 week intervals BLOCKING VACCINES AGAINST PLASMODIUM FALCIPARUM followed by a recombinant protein boost (50ug protein in Alum). Antibody INFECTION ALONGSIDE EXISTING INTERVENTIONS titers were determined by ELISA and functional activity in mosquito membrane feeding assays. Results on various test parameters as well as Robert Verity, Tom Churcher, Azra Ghani outcome of combining two different TBV target antigens will be discussed. MRC Centre for Outbreak Analysis and Modelling, Imperial College (Funded by AI47089, AI101427 and AI 103466). London, London, United Kingdom Transmission-blocking vaccines are under development with the aim that 1001 they will reduce or interrupt transmission in malaria endemic settings when used alongside existing interventions. However, their utility will depend DISTRIBUTIONAL IMPACT OF RTS,S VACCINATION IN not only on their efficacy and durability, but also on characteristics of the SUB-SAHARAN AFRICA: IMPLICATIONS FOR POLICY transmission setting including the intensity and seasonality of transmission. IMPLEMENTATION We extended a published mathematical model to identify settings in Sub- Katya Galactionova, Fabrizio Tediosi, Thomas A. Smith, Melissa Saharan Africa in which a TBV could interrupt transmission if implemented A. Penny alongside existing interventions, and the characteristics required of the TBV and of the vaccination programme. In all settings repeated annual Swiss Tropical and Public Health Institute, Basel, Switzerland rounds of vaccination will be required, with more frequent rounds required A growing body of evidence has demonstrated that many public health if the duration of protection is shorter or if the initial transmission intensity interventions developed to aid the poor are not reaching their intended is high. The protective efficacy of a typical TBV vaccine with a 1-year half- target. These concerns are relevant for the introduction of a malaria life is predicted to be substantially higher in seasonal settings compared vaccine, the most advanced of which is RTS,S, currently in Phase III clinical to perennial settings with the same average transmission intensity, with trials. Initial results indicate that RTS,S can provide modest protection greater efficacy achieved if the vaccination programme is aligned with against both clinical and severe malaria in young infants. We examine the the start of the transmission season. Overall the protective efficacy is potential distributional impact of the RTS,S vaccine in 6 African countries predicted to be greatest in areas of low transmission but the number of by evaluating differences in the relative risk of malaria against projected cases averted greatest in areas of moderate transmission. Thus the optimal vaccine coverage and health benefits across beneficiaries grouped by location to undertake Phase III trials for candidate vaccines would be in socio-economic characteristics using an asset index. To accomplish this we existing low to moderate transmission areas. first link country Demographic and Health Surveys with the distributions of entomological inoculation rate derived from the prevalence data 1000 assembled by the Malaria Atlas Program. We then combine information on transmission, access to health services and baseline vector control IMMUNOGENICITY OF DNA VACCINES ENCODING PFS48/45, interventions coverage to assess the impact of vaccine deployment on A PLASMODIUM FALCIPARUM TRANSMISSION-BLOCKING disease burden and its distribution across different population groups VACCINE ANTIGEN IN RHESUS MONKEYS BY IN VIVO using a stochastic simulator of malaria epidemiology and control. We ELECTROPORATION INCLUDING EVALUATION OF CODON estimate the extent of forgone health due to disparities in access to OPTIMIZATION AND N-LINKED GLYCOSYLATION immunization services by simulating a scenario assuming immunization coverage of the group in the highest socio-economic quintiles for the 1 1 2 Dibyadyuti Datta , Geetha Bansal , Brooke Grasperge , Mario whole vaccination cohort. We highlight the importance of malaria case 2 1 3 4 Philipp , Rajesh Kumar , Dietlind Gerloff , Drew Hannaman , management in sustaining the health gains achieved with the RTS,S by 1 Nirbhay Kumar simulating vaccine impact at levels of highest wealth quintile for both 1Tulane School of Public Health and Tropical Medicine, New Orleans, LA, immunization and case management coverage. Our findings suggest that United States, 2Tulane National Primate Research Center, Covington, LA, substantial additional reductions in burden could be realized with RTS,S United States, 3Foundation for Applied Molecular Evolution, Gainesville, by targeting the underserved population with either extensive outreach or FL, United States, 4ICHOR Medical Systems Inc., San Diego, CA, United through innovative distribution channels. We further illustrate the gains States in program effectiveness if vaccine deployment in combined with systems Antigens expressed on various sexual stages of Plasmodium falciparum strengthening to improve access to malaria case management. are being pursued as targets of transmission blocking vaccines (TBV). These include gamete surface proteins (Pfs230 and Pfs48/45) and zygote/ookinete surface protein (Pfs25) expressed after fertilization in the mosquito midgut. Ingestion of antibodies against these antigens effectively blocks parasite development in the midgut. Efforts are underway to develop vaccines based on either recombinant proteins- adjuvant formulations or as DNA vaccines. While our laboratory has previously expressed Pfs48/45 as a functionally effective recombinant astmh.org 304 1002 of recipient mice. Irraditated whole blood from vaccinated mice could adoptively transfer immunity to recipient mice. Furthermore, treatment of DEVELOPMENT OF PLASMODIUM FALCIPARUM vaccinated mice with anti-malaria chemotherapy was able to reduce the RETICULOCYTE BINDING-LIKE HOMOLOGOUS PROTEIN 2 level of immunity in vaccinated mice. Our results suggest that immunity (PFRH2) AS A BLOOD-STAGE MALARIA VACCINE CANDIDATE in mice is dependent on a persisting sub-patent attenuated infection. These results have informed our strategy to develop a P. falciparum vaccine Tajali Sahar, Alok Kumar Pandey, Archana Sharma, Amlabu with a major goal of utilizing an attenuating dose of TfA that enables a Emmanuel, K. Sony Reddy, Virander S. Chauhan, Deepak Gaur persisting sub-patent infection. International Centre for Genetic Engineering and Biotechnology, New Delhi, India 1004 The Plasmodium falciparum reticulocyte binding-like homologous (PfRH) family of proteins are key determinants of different erythrocyte THE USE OF A TRANSGENIC RODENT MALARIA CHALLENGE invasion pathways. Out of five functional PfRH proteins, we report that MODEL FOR ASSESSMENT OF NOVEL LIVER-STAGE MALARIA native PfRH2 undergoes processing yielding fragments that exhibit VACCINES differential erythrocyte binding specificities. Consistent with previous Ahmed M. Salman1, Rhea J. Longley1, Alexandra J. Spencer1, PfRH2 knockout studies, the RBC binding specificity of native PfRH2 Shahid M. Khan2, Chris J. Janse2, Adrian V.S. Hill1 was sialic acid-independent, trypsin resistant and chymotrypsin sensitive. 1 However, a smaller processed fragment bound erythrocytes with a The Jenner Institute, University of Oxford, Oxford, United Kingdom, 2 different phenotype. To further characterize the processing sequence and Leiden Malaria Research Group, Leiden University Medical Center, Leiden, localization of the resulting fragments, we have raised specific antibodies
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