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1. Human adenovirus 5-vectored Plasmodium falciparum NMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection

Author

Tamminga, Cindy, Sedegah, Martha, Maiolatesi, Santina, Fedders, Charlotte, Reyes, Sharina, Reyes, Anatalio, Vasquez, Carlos, Alcorta, Yolanda, Chuang, Ilin, Spring, Michele, Kavanaugh, Michael, Ganeshan, Harini, Huang, Jun, Belmonte, Maria, Abot, Esteban, Belmonte, Arnel, Banania, JoGlenna, Farooq, Fouzia, Murphy, Jittawadee, Komisar, Jack, Richie, Nancy O, Bennett, Jason, Limbach, Keith, Patterson, Noelle B, Bruder, Joseph T, Shi, Meng, Miller, Edward, Dutta, Sheetij, Diggs, Carter, Soisson, Lorraine A, Hollingdale, Michael R, Epstein, Judith E, and Richie, Thomas L

Published
2013

2. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA

Author

Richie, Thomas L., Charoenvit, Yupin, Wang, Ruobing, Epstein, Judith E., Hedstrom, Richard C., Kumar, Sanjai, Luke, Thomas C., Freilich, Daniel A., Aguiar, Joao C., Sacci, John B., Jr., Sedegah, Martha, Nosek, Ronald A., Jr., De La Vega, Patricia, Berzins, Mara P., Majam, Victoria F., Abot, Esteban N., Ganeshan, Harini, Richie, Nancy O., Banania, Jo Glenna, Baraceros, Maria Fe B., Geter, Tanya G., Mere, Robin, Bebris, Lolita, Limbach, Keith, Hickey, Bradley W., Lanar, David E., Ng, Jennifer, Shi, Meng, Hobart, Peter M., Norman, Jon A., Soisson, Lorraine A., Hollingdale, Michael R., Rogers, William O., Doolan, Denise L., and Hoffman, Stephen L.

Published
2012

3. Safety, tolerability, and antibody responses in humans after sequential immunization with a PfCSP DNA vaccine followed by the recombinant protein vaccine RTS,S/AS02A

Author

Epstein, Judith E, Charoenvit, Yupin, Kester, Kent E, Wang, Ruobing, Newcomer, Rhonda, Fitzpatrick, Steve, Richie, Thomas L, Tornieporth, Nadia, Heppner, D.Gray, Ockenhouse, Chris, Majam, Victoria, Holland, Carolyn, Abot, Esteban, Ganeshan, Harini, Berzins, Mara, Jones, Trevor, Freydberg, C.Nicole, Ng, Jennifer, Norman, Jon, Carucci, Daniel J, Cohen, Joe, and Hoffman, Stephen L

Published
2004
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4. Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults

Author

Sayo Renato, Banania Glenna, Legano Jennylyn, Abot Esteban, Geneshan Harini, Adu-Amankwah Susan, Ocran Josephine, Akanmori Bartholomew D, Gyan Ben, Koram Kwadwo A, Anum Dorothy, Hollingdale Michael R, Dodoo Daniel, Brambilla Donald, Kumar Sanjai, Doolan Denise L, Rogers William O, Epstein Judith, Richie Thomas L, and Sedegah Martha

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays. Methods In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart. Results In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivo ELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants. Conclusions All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between samples taken two weeks apart, indicating significant biological variability over short intervals.

Published
2011
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5. Identification of two new protective pre-erythrocytic malaria vaccine antigen candidates

Author

Patterson Noelle, Gowda Kalpana, Aguiar Joao, Limbach Keith, Abot Esteban, Sedegah Martha, Sacci John, and Richie Thomas

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Despite years of effort, a licensed malaria vaccine is not yet available. One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens. To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen. Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens. In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a Plasmodium yoelii/mouse protection model. Methods Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three P. yoelii vaccine antigens. The immunized mice were challenged with 300 P. yoelii sporozoites and evaluated for subsequent infection. Results Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a P. yoelii challenge. However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen. Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three P. yoelii antigens. The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction. Conclusions This work identifies two promising malaria vaccine antigen candidates and suggests that a multi-antigen vaccine may be more efficacious than a single antigen vaccine.

Published
2011
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6. Identification and localization of minimal MHC-restricted CD8+ T cell epitopes within the Plasmodium falciparum AMA1 protein

Author

Sedegah Martha, Kim Yohan, Peters Bjoern, McGrath Shannon, Ganeshan Harini, Lejano Jennylynn, Abot Esteban, Banania Glenna, Belmonte Maria, Sayo Renato, Farooq Fouzia, Doolan Denise L, Regis David, Tamminga Cindy, Chuang Ilin, Bruder Joseph T, King C Richter, Ockenhouse Christian F, Faber Bart, Remarque Edmond, Hollingdale Michael R, Richie Thomas L, and Sette Alessandro

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Plasmodium falciparum apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1. Methods A recombinant adenovirus serotype 5 vector expressing P. falciparum AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-γ ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-γ responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of P. falciparum AMA1 and Domain III of P. vivax AMA1 was used to map these epitopes. Results Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes), B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-γ responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure. Conclusions This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations.

Published
2010
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7. MOESM1 of New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model

Author

Limbach, Keith, Stefaniak, Maureen, Chen, Ping, Patterson, Noelle, Liao, Grant, Shaojie Weng, Krepkiy, Svetlana, Ekberg, Greg, Torano, Holly, Damodar Ettyreddy, Gowda, Kalpana, Sharvari Sonawane, Arnel Belmonte, Abot, Esteban, Sedegah, Martha, Hollingdale, Michael, Moormann, Ann, Vulule, John, Villasante, Eileen, Richie, Thomas, Brough, Douglas, and Bruder, Joseph

Abstract

Additional file 1. CD4+ T cell responses induced by the prime-boost vaccines in protection study 1.

Published
2017
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8. MOESM2 of Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity

Author

Hickey, Bradley, Lumsden, Joanne, Sharina Reyes, Sedegah, Martha, Hollingdale, Michael, Freilich, Daniel, Luke, Thomas, Yupin Charoenvit, Goh, Lucy, Berzins, Mara, Bebris, Lolita, Sacci, John, Vega, Patricia, Ruobing Wang, Harini Ganeshan, Abot, Esteban, Carucci, Daniel, Doolan, Denise, Brice, Gary, Kumar, Anita, Joao Aguiar, Nutman, Thomas, Leitman, Susan, Hoffman, Stephen, Epstein, Judith, and Richie, Thomas

Subjects
animal diseases, bacteria, chemical and pharmacologic phenomena, biochemical phenomena, metabolism, and nutrition
Abstract

Additional file 2. Adverse events experienced by two subjects who received more than six immunizations.

Published
2016
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9. New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model

Author

Limbach, Keith, primary, Stefaniak, Maureen, additional, Chen, Ping, additional, Patterson, Noelle B., additional, Liao, Grant, additional, Weng, Shaojie, additional, Krepkiy, Svetlana, additional, Ekberg, Greg, additional, Torano, Holly, additional, Ettyreddy, Damodar, additional, Gowda, Kalpana, additional, Sonawane, Sharvari, additional, Belmonte, Arnel, additional, Abot, Esteban, additional, Sedegah, Martha, additional, Hollingdale, Michael R., additional, Moormann, Ann, additional, Vulule, John, additional, Villasante, Eileen, additional, Richie, Thomas L., additional, Brough, Douglas E., additional, and Bruder, Joseph T., additional

Published
2017
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10. A Plasmodium vivax Plasmid DNA- and Adenovirus-Vectored Malaria Vaccine Encoding Blood-Stage Antigens AMA1 and MSP1 42 in a Prime/Boost Heterologous Immunization Regimen Partially Protects Aotus Monkeys against Blood-Stage Challenge

Author

Obaldia, Nicanor, primary, Stockelman, Michael G., additional, Otero, William, additional, Cockrill, Jennifer A., additional, Ganeshan, Harini, additional, Abot, Esteban N., additional, Zhang, Jianfeng, additional, Limbach, Keith, additional, Charoenvit, Yupin, additional, Doolan, Denise L., additional, Tang, De-chu C., additional, and Richie, Thomas L., additional

Published
2017
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11. Protection against Plasmodium falciparum malaria by PfSPZ Vaccine

Author

Epstein, Judith E., primary, Paolino, Kristopher M., additional, Richie, Thomas L., additional, Sedegah, Martha, additional, Singer, Alexandra, additional, Ruben, Adam J., additional, Chakravarty, Sumana, additional, Stafford, April, additional, Ruck, Richard C., additional, Eappen, Abraham G., additional, Li, Tao, additional, Billingsley, Peter F., additional, Manoj, Anita, additional, Silva, Joana C., additional, Moser, Kara, additional, Nielsen, Robin, additional, Tosh, Donna, additional, Cicatelli, Susan, additional, Ganeshan, Harini, additional, Case, Jessica, additional, Padilla, Debbie, additional, Davidson, Silas, additional, Garver, Lindsey, additional, Saverino, Elizabeth, additional, Murshedkar, Tooba, additional, Gunasekera, Anusha, additional, Twomey, Patrick S., additional, Reyes, Sharina, additional, Moon, James E., additional, James, Eric R., additional, KC, Natasha, additional, Li, Minglin, additional, Abot, Esteban, additional, Belmonte, Arnel, additional, Hauns, Kevin, additional, Belmonte, Maria, additional, Huang, Jun, additional, Vasquez, Carlos, additional, Remich, Shon, additional, Carrington, Mary, additional, Abebe, Yonas, additional, Tillman, Amy, additional, Hickey, Bradley, additional, Regules, Jason, additional, Villasante, Eileen, additional, Sim, B. Kim Lee, additional, and Hoffman, Stephen L., additional

Published
2017
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12. Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity

Author

Hickey, Bradley W., primary, Lumsden, Joanne M., additional, Reyes, Sharina, additional, Sedegah, Martha, additional, Hollingdale, Michael R., additional, Freilich, Daniel A., additional, Luke, Thomas C., additional, Charoenvit, Yupin, additional, Goh, Lucy M., additional, Berzins, Mara P., additional, Bebris, Lolita, additional, Sacci, John B., additional, De La Vega, Patricia, additional, Wang, Ruobing, additional, Ganeshan, Harini, additional, Abot, Esteban N., additional, Carucci, Daniel J., additional, Doolan, Denise L., additional, Brice, Gary T., additional, Kumar, Anita, additional, Aguiar, Joao, additional, Nutman, Thomas B., additional, Leitman, Susan F., additional, Hoffman, Stephen L., additional, Epstein, Judith E., additional, and Richie, Thomas L., additional

Published
2016
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13. Controlled Human Malaria Infection (CHMI) differentially affects cell-mediated and antibody responses to CSP and AMA1 induced by adenovirus vaccines with and without DNA-priming

Author

Sedegah, Martha, primary, Hollingdale, Michael R, additional, Farooq, Fouzia, additional, Ganeshan, Harini, additional, Belmonte, Maria, additional, Huang, Jun, additional, Abot, Esteban, additional, Limbach, Keith, additional, Chuang, Ilin, additional, Tamminga, Cindy, additional, Epstein, Judith E, additional, and Villasante, Eileen, additional

Published
2015
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14. Sterile Immunity to Malaria after DNA Prime/Adenovirus Boost Immunization Is Associated with Effector Memory CD8+T Cells Targeting AMA1 Class I Epitopes

Author

Sedegah, Martha, primary, Hollingdale, Michael R., additional, Farooq, Fouzia, additional, Ganeshan, Harini, additional, Belmonte, Maria, additional, Kim, Yohan, additional, Peters, Bjoern, additional, Sette, Alessandro, additional, Huang, Jun, additional, McGrath, Shannon, additional, Abot, Esteban, additional, Limbach, Keith, additional, Shi, Meng, additional, Soisson, Lorraine, additional, Diggs, Carter, additional, Chuang, Ilin, additional, Tamminga, Cindy, additional, Epstein, Judith E., additional, Villasante, Eileen, additional, and Richie, Thomas L., additional

Published
2014
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15. Identification of Two New Protective Pre-erythrocytic Malaria Vaccine Antigen Candidates

Author

WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD MILITARY MALARIA VACCINE PROGRAM, Limbach, Keith, Aguiar, Joao, Gowda, Kalpana, Patterson, Noelle, Abot, Esteban, Sedegah, Martha, Sacci, John, Richie, Thomas, WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD MILITARY MALARIA VACCINE PROGRAM, Limbach, Keith, Aguiar, Joao, Gowda, Kalpana, Patterson, Noelle, Abot, Esteban, Sedegah, Martha, Sacci, John, and Richie, Thomas

Abstract

Despite years of effort, a licensed malaria vaccine is not yet available. One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens. To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen. Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens. In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a Plasmodium yoelii/mouse protection model. Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three P. yoelii vaccine antigens. The immunized mice were challenged with 300 P. yoelii sporozoites and evaluated for subsequent infection. Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a P. yoelii challenge. However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen. Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three P. yoelii antigens. The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction. This work identifies two promising malaria vaccine antigen candidates and suggests that a multiantigen vaccine may be more efficacious than a single antigen vaccine., Published in Malaria Journal, v10, 2011. The original document contains color images.

Published
2011

16. Identification and Localization of Minimal MHC-restricted CD8+ T Cell Epitopes within the Plasmodium falciparum AMA1 Protein

Author

NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD, Sedegah, Martha, Kim, Yohan, Peters, Bjoern, McGrath, Shannon, Ganeshan, Harini, Lejano, Jennylynn, Abot, Esteban, Banania, Glenna, Belmonte, Maria, Sayo, Renato, NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD, Sedegah, Martha, Kim, Yohan, Peters, Bjoern, McGrath, Shannon, Ganeshan, Harini, Lejano, Jennylynn, Abot, Esteban, Banania, Glenna, Belmonte, Maria, and Sayo, Renato

Abstract

Background: Plasmodium falciparum apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1. Methods: A recombinant adenovirus serotype 5 vector expressing P. falciparum AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-g ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-g responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of P. falciparum AMA1 and Domain III of P. vivax AMA1 was used to map these epitopes. Results: Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes) B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-g responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure. Conclusions: This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations., Published in Malaria Journal, v9 n241 p1-16, 2010.

Published
2010

17. Human adenovirus 5-vectoredPlasmodium falciparumNMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection

Author

Tamminga, Cindy, primary, Sedegah, Martha, additional, Maiolatesi, Santina, additional, Fedders, Charlotte, additional, Reyes, Sharina, additional, Reyes, Anatalio, additional, Vasquez, Carlos, additional, Alcorta, Yolanda, additional, Chuang, Ilin, additional, Spring, Michele, additional, Kavanaugh, Michael, additional, Ganeshan, Harini, additional, Huang, Jun, additional, Belmonte, Maria, additional, Abot, Esteban, additional, Belmonte, Arnel, additional, Banania, JoGlenna, additional, Farooq, Fouzia, additional, Murphy, Jittawadee, additional, Komisar, Jack, additional, Richie, Nancy O, additional, Bennett, Jason, additional, Limbach, Keith, additional, Patterson, Noelle B, additional, Bruder, Joseph T, additional, Shi, Meng, additional, Miller, Edward, additional, Dutta, Sheetij, additional, Diggs, Carter, additional, Soisson, Lorraine A, additional, Hollingdale, Michael R, additional, Epstein, Judith E, additional, and Richie, Thomas L, additional

Published
2013
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18. Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP)

Author

Sedegah, Martha, primary, Kim, Yohan, additional, Ganeshan, Harini, additional, Huang, Jun, additional, Belmonte, Maria, additional, Abot, Esteban, additional, Banania, Jo Glenna, additional, Farooq, Fouzia, additional, McGrath, Shannon, additional, Peters, Bjoern, additional, Sette, Alessandro, additional, Soisson, Lorraine, additional, Diggs, Carter, additional, Doolan, Denise L, additional, Tamminga, Cindy, additional, Villasante, Eileen, additional, Hollingdale, Michael R, additional, and Richie, Thomas L, additional

Published
2013
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19. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity

Author

Chuang, Ilin, primary, Sedegah, Martha, additional, Cicatelli, Susan, additional, Spring, Michele, additional, Polhemus, Mark, additional, Tamminga, Cindy, additional, Patterson, Noelle, additional, Guerrero, Melanie, additional, Bennett, Jason W., additional, McGrath, Shannon, additional, Ganeshan, Harini, additional, Belmonte, Maria, additional, Farooq, Fouzia, additional, Abot, Esteban, additional, Banania, Jo Glenna, additional, Huang, Jun, additional, Newcomer, Rhonda, additional, Rein, Lisa, additional, Litilit, Dianne, additional, Richie, Nancy O., additional, Wood, Chloe, additional, Murphy, Jittawadee, additional, Sauerwein, Robert, additional, Hermsen, Cornelus C., additional, McCoy, Andrea J., additional, Kamau, Edwin, additional, Cummings, James, additional, Komisar, Jack, additional, Sutamihardja, Awalludin, additional, Shi, Meng, additional, Epstein, Judith E., additional, Maiolatesi, Santina, additional, Tosh, Donna, additional, Limbach, Keith, additional, Angov, Evelina, additional, Bergmann-Leitner, Elke, additional, Bruder, Joseph T., additional, Doolan, Denise L., additional, King, C. Richter, additional, Carucci, Daniel, additional, Dutta, Sheetij, additional, Soisson, Lorraine, additional, Diggs, Carter, additional, Hollingdale, Michael R., additional, Ockenhouse, Christian F., additional, and Richie, Thomas L., additional

Published
2013
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20. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stagePlasmodium falciparumDNA vaccine combined with escalating dose human GM-CSF DNA

Author

Richie, Thomas L., primary, Charoenvit, Yupin, additional, Wang, Ruobing, additional, Epstein, Judith E., additional, Hedstrom, Richard C., additional, Kumar, Sanjai, additional, Luke, Thomas C., additional, Freilich, Daniel A., additional, Aguiar, Joao C., additional, Sacci, Jr., John B., additional, Sedegah, Martha, additional, Nosek, Jr., Ronald A., additional, De La Vega, Patricia, additional, Berzins, Mara P., additional, Majam, Victoria F., additional, Abot, Esteban N., additional, Ganeshan, Harini, additional, Richie, Nancy O., additional, Banania, Jo Glenna, additional, Baraceros, Maria Fe B., additional, Geter, Tanya G., additional, Mere, Robin, additional, Bebris, Lolita, additional, Limbach, Keith, additional, Hickey, Bradley W., additional, Lanar, David E., additional, Ng, Jennifer, additional, Shi, Meng, additional, Hobart, Peter M., additional, Norman, Jon A., additional, Soisson, Lorraine A., additional, Hollingdale, Michael R., additional, Rogers, William O., additional, Doolan, Denise L., additional, and Hoffman, Stephen L., additional

Published
2012
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21. A Small Peptide (CEL-1000) Derived from the Beta-Chain of the Human Major Histocompatibility Complex Class II Molecule Induces Complete Protection Against Malaria in an Antigen-Independent Manner

Author

NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD, Charoenvit, Yupin, Brice, Gary T., Bacon, David, Majam, Victoria, Williams, Jackie, Abot, Esteban, Ganeshan, Harini, Sedegah, Martha, Doolan, Denise L., Carucci, Daniel J., Zimmerman, Daniel H., NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD, Charoenvit, Yupin, Brice, Gary T., Bacon, David, Majam, Victoria, Williams, Jackie, Abot, Esteban, Ganeshan, Harini, Sedegah, Martha, Doolan, Denise L., Carucci, Daniel J., and Zimmerman, Daniel H.

Abstract

CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2a) and C3H/HeJ (H-2k) mice but not in BALB/c (H-2d) or CAF1 (A/J BALB/c F1 hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN- ) in serum and elevated frequencies of hepatic and splenic CD4 IFN- - positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN- just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4 T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8 T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN- and is partially dependent on CD4 T cells but is independent of CD8 T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response., The original document contains color images. Antimicrobial Agents and Chemotherapy, v48 n7 p2455-2463, Jul 2004. ISSN 0066-4804. Prepared in cooperation with Walter Reed Army Institute of Research, Silver Spring, MD, Henry M. Jackson Foundation, Rockville , MD and John Hopkins University, Baltimore, MD. and CEL-SCI Corporation, Vienna VA.

Published
2004

22. Adenovirus 5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part A: Safety and Immunogenicity in Seronegative Adults

Author

Sedegah, Martha, primary, Tamminga, Cindy, additional, McGrath, Shannon, additional, House, Brent, additional, Ganeshan, Harini, additional, Lejano, Jennylynn, additional, Abot, Esteban, additional, Banania, Glenna J., additional, Sayo, Renato, additional, Farooq, Fouzia, additional, Belmonte, Maria, additional, Manohar, Nalini, additional, Richie, Nancy O., additional, Wood, Chloe, additional, Long, Carole A., additional, Regis, David, additional, Williams, Francis T., additional, Shi, Meng, additional, Chuang, Ilin, additional, Spring, Michele, additional, Epstein, Judith E., additional, Mendoza-Silveiras, Jose, additional, Limbach, Keith, additional, Patterson, Noelle B., additional, Bruder, Joseph T., additional, Doolan, Denise L., additional, King, C. Richter, additional, Soisson, Lorraine, additional, Diggs, Carter, additional, Carucci, Daniel, additional, Dutta, Sheetij, additional, Hollingdale, Michael R., additional, Ockenhouse, Christian F., additional, and Richie, Thomas L., additional

Published
2011
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23. Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

Author

Tamminga, Cindy, primary, Sedegah, Martha, additional, Regis, David, additional, Chuang, Ilin, additional, Epstein, Judith E., additional, Spring, Michele, additional, Mendoza-Silveiras, Jose, additional, McGrath, Shannon, additional, Maiolatesi, Santina, additional, Reyes, Sharina, additional, Steinbeiss, Victoria, additional, Fedders, Charlotte, additional, Smith, Kathryn, additional, House, Brent, additional, Ganeshan, Harini, additional, Lejano, Jennylynn, additional, Abot, Esteban, additional, Banania, Glenna J., additional, Sayo, Renato, additional, Farooq, Fouzia, additional, Belmonte, Maria, additional, Murphy, Jittawadee, additional, Komisar, Jack, additional, Williams, Jackie, additional, Shi, Meng, additional, Brambilla, Donald, additional, Manohar, Nalini, additional, Richie, Nancy O., additional, Wood, Chloe, additional, Limbach, Keith, additional, Patterson, Noelle B., additional, Bruder, Joseph T., additional, Doolan, Denise L., additional, King, C. Richter, additional, Diggs, Carter, additional, Soisson, Lorraine, additional, Carucci, Daniel, additional, Levine, Gail, additional, Dutta, Sheetij, additional, Hollingdale, Michael R., additional, Ockenhouse, Christian F., additional, and Richie, Thomas L., additional

Published
2011
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24. Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults

Author

Dodoo, Daniel, primary, Hollingdale, Michael R, additional, Anum, Dorothy, additional, Koram, Kwadwo A, additional, Gyan, Ben, additional, Akanmori, Bartholomew D, additional, Ocran, Josephine, additional, Adu-Amankwah, Susan, additional, Geneshan, Harini, additional, Abot, Esteban, additional, Legano, Jennylyn, additional, Banania, Glenna, additional, Sayo, Renato, additional, Brambilla, Donald, additional, Kumar, Sanjai, additional, Doolan, Denise L, additional, Rogers, William O, additional, Epstein, Judith, additional, Richie, Thomas L, additional, and Sedegah, Martha, additional

Published
2011
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26. A Small Peptide (CEL-1000) Derived from the β-Chain of the Human Major Histocompatibility Complex Class II Molecule Induces Complete Protection against Malaria in an Antigen-Independent Manner

Author

Charoenvit, Yupin, primary, Brice, Gary T., additional, Bacon, David, additional, Majam, Victoria, additional, Williams, Jackie, additional, Abot, Esteban, additional, Ganeshan, Harini, additional, Sedegah, Martha, additional, Doolan, Denise L., additional, Carucci, Daniel J., additional, and Zimmerman, Daniel H., additional

Published
2004
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27. Novel Antigen Identification Method for Discovery of Protective Malaria Antigens by Rapid Testing of DNA Vaccines Encoding Exons from the Parasite Genome

Author

Haddad, Diana, primary, Bilcikova, Erika, additional, Witney, Adam A., additional, Carlton, Jane M., additional, White, Charles E., additional, Blair, Peter L., additional, Chattopadhyay, Rana, additional, Russell, Joshua, additional, Abot, Esteban, additional, Charoenvit, Yupin, additional, Aguiar, Joao C., additional, Carucci, Daniel J., additional, and Weiss, Walter R., additional

Published
2004
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28. Safety, Tolerability, and Lack of Antibody Responses After Administration of aPfCSP DNA Malaria Vaccine via Needle or Needle-Free Jet Injection, and Comparison of Intramuscular and Combination Intramuscular/Intradermal Routes

Author

Epstein, Judith E., primary, Gorak, Edward J., additional, Charoenvit, Yupin, additional, Wang, Ruobing, additional, Freydberg, Nicole, additional, Osinowo, Oluwatoyin, additional, Richie, Thomas L., additional, Stoltz, Erin L., additional, Trespalacios, Fernando, additional, Nerges, John, additional, Ng, Jennifer, additional, Fallarme-Majam, Victoria, additional, Abot, Esteban, additional, Goh, Lucy, additional, Parker, Suezanne, additional, Kumar, Sanjai, additional, Hedstrom, Richard C., additional, Norman, Jon, additional, Stout, Richard, additional, and Hoffman, Stephen L., additional

Published
2002
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29. CD4 + T-Cell- and Gamma Interferon-Dependent Protection against Murine Malaria by Immunization with Linear Synthetic Peptides from a Plasmodium yoelii 17-Kilodalton Hepatocyte Erythrocyte Protein

Author

Charoenvit, Yupin, primary, Majam, Victoria Fallarme, additional, Corradin, Giampietro, additional, Sacci, John B., additional, Wang, Ruobing, additional, Doolan, Denise L., additional, Jones, Trevor R., additional, Abot, Esteban, additional, Patarroyo, Manuel E., additional, Guzman, Fanny, additional, and Hoffman, Stephen L., additional

Published
1999
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30. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity.

Author

Chuang, Ilin, Sedegah, Martha, Cicatelli, Susan, Spring, Michele, Polhemus, Mark, Tamminga, Cindy, Patterson, Noelle, Guerrero, Melanie, Bennett, Jason W., McGrath, Shannon, Ganeshan, Harini, Belmonte, Maria, Farooq, Fouzia, Abot, Esteban, Banania, Jo Glenna, Huang, Jun, Newcomer, Rhonda, Rein, Lisa, Litilit, Dianne, and Richie, Nancy O.

Subjects
ADENOVIRUSES, MALARIA vaccines, CIRCUMSPOROZOITE protein, APICAL membrane antigen 1, CELLULAR immunity, MALARIA prevention, ANTIBODY formation, SEROPREVALENCE
Abstract

Background: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. Methodology/Principal Findings: The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44–817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5–102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13–408; AMA1 348, range 88–1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. Significance: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection. Trial Registration: ClinicalTrials.govNCT00870987. [ABSTRACT FROM AUTHOR]

Published
2013
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31. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/ hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA.

Author

Richie, Thomas L., Charoenvit, Yupin, Wang, Ruobing, Epstein, Judith E., Hedstrom, Richard C., Kumar, Sanjai, Luke, Thomas C., Freilich, Daniel A., Aguiar, Joao C., Sacci Jr., John B., Sedegah, Martha, Nosek Jr., Ronald A., De La Vega, Patricia, Berzins, Mara P., Majam, Victoria F., Abot, Esteban N., Ganeshan, Harini, Richie, Nancy O., Banania, Jo Glenna, and Baraceros, Maria Fe B.

Published
2012
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32. Identification of two new protective preerythrocytic malaria vaccine antigen candidates.

Author

Limbach, Keith, Aguiar, Joao, Gowda, Kalpana, Patterson, Noelle, Abot, Esteban, Sedegah, Martha, Sacci, John, and Richie, Thomas

Subjects
MALARIA, VACCINATION, IMMUNOGLOBULINS, ANTIGENS, IMMUNE response
Abstract

Background: Despite years of effort, a licensed malaria vaccine is not yet available. One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens. To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen. Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens. In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a Plasmodium yoelii/mouse protection model. Methods: Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three P. yoelii vaccine antigens. The immunized mice were challenged with 300 P. yoelii sporozoites and evaluated for subsequent infection. Results: Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a P. yoelii challenge. However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen. Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three P. yoelii antigens. The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction. Conclusions: This work identifies two promising malaria vaccine antigen candidates and suggests that a multiantigen vaccine may be more efficacious than a single antigen vaccine. [ABSTRACT FROM AUTHOR]

Published
2011
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33. Identification and localization of minimalMHC-restricted CD8+ T cell epitopes withinthe Plasmodium falciparum AMA1 protein.

Author

Sedegah, Martha, Yohan Kim, Peters, Bjoern, McGrath, Shannon, Ganeshan, Harini, Lejano, Jennylynn, Abot, Esteban, Banania, Glenna, Belmonte, Maria, Sayo, Renato, Farooq, Fouzia, Doolan, Denise L., Regis, David, Tamminga, Cindy, Ilin Chuang, Bruder, Joseph T., King, C. Richter, Ockenhouse, Christian F., Faber, Bart, and Remarque, Edmond

Subjects
PLASMODIUM falciparum, MALARIA, EPITOPES, HLA histocompatibility antigens, PREVENTIVE medicine
Abstract

Background: Plasmodium falciparum apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1. Methods: A recombinant adenovirus serotype 5 vector expressing P. falciparum AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-γ ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-γ responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of P. falciparum AMA1 and Domain III of P. vivax AMA1 was used to map these epitopes. Results: Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes), B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-γ responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure. Conclusions: This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations. [ABSTRACT FROM AUTHOR]

Published
2010
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34. Human adenovirus 5-vectored Plasmodium falciparumNMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection

Author

Tamminga, Cindy, Sedegah, Martha, Maiolatesi, Santina, Fedders, Charlotte, Reyes, Sharina, Reyes, Anatalio, Vasquez, Carlos, Alcorta, Yolanda, Chuang, Ilin, Spring, Michele, Kavanaugh, Michael, Ganeshan, Harini, Huang, Jun, Belmonte, Maria, Abot, Esteban, Belmonte, Arnel, Banania, JoGlenna, Farooq, Fouzia, Murphy, Jittawadee, Komisar, Jack, Richie, Nancy O, Bennett, Jason, Limbach, Keith, Patterson, Noelle B, Bruder, Joseph T, Shi, Meng, Miller, Edward, Dutta, Sheetij, Diggs, Carter, Soisson, Lorraine A, Hollingdale, Michael R, Epstein, Judith E, and Richie, Thomas L

Abstract

Background: In a prior study, a DNA prime / adenovirus boost vaccine (DNA/Ad) expressing P. falciparumcircumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) (NMRC-M3V-D/Ad-PfCA Vaccine) induced 27% protection against controlled human malaria infection (CHMI). To investigate the contribution of DNA priming, we tested the efficacy of adenovirus vaccine alone (NMRC-M3V-Ad-PfCA ) in a Phase 1 clinical trial.Methodology/Principal Findings: The regimen was a single intramuscular injection with two non-replicating human serotype 5 adenovectors encoding CSP and AMA1, respectively. One x 1010particle units of each construct were combined prior to administration. The regimen was safe and well-tolerated. Four weeks later, 18 study subjects received P. falciparumCHMI administered by mosquito bite. None were fully protected although one showed delayed onset of parasitemia. Antibody responses were low, with geometric mean CSP ELISA titer of 381 (range < 50–1626) and AMA1 ELISA of 4.95 µg/mL (range 0.2–38). Summed ex vivo IFN-γ ELISpot responses to overlapping peptides were robust, with geometric mean spot forming cells/million peripheral blood mononuclear cells [sfc/m] for CSP of 273 (range 38–2550) and for AMA1 of 1303 (range 435–4594). CD4+ and CD8+ T cell IFN-γ responses to CSP were positive by flow cytometry in 25% and 56% of the research subjects, respectively, and to AMA1 in 94% and 100%, respectively.Significance: In contrast to DNA/Ad, Ad alone did not protect against CHMI despite inducing broad, cell-mediated immunity, indicating that DNA priming is required for protection by the adenovirus-vectored vaccine. ClinicalTrials.gov Identifier: NCT00392015.

Published
2013
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35. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparumDNA vaccine combined with escalating dose human GM-CSF DNA

Author

Richie, Thomas L., Charoenvit, Yupin, Wang, Ruobing, Epstein, Judith E., Hedstrom, Richard C., Kumar, Sanjai, Luke, Thomas C., Freilich, Daniel A., Aguiar, Joao C., Sacci, John B., Sedegah, Martha, Nosek, Ronald A., De La Vega, Patricia, Berzins, Mara P., Majam, Victoria F., Abot, Esteban N., Ganeshan, Harini, Richie, Nancy O., Banania, Jo Glenna, Baraceros, Maria Fe B., Geter, Tanya G., Mere, Robin, Bebris, Lolita, Limbach, Keith, Hickey, Bradley W., Lanar, David E., Ng, Jennifer, Shi, Meng, Hobart, Peter M., Norman, Jon A., Soisson, Lorraine A., Hollingdale, Michael R., Rogers, William O., Doolan, Denise L., and Hoffman, Stephen L.

Abstract

When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997−1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparumcircumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000–2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 μg of each plasmid plus escalating doses (0, 20, 100 or 500 μg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines.

Published
2012
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36. Safety, Tolerability, and Lack of Antibody Responses After Administration of a PfCSP DNA Malaria Vaccine via Needle or Needle-Free Jet Injection, and Comparison of Intramuscular and Combination Intramuscular/Intradermal Routes

Author

Epstein, Judith E., Gorak, Edward J., Charoenvit, Yupin, Wang, Ruobing, Freydberg, Nicole, Osinowo, Oluwatoyin, Richie, Thomas L., Stoltz, Erin L., Trespalacios, Fernando, Nerges, John, Ng, Jennifer, Fallarme-Majam, Victoria, Abot, Esteban, Goh, Lucy, Parker, Suezanne, Kumar, Sanjai, Hedstrom, Richard C., Norman, Jon, Stout, Richard, and Hoffman, Stephen L.

Abstract

Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector®) or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable anti-dsDNA antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of the three modes of delivery. However, despite improved antibody responses following both jet injection and ID delivery in animal models, no antibodies could be detected in volunteers by immunofluorescence antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA) after DNA vaccination.

Published
2002
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37. CD4+T-Cell- and Gamma Interferon-Dependent Protection against Murine Malaria by Immunization with Linear Synthetic Peptides from a Plasmodium yoelii17-Kilodalton Hepatocyte Erythrocyte Protein

Author

Charoenvit, Yupin, Majam, Victoria Fallarme, Corradin, Giampietro, Sacci, John B., Wang, Ruobing, Doolan, Denise L., Jones, Trevor R., Abot, Esteban, Patarroyo, Manuel E., Guzman, Fanny, and Hoffman, Stephen L.

Abstract

ABSTRACTMost work on protective immunity against the pre-erythrocytic stages of malaria has focused on induction of antibodies that prevent sporozoite invasion of hepatocytes, and CD8+T-cell responses that eliminate infected hepatocytes. We recently reported that immunization of A/J mice with an 18-amino-acid synthetic linear peptide from Plasmodium yoeliisporozoite surface protein 2 (SSP2) in TiterMax adjuvant induces sterile protection that is dependent on CD4+T cells and gamma interferon (IFN-γ). We now report that immunization of inbred A/J mice and outbred CD1 mice with each of two linear synthetic peptides from the 17-kDa P. yoeliihepatocyte erythrocyte protein (HEP17) in the same adjuvant also induces protection against sporozoite challenge that is dependent on CD4+T cells and IFN-γ. The SSP2 peptide and the two HEP17 peptides are recognized by B cells as well as T cells, and the protection induced by these peptides appears to be directed against the infected hepatocytes. In contrast to the peptide-induced protection, immunization of eight different strains of mice with radiation-attenuated sporozoites induces protection that is absolutely dependent on CD8+T cells. Data represented here demonstrate that CD4+T-cell-dependent protection can be induced by immunization with linear synthetic peptides. These studies therefore provide the foundation for an approach to pre-erythrocytic-stage malaria vaccine development, based on the induction of protective CD4+T-cell responses, which will complement efforts to induce protective antibody and CD8+T-cell responses.

Published
1999
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38. A Plasmodium vivaxPlasmid DNA- and Adenovirus-Vectored Malaria Vaccine Encoding Blood-Stage Antigens AMA1 and MSP142in a Prime/Boost Heterologous Immunization Regimen Partially Protects AotusMonkeys against Blood-Stage Challenge

Author

Obaldia, Nicanor, Stockelman, Michael G., Otero, William, Cockrill, Jennifer A., Ganeshan, Harini, Abot, Esteban N., Zhang, Jianfeng, Limbach, Keith, Charoenvit, Yupin, Doolan, Denise L., Tang, De-chu C., and Richie, Thomas L.

Abstract

ABSTRACTMalaria is caused by parasites of the genus Plasmodium, which are transmitted to humans by the bites of Anophelesmosquitoes. After the elimination of Plasmodium falciparum, it is predicted that Plasmodium vivaxwill remain an important cause of morbidity and mortality outside Africa, stressing the importance of developing a vaccine against P. vivaxmalaria. In this study, we assessed the immunogenicity and protective efficacy of two P. vivaxantigens, apical membrane antigen 1 (AMA1) and the 42-kDa C-terminal fragment of merozoite surface protein 1 (MSP142) in a plasmid recombinant DNA prime/adenoviral (Ad) vector boost regimen in Aotusmonkeys. Groups of 4 to 5 monkeys were immunized with plasmid DNA alone, Ad alone, prime/boost regimens with each antigen, prime/boost regimens with both antigens, and empty vector controls and then subjected to blood-stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, on the basis of their ability to induce the longest prepatent period and the longest time to the peak level of parasitemia, the lowest peak and mean levels of parasitemia, the smallest area under the parasitemia curve, and the highest self-cure rate. Overall, prechallenge MSP142antibody titers strongly correlated with a decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, the P. vivaxplasmid DNA/Ad serotype 5 vaccine encoding blood-stage parasite antigens AMA1 and MSP142in a heterologous prime/boost immunization regimen provided significant protection against blood-stage challenge in Aotusmonkeys, indicating the suitability of these antigens and this regimen for further development.

Published
2017
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39. A small peptide (CEL-1000) derived from the beta-chain of the human major histocompatibility complex class II molecule induces complete protection against malaria in an antigen-independent manner.

Author

Charoenvit Y, Brice GT, Bacon D, Majam V, Williams J, Abot E, Ganeshan H, Sedegah M, Doolan DL, Carucci DJ, and Zimmerman DH

Subjects
Amino Acid Sequence, Animals, Antibody Specificity, Cytokines blood, Enzyme-Linked Immunosorbent Assay, Female, Interferon-gamma immunology, Kinetics, Liver chemistry, Liver parasitology, Malaria immunology, Malaria parasitology, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Plasmodium berghei immunology, Plasmodium yoelii immunology, RNA chemistry, RNA isolation & purification, Reverse Transcriptase Polymerase Chain Reaction, Antigens, Protozoan immunology, Antimalarials pharmacology, Genes, MHC Class II genetics, Malaria prevention & control
Abstract

CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2(a)) and C3H/HeJ (H-2(k)) mice but not in BALB/c (H-2(d)) or CAF1 (A/J x BALB/c F(1) hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN-gamma) in serum and elevated frequencies of hepatic and splenic CD4+ IFN-gamma-positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN-gamma just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4+ T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8+ T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN-gamma and is partially dependent on CD4+ T cells but is independent of CD8+ T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response.

Published
2004
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