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Martha Sedegah,
Yohan Kim,
Harini Ganeshan,
Jun Huang,
Maria Belmonte,
Esteban Abot,
Jo Glenna Banania,
Fouzia Farooq,
Shannon McGrath,
Bjoern Peters,
Alessandro Sette,
Lorraine Soisson,
Carter Diggs,
Denise L Doolan,
Cindy Tamminga,
Eileen Villasante,
Michael R Hollingdale, Thomas L Richie
[show abstract]
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ABSTRACT: BACKGROUND: Plasmodium falciparum circumsporozoite protein (CSP) is a leading malaria vaccine candidate antigen, known to elicit protective antibody responses in humans (RTS,S vaccine). Recently, a DNA prime / adenovirus (Ad) vector boost vaccine encoding CSP and a second P. falciparum antigen, apical membrane antigen-1, also elicited sterile protection, but in this case associated with interferon gamma ELISpot and CD8+ T cell but not antibody responses. The finding that CSP delivered by an appropriate vaccine platform likely elicits protective cell-mediated immunity provided a rationale for identifying class I-restricted epitopes within this leading vaccine candidate antigen. METHODS: Limited samples of peripheral blood mononuclear cells from clinical trials of the Ad vaccine were used to identify CD8+ T cell epitopes within pools of overlapping 15mer peptides spanning portions of CSP that stimulated recall responses. Computerized algorithms (NetMHC) predicted 17 minimal class I-restricted 9-10mer epitopes within fifteen 15mers positive in ELISpot assay using PBMC from 10 HLA-matched study subjects. Four additional epitopes were subsequently predicted using NetMHC, matched to other study subjects without initial 15mer ELISpot screening. Nine of the putative epitopes were synthesized and tested by ELISpot assay, and six of these nine were further tested for CD8+ T cell responses by ELISpot CD4+ and CD8+ T cell-depletion and flow cytometry assays for evidence of CD8+ T cell dependence. RESULTS: Each of the nine putative epitopes, all sequence-conserved, recalled responses from HLA-matched CSP-immunized research subjects. Four shorter sequences contained within these sequences were identified using NetMHC predictions and may have contributed to recall responses. Five (9-10mer) epitopes were confirmed to be targets of CD8+ T cell responses using ELISpot depletion and ICS assays. Two 9mers among these nine epitopes were each restricted by two HLA supertypes (A01/B07; A01A24/A24) and one 9mer was restricted by three HLA supertypes (A01A24/A24/B27) indicating that some CSP class I-restricted epitopes, like DR epitopes, may be HLA-promiscuous. CONCLUSIONS: This study identified nine and confirmed five novel class I epitopes restricted by six HLA supertypes, suggesting that an adenovirus-vectored CSP vaccine would be immunogenic and potentially protective in genetically diverse populations.
Malaria Journal 06/2013; 12(1):185. · 3.19 Impact Factor
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Cindy Tamminga,
Michael Kavanaugh,
Charlotte Fedders,
Santina Maiolatesi,
Neethu Abraham,
Jan Bonhoeffer,
Ulrich Heininger,
Carlos Vasquez,
Vasee S Moorthy,
Judith E Epstein, Thomas L Richie
[show abstract]
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ABSTRACT: INTRODUCTION: Malaria, tuberculosis (TB) and human immunodeficiency virus (HIV) are diseases with devastating effects on global public health, especially in the developing world. Clinical trials of candidate vaccines for these diseases are being conducted at an accelerating rate, and require accurate and consistent methods for safety data collection and reporting. We performed a systematic review of publications describing the safety results from clinical trials of malaria, TB and HIV vaccines, to ascertain the nature and consistency of safety data collection and reporting. METHODS: The target for the review was pre-licensure trials for malaria, TB and HIV vaccines published in English from 2000 to 2009. Search strategies were customized for each of the databases utilized (MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Database of Reviews and Effects). Data extracted included age of trial participants, vaccine platform, route and method of vaccine administration, duration of participant follow-up, reporting of laboratory abnormalities, and the type, case definitions, severity, reporting methods and internal reporting consistency of adverse events. RESULTS: Of 2278 publications screened, 124 were eligible for inclusion (malaria: 66, TB: 9, HIV: 49). Safety data reporting was found to be highly variable among publications and often incomplete: overall, 269 overlapping terms were used to describe specific adverse events. 17% of publications did not mention fever. Descriptions of severity or degree of relatedness to immunization of adverse events were frequently omitted. 26% (32/124) of publications failed to report data on serious adverse events. CONCLUSIONS: The review demonstrated lack of standardized safety data reporting in trials for vaccines against malaria, TB and HIV. Standardization of safety data collection and reporting should be encouraged to improve data quality and comparability. LIMITATIONS: The search strategy missed studies published in languages other than English and excluded studies reporting on vaccine trials for diseases besides malaria, TB and HIV.
Vaccine 02/2013; · 3.77 Impact Factor
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Ilin Chuang,
Martha Sedegah,
Susan Cicatelli,
Michele Spring,
Mark Polhemus,
Cindy Tamminga,
Noelle Patterson,
Melanie Guerrero,
Jason W Bennett,
Shannon McGrath, [......],
Joseph T Bruder,
Denise L Doolan,
C Richter King,
Daniel Carucci,
Sheetij Dutta,
Lorraine Soisson,
Carter Diggs,
Michael R Hollingdale,
Christian F Ockenhouse, Thomas L Richie
[show abstract]
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ABSTRACT: 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. METHODOLOGYPRINCIPAL 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 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 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. 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.
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.
ClinicalTrials.govNCT00870987.
PLoS ONE 01/2013; 8(2):e55571. · 4.09 Impact Factor
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Thomas L Richie,
Yupin Charoenvit,
Ruobing Wang,
Judith E Epstein,
Richard C Hedstrom,
Sanjai Kumar,
Thomas C Luke,
Daniel A Freilich,
Joao C Aguiar,
John B Sacci, [......],
David E Lanar,
Jennifer Ng,
Meng Shi,
Peter M Hobart,
Jon A Norman,
Lorraine A Soisson,
Michael R Hollingdale,
William O Rogers,
Denise L Doolan,
Stephen L Hoffman
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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 falciparum circumsporozoite 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.
Human vaccines & immunotherapeutics. 11/2012; 8(11).
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New England Journal of Medicine 02/2012; 366(8):765. · 53.30 Impact Factor
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Expert Review of Vaccines 01/2012; 11(1):39-41. · 4.25 Impact Factor
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Narain H Punjabi,
Walter R J Taylor,
Gerald S Murphy,
Sri Purwaningsih,
Helena Picarima,
John Sisson,
James G Olson,
Samuel Baso,
Ferry Wangsasaputra,
Murad Lesmana,
Buhari A Oyofo,
Cyrus H Simanjuntak,
Decy Subekti,
Andrew L Corwin, Thomas L Richie
[show abstract]
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ABSTRACT: We conducted a prospective, inpatient fever study in malaria-endemic Papua, Indonesia to determine non-malaria fever etiologies. Investigations included malaria blood films, blood culture, paired serologic samples analysis for dengue, Japanese encephalitis, leptospirosis, scrub typhus, murine typhus, and spotted fever group rickettsia. During 1997-2000, 226 patients (127 males and 99 females) 1-80 years of age (median age = 25 years) were enrolled. Positive blood cultures (n = 34, 15%) were obtained for Salmonella Typhi (n = 13), Escherichia coli (n = 8), Streptococcus pneumoniae (n = 6), Staphylococcus aureus (n = 5), Streptococcus pyogenes (n = 1), and Klebsiella pneumoniae (n = 1). Twenty (8.8%) patients were positive for leptospirosis by polymerase chain reaction. Eighty (35.4%) of 226 patients had ≥ 1 positive serology, diagnostic for 15 rickettsial and 9 dengue cases. Acid-fast bacilli-positive sputum was obtained from three patients. Most common confirmed (81 of 226, 35.8%)/suspected diagnoses were typhoid fever (n = 41), pneumonia (n = 29), leptospirosis (n = 28), urinary tract infections (n = 20), rickettsioses (n = 19), dengue (n = 17), and meningitis/encephalitis (n = 15). There were 17 deaths, 7 (46.7%) were caused by meningitis/encephalitis. Multiple positive serologic results and few confirmed diagnoses indicate the need for improved diagnostics.
The American journal of tropical medicine and hygiene 01/2012; 86(1):46-51. · 2.59 Impact Factor
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Joseph T Bruder,
Elena Semenova,
Ping Chen,
Keith Limbach,
Noelle B Patterson,
Maureen E Stefaniak,
Svetlana Konovalova,
Charlie Thomas,
Melissa Hamilton,
C Richter King, Thomas L Richie,
Denise L Doolan
PLoS ONE 01/2012; 7(5). · 4.09 Impact Factor
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Joseph T Bruder,
Elena Semenova,
Ping Chen,
Keith Limbach,
Noelle B Patterson,
Maureen E Stefaniak,
Svetlana Konovalova,
Charlie Thomas,
Melissa Hamilton,
C Richter King, Thomas L Richie,
Denise L Doolan
[show abstract]
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ABSTRACT: The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population.
PLoS ONE 01/2012; 7(4):e33920. · 4.09 Impact Factor
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Daniel Dodoo,
Michael R Hollingdale,
Dorothy Anum,
Kwadwo A Koram,
Ben Gyan,
Bartholomew D Akanmori,
Josephine Ocran,
Susan Adu-Amankwah,
Harini Geneshan,
Esteban Abot,
Jennylyn Legano,
Glenna Banania,
Renato Sayo,
Donald Brambilla,
Sanjai Kumar,
Denise L Doolan,
William O Rogers,
Judith Epstein, Thomas L Richie,
Martha Sedegah
[show abstract]
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ABSTRACT: 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.
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.
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.
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.
Malaria Journal 06/2011; 10:168. · 3.19 Impact Factor
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ABSTRACT: Invasion of hepatocytes by Plasmodium sporozoites deposited by Anopheles mosquitoes, and their subsequent transformation into infective merozoites is an obligatory step in the initiation of malaria. Interactions between the sporozoites and hepatocytes lead to a distinct, complex and coordinated cellular and systemic host response. Little is known about host liver cell response to sporozoite invasion, or whether it is primarily adaptive for the parasite, for the host, or for both. Our present study used gene expression profiling of human HepG2-A16 liver cells infected with Plasmodium falciparum sporozoites to understand the host early cellular events and factors influencing parasite infectivity and sporozoite development. Our results show that as early as 30 min following wild-type, non-irradiated sporozoite exposure, the expressions of at least 742 genes was selectively altered. These genes regulate diverse biological functions, such as immune processes, cell adhesion and communications, metabolism pathways, cell cycle regulation, and signal transduction. These functions reflect cellular events consistent with initial host cell defense responses, as well as alterations in host cells to sustain sporozoites growth and survival. Irradiated sporozoites gave very similar gene expression pattern changes, but direct comparative analysis between liver gene expression profiles caused by irradiated and non-irradiated sporozoites identified 29 genes, including glypican-3, that were specifically up-regulated only in irradiated sporozoites. Elucidating the role of this subset of genes may help identify the molecular basis for the irradiated sporozoites inability to develop intrahepatically, and their usefulness as an immunogen for developing protective immunity against pre-erythrocytic stage malaria.
Journal of Biological Chemistry 06/2011; 286(30):26396-405. · 4.77 Impact Factor
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ABSTRACT: The development of an effective malaria vaccine remains a global public health priority. Less than 0.5% of the Plasmodium falciparum genome has been assessed as potential vaccine targets and candidate vaccines have been based almost exclusively on single antigens. It is possible that the failure to develop a malaria vaccine despite decades of effort might be attributed to this historic focus. To advance malaria vaccine development, we have fabricated protein microarrays representing 23% of the entire P. falciparum proteome and have probed these arrays with plasma from subjects with sterile protection or no protection after experimental immunization with radiation attenuated P. falciparum sporozoites. A panel of 19 pre-erythrocytic stage antigens was identified as strongly associated with sporozoite-induced protective immunity; 16 of these antigens were novel and 85% have been independently identified in sporozoite and/or liver stage proteomic or transcriptomic data sets. Reactivity to any individual antigen did not correlate with protection but there was a highly significant difference in the cumulative signal intensity between protected and not protected individuals. Functional annotation indicates that most of these signature proteins are involved in cell cycle/DNA processing and protein synthesis. In addition, 21 novel blood-stage specific antigens were identified. Our data provide the first evidence that sterile protective immunity against malaria is directed against a panel of novel P. falciparum antigens rather than one antigen in isolation. These results have important implications for vaccine development, suggesting that an efficacious malaria vaccine should be multivalent and targeted at a select panel of key antigens, many of which have not been previously characterized.
Molecular & Cellular Proteomics 05/2011; 10(9):M111.007948. · 7.40 Impact Factor
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ABSTRACT: The development of a vaccine against malaria is a major research priority given the burden of disease, death and economic loss inflicted upon the tropical world by this parasite. Despite decades of effort, however, a vaccine remains elusive. The best candidate is a subunit vaccine termed RTS,S but this provides only partial protection against clinical disease. This review examines what is known about protective immunity against pre-erythrocytic stage malaria by considering the humoral and T cell-mediated immune responses that are induced by attenuated sporozoites and by the RTS,S vaccine. On the basis of these observations a set of research priorities are defined that are crucial for the development of a vaccine capable of inducing long-lasting and high-grade protection against malaria.
Trends in Parasitology 03/2011; 27(7):306-14. · 5.14 Impact Factor
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Sócrates Herrera,
Yezid Solarte,
Alejandro Jordán-Villegas,
Juan Fernando Echavarría,
Leonardo Rocha,
Ricardo Palacios,
Oscar Ramírez,
Juan D Vélez,
Judith E Epstein, Thomas L Richie,
Myriam Arévalo-Herrera
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ABSTRACT: A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (-) subjects were randomly allocated into three (A-C) groups and were exposed to the bites of 2-4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (-) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials.
The American journal of tropical medicine and hygiene 02/2011; 84(2 Suppl):4-11. · 2.59 Impact Factor
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Alejandro Jordán-Villegas,
Anilza Bonelo Perdomo,
Judith E Epstein,
Jesús López,
Alejandro Castellanos,
María R Manzano,
Miguel A Hernández,
Liliana Soto,
Fabián Méndez, Thomas L Richie,
Stephen L Hoffman,
Myriam Arévalo-Herrera,
Sócrates Herrera
[show abstract]
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ABSTRACT: A non-human primate model for the induction of protective immunity against the pre-erythrocytic stages of Plasmodium vivax malaria using radiation-attenuated P. vivax sporozoites may help to characterize protective immune mechanisms and identify novel malaria vaccine candidates. Immune responses and protective efficacy induced by vaccination with irradiated P. vivax sporozoites were evaluated in malaria-naive Aotus monkeys. Three groups of six monkeys received two, five, or ten intravenous inoculations, respectively, of 100,000 irradiated P. vivax sporozoites; control groups received either 10 doses of uninfected salivary gland extract or no inoculations. Immunization resulted in the production low levels of antibodies that specifically recognized P. vivax sporozoites and the circumsporozoite protein. Additionally, immunization induced low levels of antigen-specific IFN-γ responses. Intravenous challenge with viable sporozoites resulted in partial protection in a dose-dependent manner. These findings suggest that the Aotus monkey model may be able to play a role in preclinical development of P. vivax pre-erythrocytic stage vaccines.
The American journal of tropical medicine and hygiene 02/2011; 84(2 Suppl):43-50. · 2.59 Impact Factor
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ABSTRACT: Humanized mice able to reconstitute a surrogate human immune system (HIS) can be used for studies on human immunology and may provide a predictive preclinical model for human vaccines prior to clinical trials. However, current humanized mouse models show sub-optimal human T cell reconstitution and limited ability to support immunoglobulin class switching by human B cells. This limitation has been attributed to the lack of expression of Human Leukocyte Antigens (HLA) molecules in mouse lymphoid organs. Recently, humanized mice expressing HLA class I molecules have been generated but showed little improvement in human T cell reconstitution and function of T and B cells.
We have generated NOD.Rag1KO.IL2RγcKO mice expressing HLA class II (HLA-DR4) molecules under the I-E(d) promoter that were infused as adults with HLA-DR-matched human hematopoietic stem cells (HSC). Littermates lacking expression of HLA-DR4 molecules were used as control.
HSC-infused HLA-DR4.NOD.Rag1KO.IL-2RγcKO mice developed a very high reconstitution rate (>90%) with long-lived and functional human T and B cells. Unlike previous humanized mouse models reported in the literature and our control mice, the HLA-DR4 expressing mice reconstituted serum levels (natural antibodies) of human IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited high titers of specific human IgG antibodies upon tetanus toxoid vaccination.
Our study demonstrates the critical role of HLA class II molecules for development of functional human T cells able to support immunoglobulin class switching and efficiently respond to vaccination.
PLoS ONE 01/2011; 6(5):e19826. · 4.09 Impact Factor
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Martha Sedegah,
Cindy Tamminga,
Shannon McGrath,
Brent House,
Harini Ganeshan,
Jennylynn Lejano,
Esteban Abot,
Glenna J Banania,
Renato Sayo,
Fouzia Farooq, [......],
Joseph T Bruder,
Denise L Doolan,
C Richter King,
Lorraine Soisson,
Carter Diggs,
Daniel Carucci,
Sheetij Dutta,
Michael R Hollingdale,
Christian F Ockenhouse, Thomas L Richie
[show abstract]
[hide abstract]
ABSTRACT: Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers.
The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites.
As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses.
ClinicalTrials.govNCT00392015.
PLoS ONE 01/2011; 6(10):e24586. · 4.09 Impact Factor
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Cindy Tamminga,
Martha Sedegah,
David Regis,
Ilin Chuang,
Judith E Epstein,
Michele Spring,
Jose Mendoza-Silveiras,
Shannon McGrath,
Santina Maiolatesi,
Sharina Reyes, [......],
Denise L Doolan,
C Richter King,
Carter Diggs,
Lorraine Soisson,
Daniel Carucci,
Gail Levine,
Sheetij Dutta,
Michael R Hollingdale,
Christian F Ockenhouse, Thomas L Richie
[show abstract]
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ABSTRACT: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.
NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1 x 1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.
The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection.
ClinicalTrials.gov NCT00392015.
PLoS ONE 01/2011; 6(10):e25868. · 4.09 Impact Factor
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ABSTRACT: RTS,S is the most advanced candidate vaccine against human malaria. During its remarkable journey from conception and design in the early 1980s to the multicenter Phase 3 trial currently underway across sub-Saharan Africa, RTS,S has overcome tremendous challenges and disproved established vaccine paradigms. In the last several years, Phase 2 studies conducted in infants and children in endemic areas have established the efficacy of RTS,S for reducing morbidity due to clinical malaria. If the results are realized in the Phase 3 trial, the chances for licensure in the near future appear high. Such progress is all the more remarkable given our lack of clear understanding regarding how the vaccine activates the human immune system, the immune correlates of protection or the mechanism whereby a vaccine targeting sporozoites and liver stage parasites can reduce the clinical disease associated with parasitemia. These unanswered questions pose important challenges to be addressed in the quest to understand the protection afforded by RTS,S and to build a more efficacious second generation vaccine against malaria. This review will focus on current knowledge about the protective efficacy of RTS,S and what we have learned regarding its impact on the human immune system.
Vaccine 07/2010; 28(31):4880-94. · 3.77 Impact Factor
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Joseph T Bruder,
Maureen E Stefaniak,
Noelle B Patterson,
Ping Chen,
Svetlana Konovalova,
Keith Limbach,
Joseph J Campo,
Damodar Ettyreddy,
Sheng Li,
Filip Dubovsky, Thomas L Richie,
C Richter King,
Carole A Long,
Denise L Doolan
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ABSTRACT: An effective malaria vaccine remains a global health priority. Recombinant adenoviruses are a promising vaccine platform, and Plasmodium falciparum apical membrane antigen 1 (AMA1) and merozoite surface protein 1-42 (MSP1(42)) are leading blood stage vaccine candidates. We evaluated the importance of surface antigen localization and glycosylation on the immunogenicity of adenovector delivered AMA1 and MSP1(42) and assessed the ability of these vaccines to induce functional antibody responses capable of inhibiting parasite growth in vitro. Adenovector delivery induced unprecedented levels of biologically active antibodies in rabbits as indicated by the parasite growth inhibition assay. These responses were as potent as published results using any other vaccine system, including recombinant protein in adjuvant. The cell surface associated and glycosylated forms of AMA1 and MSP1(42) elicited 99% and 60% inhibition of parasite growth, respectively. Antigens that were expressed at the cell surface and glycosylated were much better than intracellular antigens at inducing antibody responses. Good T cell responses were observed for all forms of AMA1 and MSP1(42). Antigen-specific antibody responses, but typically not T cell responses, were boosted by a second administration of adenovector. These data highlight the importance of rational vaccine design and support the advancement of adenovector delivery technology for a malaria vaccine.
Vaccine 02/2010; 28(18):3201-10. · 3.77 Impact Factor
