D G Heppner

Publications (37)339.91 Total impact

• Article: Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys.

  S Pichyangkul, P Tongtawe, U Kum-Arb, K Yongvanitchit, M Gettayacamin, M R Hollingdale, A Limsalakpetch, V A Stewart, D E Lanar, S Dutta, E Angov, L A Ware, E S Bergmann-Leitner, B House, G Voss, M C Dubois, J D Cohen, M M Fukuda, D G Heppner, R S Miller
  [show abstract] [hide abstract]
  ABSTRACT: In an effort to broaden the immune response induced by the RTS,S/AS02(A),vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1(42) and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1(42) and AMA1 vaccines formulated with the AS02(A) Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1(42) or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1(42) and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-gamma and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1(42) and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1(42) lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1(42) significantly reduced AMA1 IFN-gamma and IL-5 responses. MSP1(42) suppression of AMA1 IFN-gamma responses was not seen in animals receiving RTS,S+AMA1+MSP1(42) suggesting that RTS,S restored IFN-gamma responses. Conversely, AMA1 had no effect on MSP1(42) antibody and IFN-gamma and IL-5 responses. Neither AMA1 alone or combined with MSP1(42) affected RTS,S antibody or IFN-gamma and IL-5 responses. Immune interference by MSP1(42) on AMA1 antibody responses was also evident when AMA1, MSP1(42) and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.
  Vaccine 10/2009; 28(2):452-62. · 3.77 Impact Factor
• Article: Preclinical evaluation of the safety and immunogenicity of a vaccine consisting of Plasmodium falciparum liver-stage antigen 1 with adjuvant AS01B administered alone or concurrently with the RTS,S/AS01B vaccine in rhesus primates.

  S Pichyangkul, U Kum-Arb, K Yongvanitchit, A Limsalakpetch, M Gettayacamin, D E Lanar, L A Ware, V A Stewart, D G Heppner, P Mettens, J D Cohen, W R Ballou, M M Fukuda
  [show abstract] [hide abstract]
  ABSTRACT: Several lines of evidence suggest that targeting pre-erythrocytic-stage parasites for malaria vaccine development can provide sterile immunity. The objectives of this study were (i) to evaluate preclinically the safety and immunogenicity of a new recombinant pre-erythrocytic-stage antigen, liver-stage antigen 1 (LSA1), in nonhuman primates; and (ii) to investigate the potential for immune interference between LSA1 and the leading malaria vaccine candidate, RTS,S, by comparing the immune responses after single-antigen vaccination to responses after simultaneous administration of both antigens at separate sites. Using a rhesus monkey model, we found that LSA1 formulated with the GlaxoSmithKline proprietary adjuvant system AS01B (LSA1/AS01B) was safe and immunogenic, inducing high titers of antigen-specific antibody and CD4+ T-cell responses, as monitored by the production of interleukin-2 and gamma interferon, using intracellular cytokine staining. RTS,S/AS01B vaccination was well tolerated and demonstrated robust antibody and moderate CD4+ T-cell responses to circumsporozoite protein (CSP) and HBsAg. Positive CD8+ T-cell responses to HBsAg were detected, whereas the responses to CSP and LSA1 were negligible. For both LSA1/AS01B and RTS,S/AS01B, no statistically significant differences were observed between individual and concurrent administration in the magnitude or duration of antibody and T-cell responses. Our results revealed that both pre-erythrocytic-stage antigens were safe and immunogenic, administered either separately or simultaneously to rhesus monkeys, and that no significant immune cross interference occurred with concurrent separate-site administration. The comparison of the profiles of immune responses induced by separate-site and single-site vaccinations with LSA1 and RTS,S warrants further investigation.
  Infection and immunity 02/2008; 76(1):229-38. · 4.21 Impact Factor
• Article: Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

  E Macete, J J Aponte, C Guinovart, J Sacarlal, O Ofori-Anyinam, I Mandomando, M Espasa, C Bevilacqua, A Leach, M C Dubois, D G Heppner, L Tello, J Milman, J Cohen, F Dubovsky, N Tornieporth, R Thompson, P L Alonso
  [show abstract] [hide abstract]
  ABSTRACT: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.
  Tropical Medicine & International Health 02/2007; 12(1):37-46. · 2.80 Impact Factor
• Article: Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1–4 in Mozambique

  E. Macete, J. J. Aponte, C. Guinovart, J. Sacarlal, O. Ofori-Anyinam, I. Mandomando, M. Espasa, C. Bevilacqua, A. Leach, M. C. Dubois, D. G. Heppner, L. Tello, J. Milman, J. Cohen, F. Dubovsky, N. Tornieporth, R. Thompson, P. L. Alonso
  [show abstract] [hide abstract]
  ABSTRACT: Background  The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine.Objective  We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1–4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 μg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population.Method  Children were randomized to receive either RTS,S/AS02A or Engerix-B® vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs).Results  The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.Données de base  Le développement d'un vaccin antimalarique demeure une priorité de santé publique pour l'Afrique subsaharienne. Le candidat vaccin RTS,S/AS02A s'est avéré sûre et immunogénique dans des études précédentes chez des adultes et des études de doses successives chez des enfants en Gambie. Cependant, les caractéristiques génétiques et l'intensité de la transmission de la malaria peuvent modifier la sûreté et la réponse immunitaire d'un vaccin.Objectifs  Nous avons mené un essai contrôle randomisé de phase I, en double aveugle chez 60 enfants de 1 à 4 ans en Mozambique pour évaluer la sûreté, la réaction antigénique et l'immunogénicité du vaccin pédiatrique à une dose fixe (25 μg de RTS,S/AS02A dans 0,25 ml) avant d'entreprendre une étude de Phase II, plus étendue pour la preuve de concept de l'efficacité de l’étude sur la même population.Méthode  Les enfants ont été randomisés pour recevoir soit le vaccin RTS,S/AS02 ou le vaccin Engerix-B®. Le suivi de la sûreté et des réactions antigéniques comprenait des analyses cliniques et de laboratoires détaillées ainsi que l’évaluation des réactions adverses.Résultats  RTS,S/AS02A a été trouvé sûr et bien toléré. Des réactions adverses sérieuses ont été observées dans les deux groupes mais aucune n’était liée à la vaccination. La fréquence rapportée des réactions adverses pour le RTS,S/AS02A était comparable à celle d’études précédentes chez des enfants. Des réactions adverses de grade 3 étaient rares (un cas de douleur, un cas de fièvre dans chaque groupe et des enflures de plus de 20 mm de diamètre), transitoires et ont été traitées sans séquelles. RTS,S/AS02A était hautement immunogénique pour la réponse d'anticorps anti-CS et a induit une forte réponse anti-HBsAg.Antecendentes  El desarrollo de una vacuna de malaria continua siendo una prioridad de salud pública en África Subsahariana. Estudios previos en adultos, y de dosis escalonada en niños de Gambia, han demostrado que el candidato a vacuna de malaria RTS,S/AS02A es seguro e inmunogénico. Sin embargo, las características genéticas de los individuos y la intensidad de transmisión de malaria podrían modificar la seguridad y la respuesta inmune frente a la vacuna.Objetivo  Se llevó a cabo un ensayo de fase I, doble ciego, aleatorizado y controlado con 60 niños de entre 1–4 años en Mozambique, para evaluar la seguridad, reactogenicidad e inmunogenicidad de la dosis pediátrica (cantidad fija de RTS,S de 25 μg en 0.25 ml) de la vacuna RTS,S/AS02A, como paso previo a un estudio de prueba de concepto de fase 2b para evaluar la eficacia en la misma población.Método  Se aleatorizaron los niños para recibir una de dos vacunas: RTS,S/AS02A o Engerix-B®. La monitorización de la seguridad y reactogenicidad incluyó análisis clínicos y de laboratorio detallados, así como la evaluación de eventos adversos.Resultados  Se encontró que la RTS,S/AS02A es segura y bien tolerada. Los eventos adversos graves se encontraban balanceados entre ambos grupos, y ninguno de ellos estaba relacionado con la vacuna. La frecuencia de los eventos adversos reportados con la RTS,S/AS02A era comparable a la de estudios anteriores en niños. Los eventos adversos de grado 3 fueron infrecuentes (un caso de dolor, un caso de fiebre en cada uno de los grupos y alguna hinchazón de más de 20 mm de diámetro), transitorios y se resolvieron sin secuelas. La RTS,S/AS02A demostró ser muy inmunogénica en respuesta de anticuerpos anti-CS e indujo una respuesta anti-HBsAg importante.
  Tropical Medicine & International Health 10/2006; 12(1):37 - 46. · 2.80 Impact Factor
• Article: CpG oligodeoxynucleotide enhances immunity against blood-stage malaria infection in mice parenterally immunized with a yeast-expressed 19 kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19)) formulated in oil-based Montanides.

  C Hirunpetcharat, J Wipasa, S Sakkhachornphop, T Nitkumhan, Y Z Zheng, S Pichyangkul, A M Krieg, D S Walsh, D G Heppner, M F Good
  [show abstract] [hide abstract]
  ABSTRACT: The 19kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19)), an analog of the leading falciparum malaria vaccine candidate, induces protective immunity to challenge infection when formulated with complete/incomplete Freund's adjuvant (CFA/IFA), an adjuvant unsuitable for use in humans. In this study, we investigate Montanide ISA51 and Montanide ISA720 as well as CpG oligodeoxynucleotide (ODN) as adjuvants for induction of immunity to MSP1(19). Mice immunized with MSP1(19) adjuvanted with Montanide ISA51 were protected even though some mice experienced low-grade parasitemia before resolving the infection. Mice immunized with MSP1(19) adjuvanted with Montanide ISA720 showed delayed patent parasitemia with all mice ultimately succumbing to infection. Interestingly, when the synthetic CpG ODN 1826 was included in either Montanide formulation, mice were completely protected with no parasites detected in the blood. MSP1(19)-specific antibodies in MSP1(19)-immunized mice adjuvanted with Montanide ISA51 or Montanide ISA720 showed predominantly IgG1 antibody and low levels of IgG2a. CpG ODN 1826 significantly enhanced both IgG1 and IgG2a antibody responses in Montanide ISA51-adjuvanted mice but significantly enhanced only the IgG2a antibody response in Montanide ISA720-adjuvanted mice. To investigate the relative roles of antibody and CD4(+) T cells in protection, MSP1(19)-immunized mice adjuvanted with Montanide ISA720 and CpG ODN 1826 were depleted of CD4(+) T cells just prior to challenge. Results showed that three of nine immunized/T cell depleted mice died following infection. These results suggest that antibody and CD4(+) T cells are critical for protection following immunization with MSP1(19) adjuvanted with Montanide and CpG ODN and that the formulation of a human malaria vaccine candidate in Montanide ISA720 or ISA51 together with human compatible CpG ODN would be useful for improving efficacy.
  Vaccine 07/2003; 21(21-22):2923-32. · 3.77 Impact Factor
• Article: New World monkey efficacy trials for malaria vaccine development: critical path or detour?

  D G Heppner, J F Cummings, C Ockenhouse, K E Kester, J A Lyon, D M Gordon
  [show abstract] [hide abstract]
  ABSTRACT: Neither GMP malaria antigens nor GMP vaccines have been compared for efficacy in monkeys and humans. It is too risky to base categorical (go/no go) development decisions on results obtained using partially characterized (non-GMP) antigens, adjuvants that are too toxic for human use or unvalidated primate models. Such practices will lead to serious errors (e.g. failure to identify and stop flawed efforts, rejection of effective vaccine strategies) and unjustifiable delays. Successful malaria vaccine development will emphasize definitive field trials in populations at risk of malaria to define and improve vaccine efficacy.
  Trends in Parasitology 10/2001; 17(9):419-25. · 5.14 Impact Factor
• Article: Malaria rapid diagnostic devices: performance characteristics of the ParaSight F device determined in a multisite field study.

  J R Forney, A J Magill, C Wongsrichanalai, J Sirichaisinthop, C T Bautista, D G Heppner, R S Miller, C F Ockenhouse, A Gubanov, R Shafer, C C DeWitt, H A Quino-Ascurra, K E Kester, K C Kain, D S Walsh, W R Ballou, R A Gasser
  [show abstract] [hide abstract]
  ABSTRACT: Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/microl), 87% (501 to 1,000/microl), 98% (1,001 to 5,000/microl), and 98% (>5,000/microl). Device specificity was 86%.
  Journal of Clinical Microbiology 09/2001; 39(8):2884-90. · 4.15 Impact Factor
• Article: Isolation and characterization of rhesus blood dendritic cells using flow cytometry.

  S Pichyangkul, P Saengkrai, K Yongvanitchit, C Limsomwong, M Gettayacamin, D S Walsh, V A Stewart, W R Ballou, D G Heppner
  [show abstract] [hide abstract]
  ABSTRACT: Recognition of dendritic cells (DCs) as initiators and modulators of immune responses and growing use of rhesus monkeys for the preclinical optimization of vaccine formulations prompted characterization of the phenotype and function of isolated rhesus peripheral blood DCs. We developed a flow cytometric method to directly identify and isolate DCs from rhesus peripheral blood whereby a T cell depleted population negative for CD3, CD14, CD16 and CD20 but positive for CD83 yielded a cell population with surface markers, morphology, and a cytokine profile similar to human myeloid DCs. Rhesus blood DCs were more effective than monocytes and B cells in mixed lymphocyte reactions and in the presentation of recombinant malaria blood stage antigen MSP-1((42)) to autologous T cells. The ability to isolate rhesus blood DC from peripheral blood should be a useful tool for immunological investigations.
  Journal of Immunological Methods 07/2001; 252(1-2):15-23. · 2.20 Impact Factor
• Source

  Available from: Douglas S Walsh

  Article: Effects of hydroxypyridinone iron chelators in combination with antimalarial drugs on the in vitro growth of Plasmodium falciparum.

  K Pattanapanyasat, K Kotipun, K Yongvanitchit, R C Hider, D E Kyle, D G Heppner, D S Walsh
  [show abstract] [hide abstract]
  ABSTRACT: Using standard in vitro drug susceptibility methods, we assessed the antimalarial activity of 3 orally administered iron chelators (hydroxypyridinones) alone and in combination with conventional antimalarials drugs (quinine, mefloquine, artesunate, tetracycline, atovaquone) against a chloroquine-resistant Plasmodium falciparum isolate. When tested alone, all iron chelators and antimalarial compounds inhibited the growth of the parasites. IC50 values for iron chelators were 60-70 microM, whereas the IC50 values for antimalarial drugs were in nM ranges, with artesunate being the most potent. The derived isobolograms for the interaction of hydroxypyridinones and antimalarial drugs showed addition or mild antagonism, similar to desferroxamine (Sum of Fractional Inhibitory Concentration, sigma FIC < 0.5 or > 4.0). Despite the absence of synergy with conventional drugs, intrinsic antimalarial activity of hydroxypyridinones supports the continued assessment of these iron chelators as treatment adjuncts.
  The Southeast Asian journal of tropical medicine and public health 04/2001; 32(1):64-9. · 0.60 Impact Factor
• Article: Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria.

  K E Kester, D A McKinney, N Tornieporth, C F Ockenhouse, D G Heppner, T Hall, U Krzych, M Delchambre, G Voss, M G Dowler, J Palensky, J Wittes, J Cohen, W R Ballou
  [show abstract] [hide abstract]
  ABSTRACT: After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.
  The Journal of Infectious Diseases 03/2001; 183(4):640-7. · 6.41 Impact Factor
• Article: Whole blood cultures to assess the immunostimulatory activities of CpG oligodeoxynucleotides.

  S Pichyangkul, K Yongvanitchit, U Kum-arb, A M Krieg, D G Heppner, D S Walsh
  [show abstract] [hide abstract]
  ABSTRACT: Specially designed oligodeoxynucleotide (ODN) sequences known as 'CpG' ODNs elicit innate and acquired immune responses. In general, screening of new CpG ODNs has been conducted by conventional lymphoproliferative assays or expression of activation markers in peripheral blood mononuclear cell (PBMC) cultures. Here, we compared conventional in vitro human PBMC assays with whole blood assays for screening the immunostimulatory properties of CpG ODNs. Commercially available DNA preparations and mycobacterial-based adjuvants were used as comparators. Activation was assessed by flow cytometry and cytokine production. CpG ODNs, identified by four-letter codes, consisted of 2006 (strong human cell stimulant), 1826 (strong murine cell stimulant), 1840 (weak immunostimulant), and 2041, a non-CpG ODN. In both test systems, and in accordance with previous reports, 2006 was an effective up-regulator of CD40 on human dendritic cells (DC1, DC2), monocytes, and B cells, and of CD69 on NK cells. In contrast to murine cells exposed to CpG ODNs, IL-12 (p40) and IFN-gamma production in human immune cells was negligible, but greatly enhanced by adding GM-CSF. Like 2006, two comparator mycobacterial adjuvant formulations activated DC1, DC2, monocytes and natural killer (NK) cells, but only 2006 had a strong effect on B cells. The usefulness of the whole blood assay was further demonstrated by studies in small volumes of umbilical cord mononuclear cells, that like adult blood cells, showed up-regulation of CD40 expression on B cells, DC, and monocytes, and CD69 on NK cells. The whole blood assay, in conjunction with flow cytometry, is useful for assessing the immunological properties of CpG ODN sequences.
  Journal of Immunological Methods 02/2001; 247(1-2):83-94. · 2.20 Impact Factor
• Article: Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand.

  D S Walsh, S Looareesuwan, P Wilairatana, D G Heppner, D B Tang, T G Brewer, W Chokejindachai, P Viriyavejakul, D E Kyle, W K Milhous, B G Schuster, J Horton, D J Braitman, R P Brueckner
  [show abstract] [hide abstract]
  ABSTRACT: WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.
  The Journal of Infectious Diseases 11/1999; 180(4):1282-7. · 6.41 Impact Factor
• Article: Malaria vaccines: triumphs or tribulations?

  W R Ballou, K E Kester, J A Stoute, D G Heppner
  [show abstract] [hide abstract]
  ABSTRACT: A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.
  Parassitologia 10/1999; 41(1-3):403-8.
• Article: Comparison of a rapid field immunochromatographic test to expert microscopy for the detection of Plasmodium falciparum asexual parasitemia in Thailand.

  C Wongsrichanalai, N Chuanak, S Tulyayon, N Thanoosingha, A Laoboonchai, K Thimasarn, T G Brewer, D G Heppner
  [show abstract] [hide abstract]
  ABSTRACT: We assessed a rapid, Plasmodium falciparum histidine rich protein 2 (PfHRP2)-based immunochromatographic test (ICT Malaria Pf Test), for detection of asexual P. falciparum parasitemia in 551 subjects in three groups: (1) symptomatic patients self-referring for diagnosis, (2) villagers in a screening survey, and (3) patients recently treated for P. falciparum malaria. Expert light microscopy was the reference standard. ICT test performance was similar for diagnostic and screening modes. Four findings emerged: (1) test sensitivity correlated directly with parasite density, (2) test band intensity correlated directly with parasite density, (3) persistent test positivity after parasite clearance precludes its use for monitoring early therapeutic responses, and (4) a false negative test at 18,000 parasites/microl is unexplained. We conclude that a strong positive ICT test is highly predictive of falciparum asexual parasitemia for the diagnosis of new cases of falciparum malaria in Thailand, but a negative test result is inadequate to exclude parasitemia < 300/microl, and in some instances, even a higher parasitemia.
  Acta Tropica 10/1999; 73(3):263-73. · 2.72 Impact Factor
• Article: Primaquine prophylaxis against malaria.

  D G Heppner, R A Gasser, K E Kester
  Annals of internal medicine 04/1999; 130(6):536; author reply 536-7. · 16.73 Impact Factor
• Article: Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria.

  R Price, J A Simpson, P Teja-Isavatharm, M M Than, C Luxemburger, D G Heppner, T Chongsuphajaisiddhi, F Nosten, N J White
  [show abstract] [hide abstract]
  ABSTRACT: Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation.
  Antimicrobial Agents and Chemotherapy 03/1999; 43(2):341-6. · 4.84 Impact Factor
• Source

  Available from: who.int

  Article: In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.

  C Wongsrichanalai, T Wimonwattrawatee, P Sookto, A Laoboonchai, D G Heppner, D E Kyle, W H Wernsdorfer
  [show abstract] [hide abstract]
  ABSTRACT: Reported are the in vitro susceptibilities of Plasmodium falciparum to artesunate, mefloquine, quinine and chloroquine of 86 isolates and to dihydroartemisinin of 45 isolates collected from areas of high resistance to mefloquine within Thailand near the borders with Myanmar and Cambodia, and from southern Thailand where P. falciparum is generally still sensitive to mefloquine. All the isolates were highly sensitive to artesunate, but the geometric mean IC50S were higher in isolates from the Thai-Myanmar and Thai-Cambodian borders than in those from southern Thailand. The IC50S for mefloquine and artesunate were strongly correlated (Pearson r = 0.605; n = 86; P < 0.00001). As expected, the in vitro sensitivities to dihydroartemisinin and artesunate were similar and strongly correlated (at IC50, Pearson r = 0.695; n = 45; P < 0.00002). The correlation between the activity of mefloquine and artesunate requires further investigation in order to determine the potential for development of cross-resistance in nature. Our results suggest that combination with mefloquine is not the ideal way of protecting the usefulness of artemisinin and its derivatives. A search for more suitable partner drugs to these compounds and careful regulation of their use are necessary in the interest of ensuring their long therapeutic life span.
  Bulletin of the World Health Organisation 01/1999; 77(5):392-8. · 4.64 Impact Factor
• Article: Malaria in 1998: advances in diagnosis, drugs and vaccine development.

  D G Heppner, W R Ballou
  [show abstract] [hide abstract]
  ABSTRACT: Malaria threatens almost half the world's population. Although a concerted worldwide effort might control this disease, the reality is that inadequate and ineffective laboratory diagnosis and treatment conspire in the yearly deaths of 2,000,000 children from malaria. The failure to institute and implement safeguards to maintain the efficacy of new antimalarial drugs is likely to accelerate the emergence of untreatable malaria, creating an ominous parallel to tuberculosis. There is hope. Field expedient, simple and affordable malaria diagnostics are at hand. Artemisinin derivatives remain surprisingly effective against the multiply drug-resistant falciparum malaria of southeast Asia, despite the widespread and unregulated use of these agents. Human trials have begun of WR238605, a promising primaquine replacement that has prophylactic, treatment and transmission-blocking potential. After demonstrating unprecedented protection against homologous challenge, RTS,S, a new sporozite-based malaria vaccine candidate, is now in field trials.
  Current Opinion in Infectious Diseases 11/1998; 11(5):519-30. · 4.93 Impact Factor
• Source

  Available from: ajtmh.org

  Article: Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria.

  A Sabchareon, P Attanath, P Chanthavanich, P Phanuaksook, V Prarinyanupharb, Y Poonpanich, D Mookmanee, P Teja-Isavadharm, D G Heppner, T G Brewer, T Chongsuphajaisiddhi
  [show abstract] [hide abstract]
  ABSTRACT: A randomized pilot study to compare the safety and efficacy of artesunate suppositories (15 mg/kg/day for three days) versus oral artesunate (6 mg/kg/day for three days), both in combination with mefloquine (25 mg/kg), was conducted in 52 Thai children with uncomplicated multidrug-resistant falciparum malaria. Forty-five patients (87%) had a full 28-day follow-up in the hospital to assess efficacy and exclude reinfection. Mean [range] times to fever clearance of the two groups were similar (42 hr [15-104] versus 42 hr [6-119]). Artesunate suppositories resulted in significantly longer times to achieve 50% and 90% reductions of the initial parasite counts (17 and 26 hr versus 9 and 15 hr; P < 0.05 and P < 0.001). Time [range] to parasite clearance was longer in the artesunate suppositories group (42 hr [14-93] versus 35 hr [16-69]), but the difference was not significant. The cure rates by days 28 were not significantly different, 92% for artesunate suppository-treated patients and 100% for oral artesunate-treated patients. Both drug regimens are safe and effective. Further studies are needed to characterize the pharmacokinetic properties and the optimum regimen of artesunate suppositories for the treatment of severe malaria.
  The American journal of tropical medicine and hygiene 01/1998; 58(1):11-6. · 2.59 Impact Factor
• Article: Regulation of leukocyte adhesion molecules CD11b/CD18 and leukocyte adhesion molecule-1 on phagocytic cells activated by malaria pigment.

  S Pichyangkul, P Saengkrai, K Yongvanitchit, D G Heppner, D E Kyle, H K Webster
  [show abstract] [hide abstract]
  ABSTRACT: There is increasing evidence that inappropriate immune activation induced by parasite products occurs in malaria disease. To further elucidate the role of Plasmodium falciparum-derived products on host immune activation, we studied the expression of leukocyte adhesion molecules (CD11b/CD18 and LAM-1) on neutrophils and monocytes in response to malaria pigment using flow cytometry. Exposure of leukocytes to isolated malaria pigment derived from ruptured schizonts resulted in significant up-regulation of CD11b/CD18 expression and down-regulation of LAM-1 on both neutrophils and monocytes. In contrast, culture supernatants (pigment free) from ruptured schizonts did not alter the expression of CD11b/CD18 and LAM-1. The increase of CD11b/CD18 and the loss of LAM-1 expression occurred simultaneously with the earliest response detected at 10 min and a plateau reached by 60 min. The effect of malaria pigment on leukocyte adhesion molecules was inhibited by EDTA in a dose-dependent manner. Phagocytosis of malaria pigment was also suppressed by EDTA. This observation suggests that phagocytosis of malaria pigment may be a prerequisite for the effect of malaria pigment on the regulation of CD11b/CD18 and LAM-1 expression. Regulation of leukocyte adhesion molecules through up-regulation of CD11b/CD18 and down-regulation of LAM-1 by malaria pigment could promote leukocyte adherence to endothelium in vivo. This increased adherence of malaria pigment-activated leukocytes might induce cytokine (tumor necrosis factor alpha and interleukin-1beta)-mediated increases in capillary permeability resulting in local tissue edema, and a cytokine-mediated increase in adhesion molecule expression causing vascular clogging by adherent red blood cells, and in severe disease by adherent leukocytes.
  The American journal of tropical medicine and hygiene 11/1997; 57(4):383-8. · 2.59 Impact Factor