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S L Hoffman

Publications and source records attributed to S L Hoffman.

At least 109 records · Page 6Linked to original sources
PubMed1997

Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles.

We recently described human leukocyte antigen (HLA) A2, A3 and B7 supertypes, characterized by largely overlapping peptide-binding specificities and represented in a high percentage of different populations. Here, we identified 17 Plasmodium falciparum peptides capable of binding these supertypes and assessed antigenicity in both vaccinated and naturally exposed populations. Positive cytotoxic T lymphocyte recall and cytokine (interferon-gamma and tumor necrosis factor alpha) responses were detected for all peptides; all were recognized in the context of more than one HLA class I molecule; and at least 12 of the 17 were recognized in the context of all HLA alleles studied. These data validate the concept of HLA supertypes at the biological level, show that highly degenerate peptides are almost always recognized as epitopes, and demonstrate the feasibility of developing a universally effective vaccine by focusing on a limited number of peptide specificities.

Alleles↗
PubMed1997

Toward clinical trials of DNA vaccines against malaria.

In mid 1997 the first malaria DNA vaccine will enter clinical trials. This single gene DNA vaccine encoding the Plasmodium falciparum circumsporozoite protein (PfCSP) will be studied for safety and immunogenicity. If these criteria are met, a multi-gene DNA vaccine designed to induce protective CD8+ T cell responses against P. falciparum infected hepatocytes will be subsequently assessed for safety, immunogenicity and capacity to protect immunized volunteers against experimental challenge with P. falciparum sporozoites. Our perspectives on malaria vaccine development in general, and on a multi-gene DNA vaccine in particular, have been recently reviewed. Herein, we review the rationale and experimental foundation for the anticipated P. falciparum DNA vaccine trials.

Animals↗
PubMed1997

Sterile protection of monkeys against malaria after administration of interleukin-12.

An estimated 300-500 million new infections and 1.5-2.7 million deaths attributed to malaria occur annually in the developing world, and every year tens of millions of travelers from countries where malaria is not transmitted visit countries with malaria. Because the parasites that cause malaria have developed resistance to many antimalarial drugs, new methods for prevention are required. Intraperitoneal injection into mice of one dose of 150 ng (approximately 7.5 micrograms per kg body weight) recombinant mouse interleukin-12 (rmIL-12) 2 days before challenge with Plasmodium yoelii sporozoites protects 100% of mice against malaria. We report that one subcutaneous injection of 10 micrograms/kg recombinant human IL-12 (rhIL-12) 2 days before challenge with P. cynomolgi sporozoites protected seven of seven rhesus monkeys. Protection was associated with marked increases in plasma levels of interferon-gamma (IFN-gamma), and relative increases of lymphoid cell messenger RNA coding for IFN-gamma and several other cytokines. We speculate that rIL-12 protects monkeys through IFN-gamma-dependent elimination of P. cynomolgi-infected hepatocytes. This first report of rIL-12-induced protection of primates against an infectious agent supports assessment of rhIL-12 for immunoprophylaxis of human malaria.

Animals↗
PubMed1997

Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia.

The combination of halofantrine and primaquine therapies was calculated as a regimen for achieving radical curve of falciparum or vivax malaria in Irian Jaya, Indonesia, and compared with combined chloroquine and primaquine therapies. The patients who volunteered for the study [adult, male, Indonesian immigrants with no previous exposure to endemic malaria, normal glucose-6-phosphate dehydrogenase (G6PD) activity, uncomplicated malaria illness, no prior use of antimalarials, and parasitaemias of 0.001%-1.1%] were randomized to receive either halofantrine (24 mg base/kg bodyweight, in three equal doses over 12 h) or chloroquine (25 mg base/kg bodyweight over 48 h, in doses of 10, 10 and 5 mg base/kg at 24-h intervals). Each patient also received concurrent daily primaquine (0.5 mg base/kg bodyweight) for 14 days followed by the same dose on alternate days to day 28. A recurrent parasitaemia during the 28 days of follow-up constituted drug failure. Of the 40 cases of falciparum malaria and 26 cases of vivax malaria treated with halofantrine-primaquine, none had a recurrent parasitaemia (100% efficacy). In contrast, 20 of 30 patients with falciparum malaria and three of 27 with vivax malaria had recurrent parasitaemias after chloroquine-primaquine, giving efficacies of 33% and 89%, respectively. Halofantrine-primaquine was significantly more effective than chloroquine-primaquine against falciparum malaria (P < 0.001) but was similarly efficacious against vivax malaria (P = 0.23). On average, fever associated with falciparum or vivax malaria cleared 17 h faster with halofantrine-primaquine (P < 0.01) although there were no significant differences (P > 0.4) in parasite-clearance times between the two regimens. The halofantrine-primaquine regimen was also associated with a more rapid and significant decline in malaria-related physical complaints.

Adult↗
PubMed1997

Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge.

To determine the characteristics of clinical illness accompanying Plasmodium falciparum infection induced by controlled exposure to infected mosquitoes, records of 118 volunteers participating in studies conducted between 1985 and 1992 were reviewed. One hundred fourteen volunteers (97%) reported at least one symptom attributable to malaria, with fatigue, myalgias or arthralgias, headache, and chills most commonly reported. The median duration of symptoms was 3 days. Fever was recorded in 61% of volunteers; 4 volunteers had temperatures >40 degrees C. Neutropenia and thrombocytopenia were present in 9% and 12% of volunteers, respectively. Despite counts as low as 658/microL (neutrophils) or 73,000/microL (platelets), no secondary infectious or hemorrhagic complications occurred. In all cases, volunteers recovered completely and laboratory values returned to baseline after specific antimalarial therapy. Recrudescence did not occur in any volunteer. In this model, mosquito inoculation of P. falciparum is a reliable, safe, and well-tolerated method of experimental challenge.

Adolescent↗
PubMed1997

Lymphocyte response to tetanus toxoid among Indonesian men immunized with tetanus-diphtheria during extended chloroquine or primaquine prophylaxis.

Immune suppression, a potential side effect of long-term chemoprophylaxis, was evaluated as part of a randomized, placebo-controlled trial that compared daily primaquine against weekly chloroquine for malaria prevention. In the last month of the year-long trial, baseline in vitro lymphoproliferative responses to tetanus toxoid were measured, and a tetanus-diphtheria (Td) immunization was administered. Proliferative responses to tetanus toxoid in each Td-immunized group increased significantly over pre-Td baselines and those of the unvaccinated control. Highest initial responses were measured in the primaquine group. The proportion of responders and the magnitude of proliferation was consistently low in the chloroquine group, and end point responses in this group were significantly below those of the placebo. These results suggest that the development and duration of the cellular response to tetanus immunization was impaired by long-term weekly chloroquine prophylaxis, while daily primaquine prophylaxis over the same time period had no inhibitory effect.

Adult↗
PubMed1997

Development of two monoclonal antibodies against Plasmodium falciparum sporozoite surface protein 2 and mapping of B-cell epitopes.

The Plasmodium yoelii sporozoite surface protein 2 (PySSP2) is the target of protective cellular immunity. Cytotoxic T cells specific for the Plasmodium falciparum analog PfSSP2, also known as thrombospondin-related anonymous protein (TRAP), are induced in human volunteers immunized with irradiated sporozoites. PfSSP2 is an important candidate antigen for a multicomponent malaria vaccine. We generated and characterized three monoclonal antibodies (MAbs) specific for PfSSP2/TRAP. The MAbs PfSSP2.1 (immunoglobulin G1 [IgG1]), PfSSP2.2 (IgG2a), and PfSSP2.3 (IgM) were species specific and identified three distinct B-cell epitopes containing sequences DRYI, CHPSDGKC, and TRPHGR, respectively. PfSSP2.1 partially inhibited P. falciparum liver-stage parasite development in human hepatocyte cultures (42 and 86% in two experiments at 100 microg/ml). Mice immunized with vaccinia virus expressing full-length PfSSP2 protein produced antibodies to (DRYIPYSP)3, and humans living in malaria-endemic areas (Indonesia and Kenya), who have lifelong exposure and partial clinical immunity to malaria, had antibodies to both (DRYIPYSP)3 and (CHPSDGKCN)2. Mice immunized with multiple antigen peptides MAP4 (DRYIPYSP)3P2P30 and MAP4 (CHPSDGKCN)3P2P30 in TiterMax developed antibodies to sporozoites that partially inhibited sporozoite invasion of human hepatoma cells (39 to 71% at a serum dilution of 1:50 in three different experiments). The modest inhibitory activities of the MAbs and the polyclonal antibodies to PfSSP2/TRAP epitopes do not suggest that a single-component vaccine designed to induce antibodies against PfSSP2/TRAP will be protective. Nonetheless, the MAbs directed against PfSSP2, and the peptides recognized by these MAbs, will be essential reagents in the development of PfSSP2/TRAP as a component of a multivalent P. falciparum human malaria vaccine.

Amino Acid Sequence↗
PubMed1997

Plasmodium falciparum gametocytemia in Kenyan children: associations among age, intensity of exposure to transmission, and prevalence and density of subsequent gametocytemia.

Recently, an association was described between the density of Plasmodium falciparum asexual parasitemia in Kenyan children and the entomologic inoculation rate (EIR) measured prior to measurement of asexual parasitemia. This study examined whether transmission pressure, as represented by the EIR, was associated with the prevalence or density of gametocytemia in Kenyan children. Each month for 19 months, a cohort of approximately 50 children was given a radical cure and enrolled in the study. Blood films were taken on days 0, 7, and 14. The EIR was calculated for the 28-day period ending 14 days prior to enrollment: the relationship between blood film data from day 7 and exposure variables was explored. We found that younger children were more likely to be gametocytemic than older children and, if gametocytemic, were more likely to have a dense gametocytemia. There was an inverse relationship between the number of infective bites per night received and prevalence but not density of gametocytemia, even after age adjustment. Concordance of gametocytemia prevalence on days 0 (64%), 7 (66%), and 14 (52%) was poor; 84% of the children were positive on at least one day. This indicates that in many subjects the detectable gametocytemia varied over the 14 days. Under these holoendemic transmission conditions, the EIR is inversely correlated with prevalence of gametocytemia, and point measurements of gametocytemia by conventional microscopy underestimate the number of infective donor hosts.

Age Factors↗
PubMed1997

Malaria in a nonimmune population after extended chloroquine or primaquine prophylaxis.

Extended chemoprophylaxis against endemic malaria raises concern with regard to susceptibility after ceasing use of the drug. In this study, we measured attack rates of malaria among adult men for 28 weeks after they ended one year of prophylaxis using either weekly chloroquine (5 mg base/kg, n = 20), daily primaquine (0.5 mg base/kg, n = 30), or a placebo of primaquine (n = 41). The 28-week incidence densities, times to parasitemia, parasite densities, and symptoms of primary post-prophylaxis infections were not significantly different among the former primaquine, chloroquine, and placebo groups. However, the incidence of Plasmodium falciparum infection in the post-chloroquine group was significantly greater than in the post-primaquine group during the first (P = 0.03) and second (P = 0.02) months post-prophylaxis. Six of 10 primary P. falciparum and three of 10 P. vivax infections occurred in the former chloroquine group within one month after ending prophylaxis and the mean time to infection was 30-35 days. In contrast, only one P. falciparum and no P. vivax infections occurred during the first month after ending primaquine prophylaxis. The mean time to first parasitemia by either species of malaria parasite in this group was 72-77 days. There was no indication that daily use of primaquine for one year placed subjects at greater risk of malaria infection or to more severe clinical symptoms of malaria than subjects who had taken placebo or chloroquine, despite the potential for some degree of immunity to have been acquired in these latter two groups during the year-long prophylaxis period. The results do suggest that chloroquine suppressed P.falciparum infections until drug levels decreased, and that primaquine had effectively prevented the establishment of liver-stage parasites.

Antimalarials↗
PubMed1997

Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels.

To develop criteria for the diagnosis of resistance to chloroquine using an in vivo test, we examined published records of early clinical trials of quinine and chloroquine against Plasmodium vivax. These data established the timing of relapse by tropical P. vivax relative to therapy by these drugs. The first relapse occurred 17 days after initiating and three days after terminating quinine therapy. The median day of relapse was day 23, and 59% of the patients had relapsed by day 30 (n = 333). In contrast, no relapse occurred until day 36 following chloroquine treatment (n = 256). Data from our laboratory may help explain this difference; among 91 Indonesian patients with malaria, the mean whole blood levels of chloroquine (CQ) and desethylchloroquine (DCQ) were 141 ng/ml (95% confidence interval = 115-167) on day 28 after initiating standard therapy (25 mg base/kg in three doses over a 48-hr period). This exceeds the estimated minimal effective concentration of chloroquine (100 ng/ml of whole blood). Thus, chloroquine lingering in the blood for at least 28 days after starting standard therapy was sufficient to eliminate or at least suppress chloroquine-sensitive tropical P. vivax. We conclude that a parasitemia by P. vivax recurring in the 28 days after full compliance to standard chloroquine therapy demonstrates resistance. If the recurrence appears before day 16, it is almost certainly a recrudescence and between days 17 and 28 it may be either a recrudescence or a relapse by chloroquine-resistant parasites. Recurrences beyond day 28 could be relapse by chloroquine-sensitive P. vivax.

Animals↗
PubMed1997

Assessment of age-dependent immunity to malaria in transmigrants.

Sixty-six Javanese transmigrants moving from Java, an area of very low malaria transmission, to Irian Jaya, an area of high malaria transmission, were monitored to evaluate the effects of exposure to malaria transmission and age on resistance to infection and the induction of humoral immunity. The risk of acquiring Plasmodium falciparum parasitemia was not statistically greater in children (5-15 years of age) than in adults (> 15 years of age) during the first 14 months of exposure. However, during the cross-sectional survey at 14 months of exposure. children did have significantly higher P. falciparum asexual blood-stage parasite densities. Serum antibody titers to R32LR, a peptide containing sequences from the P. falciparum circumsporozoite repeat region, and MSP19, a proteolytic fragment of merozoite surface protein-1 (MSP-1) from P. falciparum, were measured by enzyme-linked immunosorbent assay. Exposure for both six and 14 months produced statistically significant increased antibody titers to both R32LR and MSP-1; no age-dependent difference in antibody titers was observed. In this population, exposure to malaria transmission induced antibodies to antigens associated with immunity to malaria. In addition, we noted an age-dependent difference in the parasitemia density of P. falciparum.

Adolescent↗
PubMed1997

DNA vaccines for malaria: the past, the present, & the future.

The first clinical trial of a DNA vaccine designed to protect against malaria has just commenced. This vaccine has been designed to induce protective CD8+ T cell responses against Plasmodium falciparum infected hepatocytes. Herein, we review the rationale behind the development of vaccines that induce protective CD8+ T cells, the strategy for the development of a DNA vaccine designed to protect against falciparum malaria, and the experimental data in rodent models and nonhuman primates which has provided the foundation for trials of DNA vaccines against P. falciparum malaria in humans.

Animals↗
PubMed1996

Protection against malaria by Plasmodium yoelii sporozoite surface protein 2 linear peptide induction of CD4+ T cell- and IFN-gamma-dependent elimination of infected hepatocytes.

Plasmodium falciparum sporozoite surface protein 2 (SSP2), also known as TRAP, is included in experimental human malaria vaccines because Plasmodium yoelii SSP2 is the target of protective CD8+ CTL that eliminate P. yoelii-infected hepatocytes in mice. We now report that immunization with a synthetic branched-chain peptide including four copies of a PySSP2 sequence, NPNEPS, and two tetanus toxin T helper epitopes in the adjuvant TiterMax, or with an 18 amino acid peptide (NPNEPS)3 in the adjuvant protects A/J, but not BALB/c or C57BL/6 mice. Transfer of T lymphocyte-enriched immune splenocytes protects naive mice; in vivo depletion of CD4+ T cells eliminates vaccine-induced protection; and in vivo treatment with anti-IFN-gamma reverses vaccine-induced activity against infected hepatocytes. Lymph node cells from immunized A/J, BALB/c, and C57BL/6 mice recognize the (NPNEPS)3 peptide in vitro. However, the protected A/J mice respond with a predominantly Th1 pattern of lymphocyte response, and the non-protected strains of mice respond with a Th2 pattern. There are many examples of CD4+ T cells transferring protection against infectious organisms. However, to our knowledge, this is the first formal demonstration that immunization with a linear synthetic peptide induces CD4+ T cell-dependent, IFN-gamma dependent, genetically restricted sterile protective immunity against an infectious agent.

Adoptive Transfer↗
PubMed1996

Identification and characterization of the protective hepatocyte erythrocyte protein 17 kDa gene of Plasmodium yoelii, homolog of Plasmodium falciparum exported protein 1.

We recently reported the discovery of a 17-kDa Plasmodium yoelii protein expressed in infected hepatocytes and erythrocytes, P. yoelii hepatocyte erythrocyte protein 17 (PyHEP17), and have demonstrated that this protein is a target of protective antibodies and T cells. Here, we report the identification and characterization of the gene encoding this protein and reveal that it is composed of two exons. Immunization of mice with PyHEP17 plasmid DNA induces antibodies, cytotoxic T lymphocytes, and protective immunity directed against the infected hepatocyte. Based on extensive sequence homology, expression pattern, and antigenic cross-reactivity, the Plasmodium falciparum homolog of PyHEP17 is identified as the protein known as exported protein-1 (PfExp-1), also called antigen 5.1, circumsporozoite related antigen, or QF116. Identity between PyHEP17 and PfExp-1 is 37% at the amino acid level (60/161 residues), mapping primarily to two regions within the second exon of 73% (16/22 residues) and 71% (25/35 residues) identity. On this basis, PfExp-1 is proposed as an important component of pre-erythrocytic human malaria vaccines.

Amino Acid Sequence↗
PubMed1996

Circumventing genetic restriction of protection against malaria with multigene DNA immunization: CD8+ cell-, interferon gamma-, and nitric oxide-dependent immunity.

Despite efforts to develop vaccines that protect against malaria by inducing CD8+ T cells that kill infected hepatocytes, no subunit vaccine has been shown to circumvent the genetic restriction inherent in this approach, and little is known about the interaction of subunit vaccine-induced immune effectors and infected hepatocytes. We now report that immunization with plasmid DNA encoding the plasmodium yoelii circumsporozoite protein protected one of five strains of mice against malaria (H-2d, 75%); a PyHEP17 DNA vaccine protected three of the five strains (H-2a, 71%; H-2k, 54%; H-2d, 26%); and the combination protected 82% of H-2a, 90% of H-2k, and 88% of H-2d mice. Protection was absolutely dependent on CD8+ T cells, INF-gamma, or nitric oxide. These data introduce a new target of protective preerythrocytic immune responses, PyHEP 17 and its P. falciparum homologue, and provide a realistic perspective on the opportunities and challenges inherent in developing malaria vaccines that target the infected hepatocyte.

Animals↗
PubMed1996

Class I HLA-restricted cytotoxic T lymphocyte responses against malaria--elucidation on the basis of HLA peptide binding motifs.

In animal models, CD8+ T cells are a critical effector mechanism in the protective immunity against malaria. Conventional approaches to the development of many vaccines, including those against malaria, have however proved inadequate. In particular, an alternative approach is needed for the development of vaccines designed to induce a cellular immune response mediated by CD8+ T cells. Advances in the field of molecular immunology during the past decade have provided an insight into the presentation of peptides by MHC class I molecules and their recognition by CD8+ T cells. These studies have provided a conceptual basis for the development of efficacious parasitic and viral vaccines. By a combination of immunochemical and cellular immunologic analyses based on specific peptide binding motifs, a subunit malaria vaccine that includes CD8+ T cell epitopes restricted by the most common class I HLA alleles, including HLA-A2, can now be constructed.

Amino Acid Sequence↗
PubMed1996

Protective efficacy against malaria of a combination sporozoite and erythrocytic stage vaccine.

Most malariologists believe that optimal malaria vaccines will induce protective immune responses against different stages of the parasite's life cycle. A multiple antigen peptide (MAP) vaccine based on the Plasmodium yoelii circumsporozoite protein (PyCSP) protects mice against sporozoite challenge by inducing antibodies that prevent sporozoites from invading hepatocytes. A purified recombinant protein vaccine based on the P. yoelii merozoite surface protein-1 (PyMSP-1) protects mice against challenge with infected erythrocytes, presumably by inducing antibodies against the erythrocytic stage of the parasite. We now report studies designed to determine if the PyMSP-1 vaccine protects against challenge with sporozoites, the stage encountered in the field, and if immunization with a combination of the PyCSP and PyMSP-1 vaccines provides additive or synergistic protection against sporozoite challenge. In two experiments, using TiterMax or Ribi R-700 as adjuvant, 3 of 19 mice immunized with the PyMSP-1 vaccine were completely protected against sporozoite challenge. The remaining mice had significantly delayed onset and lower levels of peak parasitemia than did control mice (11.1 +/- 2.8% vs. 36.7 +/- 1.6% in experiment #2, P < 0.01). Immunization with the combination vaccine reduced by approximately 50% the level of antibodies induced to PyCSP and PyMSP-1, as compared to that induced by the individual components. However, in two experiments, there was evidence of additive protection. Six of 19 (31.6%) immunized with the PyCSP vaccine, 3 of 19 (15.8%) immunized with the PyMSP-1 vaccine, and 10 of 19 (52.6%) immunized with the combination were completely protected against sporozoit challenge. This modest increase in protection in the combination group may be a reflection of additive anti-PyCSP and anti-PyMSP-1 immunity, since mice in the combination group had diminished levels of antibodies to each components. These studies indicate that considerable work may be required to optimize the construction, delivery, and assessment of multi-stage malaria vaccines.

Animals↗