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Biomedical subjects

P E Duffy

Publications and source records attributed to P E Duffy.

At least 19 recordsLinked to original sources
PubMed2001

Pre-erythrocytic immunity to Plasmodium falciparum: the case for an LSA-1 vaccine.

A vaccine is urgently needed to stem the global resurgence of Plasmodium falciparum malaria. Vaccines targeting the erythrocytic stage are often viewed as an anti-disease strategy. By contrast, infection might be completely averted by a vaccine against the liver stage, a pre-erythrocytic stage during which the parasite multiplies 10000-fold within hepatocytes. Sterilizing immunity can be conferred by inoculating humans with irradiated pre-erythrocytic parasites, and a recombinant pre-erythrocytic vaccine partially protects humans from infection. Liver-stage antigen-1, one of a few proteins known to be expressed by liver-stage parasites, holds particular promise as a vaccine. Studies of naturally exposed populations have consistently related immune responses against this antigen to protection.

Adolescent↗
PubMed2001

Human resistance to Plasmodium falciparum increases during puberty and is predicted by dehydroepiandrosterone sulfate levels.

Immunity to Plasmodium falciparum develops slowly in areas of endemicity, and this is often ascribed to poorly immunogenic or highly variant parasite antigens. However, among populations newly exposed to malaria, adults acquire immunity more rapidly than children. We examined the relationship between pubertal development and resistance to P. falciparum. During two transmission seasons in western Kenya, we treated the same cohort of young males to eradicate P. falciparum and then obtained blood smears each week for 4 months. We determined pubertal development by Tanner staging and by levels of dehydroepiandrosterone sulfate (DHEAS) and testosterone in plasma. In multivariate and age-stratified analyses, we examined the effect of pubertal development on resistance to malaria. In both seasons (n = 248 and 144 volunteers, respectively), older males were less susceptible than younger males. Age-related decreases in the frequency and density of parasitemia were greatest during puberty (15- to 20-year-olds). DHEAS and testosterone were significant independent predictors of resistance to P. falciparum parasitemia, even after accounting for the effect of age. Fifteen- to 20-year-old males with high DHEAS levels had a 72% lower mean parasite density (P<0.01) than individuals with low DHEAS levels. Similarly, 21- to 35-year-old males with high DHEAS levels had a 92% lower mean parasite density (P<0.001) and 48% lower frequency of parasitemia (P<0.05) than individuals with low DHEAS levels. These data suggest that the long period needed to attain full immunity could be explained as a consequence of host development rather than as the requirement to recognize variant or poorly immunogenic parasite antigens.

Adolescent↗
PubMed1999

Malaria during pregnancy: parasites, antibodies and chondroitin sulphate A.

CSA-binding forms of P. falciparum appear uncommonly in non-pregnant hosts but are selected by the human placenta for growth. Parasites are presumably selected by adherence to CSA within the vascular compartment of the placenta, allowing IRBCs to sequester and multiply to high density. Chondroitin sulphate appears on the surface of placental syncytiotrophoblasts, and CSA is a component of PGs found in the placenta [42], but the identification of the CSA-containing PG(s) mediating IRBC adhesion in vivo requires further study. Anti-adhesion antibodies against CSA-binding parasites are associated with protection from maternal malaria, but these antibodies develop only over successive pregnancies, accounting for the susceptibility of primigravidas to infection. PfCSA-L, the parasite ligand mediating adhesion to CSA, has not yet been identified but is known to be antigenically conserved among isolates from around the world. An anti-adhesion vaccine delivered to women before first pregnancy could confer protection from maternal malaria and might be globally effective.

Cell Adhesion↗
PubMed1999

Interleukin-10 responses to liver-stage antigen 1 predict human resistance to Plasmodium falciparum.

The design of an effective vaccine against Plasmodium falciparum, the most deadly malaria parasite of humans, requires a careful definition of the epitopes and the immune responses involved in protection. Liver-stage antigen 1 (LSA-1) is specifically expressed during the hepatic stage of P. falciparum and elicits cellular and humoral immune responses in naturally exposed individuals. We report here that interleukin-10 (IL-10) production in response to LSA-1 predicts resistance to P. falciparum after eradication therapy. Resistance was not related to gamma interferon or tumor necrosis factor alpha production. This is the first report that human IL-10 responses are associated with resistance after eradication therapy, and our findings support the inclusion of LSA-1 in a vaccine against malaria.

Animals↗
PubMed1999

Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children.

The cause of the anemia associated with chronic, intermittent, asymptomatic, low-level parasitemia in children in malaria-endemic endemic areas is not well understood. Nitric oxide (NO) decreases erythropoiesis, and it is likely an important mediator of anemia of chronic disease. Production of NO is decreased in acute uncomplicated and cerebral malaria, but it is increased in asymptomatic Tanzanian children (with or without parasitemia). We hypothesized that chronic overproduction of NO in these asymptomatic children contributes to the anemia associated with subclinical/subpatent malaria. In 44 fasting, asymptomatic, malaria-exposed, Tanzanian children, NO production (measured using fasting urine NOx excretion) was inversely associated with hemoglobin concentration (P = 0.03, controlling for age and gender). Using multiple linear regression, hemoglobin concentration was negatively associated with parasitemia (P = 0.005). After controlling for age and parasitemia, NO was no longer an independent predictor of anemia. One of the mechanisms of parasite-related anemia in such children may be through the adverse hematologic effects of parasite-induced NO production.

Anemia↗
PubMed1999

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.

Aging↗
PubMed1998

Malaria elicits type 1 cytokines in the human placenta: IFN-gamma and TNF-alpha associated with pregnancy outcomes.

Pregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants. Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear. We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-gamma and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-alpha and TGF-beta concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area. Among primigravidas, placental TNF-alpha concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-gamma and TNF-alpha were significantly elevated when a low birth weight, rather than normal weight, infant was delivered. We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-gamma, IL-2, and TNF-alpha in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.

Cytokines↗
PubMed1998

Maternal malaria and parasite adhesion.

Malaria during pregnancy continues to be a major health problem in endemic countries, with clinical consequences, including death, for both mother and child. Just as cerebral malaria results from parasite sequestration in the brain, maternal malaria results from parasite sequestration in the placenta, and a distinct subpopulation of parasites which bind chondroitin sulfate A but not CD36 causes the syndrome. Women have little or no immunological experience with this parasite prior to first pregnancy, making primigravid women particularly vulnerable to infection. Parasites adhere to the surface of trophoblastic villi, eliciting the accumulation of inflammatory leukocytes in the intervillous space, and the necrosis of adjacent placental tissue. Maternal malaria results in poor pregnancy outcomes, although the responsible mechanisms have not been defined. In holoendemic areas both placental infection and poor outcome decrease in frequency with successive pregnancies; protection may result from control of parasite adhesion, suggesting an attractive target for new therapies.

Animals↗
PubMed1998

Immunization with SPf66 and subsequent infection with homologous and heterologous Plasmodium falciparum parasites.

In an area of intense transmission, a malaria vaccine could reduce infection due to the parasite types represented in the vaccine, but have no detectable effect on the overall frequency of infection if it did not protect against infection with heterologous parasites. These studies were performed to determine whether immunization with SPf66 decreased infection with homologous parasites containing the 11 amino acid peptide from merozoite surface protein-1 (MSP-1) in SPf66, or increased infection due to heterologous parasites containing heterologous (alternative) MSP-1 sequences. Based on this 11 amino acid peptide (YSLFQKEKMVL), three forward primers (S,Q,V) were designed to amplify the MSP-1 sequence present in SPf66, and 3 additional forward primers (G,H,I) to amplify the alternative MSP-1 sequence (YGLFHKEKMIL). This strategy was validated by polymerase chain reaction (PCR) amplification and dideoxy sequencing with 14 cloned laboratory isolates, which demonstrated that each primer amplified one MSP-1 sequence or the other, but not both. The technique was then used to examine filter paper blots from an SPf66 vaccine study of 69 subjects in Saradidi, Kenya. In that study, the prevalence of infection with YSLFQKEKMVL or YGLFHKEKMIL type parasites was unaffected by immunization with SPf66 (based on PCR amplification with the S, Q, V, G, H and I primers, respectively). These results suggest that immunization with SPf66 does not produce a selective effect in vivo. They demonstrate a molecular method to test for selection in vivo as an indirect measure of vaccine efficacy.

Adolescent↗
PubMed1997

A novel malaria protein, Pfs28, and Pfs25 are genetically linked and synergistic as falciparum malaria transmission-blocking vaccines.

Antibodies to Pfs28 block Plasmodium falciparum transmission and when combined with antibodies to Pfs25 provide synergy in blocking transmission. Pfs28 and Pfs25 are immunogenic, have limited antigenic diversity, and are structurally similar and genetically linked on chromosome 10. Pfs28 may prove a useful addition to Pfs25 in an effective transmission-blocking vaccine.

Amino Acid Sequence↗
PubMed1996

Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta.

Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.

Adhesiveness↗
PubMed1996

Phase I safety and immunogenicity testing of clinical lots of the synthetic Plasmodium falciparum vaccine SPf66 produced under good manufacturing procedure conditions in the United States.

Two clinical lots of alum-adsorbed SPf66 vaccine produced in the United States were evaluated in separate, open-label, Phase I clinical trials involving 15 healthy, malaria-naive, 18-45-year old men and women. Subjects received 2 mg doses subcutaneously in alternate arms at 0, one, and six months. Safety was assessed by monitoring local and systemic reactions and laboratory parameters. The most common side effects were erythema and local tenderness at the site of injection, which increased in frequency with subsequent doses of vaccine. These local reactions were considered mild and resolved within 24-48 hr. Eleven of 14 volunteers who received all three doses of vaccine seroconverted by enzyme-linked immunosorbent assay. The distribution of high, medium, and low nonresponders was comparable with that seen in trials of Colombian-produced vaccine. One high responder developed antibodies reactive with asexual stage parasite antigens by immunofluorescence and immunoblot. The results indicated that at full adult doses, SPf66 of U.S. origin is mildly reactogenic and induces immune responses similar to those reported for SPf66 of Colombian origin.

Adult↗
PubMed1993

Pgs28 belongs to a family of epidermal growth factor-like antigens that are targets of malaria transmission-blocking antibodies.

Although Pgs28, a 28-kD surface protein of Plasmodium gallinaceum oökinetes, was previously thought not to be a target of transmission-blocking antibodies, we found that polyclonal antisera to Pgs28 completely blocked parasite infectivity to Aedes aegypti mosquitoes. Antisera raised against reduced Pgs28 were less effective in blocking transmission than were antisera to nonreduced Pgs28; thus, the target epitope(s) of transmission-blocking antibodies appears to be conformation dependent. In stage-specific assays, polyclonal antisera impaired the in vitro transformation of zygotes to mature oökinetes, as well as the in vivo development of mature oökinetes to oöcysts. Using microsequence of immunoaffinity-purified Pgs28, we cloned the 666-bp open reading frame of the Pgs28 gene. The deduced amino acid sequence of Pgs28 is strikingly similar to that of a P. gallinaceum zygote surface protein, Pgs25, and its P. falciparum analogue, Pfs25. Pgs28, like Pgs25 and Pfs25, has a presumptive secretory signal sequence, followed by four epidermal growth factor-like domains, and a terminal hydrophobic region.

Amino Acid Sequence↗