Treatment of gastrointestinal infections.
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
R Edelman
Publications and source records attributed to R Edelman.
Dengue virus-specific, human CD4+ cytotoxic T lymphocytes generated in short-term culture.
We previously reported cytotoxic activity of dengue virus-specific CD4+ CD8- T cell clones established in long-term in vitro culture. In the present experiments we tried to determine whether dengue virus-specific CD4+ CD8- CTL3 are present in short-term bulk cultures. Peripheral blood mononuclear cells (PBMC)3 from a donor who had been immunized with an experimental live attenuated dengue 1 vaccine 8 months earlier were used. PBMC were incubated with noninfectious dengue 1 antigen (Ag)3 for 7 days, and were examined for dengue 1-specific cytotoxic activity. PBMC cultured with dengue 1 Ag lysed autologous lymphoblastoid cell line (LCL)3 pulsed with noninfectious dengue 1 Ag, but did not lyse LCL pulsed with Ag of other dengue serotype, West Nile virus, or yellow fever virus, or control Ag. Treatment of cultured PBMC with monoclonal antibody to CD3 or CD4 and complement abrogated the cytotoxic activity but treatment with a monoclonal antibody to CD8 and complement did not. A time course study showed that dengue 1 Ag-specific CTL were first detected in 5 day cultures. Lysis of target cells by these CD4+ CTL were restricted by HLA class II, and HLA DQw1 and HLA DRw52 were determined to be the restriction molecules. These results indicate that dengue virus-specific CD4+ CD8- CTL are generated in short-term bulk cultures as well as in long-term-cultured cell lines, and support the concept that CD4+ CTL may be generated in vivo during infection.
Antigens, Viral↗
The epidemiology of antibody to hepatitis C in Egypt.
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Adolescent↗
Long-term persistence of sterile immunity in a volunteer immunized with X-irradiated Plasmodium falciparum sporozoites.
Three volunteers were immunized by repeated exposure to the bites of Plasmodium falciparum-infected, X-irradiated mosquitoes to characterize immunologic responses and duration of protective immunity. A primary series of immunizations had been shown previously to induce sterile immunity in these volunteers against sporozoite-induced P. falciparum malaria. In the current study, antibodies to sporozoites circulated at high levels for at least 9-12 months after the volunteers were administered booster bites from X-irradiated infective mosquitoes. One volunteer challenged a second time with P. falciparum 9 months after his last immunization was again shown to be protected, whereas all 5 control subjects developed patent infections. These results set a new standard for persistence of sterile immunity against experimental P. falciparum infection.
Adult↗
Safety and immunogenicity of live oral cholera vaccine candidate CVD 110, a delta ctxA delta zot delta ace derivative of El Tor Ogawa Vibrio cholerae.
The current pandemic of cholera is caused primarily by Vibrio cholerae O1 of the El Tor biotype. Live attenuated classical biotype V. cholerae vaccine strains prevent severe and moderate cholera due to either biotype in challenged volunteers but may provide less protection against mild cholera due to El Tor organisms. CVD 110, a new ctxA-deleted vaccine strain derived from an El Tor Ogawa parent, lacks zona occludens toxin (Zot), accessory cholera enterotoxin (Ace), and hemolysin/enterotoxin. Ten healthy adult volunteers were given 10(8) cfu of CVD 110 with buffer; 7 developed diarrhea (mean stool volume, 861 mL). Vaccine organisms were shed in stool by all vaccines and were recovered from duodenal fluid in three-quarters of vaccinees. After vaccination, the geometric mean peak reciprocal vibriocidal titer among vaccinees was 17,829. CVD 110 is a powerful immunogen but insufficiently attenuated despite the absence of known potential enterotoxins of V. cholerae. Another unrecognized toxin or colonization alone may be responsible for diarrhea after ingestion of this strain.
Administration, Oral↗
Dengue virus-specific human CD4+ T-lymphocyte responses in a recipient of an experimental live-attenuated dengue virus type 1 vaccine: bulk culture proliferation, clonal analysis, and precursor frequency determination.
We analyzed the CD4+ T-lymphocyte responses to dengue, West Nile, and yellow fever viruses 4 months after immunization of a volunteer with an experimental live-attenuated dengue virus type 1 vaccine (DEN-1 45AZ5). We examined bulk culture proliferation to noninfectious antigens, determined the precursor frequency of specific CD4+ T cells by limiting dilution, and established and analyzed CD4+ T-cell clones. Bulk culture proliferation was predominantly dengue virus type 1 specific with a lesser degree of cross-reactive responses to other dengue virus serotypes, West Nile virus, and yellow fever virus. Precursor frequency determination by limiting dilution in the presence of noninfectious dengue virus antigens revealed a frequency of antigen-reactive cells of 1 in 1,686 peripheral blood mononuclear cells (PBMC) for dengue virus type 1, 1 in 9,870 PBMC for dengue virus type 3, 1 in 14,053 PBMC for dengue virus type 2, and 1 in 17,690 PBMC for dengue virus type 4. Seventeen CD4+ T-cell clones were then established by using infectious dengue virus type 1 as antigen. Two patterns of dengue virus specificity were found in these clones. Thirteen clones were dengue virus type 1 specific, and four clones recognized both dengue virus types 1 and 3. Analysis of human leukocyte antigen (HLA) restriction revealed that five clones are HLA-DRw52 restricted, one clone is HLA-DP3 restricted, and one clone is HLA-DP4 restricted. These results indicate that in this individual, the CD4+ T-lymphocyte responses to immunization with live-attenuated dengue virus type 1 vaccine are predominantly serotype specific and suggest that a multivalent vaccine may be necessary to elicit strong serotype-cross-reactive CD4+ T-lymphocyte responses in such individuals.
Adult↗
Effects of ingested human anti-sporozoite sera on Plasmodium falciparum sporogony in Anopheles stephensi.
We investigated the effects of human anti-sporozoite antibodies on the sporogonic development of Plasmodium falciparum in Anopheles stephensi. Equal volumes of washed human erythrocytes and human sera from 1) volunteers with protective immunity induced by immunization with irradiated P. falciparum sporozoites, 2) the same volunteers before immunization, or 3) Kenyans exposed to natural sporozoite transmission, were fed to cohorts of P. falciparum-infected A. stephensi on either day 5, 8, or 11 after infection. A fourth group of infected mosquitoes from the same cohort were not refed. In two experiments, the effects of anti-sporozoite antibodies were evaluated by determining the infection rates and parasite densities for oocysts and salivary gland sporozoites. There was no evidence that anti-sporozoite antibodies had any effect on the development or intensity of P. falciparum infection in A. stephensi. However, accelerated oocyst maturation was associated with mosquitoes taking a second blood meal, independent of serum source. Salivary gland sporozoites from mosquitoes that fed on immune human sera contained bound human IgG, which was detectable by indirect immunofluorescence assay. The infectivity and transmission potential of human IgG-coated sporozoites is unknown.
Animals↗
Risk factors associated with a high seroprevalence of hepatitis C virus infection in Egyptian blood donors.
We performed serologic tests for hepatitis C virus (HCV) infection on sera obtained from 163 volunteer blood donors seen at one Cairo hospital. We found HCV infection in 36 donors (22%) measured by a second generation enzyme immunoassay. Thirty-five of these 36 positive sera were tested with a second generation recombinant immunoblot assay (RIBA-2); 22 (63%) were reactive and another 12 (34%) showed an indeterminate reaction. Overall, 13.6% (95% confidence interval [CI] = 8.3-18.9%) of these Egyptian blood donors were serologically confirmed to be infected with HCV. Of several demographic variables and medical risk factors examined, the serologically confirmed (RIBA-2 reactive) donors were significantly older than nonreactive donors, and the age-adjusted risk of being HCV-positive was significantly greater in individuals residing outside Cairo. A knowledge of having received injections, of having a history of schistosomiasis, or of having concomitant hepatitis B surface antigen or antibody were significantly associated with an increased risk of HCV-seropositivity; however, after adjusting for confounding demographic factors, only schistosomiasis (odds ratio = 8.9, 95% CI = 2.35-33.52) was significantly associated with HCV infection. The HCV seropositive rate of 13.6% among Egyptians is 5-35-fold higher than that reported from volunteer blood donors in other countries. Screening for HCV should be instituted in Egyptian blood banks. Blood banks that do not test for HCV should include a history of schistosomiasis in their exclusion criteria used for routine screening of blood donors.
Adolescent↗
Safety and immunogenicity in volunteers of a recombinant Plasmodium falciparum circumsporozoite protein malaria vaccine produced in Lepidopteran cells.
A recombinant Plasmodium falciparum circumsporozoite (CS) antigen (rPfCSA) was produced in insect cells using a baculovirus expression vector containing the entire CS gene. This near full-length CS antigen was adsorbed onto aluminium phosphate for use as a malaria vaccine. In a study of safety and immunogenicity, 20 volunteers were divided into four groups of five each and inoculated intramuscularly with 10, 100, 500 or 1000 micrograms of vaccine. Primary vaccinations were followed by two booster immunizations at 2 and 6 months. Three volunteers developed prominent local reactions manifested as tenderness, redness and swelling at the injection site following the second or third vaccination. All symptoms resolved spontaneously within 72 h. Postimmunization sera from six of 20 volunteers showed seroconversions as measured by Western blot, using rPfCSA as antigen. However, specific anti-CS protein antibody could not be detected by indirect immunoflourescence against intact sporozoites or by ELISA using rPfCSA or peptide to the repeat region. In addition, 18 of 20 volunteers developed antibody to baculovirus proteins as determined by ELISA and/or Western blot. Antigen-driven replication studies using peripheral blood mononuclear cells from vaccinees failed to detect proliferative responses specific to CS protein. This recombinant CS protein vaccine, as formulated, was minimally immunogenic in humans.
Adult↗
Initial safety and immunogenicity studies of an oral recombinant adenohepatitis B vaccine.
Orally administered adenovirus may be a useful vaccine carrier of cloned antigens of other pathogens. A recombinant adenohepatitis vaccine Wy-Ad7HZ6-1, which expressed hepatitis B surface antigen and contained a large deletion in early region 3 (E3), was constructed and studied in humans. Volunteers received Wy-Ad7HZ6-1 (n = 3), adenovirus type 7 vaccine (n = 3) or placebo (n = 3). Recipients of Wy-Ad7HZ6-1 shed less vaccine virus in the stool for a shorter period and had a lower titre of anti-adenovirus type 7 antibodies than recipients of the adenovirus 7 vaccine. None of the three Wy-Ad7HZ6-1 vaccinees developed antibody to hepatitis B surface antigen after this one dose primary immunization regimen. The E3 region may be required for optimal enteric growth of adenovirus-vectored vaccines.
Adenoviruses, Human↗
Clinical acceptability and immunogenicity of CVD 908 Salmonella typhi vaccine strain.
An attenuated Salmonella typhi strain has been sought as an improved oral typhoid vaccine and as a carrier of protective antigens of other pathogens to make hybrid vaccines. Ideally, such a strain would be safe and induce protective immune responses after a single oral dose. CVD 908 is a mutant of S. typhi wild-type strain Ty2 with recombinant deletions in two genes, aroC and aroD. In phase 1 testing to date, this strain has not produced febrile responses or other significant adverse reactions in adult volunteers given doses of 5 x 10(4) to 5 x 10(7) organisms with sodium bicarbonate. In addition, after just a single oral dose of 5 x 10(7) colony-forming units, this strain induced IgG seroconversion to S. typhi lipopolysaccharide in 83% of vaccinees and stimulated specific IgA-secreting gut-derived lymphocytes in 100% of vaccinees. CVD 908 is a new oral typhoid vaccine that should be further investigated as a carrier for expressing foreign antigens in recombinant vaccine constructs.
Administration, Oral↗
An update on vaccine adjuvants in clinical trial.
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Adjuvants, Immunologic↗
Onset and duration of protective immunity in challenged volunteers after vaccination with live oral cholera vaccine CVD 103-HgR.
CVD 103-HgR is a live oral cholera vaccine that, in phase I and II studies to date, has been well tolerated and immunogenic. In challenge studies of US volunteers conducted 4-5 weeks after vaccination, CVD 103-HgR provided significant protection against experimental cholera due to classical and El Tor Vibrio cholerae O1. To determine the onset and duration of protection, two volunteer challenge studies were conducted: the first, 6 months after vaccination and the second, 8 days after vaccination. In both studies, CVD 103-HgR was 100% protective against diarrhea and significantly reduced the rate of shedding of vibrios after challenge with V. cholerae classical Inaba strain 569B, the virulent parent strain of CVD 103-HgR. Previously vaccinated subjects were less likely than naive controls to develop rises in titer of vibriocidal antibodies after challenge (P = .002), and the mean peak titer of vibriocidal antibodies was less than among controls. CVD 103-HgR can provide homologous protective immunity as soon as 8 days after vaccination and protection can persist for at least 6 months.
Administration, Oral↗
Comparison of the safety and immunogenicity of delta aroC delta aroD and delta cya delta crp Salmonella typhi strains in adult volunteers.
Three attenuated Salmonella typhi strains have been constructed by introducing deletions in aroC and aroD or deletions in cya and crp into one of two wild-type parent strains, Ty2 or ISP1820. These mutant strains were designated CVD 906 (ISP1820 delta aroC delta aroD), CVD 908 (Ty2 delta aroC delta aroD), and chi 3927 (Ty2 delta cya delta crp). Two studies were conducted with 36 healthy adult inpatient volunteers to determine in a double-blind fashion the safety and immunogenicity of approximately 5 x 10(4) and 5 x 10(5) CFU of each of these three vaccine candidates given as a single dose. No statistically significant difference in the incidence of reactions among vaccinees was observed. Fever (oral temperature greater than or equal to 38.2 degrees C) occurred in 2 of 12 volunteers who received CVD 906, in 0 of 12 who received CVD 908, and in 1 of 12 who received chi 3927. Vaccine bacteremia without symptoms occurred in 1 of 12 vaccinees who received CVD 906, in 0 of 12 who received CVD 908, and in 2 of 12 who received chi 3927. Overall, 19 (53%) of 36 vaccinees developed immunoglobulin G antibody to S. typhi lipopolysaccharide after vaccination, with no statistically significant differences in the rate of seroconversion among volunteers in the three groups. We conclude that defined mutations in the aromatic biosynthetic pathway and in the cyclic AMP global regulatory system attenuate S. typhi. Mutant strains CVD 906, CVD 908, and chi 3927 are highly (and approximately equally) immunogenic but possibly differ in their propensity to induce fever. Further studies are needed to document the apparent relative safety of CVD 908 as a typhoid vaccine and as a vaccine carrier of foreign antigens.
Adolescent↗
Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge.
Serum cytokine profiles were evaluated in immunized and nonimmunized human volunteers after challenge with infectious Plasmodium falciparum sporozoites. Three volunteers had been immunized with x-irradiated sporozoites and were fully protected from infection. Four nonimmune volunteers all developed symptomatic infection at which time they were treated. Sera from all volunteers were collected at approximately 20 time points during the 28-d challenge period; levels of IL-1 alpha, IL-1 beta, IL-2, IFN-gamma, tumor necrosis factor-alpha, IL-4, IL-6, granulocyte macrophage-colony-stimulating factor, and soluble CD4, CD8, and IL-2 receptor (sCD4, sCD8, and sIL-2R, respectively) were determined by ELISA. C-reactive protein (CRP) was assayed by radial immunodiffusion. Parasitemic subjects developed increases in CRP and IFN-gamma, with less marked increases in sIL-2R and sCD8; the other cytokines tested did not change. CRP increases were abrupt and occurred at the onset of fever (day 14 after challenge). IFN-gamma increases were also abrupt, preceding those of fever and CRP by one day. Increases in sIL-2R and sCD8 were more gradual. Increases in fever, CRP, IFN-gamma, and sCD8 were concordant in each volunteer. Early IL-6 increases were noted in the protected vaccinees. Thus, after challenge with virulent P. falciparum, unique systemic cytokine profiles were detectable both in immunized, nonparasitemic volunteers and in unvaccinated, parasitemic subjects. The contrasting cytokine profiles in the two groups may relate to mechanisms of protection and immunopathology in experimental human malaria.
Animals↗
T cell responses to repeat and non-repeat regions of the circumsporozoite protein detected in volunteers immunized with Plasmodium falciparum sporozoites.
The design of a malarial vaccine based on the circumsporozoite (CS) protein, a major surface antigen of the sporozoite stage of the malaria parasite, requires the identification of T and B cell epitopes for inclusion in recombinant or synthetic vaccine candidates. We have investigated the specificity and function of a series of T cell clones, derived from volunteers immunized with Plasmodium falciparum sporozoites, in an effort to identify relevant epitopes in the immune response to the pre-erythrocytic stages of the parasite. CD4+ T cell clones were obtained which specifically recognized a repetitive epitope located in the 5' repeat region of the CS protein. This epitope, when conjugated to the 3' repeat region in a synthetic MAPs construct, induced high titers of antisporozoite antibodies in C57BL mice. A second T cell epitope, which mapped to aa 326-345 of the carboxy terminal, was recognized by lytic, as well as non-lytic, CD4+ T cells derived from the sporozoite-immunized volunteers. The demonstration of CD4+ CTL in the human volunteers, and the recent studies in the rodent model (Renia et al., 1991; Tsuji et al., 1990), suggest that CS-specific CD4+ T cells, in addition to their indirect role as helper cells in the induction of antibody and CD8+ effector cells, may also play a direct role in protection against sporozoite challenge by targeting EEF within the liver.
Amino Acid Sequence↗
Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge.
The protective efficacy of oral bovine immunoglobulin concentrates derived from colostrum against challenge with Shigella flexneri was studied in healthy adult volunteers in a randomized, double-blind fashion. Volunteers were given a product consisting of hyperimmune immunoglobulin concentrate with a high titer of anti-S. flexneri 2a lipopolysaccharide (LPS) with sodium bicarbonate or a control preparation with sodium bicarbonate three times a day for seven days. On the third day of treatment, volunteers received a challenge of 10(3) colony-forming units of S. flexneri 2a strain 2457T. None of the volunteers who received the high-titered hyperimmune product became ill, compared with 45% of volunteers who received the placebo (P less than 0.05). The duration of shedding of the challenge organism was decreased, and the active immune responses to S. flexneri LPS were less frequent and of lower magnitude in volunteers given the immunoglobulin concentrate than in those in the control group. High-titered, orally administered bovine immunoglobulin concentrate protects against shigellosis and may be useful in preventing shigellosis among travelers, military personnel, and individuals at risk during a Shigella outbreak.
Animals↗
Perspective on the development of vaccines against Lyme disease.
Lyme disease, the multisystem illness caused by the tick-borne spirochaete, Borrelia burgdorferi, has emerged as a threat to public health worldwide. It is a particularly vexing problem in the United States where it is growing in range and intensity. In fact, in some hyperendemic regions of New York and New England, Lyme disease is now such a threat that it interferes with all sorts of outdoor activities, and has even led to depreciation of real estate values. Family dogs in these areas seem to have been particularly hard hit by a near epidemic of lameness caused by Lyme arthritis. Persons at high risk for infection, such as outdoor workers, campers and hikers, suburbanites with lawns to cut, and pregnant women exposed to potentially infected Ixodes ticks, are clamouring for some means of protection beyond simple behaviour modification and tick avoidance which are known not always to work. Hence, the interest in human and veterinary vaccines against Lyme disease is growing.
Antibodies, Bacterial↗