Oral priming with Salmonella Typhi vaccine strain CVD 909 followed by parenteral boost with the S. Typhi Vi capsular polysaccharide vaccine induces CD27+IgD-S. Typhi-specific IgA and IgG B memory cells in humans.

Attenuated live oral typhoid vaccine candidate CVD 909 constitutively expresses Salmonella Typhi capsular polysaccharide antigen (Vi). A randomized, double-blind, heterologous prime-boost clinical study was conducted to determine whether immunity to licensed parenteral Vi vaccine could be enhanced by priming with CVD 909. Priming with CVD 909 elicited higher and persistent, albeit not significant, anti-Vi IgG and IgA following immunization with Vi, than placebo-primed recipients.

Adjuvanted intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that express homing receptors for mucosal and peripheral lymphoid tissues.

Background: Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide.

Methods: We conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan.

Relatedness of Vibrio cholerae O1/O139 isolates from patients and their household contacts, determined by multilocus variable-number tandem-repeat analysis.

The genetic relatedness of Vibrio cholerae O1/O139 isolates obtained from 100 patients and 146 of their household contacts in Dhaka, Bangladesh, between 2002 and 2005 was assessed by multilocus variable-number tandem-repeat analysis. Isolate genotypes were analyzed at five loci containing tandem repeats. Across the population, as well as within households, isolates with identical genotypes were clustered in time.

Vaginal microbiome of reproductive-age women.

The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities clustered into five groups: four were dominated by Lactobacillus iners, L.

Translation of clinical research into practice: defining the clinician scientist.

Family medicine has evolved into a specialty deeply rooted in clinical service. Because of high demands for clinical practice productivity, family physicians have drifted away from participation in scientific inquiry. There is even an effort in some institutions to reinvent family medicine as a community-based ambulatory specialty, resulting in a further "disconnect" between research and family physicians.

Plant-based oral vaccines: results of human trials.

Vaccines consisting of transgenic plant-derived antigens offer a new strategy for development of safe, inexpensive vaccines. The vaccine antigens can be eaten with the edible part of the plant or purified from plant material. In phase 1 clinical studies of prototype potato- and corn-based vaccines, these vaccines have been safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Generation of specific effector and memory T cells with gut- and secondary lymphoid tissue- homing potential by oral attenuated CVD 909 typhoid vaccine in humans.

Induction of effective memory T cells is likely to be critical to the level and duration of protection elicited by novel live oral typhoid vaccines. Using cells from volunteers who ingested Salmonella Typhi vaccine strain CVD 909, we characterized the induction of interferon (IFN)-gamma-secreting central (T(CM), CD45RO(+)CD62L(+)) and effector (T(EM), CD45RO(+)CD62L(-)) memory T populations, and their gut-homing potential based on integrin alpha4/beta7 expression. Both CD4(+) T(EM) and T(CM) populations secreted IFN-gamma.

Plant-based vaccines against diarrheal diseases.

Every year 1.6 million deaths occur due to diarrhea related to unsafe water and inadequate sanitation-the vast majority in children under 5 years old. Safe and effective vaccines against enteric infections could contribute to control of these diseases.

CVD 908, CVD 908-htrA, and CVD 909 live oral typhoid vaccines: a logical progression.

Typhoid fever remains an important public health problem in many parts of the world. Despite the availability of oral Ty21a (Vivotif; Berna Biotech) and parenteral Vi polysaccharide vaccine (Typhim Vi; Aventis Pasteur), improved typhoid fever vaccines have been sought. These include a series of vaccine candidates developed at the Center for Vaccine Development, University of Maryland, based on attenuation of Salmonella enterica serovar Typhi by deletions in the aroC, aroD, and htrA genes.

Cell-mediated immune responses in humans after immunization with one or two doses of oral live attenuated typhoid vaccine CVD 909.

CVD 909 is a novel live attenuated S. Typhi oral vaccine candidate derived from strain CVD 908-htrA which constitutively expresses Vi. Herein we investigated whether the genetic manipulations involved in modifying CVD 908-htrA altered its ability to induce potent T-cell immune responses (CMI) after a single dose (five subjects) and, in a separate trial, whether a second dose (eight subjects) further enhanced its immunogenicity.

Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody c alpha Stx2 administered intravenously to healthy adult volunteers.

Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing Escherichia coli. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to E. coli.

Plant-derived vaccines against diarrheal diseases.

Transgenic plants present a novel system for both production and oral delivery of vaccine antigens. Production of protein antigen in food plants is substantially cheaper than production in bacterial, fungal, insect cell, or mammalian cell culture. Edible plants themselves can also serve as the oral vaccine delivery system.

Garden-variety vaccines: antigens derived from transgenic plants.

The discovery of new vaccines can result from deletion of virulence determinants from a specific pathogen or from identification of target antigens that stimulate a protective immune response. Vaccine development will become less empirical as applications of genomics, proteomics and reverse vaccinology are exploited, and new protective antigens will emerge for inclusion in the vaccines of the future. However, production and purification of these new antigens for oral and parenteral use using traditional expression systems, will be expensive and unattractive to vaccine manufacturers who see the vaccine market as economically uninviting.

Immunogenicity of recombinant LT-B delivered orally to humans in transgenic corn.

Previous clinical studies have demonstrated the feasibility of using edible transgenic plants to deliver protective antigens as new oral vaccines. Transgenic corn is particularly attractive for this purpose since the recombinant antigen is stable and homogeneous, and corn can be formulated in several edible forms without destroying the cloned antigen. Transgenic corn expressing 1 mg of LT-B of Escherichia coli without buffer was fed to adult volunteers in three doses, each consisting of 2.

Immune responses to an oral typhoid vaccine strain that is modified to constitutively express Vi capsular polysaccharide.

Protection against typhoid fever might be best achieved by a vaccine that stimulates IgG antibody to Vi capsular polysaccharide (Vi) in serum, IgG antibody to O antigen in serum, and cell-mediated immune responses. Live typhoid vaccines have not elicited anti-Vi antibody, presumably because Vi expression is highly regulated. CVD 909 is an oral attenuated typhoid vaccine candidate that is engineered to constitutively express Vi.

Plant-derived vaccines against diarrhoeal diseases.

Transgenic plant-derived vaccines offer a new strategy for the development of safe, inexpensive vaccines against diarrhoeal diseases. In animal and Phase I clinical studies, these vaccines have been safe and immunogenic without the need for a buffer or vehicle other than the plant cell. This review examines some early attempts to develop oral transgenic plant vaccines against enteric infections such as enterotoxigenic Escherichia coli infection, cholera and norovirus infection.

Dose-dependent neutralizing-antibody responses to vaccinia.

To evaluate the humoral immune responses to smallpox-vaccine stocks currently available in the United States (Dryvax; Wyeth) and to generate data for comparison of responses to newly produced lots of smallpox vaccine, we evaluated dose-response effects, using undiluted and diluted smallpox vaccine. At 28 and 56 days after vaccination, serum samples were obtained from vaccinated subjects (N=674) who had participated in a randomized, single-blinded trial of an undiluted or a 1 : 5 or 1 : 10 dilution of smallpox vaccine and who subsequently were tested for plaque-reduction neutralizing-antibody titer. All subjects who developed a vesicle after vaccination also developed neutralizing antibodies by day 28.

Phase 1 studies of Walter Reed Army Institute of Research candidate attenuated dengue vaccines: selection of safe and immunogenic monovalent vaccines.

We describe the results of initial safety testing of 10 live-attenuated dengue virus (DENV) vaccine candidates modified by serial passage in primary dog kidney (PDK) cells at the Walter Reed Army Institute of Research. The Phase 1 studies, conducted in 65 volunteers, were designed to select an attenuated vaccine candidate for each DENV serotype. No recipient of the DENV candidate vaccines sustained serious injury or required treatment.

Humoral, mucosal, and cellular immune responses to oral Norwalk virus-like particles in volunteers.

Norwalk virus-like particles (VLPs), made from recombinant capsid protein, are a promising vaccine. Thirty-six healthy adult volunteers received 250 microg (n = 10), 500 microg (n = 10), or 2000 microg (n = 10) of orally administered VLP or placebo (n = 6). All vaccinees developed significant rises in IgA anti-VLP antibody-secreting cells.

Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with Salmonella enterica serovar typhi strain CVD 908-htrA.

Type 1 cell-mediated immunity might play an important role in protection from typhoid fever. We evaluated whether immunization with Salmonella enterica serovar Typhi (S. Typhi) strain CVD 908-htrA (a Delta aroC Delta aroD Delta htrA mutant), a leading live oral typhoid vaccine candidate, elicits specific CD4(+) and CD8(+) S.

Clinical responses to undiluted and diluted smallpox vaccine.

Background: To evaluate the potential to increase the supply of smallpox vaccine (vaccinia virus), we compared the response to vaccination with 10(8.1), 10(7.2), and 10(7.

Host-Salmonella interaction: human trials.

Human clinical trials, including experimental challenges of volunteers with pathogenic Salmonella enterica serovar Typhi, small phase I and II trials that monitor the immune responses to vaccines, and large-scale controlled field trials that assess vaccine efficacy under conditions of natural challenge, have helped elucidate the interactions between Salmonella typhi and human hosts.

Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218.

We conducted a phase II, randomized, double-blind, placebo-controlled, safety and immunogenicity study of a serially passaged, plaque-purified live chikungunya (CHIK) vaccine in 73 healthy adult volunteers. Fifty-nine volunteers were immunized one time subcutaneously with the CHIK vaccine and 14 were immunized with placebo (tissue culture fluid). Vaccinees were clinically evaluated intensively for one month, and had repeated blood draws for serological assays (50% plaque-reduction neutralization test) for one year.