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Biomedical subjects

Richard I Walker

Publications and source records attributed to Richard I Walker.

9 recordsLinked to original sources
PubMed2006

Analysis of strategies to successfully vaccinate infants in developing countries against enterotoxigenic E. coli (ETEC) disease.

Enterotoxigenic Escherichia coli (ETEC) is the most common bacterial cause of diarrhoea in the world, annually affecting up to 400,000,000 children under 5 years of age living in developing countries (DCs). Although ETEC possesses numerous antigens, the relatively conserved colonization factor (CF) antigens and the heat labile enterotoxin (LT) have been associated with protection and most vaccine candidates have exploited these antigens. A safe and effective vaccine against ETEC is a feasible goal as supported by the acquisition of protective immunity. The success of an ETEC vaccine targeting infants and children in DCs will depend on a combination of maximally antigenic vaccine preparations and regimens for their delivery which will produce optimal immune responses to these antigens. Vaccine candidates having a high priority for accelerated development and clinical testing for eventual use in infants would include inactivated ETEC or Shigella hybrids expressing ETEC antigens as well as attenuated ETEC strains which express the major CF antigens and LT toxin B-subunit, as well as attenuated Shigella, Vibrio cholerae and Salmonella typhi hybrids engineered to deliver antigens of ETEC. Candidates for an ETEC vaccine would have to meet the minimal requirement of providing at least 50% protection against severe disease in DCs during the first 2 years of life. The critical roadblock to achieving this goal has not been the science as much as the lack of a sufficiently funded and focused effort to bring it to realization. However, a Product Development Partnership to overcome this hurdle could accelerate the time lines towards when control of ETEC disease in DCs is substantially closer.

Adhesins, Escherichia coli↗
PubMed2006

Vaccine potential for inactivated shigellae.

We used human monocyte-derived dendritic cells (DC) and Balb/c mice as models to establish the immunogenic and protective potential of formalin-inactivated Shigella spp. Incubation of DC with inactivated or live bacteria induced DC maturation and cytokine release. Mice immunized orally or intranasally with killed S. flexneri, S. sonnei, or S. dysenteriae developed IgG and fecal IgA titers to the homologous LPS. Following respiratory challenge with the live homologous organisms, 80-100% survival was seen in all vaccinated groups compared to negligible survival in mice given PBS. Oral or intranasal immunization with an inactivated S. flexneri 2a strain (CVD1203) expressing the CFA/I and CS3 antigens of enterotoxigenic Escherichia coli induced IgG responses to both heterologous antigens. These in vivo and in vitro data indicate that inactivated shigellae retain the ability to interact effectively with key antigen presenting cells and induce protective immune responses in mice.

Animals↗
PubMed2005

Prevention of disease in ferrets fed an inactivated whole cell Campylobacter jejuni vaccine.

Ferrets were used to demonstrate the potential of a killed whole cell vaccine prepared from Campylobacter jejuni to protect against disease. C. jejuni strain 81-176 was grown in BHI broth, formalin-fixed, and resuspended in PBS to a concentration of 10(10) cells per ml. This vaccine (CWC) or live organisms were delivered orally with a nasogastric tube into anesthetized animals treated to reduce gastric acidity and intestinal motility. When 5x10(10) CFU of the vaccine strain (Lior serotype 5) or one of two other serotypes, CGL-7 (Lior 4) or BT44 (Lior 9), was used to challenge the ferrets, all of the animals developed a mucoid diarrhea. If the animals had been challenged with 5x10(9) CFU of the homologous strain 1 month before challenge with 10(10) CFU, 80-100% protection against disease was seen. This protection was also obtained after an initial exposure to the 81-176 strain followed by challenge with either of the heterologous strains. CWC was used to see if protection demonstrated with the live organisms could be produced with the non-living preparation. When 10(9) cells of CWC was given as two doses 7 days apart with or without 25mug of a coadministered mucosal adjuvant, LT(R192G), only 40-60% of the animals were protected. If the regimen was changed to four doses given 48h apart, 80% of the animals were free of diarrhea after subsequent challenge. Increasing the number of cells in the four dose regimen to 10(10) cells did not improve protection. Animals given four doses of 10(10) cells combined with LT(R192G) were subsequently challenged with 10(10) cells of the homologous strain or the heterologous strain CGL-7. The CWC protected against both strains. Serum IgG antibody titers determined by ELISA showed little increase following the CWC four dose vaccination regimen, compared to animals given one dose of the live organism. On subsequent challenge, however, both CWC vaccinated and live-challenged ferrets showed comparable antibody titer increases above those obtained following the initial challenge or vaccination. Western blots were used to show that the immunodominant antigen in vaccinated animals was a 45kDa protein, while in ferrets challenged with live organisms the immunodominant antigen was a 62kDa protein. These data show that the CWC can be used to protect against disease caused by Campylobacter. They also show that protection and serum IgG responses do not depend upon the use of the mucosal adjuvant and that cross protection among some of the major serotypes of Campylobacter responsible for human disease is possible.

Animals↗
PubMed2005

Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in children in developing countries.

Enteric pathogens constitute a major pediatric threat in the developing world through their impact on morbidity and mortality, physical and cognitive development and cause and effect relationship with malnutrition. Although many bacterial pathogens can cause diarrheal diseases, a group of less than 10 including Shigella spp., enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, and possibly, Campylobacter jejuni account for a significant percentage of these diseases in developing countries. Rotavirus is also a major cause of diarrheal diseases. Vaccines against these agents offer a potentially effective control measure against these diseases, but safe, practical, and effective vaccines for many of these agents have yet to be realized. Many vaccine development approaches are under investigation, but the one that is currently most advanced and that has been most widely applied to enteric pathogens is the use of orally administered live or killed whole pathogen preparations. If inactivated, these vaccines will probably be administered as multiple doses with approximately 10(10) to 10(11) total particles per dose, but they are relatively safe for oral administration. Further, they may not require a buffer for delivery and can be stored in liquid formulations. Fewer doses may be required for some live attenuated pathogen vaccines, but a buffer will most likely be required for oral delivery and the product must be stored in a dried formulation. Also, safety becomes more of a concern with live pathogens depending on the degree of attenuation, host immunocompetence, and the total number and kinds of attenuated pathogens which may be present in a combined agent vaccine. Both live and killed whole pathogen vaccines can be immunogenic and have the possibility to serve as vectors for other antigens. Although many organisms and serotypes are clinically important, by exploiting antigenic cross reactivity and using some pathogen components as vectors for cloned antigens of other pathogens, it could be possible to induce immunity against major enteric pathogens/serotypes with <10 whole pathogen components in a multi-agent vaccine. Safe and effective mucosal adjuvants may in the future be useful in whole pathogen vaccines, but they do not seem to be essential for immunization. Further, dietary supplements such as zinc, mixed routes of delivery and new regimens are under study which may in the future enhance further the effectiveness of the whole pathogen vaccines which now seem realizable in the near term. For this to happen, however, a coordinated and committed effort is necessary now to address the immunologic, regulatory, manufacturing, testing and implementation issues which will be involved in the realization of this important product to benefit children's health worldwide.

Bacterial Vaccines↗
PubMed2005

Enteric vaccines for pediatric use. Workshop summary.

Diarrheal diseases remain a major cause of death in children under 5 in less developed countries (LDCs). Vaccine development and implementation offers the best near-term approach to alleviating this problem. For this reason, a workshop to examine the possibilities for making enteric vaccines available to meet the specific needs of children in LDCs was convened in Virginia on April 24-26, 2004. Discussants considered research and development needs, regulatory and business issues, and previous experiences with enteric vaccine development and implementation. No insurmountable roadblocks to progress in this area were noted, and the possibility currently exists that properly supported efforts will enable the realization of enteric vaccines for pediatric use.

Bacterial Vaccines↗
PubMed2005

New vaccines against enteric bacteria for children in less developed countries.

Diarrheal diseases represent a major threat to infant survival in less developed countries. A real opportunity now exists to help alleviate this problem through the development of safe and effective multicomponent whole-bacterial cell vaccine(s) against enterotoxigenic Escherichia coli and Shigella, two important pathogens for which no licensed vaccine exists. What is preventing realization of this achievement is a lack of focus on the unique needs of children in less developed countries, along with committed and sufficient funding directed toward this goal. Live-attenuated and inactivated whole-cell vaccine candidates, some of which have languished too long, are available for testing, which, if performed in a coordinated fashion, can answer key unresolved issues concerning mucosal vaccination against enteric diseases. These candidate vaccines potentially provide a relatively simple intervention which could, if implemented, reduce the impact of these diseases upon the life and productivity of children.

Bacterial Vaccines↗
PubMed2004

In vivo phase variation and serologic response to lipooligosaccharide of Campylobacter jejuni in experimental human infection.

Some Campylobacter jejuni strains which exhibit mimicry of gangliosides in their lipooligosaccharides (LOSs) are associated with development of Guillain-Barré syndrome, which complicates the selection of a suitable C. jejuni strain in a live-attenuated vaccine. C. jejuni 81-176 is the most well characterized strain available, but structurally, LOS of C. jejuni 81-176 exhibits mimicry of predominantly GM2 and GM3 gangliosides. We compared the antiganglioside human serologic responses of 22 volunteers post-oral vaccination (two-dose series, 14 days apart) with a killed whole-cell C. jejuni vaccine, those of volunteers (22 following initial challenge and 5 upon rechallenge) experimentally infected with the homologous C. jejuni vaccine strain 81-176, and those of 12 volunteers used as controls (placebo recipients). All volunteers were evaluated using thin-layer chromatography immuno-overlay and a panel of nine gangliosides at days 0, 21, and 28 either postvaccination or postinoculation. Antiganglioside antibodies were identified at baseline in 6 of the 61 volunteers (9.8%). There were no antiganglioside antibodies observed following vaccination or experimental infection rechallenge. Evidence of seroconversion was observed in 2 of 22 (9.1%) in the initial infection challenge group, comparable to 1 of 12 (8.3%) in the placebo recipients. Additional testing of seven selected volunteers in the initial challenge group at days 0, 3, 7, 10, 21, 28, and 60 showed that when antiganglioside antibodies occurred (mostly anti-GM1 and -GM2), responses were weak and transient. Furthermore, evidence from serologic probing of LOSs of isolates recovered from stools of six volunteers indicated that the isolates had undergone antigenic phase variation in ganglioside mimicry during passage in vivo. Collectively, with the exception of one volunteer with anti-GM2 antibodies at day 60, the results show an absence of persistent antiganglioside antibodies after experimental infection with C. jejuni or following administration of a killed C. jejuni whole-cell oral vaccine, although LOS phase variation occurred.

Antibodies, Bacterial↗
PubMed2003

B cell responses in gastric antrum and duodenum following oral inactivated Helicobacter pylori whole cell (HWC) vaccine and LT(R192G) in H pylori seronegative individuals.

To investigate whether B cell-specific responses could be elicited in the gastric mucosa of Helicobacter pylori (HP) naive subjects, five volunteers ingested three doses of a HP killed whole cell (HWC) vaccine with 25 microg of recombinant heat-labile toxin (LT(R192G)). Two of three subjects had detectable LT(R192G) and HWC IgA antibody secreting cell (ASC) gastric responses. LT(R192G) and HWC responses in duodenal were 5-14-fold higher than those detected in antral biopsies (P<0.01 and P=0.05, respectively). These results provide the first evidence that specific gastric B cell responses can be induced in HP-non-infected individuals following oral immunization.

Adult↗