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Novel vaccination strategies for the control of mucosal infection
AbstrGcts Sessions 1 & 2: Epidemiology and Immunology
Epidemiology of diarrheal diseases: implications for control by vaccines Robert E. Black
Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD, USA Understanding the epidemiology of diarrheal diseases, including the etiologic agents and their virulence and pathogenicity, along with the evidence for acquired immunity, is fundamental to the formulation of strategies for their control by vaccines. Studies of etiologic agents in developing countries have found a wide range of bacterial, viral, and parasitic organisms associated with diarrhea, with various forms of pathogenic Escherichia coli often being the most frequent. These studies also permit examination of the apparent virulence of the infection as assessed by the severity of disease that occurs. This dimension is important if control efforts are to be directed toward the etiologic agents most likely to cause severe and potentially life-threatening illnesses. In this regard, rotavirus appears to stand out as the most important cause of severe diarrhea in young children and cholera is a serious problem in some areas. Other agents, e.g. Shigella sp. may be particularly important contributors to morbidity, malnutrition, and mortality is some settings.
Exposure to enteropathogens in developing countries is extensive and does not always cause diarrhea. The likelihood that an agent will result in illness, or the pathogenicity, is variable and is related to the organisms itself, as well as to the conditions of exposure and the resistance of the host. Review of this information for selected enteropathogens yields important guides for vaccine development and application. In particular, studies of passively or actively acquired immunity reveal what may be anticipated with enteric vaccines. The frequent exposure to enteropathogens that begins early in life present a challenge to a vaccine control stragety, but even more importantly, the observation of limited acquired immunity after illness suggests that protective immunity is highly specific and that several exposures to etiologic agents may often be needed for the development of substantial protection. The implications for control of diarrheal diseases will be discussed.
Novel vaccination strategies for the control of mucosal infection Alan J. Husband
Faculty of Medic&e, The University of Newcastle, Royal Newcastle Hospital Newcastle, NSW 2300, Australia Control of mucosal infections through vaccination requires immunization strategies which encourage the production at subepithelial locations of both IgA-producing plasma cells and appropriate regulatory T cells. Recent advances in the understanding of control mechanisms for mucosal immune defence have assisted in the design of novel vaccination strategies. It is now apparent that the induction of IgA plasma cell responses from gut associated lymphoid tissue and their dissemination to and proliferation at lamina propria effector sites is under the stringent control of subsets of T helper cells. Whereas cognate T cell help is required in the inductive phase, the regulatory signals derived from T helper cells in effector sites appears to operate in a non-cognate fashion, probably
through the effects of cytokines. The balance of help and suppression in the intestinal lamina propria appears to be dependent on the nature of antigen processing and epithelial presentation appears to favour a down regulation of immune responsiveness. These observations have enabled the development of a vaccination strategy dependent on serosal presentation of antigen via the intraperitoneal route. Antigens administered in appropriate adjuvant/vehicle formulations can stimulate a protective immune response in the intestine and indeed in remote mucosal sites. Data will be presented to demonstrate the potential for this vaccination regime to protect against both enteritis due to Escherichia coli infection and pneumonia due to Mycoplasma spp. and Actinobacillus spp.
Induction of lgA by oral administration of Pertussis and Cholera toxin A.D. Wilson*, C.R. Stokes*, L. Irons, A. Robinson
*Dept. Veterinary Medicine University of Bristol, Bristol, UK and PHLS, Porton, Salisbury, Wilts, UK Fed Cholera toxin (CT) is a potent stimulator of IgA responses. the Gm 1 binding B-subunit on its own is a poor stimulator of IgA but does induce an IgG response. Pertussis toxin (PT) can activate adenylate cyctase but does not induce an IgA response. When both CT-B and PT are fed simultaneously the IgA response to the B-subunit is restored to the level of that induced by whole CT. After feeding CT was present in the epithelial cells throughout the intestine and it had a predilection 0264-410X/92/040261-32 © 1991 Butterworth-HeinemannLtd
for Peyers patch epithelium. PT was mainly bound to the mucous in the upper duodenum. We conclude that whilst the Gm 1 binding properties of CT are important in enhancing antigen uptake, an optimum IgA response is dependant on the activation of adenylate cyclase. Pertussis toxin is not absorbed in sufficient quantity to act as an antigen but can enhance the IgA response to Cholera toxin B-subunit.
Vaccine, Vol. 10, Issue 4, 1992 261
Epidemiology of diarrheal diseases: implications for control by vaccines Robert E. Black
Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD, USA Understanding the epidemiology of diarrheal diseases, including the etiologic agents and their virulence and pathogenicity, along with the evidence for acquired immunity, is fundamental to the formulation of strategies for their control by vaccines. Studies of etiologic agents in developing countries have found a wide range of bacterial, viral, and parasitic organisms associated with diarrhea, with various forms of pathogenic Escherichia coli often being the most frequent. These studies also permit examination of the apparent virulence of the infection as assessed by the severity of disease that occurs. This dimension is important if control efforts are to be directed toward the etiologic agents most likely to cause severe and potentially life-threatening illnesses. In this regard, rotavirus appears to stand out as the most important cause of severe diarrhea in young children and cholera is a serious problem in some areas. Other agents, e.g. Shigella sp. may be particularly important contributors to morbidity, malnutrition, and mortality is some settings.
Exposure to enteropathogens in developing countries is extensive and does not always cause diarrhea. The likelihood that an agent will result in illness, or the pathogenicity, is variable and is related to the organisms itself, as well as to the conditions of exposure and the resistance of the host. Review of this information for selected enteropathogens yields important guides for vaccine development and application. In particular, studies of passively or actively acquired immunity reveal what may be anticipated with enteric vaccines. The frequent exposure to enteropathogens that begins early in life present a challenge to a vaccine control stragety, but even more importantly, the observation of limited acquired immunity after illness suggests that protective immunity is highly specific and that several exposures to etiologic agents may often be needed for the development of substantial protection. The implications for control of diarrheal diseases will be discussed.
Novel vaccination strategies for the control of mucosal infection Alan J. Husband
Faculty of Medic&e, The University of Newcastle, Royal Newcastle Hospital Newcastle, NSW 2300, Australia Control of mucosal infections through vaccination requires immunization strategies which encourage the production at subepithelial locations of both IgA-producing plasma cells and appropriate regulatory T cells. Recent advances in the understanding of control mechanisms for mucosal immune defence have assisted in the design of novel vaccination strategies. It is now apparent that the induction of IgA plasma cell responses from gut associated lymphoid tissue and their dissemination to and proliferation at lamina propria effector sites is under the stringent control of subsets of T helper cells. Whereas cognate T cell help is required in the inductive phase, the regulatory signals derived from T helper cells in effector sites appears to operate in a non-cognate fashion, probably
through the effects of cytokines. The balance of help and suppression in the intestinal lamina propria appears to be dependent on the nature of antigen processing and epithelial presentation appears to favour a down regulation of immune responsiveness. These observations have enabled the development of a vaccination strategy dependent on serosal presentation of antigen via the intraperitoneal route. Antigens administered in appropriate adjuvant/vehicle formulations can stimulate a protective immune response in the intestine and indeed in remote mucosal sites. Data will be presented to demonstrate the potential for this vaccination regime to protect against both enteritis due to Escherichia coli infection and pneumonia due to Mycoplasma spp. and Actinobacillus spp.
Induction of lgA by oral administration of Pertussis and Cholera toxin A.D. Wilson*, C.R. Stokes*, L. Irons, A. Robinson
*Dept. Veterinary Medicine University of Bristol, Bristol, UK and PHLS, Porton, Salisbury, Wilts, UK Fed Cholera toxin (CT) is a potent stimulator of IgA responses. the Gm 1 binding B-subunit on its own is a poor stimulator of IgA but does induce an IgG response. Pertussis toxin (PT) can activate adenylate cyctase but does not induce an IgA response. When both CT-B and PT are fed simultaneously the IgA response to the B-subunit is restored to the level of that induced by whole CT. After feeding CT was present in the epithelial cells throughout the intestine and it had a predilection 0264-410X/92/040261-32 © 1991 Butterworth-HeinemannLtd
for Peyers patch epithelium. PT was mainly bound to the mucous in the upper duodenum. We conclude that whilst the Gm 1 binding properties of CT are important in enhancing antigen uptake, an optimum IgA response is dependant on the activation of adenylate cyclase. Pertussis toxin is not absorbed in sufficient quantity to act as an antigen but can enhance the IgA response to Cholera toxin B-subunit.
Vaccine, Vol. 10, Issue 4, 1992 261