Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers

Kirkpatrick, Beth D.; McKenzie, Robin; O’Neill, J. Patrick; Larsson, Catherine J.; Bourgeois, A. Louis; Shimko, Janet; Bentley, M. G.; Makin, J.; Chatfield, Steven N.; Hindle, Zoë; Fidler, Christine; Robinson, Brad E.; Ventrone, Cassandra H.; Bansal, Nivedita; Carpenter, Colleen; Kutzko, Deborah; Hamlet, Sandra; Lapointe, C; Taylor, David N.

doi:10.1016/j.vaccine.2005.08.008

Cited by 96 publications

(55 citation statements)

References 35 publications

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“…As only IgG antibodies have been analyzed in opsonization studies thus far, the role of IgA in opsonization and complement-mediated killing should be further explored. This is particularly important given that both IgG and IgA S. Typhi-specific LPS antibodies were detected in a majority of ZH9 vaccinees, suggesting that both classes of antibodies may play a role in protection against S. Typhi infections, particularly after oral vaccination (21,31). It is also possible that different functions, such as opsonization and antibody-mediated, complement-dependent killing of bacteria, may be attributable to different classes of antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…We suspected that S. Typhi-specific antibodies (IgG, IgA, and IgM at early time points) were the immune opsonins primarily responsible for the observed increases in phagocytosis of S. Typhi. Previous studies showed that all subjects tested in the opsonophagocytosis assays produced IgG and IgA specific to S. Typhi lipopolysaccharide (LPS) following vaccination with ZH9 (21,22,31). All serum samples used in the opsonophagocytosis assays were heat treated (56°C; 30 min) to inactivate the complement system and remove its contribution to phagocytic uptake.…”

Section: Postvaccination Opsonins Increase Uptake Of Wild-type Smentioning

confidence: 99%

“…A better understanding of the function of antibodies mounted in response to disease or vaccination addresses major challenges in understanding humoral immune responses to typhoid disease and aids in the evaluation of new typhoid vaccines. This work capitalizes on clinical specimens following study of the candidate typhoid vaccine M01ZH09 (S. Typhi Ty2 ⌬aroC ⌬ssaV, here called ZH9), a single-oraldose live attenuated vaccine with two independently attenuating mutations in healthy American adults (21,22,31). We describe the functional role of opsonins generated following vaccination with ZH9 in the uptake and killing of wild-type S. Typhi.…”

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confidence: 99%

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Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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Although vaccines have been available for over a century, a correlate of protection for typhoid fever has yet to be identified. Antibodies are produced in response to typhoid infection and vaccination and are generally used as the gold standard for determining vaccine immunogenicity, even though their role in clearance of Salmonella enterica serovar Typhi infections is poorly defined. Here, we describe the first functional characterization of S. Typhi-specific antibodies following vaccination with a new vaccine, M01ZH09 (Ty2 ⌬aroC ⌬ssaV). We determined that postvaccination sera increased the uptake of wild-type S. Typhi by human macrophages up to 2.3-fold relative to prevaccination (day 0) or placebo samples. These results were recapitulated using immunoglobulins purified from postvaccination serum, demonstrating that antibodies were largely responsible for increases in uptake. Imaging verified that macrophages internalized 2-to 9.5-fold more S. Typhi when the bacteria were opsonized with postvaccination sera than when the bacteria were opsonized with day 0 or placebo sera. Once inside macrophages, the survival of S. Typhi was reduced as much as 50% when opsonized with postvaccination sera relative to day 0 or placebo serum samples. Lastly, bactericidal assays indicated that antibodies generated postvaccination were recognized by complement factors and assisted in killing S. Typhi: mean postvaccination bactericidal antibody titers were higher at all time points than placebo and day 0 titers. These data clearly demonstrate that there are at least two mechanisms by which antibodies facilitate killing of S. Typhi. Future work could lead to improved immunogenicity tests associated with vaccine efficacy and the identification of correlates of protection against typhoid fever.

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Section: Discussionmentioning

confidence: 99%

Section: Postvaccination Opsonins Increase Uptake Of Wild-type Smentioning

confidence: 99%

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Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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“…These results suggest that measurement of the MP IgA responses warrants further development as a diagnostic test for individuals with suspected typhoid. The MP includes (15), and ASC and ALS responses that measure transient presence of mucosal lymphocytes in peripheral circulation after intestinal activation have been reported in vaccinees receiving oral attenuated strains of serovar Typhi (21,22,24) but have not been previously described in individuals with wild-type infection. The ALS specimen that we have used to measure the responses are those derived from cells which have mucosal priming in the gut.…”

Section: Discussionmentioning

confidence: 99%

Salmonella enterica Serovar Typhi-Specific Immunoglobulin A Antibody Responses in Plasma and Antibody in Lymphocyte Supernatant Specimens in Bangladeshi Patients with Suspected Typhoid Fever

Sheikh

Bhuiyan

Khanam

et al. 2009

Clin Vaccine Immunol

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Many currently available diagnostic tests for typhoid fever lack sensitivity and/or specificity, especially in areas of the world where the disease is endemic. In order to identify a diagnostic test that better correlates with typhoid fever, we evaluated immune responses to Salmonella enterica serovar Typhi (serovar Typhi) in individuals with suspected typhoid fever in Dhaka, Bangladesh. We enrolled 112 individuals with suspected typhoid fever, cultured day 0 blood for serovar Typhi organisms, and performed Widal assays on days 0, 5, and 20. We harvested peripheral blood lymphocytes and analyzed antibody levels in supernatants collected on days 0, 5, and 20 (using an antibody-in-lymphocyte-supernatant [ALS] assay), as well as in plasma on these days. We measured ALS reactivity to a serovar Typhi membrane preparation (MP), a formalin-inactivated whole-cell preparation, and serovar Typhi lipopolysaccharide. We measured responses in healthy Bangladeshi, as well as in Bangladeshi febrile patients with confirmed dengue fever or leptospirosis. We categorized suspected typhoid fever individuals into different groups (groups I to V) based on blood culture results, Widal titer, and clinical features. Responses to MP antigen in the immunoglobulin A isotype were detectable at the time of presentation in the plasma of 81% of patients. The ALS assay, however, tested positive in all patients with documented or highly suspicious typhoid, suggesting that such a response could be the basis of improved diagnostic pointof-care-assay for serovar Typhi infection. It can be important for use in epidemiological studies, as well as in difficult cases involving fevers of unknown origin.Salmonella enterica serovar Typhi (serovar Typhi) is the cause of typhoid fever, an illness that affects over 20,000,000 individuals worldwide each year, killing over 200, 000 (5, 8, 16). The largest burden of typhoid fever is borne by impoverished individuals in resource-poor areas of the world. Serovar Typhi is a human-restricted invasive enteric pathogen which, after ingestion, crosses the intestinal mucosa, is taken up by gutassociated lymphoreticular tissues, and enters the systemic circulation. Both mucosal and systemic host immune responses are stimulated after infection. Serovar Typhi is an intracellular pathogen, and antibody and cell-mediated immune responses occur after infection or immunization with live oral attenuated typhoid vaccines (10,25,34).Diagnostic tests for typhoid fever often lack sensitivity and/or specificity, especially in areas of the world that are endemic for typhoid fever, where clinically distinguishing typhoid fever from other febrile illnesses is difficult (5, 17, 39). Microbiologic culturing of blood is approximately 30 to 70% sensitive, with the highest sensitivity being associated with an absence of prior use of antibiotics and the culturing of larger volumes of blood, features that complicate this mode of diagnosis in young children (5,6,8,36). Microbiologic culturing of bone marrow aspirates is more sensitive than bl...

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“…Other published research agreed that cell mediated immunity determines the overall defense against systemic salmonellosis [64,66] probably even in the intestine [67]. Several studies have reported that live vaccines are more effective and provide greater protection than killed vaccines in protecting birds from S. Enteritidis infection [61,[68][69][70]. Much earlier work indicated that compared with a live vaccine killed bacteria do not induce as strong a protective response in controlling fowl typhoid [71], and also disease-free intestinal carriage of Salmonella [19,20] as indicated previously.…”

Section: Atmentioning

confidence: 99%

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2017

JMEN

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Salmonella enterica can be considered as one of the most important causes of foodpoisoning with poultry thought to be the main source. Although S. Typhimurium, S. Enteritidis and the vast majority of other Salmonella serovars generally produce little systemic disease in adult chickens, they are able to colonize the alimentary tract of poultry. The two caeca are the main sites of the colonization of Salmonellae in chickens, and the bacteria can be easily harvested from the caeca for analysis. Bacterial proteins analyses utilizing SDS-PAGE showed differences between in vitro and in vivo that out of about 40 protein bands of in vitro preparation only a few (3-5) bands can be visualized from in vivo preparations. We suggested that some avian proteases might be responsible. Accordingly, and to investigate the hypothesis that an inactivated vaccine harvested from chickens is thought to be more protective than bacteria grown in broth culture, the immunogenicity of inactivated vaccines, either proteins or formalin killed bacteria (S. Enteritidis) harvested from chicken intestine and those from broth culture (in vitro), were compared using bacterial proteins or formalin killed bacteria as an orally inoculated vaccine candidate in chicken. The results demonstrated that sonicated proteins extracts in general have a stronger effect as vaccines against S. Enteritidis colonization in chickens than formalin killed bacteria. In contrast, the in vitro sonicated proteins obtained from a nutrient broth culture had a much better protective vaccine effect than the in vivo sonicated proteins preparations harvested from bacteria grown in chickens. IntroductionMany bacterial pathogens such as Clostridium, Staphylococcus, Campylobacter and many other bacterial strains are capable of causing food-poisoning, and Salmonella enterica can be considered as one of the most important causes with poultry thought to be the main source. Although S. Typhimurium, S. Enteritidis and the vast majority of other Salmonella serovars generally produce little systemic disease in adult chickens, they are able to colonize the alimentary tract of poultry, resulting in contamination of poultry carcasses and entry into the human food chain. However, there is a great demand to control food-poisoning salmonellosis at both breeder and layer levels at the national and global level in order to produce Salmonelle-free poultry products, due to the current correlation between S. Enteritidis PT4 and poultry products. Salmonellosis costs the European Union a minimum of 500-900 million Euros annually. Salmonellosis in food animals is a major target for reduction of human infection by the European Union. Legislation has been introduced to monitor the most important Salmonellae serovars. The major Salmonellae serovars of public health consequence are S. Typhimurium and S. Enteritidis (causing 15% and 60% respectively of all cases in Europe in 2002).Elazomi and Dhawi studied newly-hatched chickens infected with S. Enteritidis. They analyzed proteins of S. Enteritidis...

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Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers

Cited by 96 publications

References 35 publications

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Salmonella enterica Serovar Typhi-Specific Immunoglobulin A Antibody Responses in Plasma and Antibody in Lymphocyte Supernatant Specimens in Bangladeshi Patients with Suspected Typhoid Fever

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