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8. Role of the eaeA gene in experimental enteropathogenic Escherichia coli infection

Author

Donnenberg, M. S., Tacket, C. O., James Kaper, Losonsky, G., Nataro, J. P., Wasserman, S. S., Kaper, J. B., and Levine, M. M.

Subjects
Research Article
Abstract

Enteropathogenic Escherichia coli (EPEC) infections are a leading cause of infant diarrhea in developing countries. Recently eaeA, a gene necessary for the characteristic intimate attachment of EPEC to epithelial cells in tissue culture, was described. We conducted a randomized, double-blind study to determine the role of the eaeA gene in human EPEC infection. 11 adult volunteers ingested 2 x 10(10) colony-forming units of O127:H6 EPEC strain E2348/69, and an equal number received the same dose of an isogenic eaeA deletion mutant constructed from E2348/69. Volunteers were monitored for the development of diarrhea, fever, and systemic and gastrointestinal complaints. Diarrhea developed in all 11 volunteers who received E2348/69 and in 4 of 11 who received the mutant (P = 0.002). Fever was more common in recipients of the wild-type strain (P = 0.024). Stool volumes were lower in recipients of the mutant. All volunteers seroconverted to E2348/69 LPS, but the geometric mean peak titers of serum IgG and IgA in recipients of the mutant were lower than those of recipients of the wild-type strain. IgA against LPS was detected in the jejunal fluid of six of six recipients of E2348/69 and 5/6 recipients of the mutant. This study unambiguously assigns a role for eaeA as an EPEC virulence gene, but the residual diarrhea seen in recipients of the mutant indicates that other factors are involved.

Published
1993

9. Immunoprophylaxis of RSV Infection: Advancing from RSV-IGIV to Palivizumab and Motavizumab.

Author

Compans, Richard W., Cooper, Max D., Honjo, Tasuku, Koprowski, Hilary, Melchers, Fritz, Oldstone, Michael B. A., Olsnes, Sjur, Vogt, Peter K., Dessain, Scott K., Wu, H., Pfarr, D. S., Losonsky, G. A., and Kiener, P. A.

Abstract

Antibodies mediate humoral immune responses and play key roles in the defense of viral infection by the recognition, neutralization, and elimination of viruses from the circulation. For the prevention of respiratory syncytial virus (RSV) infection, the natural immune response to RSV from pooled human plasma has been harvested and successfully developed as a prophylactic polyclonal RSV hyperimmune globulin, RespiGam (RSV-IGIV; MedImmune, Gaithersburg, MD). The success of RSV-IGIV validated the immunoprophylaxis approach for RSV prevention and led to the development of Synagis (palivizumab; MedImmune, Gaithersburg, MD), a humanized monoclonal antibody (mAb) that binds to the RSV F protein. Palivizumab is a potent anti-RSV mAb that is about 50-fold more potent than RSV-IGIV, and since obtaining regulatory approval in 1998 it has been used extensively to help prevent severe RSV disease in high-risk infants and children. However, a very small number of patients receiving the drug do not appear to be adequately protected. To further improve protection against RSV, we have applied a directed evolution approach to enhance the binding of palivizumab to F protein by manipulation of both the on and off rates. These efforts have yielded a more potent second-generation mAb, motavizumab, which is currently under study in phase III clinical trials. Most recently, a third generation mAb, Numax-YTE, has been generated with the intent to extend the serum half-life of the mAb in humans. If successfully developed, this drug may offer the opportunity for less frequent dosing, obviating the need for the monthly treatments that are required with palivizumab. The development of these anti-RSV approaches exemplifies the accelerated pace of drug development made possible with cutting-edge antibody engineering technologies. [ABSTRACT FROM AUTHOR]

Published
2008
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27. Salmonella typhi Vaccine Strain CVD 908 Expressing the Circumsporozoite Protein of Plasmodium falciparum: Strain Construction and Safety and Immunogenicity in Humans

Author

Gonzalez, C., primary, Hone, D., additional, Noriega, F. R., additional, Tacket, C. O., additional, Davis, J. R., additional, Losonsky, G., additional, Nataro, J. P., additional, Hoffman, S., additional, Malik, A., additional, Nardin, E., additional, Sztein, M. B., additional, Heppner, D. G., additional, Fouts, T. R., additional, Isibasi, A., additional, and Levine, M. M., additional

Published
1994
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