Pathogenic Vibrio cholerae 01 cause disease by colonizing the human small intestine, where they produce a potent enterotoxin (1). Many elements of the vibrio cell surface have been postulated to be involved in colonization, but an actual molecular component or morphological structure responsible for adherence to the human intestinal mucosa has not previously been conclusively demonstrated .In the classical Ogawa V . cholerae 01 strain 395, a regulatory protein, ToxR, controls expression of cholera toxin (2). ToxR also regulates the expression of a rigid pilus, TcpA, in a coordinate manner with cholera toxin (3). Recently, tc,6A and toxR insertion mutants of V . cholerae Ol were shown to be defective in colonization in suckling mice (3). To determine the role of TcpA in colonization of the human intestine, the bacteriology, and clinical and immunologic responses of healthy adult volunteers who ingested three Ogawa 395 mutants were assessed .

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 1010 colony-forming units of 0127: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 wildtype 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 in-

Compared with vaccine delivery by injection, oral vaccines offer the hope of more convenient immunization strategies and a more practical means of implementing universal vaccination programs throughout the world. Oral vaccines act by stimulating the immune system at effector sites (lymphoid tissue) located in the gut. Genetic engineering has been used with variable success to design living and non-living systems as a means to deliver antigens to these sites and to stimulate a desired immune response. More recently, plant biotechnology techniques have been used to create plants which contain a gene derived from a human pathogen; the resultant plant tissues will accumulate an antigenic protein encoded by the foreign DNA. In pre-clinical trials, we found that antigenic proteins produced in transgenic plants retained immunogenic properties when purified; if injected into mice the antigen caused production of protein-specific antibodies. Moreover, in some experiments, if the plant tissues were simply fed to mice, a mucosal immune response occurred. The present study was conducted as a proof of principle to determine if humans would also develop a serum and/or mucosal immune response to an antigen delivered in an uncooked foodstuff.

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The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (n ‫؍‬ 31) were randomized to receive a single intravenous (i.v.) dose of motavizumab-YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (t 1/2 ) was 2-to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. (This study has been registered at ClinicalTrials.gov under registration no. NCT00578682.) R espiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children (1). No vaccine is currently approved for the prevention of RSV illness; however, palivizumab (MedImmune, Gaithersburg, MD) is available as prophylaxis against serious RSV disease in high-risk children. These high-risk children include infants born prematurely, children with chronic lung disease of prematurity (bronchopulmonary dysplasia), and children with congenital heart disease (2). RSV prophylaxis with palivizumab requires monthly intramuscular administration throughout the RSV season to maintain adequate serum concentrations. This monthly administration is necessary as immunoglobulin G (IgG) monoclonal antibodies (MAbs) are subject to proteolytic degradation and elimination, resulting in a serum half-life of approximately 20 days (3). An antibody with an extended half-life would reduce the required dosing frequency during the RSV season.A growing body of evidence identifies the major histocompatibility complex class I-related neonatal Fc receptor (FcRn) as a critical receptor in maintaining IgG homeostasis and extending the serum half-life of IgG and albumin in humans (4, 5). FcRn was originally identified in the transport of maternal antibodies across the placenta and the fetal small intestines in rats (6). In adult tissues, FcRn localized on vascular endothelium is a key component in the antibody salvage pathway whereby serum IgG undergoes endocytosis and is sequestered in lysosomes (7).A distinguishing characteristic of the IgG-FcRn pathway is obligate pH dependence. IgG-FcRn binding is driven by acidic pH (6.0) in the lysosome, whereas disassociation occurs at the neutral pH (7.4) of the extracellular environment (3). Acidification (pH 6.0 to 6.5) in the lysosomes enable...