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Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of travelers’ diarrhea and of diarrhea among young children in developing countries. Experimental challenge studies in adult volunteers have played a pivotal role in establishing ETEC as an enteric pathogen, elucidating its pathogenesis by identifying specific virulence attributes, characterizing the human immune response to clinical and sub-clinical ETEC infection and assessing preliminarily the clinical acceptability, immunogenicity and efficacy of prototype ETEC vaccines. This review provides a historical perspective of experimental challenge studies with ETEC. It summarizes pioneering early studies carried out by investigators at the University of Maryland School of Medicine to show how those studies provided key information that influenced the directions taken by many research groups to develop vaccines to prevent ETEC. In addition, key experimental challenge studies undertaken at other institutions will also be cited.

Bacteremia and healthcare-associated infections (HAIs) continue to rise in industrialized countries, in line with population aging and increased healthcare needs. Escherichia coli and Staphylococcus aureus are the most common pathogens causing HAIs and bacteremia.This review discusses risk factors in the healthcare setting contributing to the rise in bacteremia and other invasive bacterial HAIs in older populations in general, and attributed to E. coli and S. aureus. Treatment of infections is becoming increasingly difficult due to emerging antimicrobial resistance. Prophylactic vaccines may be the solution to lowering the burden of serious infections in the elderly.E. coli and S. aureus vaccines routinely administered to older adults and to people undergoing prescheduled procedures with high infection risks could prevent a significant proportion of severe disease, and could potentially also limit the further emergence of antimicrobial resistance.

Autogenous Escherichia coli vaccines to prevent the E. coli peritonitis syndrome (EPS) in laying hens are often used in the field, although their effectiveness has not been demonstrated yet. Therefore, in this study, which consisted of two experiments, their efficacy was assessed. In the first experiment, the EPS-inducing ability of three E. coli isolates originating from bone marrow of hens that died due to EPS and with different Pulsed-Field Gel Electrophoresis patterns, was examined by intravenous inoculation of the isolates in 17-week-old brown layers. Based on the results one isolate was chosen for the preparation of the vaccines and for homologous challenge and another one for heterologous challenge performed in the second experiment. In the named experiment, groups of laying hens which had been vaccinated intramuscularly at 14 and 18 weeks of age with inactivated vaccine either formulated as aqueous suspension or as water-in-oil emulsion were homologously or heterologously challenged per aerosol at 30 weeks of age. The vaccines contained ≥10

In poultry production Escherichia coli autogenous vaccines are often used. However, the efficacy of autogenous E. coli vaccinations has not been evaluated experimentally in chickens after start of lay. The aim of the present study was to evaluate the protective effect of an autogenous E. coli vaccine in broiler breeders. Three groups of 28 weeks old broiler breeders (unvaccinated, vaccinated once and twice, respectively) were challenged with a homologous E. coli strain (same strain as included in the vaccine) or a heterologous challenge strain in an experimental ascending model. The clinical outcome was most pronounced in the unvaccinated group; however, the vast majority of chickens in the vaccinated groups had severe pathological manifestations similar to findings in the unvaccinated group after challenge with a homologous as well as a heterologous E. coli strain. Although significant titer rises in IgY antibodies were observed in the twice vaccinated group, antibodies did not confer significant protection in terms of pathological impact. Neither could transfer of maternal derived antibodies to offspring be demonstrated. In conclusion, with the use of the present model for ascending infection, significant protection of an autogenous E. coli vaccine against neither a homologous nor a heterologous E. coli challenge could not be documented.

Oral administration of vaccines is simpler and more acceptable than injection via needle and syringe, particularly for infants (Fig. 1) This route is promising for new vaccines in development against enterotoxigenic Escherichia coli (ETEC) and Shigella that cause childhood diarrhea with devastating consequences in low-resource countries. However, vaccine antigens and adjuvants given orally need buffering against the degradative effects of low stomach pH, and the type and volume of antacid buffer require special attention for infants. In addition, container/closure systems must be compatible with vaccine formulations, protect against water and gas transfer, and have minimal impact on the cold chain. Health care workers in demanding low-resource settings need an administration device that is easy to use, yet will accurately measure and safely deliver the correct vaccine dose. Developers must consider manufacturing capabilities, and immunization program managers want affordable vaccines. As new combination enteric vaccine candidates advance into clinical evaluation, features of the final vaccine presentation—liquid or dry format, diluent, buffer, primary and secondary packaging, and administration device—should be taken into account early in product development to achieve the greatest possible impact for the vaccine.

Background . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. Methods . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). Results . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. Conclusions . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality caused by diarrhea in children less than 5 years of age in low- and middle-income countries. Despite a wealth of research elucidating the mechanisms of disease, the immunological responses and vaccine development, ETEC is still relatively uncharacterized when it comes to regulation of virulence and detailed immune mechanisms. The recent emergence of next-generation sequencing now offers the possibility to screen genomes of ETEC strains isolated globally to identify novel vaccine targets in addition to those already established. In this review, we discuss how recent findings on ETEC genomics using novel sequencing techniques will aid in finding novel protective antigens that can be used in vaccine approaches.

Enterotoxigenic Escherichia coli (ETEC) are the most common bacterial pathogens causing diarrhea in developing countries where they lead to hundreds of thousands of deaths, mostly in children. These organisms are a leading cause of diarrheal illness in travelers to endemic countries. ETEC pathogenesis, and consequently vaccine approaches, have largely focused on plasmid-encoded enterotoxins or fimbrial colonization factors. To date these approaches have not yielded a broadly protective vaccine. However, recent studies suggest that ETEC pathogenesis is more complex than previously appreciated and involves additional plasmid and chromosomally encoded virulence molecules that can be targeted in vaccines. Here, we review recent novel antigen discovery efforts, potential contribution of these proteins to the molecular pathogenesis of ETEC and protective immunity, and the potential implications for development of next generation vaccines for important pathogens. These proteins may help to improve the effectiveness of future vaccines by making them simpler and possibly broadly protective because of their conserved nature.

Uncomplicated urinary tract infections (UTIs) are common, with nearly half of all women experiencing at least one UTI in their lifetime. This high frequency of infection results in huge annual economic costs, decreased workforce productivity and high patient morbidity. At least 80% of these infections are caused by uropathogenic Escherichia coli (UPEC). UPEC can reside side by side with commensal strains in the gastrointestinal tract and gain access to the bladder via colonization of the urethra. Antibiotics represent the current standard treatment for UTI; however, even after treatment, patients frequently suffer from recurrent infection with the same or different strains. In addition, successful long-term treatment has been complicated by a rise in both the number of antibiotic-resistant strains and the prevalence of antibiotic-resistance mechanisms. As a result, preventative approaches to UTI, such as vaccination, have been sought. This review summarizes recent advances in UPEC vaccine development and outlines future directions for the field.

In the present investigation 20,000 broiler parents were vaccinated during rearing with Nobilis Escherichia coli vaccine and were placed in two out of four identical houses, with the remaining two houses on the same farm accommodating 20,000 unvaccinated control birds. During the production period a total of 335 dead birds (including 171 vaccinated and 164 control birds) randomly selected from the four houses were subjected to post-mortem examination. Although the overall mortality between the vaccinated and control flocks did not differ, mortality due to E. coli infections made up only 8.2% in vaccinated birds compared with 24.6% in unvaccinated birds. All E. coli isolates recovered from internal organs were assigned to the same phylogenetic group (B2), but a major genetic diversity was outlined by multilocus sequence typing. Only a single isolate was demonstrated to harbour a gene encoding the P-fimbriae variant F11, a key component of the Nobilis vaccine. Significant differences in average first week mortality, calculated average weight at 38 days and food conversion rate among broiler flocks originating from vaccinated and control birds, respectively, were not found. Further investigations are needed to explain the protection observed and the impact on the genetic diversity of E. coli.

Enterhemorrhagic Escherichia coli (EPEC), an important cause of severe infantile diarrheal disease in many parts of the developing world, produced several recently described virulence determinations. Several of its virulence factors are secreted by type III secretion including EspA, which forms filamentous structures on bacterial surface bridging to the host cell's surface. These structures on bacterial surfaces may deliver other virulence factors directly into the host cell from EHEC. In this study, EspA was expressed in Lactococcus lactis NZ9000 (L. lactis NZ9000). BALB/C mice were immunized by recombinant EspA, and mice sera were assayed for the disruption of E. coli O157:H7 interaction with the host cell. BALB/C mice which were immunized with recombinant EspA produced specific antibody titers, and the difference between the control group and the immune group is marked (P

There is currently only one vaccine available that provides protection against diarrhea caused by Vibrio cholerae and, to a lesser degree, enterotoxigenic Escherichia coli (ETEC). Adverse events of this oral whole-cell/recombinant B-subunit vaccine have been negligible. Protective efficacy against cholera is 85%, while protection against the heat-labile toxin of ETEC reaches 67%. There is still a need for data on protection of Western travelers against travelers’ diarrhea in general by Dukoral® vaccination. However, current studies show a protective effect of up to 43%. Although the vaccine is only licensed for vaccination against cholera in most Western countries, there is mounting evidence that the oral cholera vaccine is a valuable option to those traveling to high-risk endemic areas. Vaccination against cholera and ETEC should be recommended for at-risk travelers, in particular those with high exposure at their travel destination or high personal risks through fluid loss.

Over a quarter century after the discovery of verocytotoxin and the first report by Karmali and colleagues of cases of postdiarrheal hemolytic uremic syndrome (HUS) caused by verotoxigenic Escherichia coli (VTEC), otherwise known as Shiga-toxigenic E. coli (STEC), successful treatment of these infections has remained elusive. This is because the pathological insult producing the clinical picture of HUS occurs early in the disease process and curtails quickly, making treatment intervention a largely vain hope. Nevertheless, understanding of the pathogenesis of HUS has expanded and, as a result, we can expect a future breakthrough in the treatment of this life-threatening condition. This review examines the pathogenesis of HUS and explores targets for treatment, including the reasons why certain therapies have failed and why future therapies could be successful. This review also examines the status of vaccine development in prevention of VTEC/STEC disease.

Enterotoxigenic Escherichia coli (ETEC) is recognized as one of the major causes of infectious diarrhea in developing countries. Worldwide, the incidence of ETEC infections is estimated to result in 650 million cases of diarrhea and 380,000 deaths in children under 5 years of age. ETEC is also an important cause of travelers' diarrhea in people traveling to endemic regions of the world. Although ETEC is an uncommon cause of infections in the USA, there have been 14 reported outbreaks of ETEC in the USA and seven on cruise ships over the 20-year period between 1975 and 1995. ETEC strains are comprised of a large number of serotypes that produce a variety of colonization factors and enterotoxins. On infection, ETEC first establishes itself by adhering to the epithelium of the small intestine via one or more colonization factor antigens or coli surface proteins. Once established, ETEC expresses one or more enterotoxin(s), which results in the production of secretory diarrhea. While the need for an efficacious, easily administered vaccine is great, there are currently no licensed ETEC vaccines available for use in endemic countries or for US travelers.

Enteropathogenic and enterohemorrhagic Escherichia coli are important causal agents of infectious diarrhea, particularly amongst pediatric populations. While enteropathogenic E. coli is a significant health threat in developing countries, enterohemorrhagic E. coli causes sporadic, sometimes deadly outbreaks of hemorrhagic colitis, with a serious complication, hemolytic uremic syndrome, ocurring in a proportion of cases. This review discusses the pathogenesis of enterohemorrhagic and enteropathogenic E. coli, the host immune response and the current application of this knowledge towards efficacious vaccine strategies. Several lines of investigation indicate the feasibility of such strategies and justify further development of a vaccine targeting these significant intestinal pathogens.