Short communication: J-5 Escherichia coli vaccination does not influence severity of an Escherichia coli intramammary challenge in primiparous cows.

The objective of the present study was to evaluate the efficacy of a J-5 Escherichia coli vaccine in a mild to moderate inflammatory challenge model using primiparous dairy cows for inoculation only. We hypothesized a clinical difference between placebo and J-5 E. coli vaccinated animals with the mild to moderate inflammatory challenge model. In case the null hypothesis could not be confirmed, the alternate hypothesis was no clinical difference between both treatment groups. Therefore, 23 primiparous cows in mo 7 of pregnancy were randomly assigned to 1 of 2 treatment groups: J-5 E. coli vaccine (n = 12) or placebo (n = 11). Animals were vaccinated 3 times at 56 (±7) and 28 (±7) d before expected calving date and within 14 d postcalving (DIM 5 ± 3). All cows were challenged by infusion with E. coli P4:O32 into 2 left mammary quarters between 14 and 28 d postparturition, at least 10 d after the 3rd vaccination, immediately after the morning milking. Clinical observations and blood and milk samples were collected at several time points from 7 d pre-challenge until 13 d post-challenge. Primiparous cows responded mild to moderately to intramammary E. coli challenge with little clinical difference between treatment groups. Rectal temperature increased earlier in the vaccinated animals, which also eliminated bacteria faster during the early hours after intramammary E. coli challenge. At post-infusion hour 9, the bacterial population was significantly lower in the infected quarters of the vaccinated animals. Blood leukocyte number was only numerically higher in the vaccinated animals, in combination with a numerically higher percentage of late immature polymorphonuclear leukocytes (band cells) in circulation. Even in the nonvaccinated animals, the E. coli challenge in the primiparous cows elicited only a mild to moderate response. The absence of a pronounced clinical difference between vaccinated and nonvaccinated animals was therefore not surprising.

Vaccines Against Escherichia coli.

Escherichia coli has a complex and versatile nature and continuously evolves from non-virulent isolates to highly pathogenic strains causing severe diseases and outbreaks. Broadly protective vaccines against pathogenic E. coli are not available and the rising in both, multi-drug resistant and hypervirulent isolates, raise concern for healthcare and require continuous efforts in epidemiologic surveillance and disease monitoring. The evolving knowledge on E. coli pathogenesis mechanisms and on the mediated immune response following infection or vaccination, together with advances in the "omics" technologies, is opening new perspectives toward the design and development of effective and innovative E. coli vaccines.

Prospective Observational Cohort Study of the Efficacy of Bacterial Immune Prophylaxis in the Prevention of Uncomplicated, Recurrent Urinary Tract Infections.

OBJECTIVE: To investigate the long-term prophylactic effect of a vaccine on lower urinary tract infections (UTI) of bacterial and the impact of the intensity of the symptoms on the quality of life (QoL). METHODS: Adult female could be enrolled in this study if they had acute UTI at the enrolment visit and bacterial microbiological count of ≥103 CFU/mL of Escherichia coli. RESULTS: A total of 21 patients were included. Fifteen days after the administration of a vaccine for 3 months, the number of infections dropped almost to zero. Significant differences were observed in the QoL score (p < 0.05). The safety profile was good. CONCLUSIONS: In patients diagnosed with recurrent UTI and treated for 3 months with the vaccine the number of UTI episodes fell very quickly (15 days), and patients remained free of episodes and improved their QoL significantly for 1 year. These results suggest that bacterial vaccines are a possible effective alternative in the prevention of recurrent UTI.

Intramammary immunization with ultraviolet-killed Escherichia coli shows partial protection against late gestation intramammary challenge with a homologous strain.

The objective of this study was to evaluate the efficacy of intramammary immunization with UV-killed Escherichia coli ECC-Z on prevention of intramammary colonization after a challenge with a dose of the homologous E. coli ECC-Z live bacteria. A total of 10 cows were included in a study to evaluate the efficacy of intramammary immunization. All 10 cows received an intramammary immunization of 100 cfu of UV-killed E. coli ECC-Z bacteria into one hind quarter at the time of dry off. Approximately 2wk before the anticipated calving date, both hind quarters of all cows were challenged with 100 cfu of live E. coli ECC-Z bacteria. Five of the cows were vaccinated parenterally with a commercial J5 bacterin, and 5 cows served as controls with no parenteral vaccination. The cows were then followed over time and infection risk, clinical scores, somatic cell count, and milk production were observed over time. The results of these 10 cows showed partial protection of intramammary immunization on the outcome of a subsequent homologous intramammary challenge. Immunization resulted in a lower probability of infection, a lower bacteria count, lower somatic cell counts and milk conductivity, a lower clinical mastitis score, and increased milk production compared with unimmunized control quarters. Once the analysis was corrected for immunization, parenteral J5 vaccination had no significant effect on any of the measured parameters. These results provide the first evidence that intramammary immunization may improve the outcome of an intramammary E. coli infection in late gestation and onset of mastitis immediately following parturition. Unlike systemic vaccination, which generally does not reduce the intramammary infection risk, the intramammary immunization did show a 5-times reduced odds of an established intramammary infection after challenge. Cytokine profiles indicated a local return of proinflammatory response after challenge as the data showed a more pronounced increase in in IFN-γ with a subsequent negative feedback due to a spike in the level of IL-10 in immunized quarters relative to nonimmunized quarters. Although these results are preliminary and obtained on only 10 cows, the results provide insight into the biological benefits of triggering mucosal immunity in the mammary gland.

An analysis of cattle farmers' perceptions of drivers and barriers to on-farm control of Escherichia coli O157.

Structural equation modelling and survey data were used to test determinants' influence on farmers' intentions towards Escherichia coli O157 on-farm control. Results suggest that farmers more likely to show willingness to spend money/time or vaccinate to control Escherichia coli O157 are those: who think farmers are most responsible for control; whose income depends more on opening farms to the public; with stronger disease control attitudes; affected by outbreaks; with better knowledge and more informed; with stronger perceptions of biosecurity measures' practicality; using a health plan; who think farmers are the main beneficiaries of control; and whose farms are dairy rather than beef. The findings might suggest that farmers may implement on-farm controls for E. coli O157 if they identify a clear hazard and if there is greater knowledge of the safety and efficacy of the proposed controls.

Evaluation of an alternative dosing regimen of a J-5 mastitis vaccine against intramammary Escherichia coli challenge in nonlactating late-gestation dairy cows.

The objective of the study was to evaluate the efficacy of an alternative vaccination regimen of a J-5 bacterin against intramammary Escherichia coli challenge in nonlactating late-gestation dairy cows. The parameters analyzed to assess the effect of vaccination were milk yield, milk conductivity, somatic cell count, J-5-specific serum IgG titers, and clinical signs. Twenty multiparous Holstein cows from the Cornell teaching and research dairy herd were paired by days in milk and were randomly selected to receive either the alternative off-label regimen of commercial J-5 bacterin or act as nonvaccinated controls. Cows received a first dose of bacterin 15 d before dry off, a second dose with the same product at the day of dry off, and the third dose 2 wk after dry off. The cows in both groups were challenged 10 d before the expected calving date. Serum IgG (total, IgG1 and IgG2) levels were higher in vaccinates compared with control cows. Eighty-five percent of challenged quarters became infected between both groups of animals. Eight of the 10 vaccinated and 9 of the 10 control cows showed signs of clinical mastitis postfreshening. A non-severe clinical mastitis was observed 24 to 48 h postparturition, characterized by flakes or clots in milk and mild swelling or pain. Off-label vaccination did reduce the clinical severity of clinical mastitis in the vaccinated group of cows as evidenced by reduced California mastitis test score, fewer flakes and lower overall clinical mastitis score. No significant differences between vaccinated and control groups were detected for rectal temperature. In conclusion, the alternative off-label vaccination scheme used in our study and evaluated in a novel E. coli challenge model did not prevent new intramammary infections but reduced clinical severity of experimentally induced E. coli mastitis.

Assessment of heterogeneity of efficacy of a three-dose regimen of a type III secreted protein vaccine for reducing STEC O157 in feces of feedlot cattle.

Preharvest control of Escherichia coli O157:H7 (STEC O157) may prevent human illness by reducing the presence of STEC O157 throughout the beef production chain. Immunization of cattle with a type III secreted protein vaccine inhibits colonization of cattle with STEC O157 and reduces the probability of fecal shedding and hide contamination. Our objectives were to perform a meta-analysis to estimate efficacy of a three-dose regimen of TTSP vaccine at reducing the presence of STEC O157 in the feces of feedlot cattle and to test factors that might modify vaccine efficacy. Pen-level data (n=184 pens, 1462 cattle) from four randomized controlled vaccine trials conducted from 2002 to 2008 at the University of Nebraska-Lincoln were analyzed. Factors explaining a culture-positive fecal sample were tested in generalized estimating equations logistic regression and log-binomial models. An autoregressive correlation structure was defined to account for clustering of repeated test-periods within block. Clustering or potential confounding by study was accounted for by treating study as a fixed effect. STEC O157 was detected from 661 of 5451 postvaccination fecal samples. The probability to detect STEC O157 postvaccination was 8.4% and 15.8% in vaccinated and unvaccinated cattle, respectively. Interactions between vaccination and (1) study; (2) prevalence of control pens within each time-place cluster; and (3) days from vaccination were not significant or fit poorly with observed data. Adjusting for study, cattle in pens receiving three doses of vaccine were less likely to shed STEC O157 (odds ratio=0.46, p<0.0001). Model-adjusted vaccine efficacy was 48% (95% confidence interval: 0.37-0.57). We concluded that a three-dose regimen type III secreted protein vaccine was efficacious at reducing the probability of detecting STEC O157 in the feces of cattle and that vaccine efficacy was not modified by study or level of prevalence observed in control pens.

Eliciting expert opinion on the effectiveness and practicality of interventions in the farm and rural environment to reduce human exposure to Escherichia coli O157.

Few hard data are available on emergent diseases. However, the need to mitigate and manage emergent diseases has prompted the use of various expert consultation and opinion elicitation methods. We adapted best-worst scaling (BWS) to elicit experts' assessment of the relative practicality and effectiveness of measures to reduce human exposure to E. coli O157. Cattle vaccination was considered the most effective and hand-washing was considered the most practical measure. BWS proved a powerful tool for expert elicitation as it breaks down a cognitively burdensome process into simple, repeated, tasks. In addition, statistical analysis of the resulting data provides a scaled set of scores for the measures, rather than just a ranking. The use of two criteria (practicality and effectiveness) within the BWS process allows the identification of subsets of measures judged as potentially performing well on both criteria, and conversely those judged to be neither effective nor practical.

An outcomes model to evaluate risks and benefits of Escherichia coli vaccination in beef cattle.

We developed a stochastic simulation model to evaluate the impact of Escherichia coli O157:H7 (O157) vaccination on key epidemiological outcomes. The model evaluated a reduction in the O157 prevalence in feedlot cattle as well as concentration in cattle feces due to vaccination. The impact of this reduction on outcomes at slaughter/harvest and consumption was evaluated by simulating the relationships between the O157 prevalence and concentration at various points in the ground beef supply chain. The uncertainty and variability associated with the O157 contamination was explicitly modeled in production, slaughter, and consumption modules. Our results show that vaccination can have a significant benefit with respect to relevant outcomes such as (1) the number of human O157 illnesses due to the consumption of ground beef, (2) the number of production lots with high O157 contamination levels, (3) the likelihood of detection by U.S. Department of Agriculture Food Safety and Inspection Service testing, and (4) the probability of multiple illnesses due to ground beef servings from the same lot. These results show that these outcomes are strongly impacted by preharvest vaccination. For example, if the vaccine is used so as to reduce the prevalence of E. coli shedding cattle by 80% and if all U.S. steers and heifers were vaccinated, the expected number of human illnesses from ground beef-associated O157 would be reduced almost 60%. If the vaccine is 60% or 40% effective, the illness rate would be reduced approximately 45% or 40%, respectively. The number of production lots (10,000-lb lots) with high O157 contamination levels (> 1000 servings) would be reduced by 96% if all steers and heifers received an 80% effective vaccine regimen. The analysis shows that resulting reduction in the number of shedding animals and the reduced concentration of E. coli on carcasses can combine to reduce human illnesses and cost to beef packers.

In silico analysis and in vivo assessment of a novel epitope-based vaccine candidate against uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) are common pathogens in urinary tract infections (UTIs), which show resistance to antibiotics. Therefore, there is a need for a vaccine to reduce susceptibility to the infection. In the present study, bioinformatics approaches were employed to predict the best B and T-cell epitopes of UPEC virulence proteins to develop a multiepitope vaccine candidate against UPEC. Then, the efficacy of the candidate was studied with and without Freund adjuvant. Using bioinformatics methods, 3 epitope-rich domains of IutA and FimH antigens were selected to construct the fusion. Molecular docking and Molecular dynamics (MD) simulation were employed to investigate in silico interaction between designed vaccine and Toll-like receptor 4 (TLR4). Our results showed that the levels of IgG and IgA antibodies were improved in the serum and mucosal samples of the vaccinated mice, and the IgG responses were maintained for at least 6 months. The fusion protein was also able to enhance the level of cytokines IFN.γ (Th1), IL.4 (Th2), and IL.17. In challenge experiments, all vaccine combinations showed high potency in the protection of the urinary tract even after 6 months post first injection. The present study indicates that the designed candidate is able to evoke strong protective responses which warrant further studies.

Use of a patch containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the rate of diarrhoea attacks, safety, and feasibility of a vaccine containing heat-labile enterotoxin (LT) from ETEC delivered to the skin by patch in travellers to Mexico and Guatemala. METHODS: In this phase II study, healthy adults (aged 18-64 years) who planned to travel to Mexico or Guatemala and had access to a US regional vaccination centre were eligible. A centralised randomisation code was used for allocation, which was masked to participants and site staff. Primary endpoints were to investigate the field rate of ETEC diarrhoea, and to assess the safety of heat-labile toxins from E coli (LT) delivered via patch. Secondary endpoints included vaccine efficacy against travellers' diarrhoea and ETEC. Participants were vaccinated before travel, with two patches given 2-3 weeks apart. Patches contained either 37.5 mug of LT or placebo. Participants tracked stool output on diary cards in country and provided samples for pathogen identification if diarrhoea occurred. Diarrhoea was graded by the number of loose stools in 24 h: mild (three), moderate (four or five), and severe (at least six). Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT00516659. FINDINGS: Recruitment closed after 201 participants were assigned patches. 178 individuals received two vaccinations and travelled and 170 were analysed. 24 (22%) of 111 placebo recipients had diarrhoea, of whom 11 (10%) had ETEC diarrhoea. The vaccine was safe and immunogenic. The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea (protective efficacy [PE] 75%, p=0.0070) and severe diarrhoea (PE 84%, p=0.0332). LT-patch recipients who became ill had shorter episodes of diarrhoea (0.5 days vs 2.1 days, p=0.0006) with fewer loose stools (3.7 vs 10.5, p<0.0001) than placebo. INTERPRETATION: Travellers' diarrhoea is a common ailment, with ETEC diarrhoea illness occurring in 10% of cases. The vaccine patch is safe and feasible, with benefits to the rate and severity of travellers' diarrhoea.

Alternative treatment approaches of urinary tract infections caused by uropathogenic Escherichia coli strains.

Urinary tract infections (UTIs) are the most widespread and annoying infections affecting millions of people every year annually. The biggest problems of urinary diseases are recurrences, increasing resistance of uropathogens to commonly used antibiotics, as well as the high health care costs of afflicted persons. Uropathogenic Escherichia coli strains (UPECs) are the most dominant etiologic agents of community-acquired infections of this type. During UTI pathogenesis, UPECs utilize various virulence factors, especially mono- and polyadhesive appendages of the chaperone-usher secretion pathway (CUP) required for adhesion, invasion and biofilm formation. Commonly used antibiotics for UTI treatment are usually effective, but their long-term utility may affect gut microbiota of the treated individuals and cause selection of drug resistant uropathogenic variants. Due to increasing resistance of UPEC strains to antibiotics via the evolution of specific defense mechanisms, there is a need to develop alternative methods and therapeutic strategies to fight UTIs (vaccines, receptor analogues, pilicides and curlicides, bacterial interference or phagotherapy). Such therapeutic approaches usually target processes enabling uropathogens to survive within the urinary tract and cause recurrent infections.

Vaccine Development for Urinary Tract Infections: Where Do We Stand?

Urinary tract infections (UTIs) are among the most common bacterial infections. Its management has become increasingly challenging due to antimicrobial resistance. The four mainstays to tackle this crisis rely on the development of new antibiotic agents, the introduction of preventive and alternative antimicrobial strategies, the concept of antimicrobial stewardship, and effective hygiene measures. One of the most effective approaches to prevent UTIs is the design of a potent vaccine. OM-89 is a lyophilised preparation of membrane proteins from 18 different uropathogenic Escherichia coli strains. The safety and efficacy of this immunoactive agent is well documented; therefore, it is recommended for the prophylaxis of UTI according to the current European Association of Urology guidelines on urological infections. In terms of a true vaccine designed to target specifically pathogenic bacteria, no substance is currently available. ExPEC4V, a novel tetravalent bioconjugate vaccine against extraintestinal pathogenic E. coli, was evaluated for safety, immunogenicity, and clinical efficacy in a randomised, single-blinded, placebo-controlled phase 1b trial. The vaccine was well tolerated and elicited a robust antibody response in patients suffering from recurrent UTIs. Although the first clinical data suggested a reduced incidence of UTIs after vaccination, especially for higher bacterial loads, further randomised controlled trials are necessary to determine its true clinical benefit.

Molecular evolution of Salmonella enterica serovar Typhimurium and pathogenic Escherichia coli: from pathogenesis to therapeutics.

Salmonella enterica serovar Typhimurium (S. Typhimurium) and certain Escherichia coli are human pathogens that have evolved through the acquisition of multiple virulence determinants by horizontal gene transfer. Similar genetic elements, as pathogenicity islands and virulence plasmids, have driven molecular evolution of virulence in both species. In addition, the contribution of prophages has been recently highlighted as a reservoir for pathogenic diversity. Characterization of horizontally acquired virulence genes has several clinical implications. First, identification of virulence determinants that have a sporadic distribution and are specifically associated with a pathotype and/or a pathology can be useful markers for risk assessment and diagnosis. Secondly, virulence factors widely distributed in pathogenic strains, but absent from non-pathogenic bacteria, are interesting targets for the development of novel antimicrobial chemotherapies and vaccines. Here, we summarize the horizontally acquired virulence factors of S. Typhimurium, enterohemorrhagic E. coli O157:H7 and uropathogenic E. coli, and we describe their use in novel therapeutic approaches.

Bacterial ghost of avian pathogenic E. coli (APEC) serotype O78:K80 as a homologous vaccine against avian colibacillosis.

Avian Colibacillosis is among the major causes of economic loss in the poultry industry worldwide, with a more vivid impact on developing countries. The involvement of several bacteria has made it challenging to develop effective vaccines for this disease, particularly because it is notoriously difficult to make a vaccine that contains all the contributing pathogenic bacteria. Here, we report the design and fabrication of a bacterial ghost (BG) of E. coli O78:K80, which is among the major bacterial serotypes responsible for this disease. The generated ghost is then exploited as a homologous vaccine against Avian Colibacillosis. We demonstrate that hole formation in the cell wall of E. coli O78:K80 can happen properly in optical densities as high as 0.8 compared to the 0.3-0.4 standard for bacteria like E. coli TOP10. This is especially advantageous for mass production of this ghost which is a vital factor in development of any BG-based vaccine. Compared to E. coli TOP10, we faced a great challenge in transforming the wild type bacteria with the E-lysis plasmid which was probably due to higher thickness of the cell wall in O78:K80. This, however, was addressed by treating the cell wall with a different combination of ions.The vaccine was administered to Ross 308 broiler chickens via injection as well as through their respiratory system at a dose of 1010 BGs, repeated 3 times at weekly intervals. Chickens were then challenged with the wild type O78:K80 at a dose of 1011 bacteria together with Infectious Bronchitis H120 vaccine (as immunosuppressant) one week after the last immunization. Air sac lesions were significantly reduced in BG vaccinated groups in comparison with the control group. The levels of IFNγ, IgA and IgY were measured in the serum of immunized chickens as an indication of immune response and were compared with those of the chickens vaccinated with killed bacteria. The results show that O78:K80 BG can be used as an efficient homologous vaccine against Colibacillosis disease in poultry. We expect our findings can serve as the starting point for designing more sophisticated vaccines that contain all three major pathogenic bacteria involved in avian Colibacillosis.

Efficacy of a recombinant Intimin, EspB and Shiga toxin 2B vaccine in calves experimentally challenged with Escherichia coli O157:H7.

Escherichia coli O157:H7 is a zoonotic pathogen of global importance and the serotype of Shiga toxin-producing E.coli (STEC) most frequently associated with Hemolytic Uremic Syndrome (HUS) in humans. The main STEC reservoir is cattle. Vaccination of calves with the carboxy-terminal fraction of Intimin γ (IntC280) and EspB can reduce E.coli O157:H7 fecal shedding after experimental challenge. Shiga toxin (Stx) exerts local immunosuppressive effects in the bovine intestine and Stx2B fused to Brucella lumazine synthase (BLS-Stx2B) induces Stx2-neutralizing antibodies. To determine if an immune response against Stx could improve a vaccine's effect on fecal shedding, groups of calves were immunized with EspB + IntC280, with EspB + IntC280 + BLS-Stx2B, or kept as controls. At 24 days post vaccination calves were challenged with E.coli O157:H7. Shedding of E.coli O157:H7 was assessed in recto-anal mucosal swabs by direct plating and enrichment followed by immunomagnetic separation and multiplex PCR. Calves were euthanized 15 days after the challenge and intestinal segments were obtained to assess mucosal antibodies. Vaccination induced a significant increase of IntC280 and EspB specific antibodies in serum and intestinal mucosa in both vaccinated groups. Antibodies against Stx2B were detected in serum and intestinal mucosa of animals vaccinated with 3 antigens. Sera and intestinal homogenates were able to neutralize Stx2 verocytotoxicity compared to the control and the 2-antigens vaccinated group. Both vaccines reduced E.coli O157:H7 shedding compared to the control group. The addition of Stx2B to the vaccine formulation did not result in a superior level of protection compared to the one conferred by IntC280 and EspB alone. It remains to be determined if the inclusion of Stx2B in the vaccine alters E.coli O157:H7 shedding patterns in the long term and after recurrent low dose exposure as occurring in cattle herds.

Subunit vaccines based on intimin and Efa-1 polypeptides induce humoral immunity in cattle but do not protect against intestinal colonisation by enterohaemorrhagic Escherichia coli O157:H7 or O26:H-.

Enterohaemorrhagic Escherichia coli (EHEC) infections in humans are an important public health concern and are commonly acquired via contact with ruminant faeces. Cattle are a key control point however cross-protective vaccines for the control of EHEC in the bovine reservoir do not yet exist. The EHEC serogroups that are predominantly associated with human infection in Europe and North America are O157 and O26. Intimin and EHEC factor for adherence (Efa-1) play important roles in intestinal colonisation of cattle by EHEC and are thus attractive candidates for the development of subunit vaccines. Immunisation of calves with the cell-binding domain of intimin subtypes beta or gamma via the intramuscular route induced antigen-specific serum IgG1 and, in some cases salivary IgA responses, but did not reduce the magnitude or duration of faecal excretion of EHEC O26:H- (Int(280)-beta) or EHEC O157:H7 (Int(280)-gamma) upon subsequent experimental challenge. Similarly, immunisation of calves via the intramuscular route with the truncated Efa-1 protein (Efa-1') from EHEC O157:H7 or a mixture of the amino-terminal and central thirds of the full-length protein (Efa-1-N and M) did not protect against intestinal colonisation by EHEC O157:H7 (Efa-1') or EHEC O26:H- (Efa-1-N and M) despite the induction of humoral immunity. A portion of the serum IgG1 elicited by the truncated recombinant antigens in calves was confirmed to recognise native protein exposed on the bacterial surface. Calves immunised with a mixture of Int(280)-gamma and Efa-1' or an EHEC O157:H7 bacterin via the intramuscular route then boosted via the intranasal route with the same antigens using cholera toxin B subunit as an adjuvant were also not protected against intestinal colonisation by EHEC O157:H7. These studies highlight the need for further studies to develop and test novel vaccines or treatments for control of this important foodborne pathogen.

Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial.

BACKGROUND: Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). METHODS: In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. FINDINGS: Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). INTERPRETATION: This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. FUNDING: GlycoVaxyn, Janssen Vaccines.

Efficacy of an avian colibacillosis live vaccine for layer breeder in Japan.

Colibacillosis is one of an economically significant disease in the poultry industry, especially for meat breed chickens. Recently it has become a serious problem for layer especially when the birds start laying and also at the later stage of laying. In Japan, the productivity of field laying hens improved when the Δcrp avian colibacillosis live vaccine ("Gall N tect CBL") was used. The survival rate and egg laying rate increased during almost all of the laying period when compared with the control group. The improvement in productivity was clearly demonstrated by comparing the number of eggs laid per day. The use of an avian colibacillosis live vaccine proved to be cost-effective in laying hens.

Vaccines against traveler's diarrhoea and rotavirus disease - a review.

Diarrheal diseases constitute one of the most important health problems worldwide, preferentially in developing countries with a morbidity of estimated 5 billion and a mortality of 5 million cases per year. Children less than 5 years are particularly in danger with respect to the incidence and severity of the gastrointestinal symptoms. Travelers to developing countries are also at risk to develop diarrheal disorders; around 30-50% of them acquire so called "travelers's diarrhea" caused by bacteria, viruses or protozoa. It has been estimated that approximately 30-70% of diarrhea are due to bacteria, of which the most frequently detected enteric pathogens are non-invasive, enterotoxigenic Escherichia coli (ETEC). Their exotoxins, the heat stabile (ST) and the heat labile (LT) toxins are in large part responsible for the pathogenicity of the bacteria. About 20% of cases of traveler's diarrhea are caused by LT producing ETEC. This heat labile toxin exhibits a 80% sequence homology with cholera toxin. The presently available vaccine against cholera (Dukoral) contains inactivated Vibrio cholerae bacteria and the recombinant non-toxic B subunit of cholera toxin. Consequently, this vaccine displays also some efficacy against traveler's diarrhoea with up to 25% of travelers being protected against this disease. Rotaviruses are the leading recognized cause of diarrhoea-related illness and deaths among infants worldwide in developing and industrialized countries. Based on the high incidence of this disease two oral vaccines have been developed and will be available in Europe in 2006. Due to the impact of rotavirus diseases also in Austria vaccination against this disease has been already suggested in the Austrian vaccination schedules for infants from 6-24 weeks of age. One of the two vaccines, Rotarix, is an attenuated monovalent vaccine with a broad cross-reactivity against the most frequent serotypes. The second one, RotaTeq, is a pentavalent attenuated vaccine containing 5 human-bovine reassortants. Both vaccines display 85-98% efficacy against severe rotavirus disease and an excellent tolerability with no difference in side reactions to the placebo controls, particularly with respect to intussusceptions. With respect to increasing travel habits with infants and small children, particularly when visiting friends and relatives, vaccination against rotavirus infections will also be important in international travel.