Bovine colostrum and product intervention associated with relief of childhood infectious diarrhea.

This meta-analysis aimed to investigate the protective effects of bovine colostrum against childhood infectious diarrhea. A systematic search was conducted using PubMed, Cochrane Library databases and clinicaltrial.gov. Among 166 research articles, only five RCTs were included into final analysis. Review manager (version 5.2) was used to pool the effect-size across studies. Sensitivity and risk of bias were estimated accordingly. Under a pooled analysis, bovine colostrum consumption correlated with a significant reduction in stool frequency of infectious diarrhea, by 1.42 times per day (95% CI: -2.70, -0.14). Bovine colostrum intervention also reduced occurrence of diarrhea by 71% (pooled OR = 0.29, 95%CI 0.16, 0.52). The OR of positive detection of pathogen in the stool was 0.29 (95%CI 0.08, 0.71) in bovine colostrum treated group, compared with placebo group. In the sensitivity analysis of studies with low risk of biases, bovine colostrum significantly reduced stool frequency, occurrence of diarrhea and pathogen detection. BC and related products have a significant benefit in reducing the frequency and relieving the symptoms of childhood infectious diarrhea.

WHO consultation on ETEC and Shigella burden of disease, Geneva, 6-7th April 2017: Meeting report.

According to the 2015 Global Burden of Disease Study, diarrhea ranked ninth among causes of death for all ages, and fourth among children under 5 years old, accounting for an estimated 499,000 deaths in this young age group. It was also the second most common cause of years lived with disability (2.39 billion YLDs). The goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhea (GAPPD) is to reduce deaths from diarrhea in children under 5 years of age to less than 1 per 1000 live births, by 2025. Development of new and improved vaccines against diarrheal infections is a fundamental element of the strategy towards achieving this goal. Enterotoxigenic Escherichia coli (ETEC) and Shigella are enteropathogens that cause significant global mortality and morbidity, particularly in low- and middle-income countries. In 2016, WHO's Product Development for Vaccines Advisory Committee (PDVAC) recommended that the WHO's Initiative for Vaccine Research (IVR) engage in this area, based on PDVAC's criteria of prioritizing the development of vaccines against pathogens that will address a major unmet public health need, and for which clinical candidates with a good probability of technical success are in the pipeline. As a first step, WHO's IVR convened global subject matter experts to discuss the current global ETEC and Shigella disease burden estimates, including the current understanding of the long-term indirect effects of ETEC and Shigella infection, and how these data may affect future decision making on vaccine development for both pathogens. The available global burden estimates for ETEC and Shigella differ with respect to the relative importance of these two pathogens. The mortality estimates vary between iterations published by the same group, as well as between estimates of different groups, although the uncertainty intervals are broad and overlapping. These variances are attributable to differences in the data available and incorporated in the models; the methods used to detect the pathogens; the modelling methodologies; and, to actual changes in the total number of diarrheal deaths over time. The changes in the most recently reported mortality estimates for these pathogens, as compared to previous iterations, has led to debate as to whether investment in development of stand-alone vaccines, rather than combined vaccines, is warranted from cost-effectiveness and vaccine impact perspectives. Further work will be needed to understand better the variances and uncertainties in the reported mortality estimates to support investment decision making, and ultimately policy recommendations for vaccine use. In addition, a comprehensive assessment of the value proposition for vaccines against these pathogens is needed and will be strengthened if the long-term health consequences associated with diarrhea and dysentery due to these pathogens are better defined.

Immune response, ciprofloxacin activity, and gender differences after human experimental challenge by two strains of enterotoxigenic Escherichia coli.

In order to test vaccines against enterotoxigenic Escherichia coli (ETEC)-induced diarrhea, challenge models are needed. In this study we compared clinical and immunological responses after North American volunteers were orally challenged by two ETEC strains. Groups of approximately eight volunteers received 10(9) or 10(10) CFU of E. coli B7A (LT+ ST+ CS6+) or 10(8) or 10(9) CFU of E. coli H10407 (LT+ ST+ CFA/I+). About 75% of the volunteers developed diarrhea after challenge with 10(10) CFU B7A or either dose of H10407. B7A had a shorter incubation period than H10407 (P = 0.001) and caused milder illness; the mean diarrheal output after H10407 challenge was nearly twice that after B7A challenge (P = 0.01). Females had more abdominal complaints, and males had a higher incidence of fever. Ciprofloxacin generally diminished or stopped symptoms and shedding by the second day of antibiotic treatment, but four subjects shed for one to four additional days. The immune responses to colonization factors CS6 and colonization factor antigen I (CFA/I) and to heat-labile toxin (LT) were measured. The responses to CFA/I were the most robust responses; all volunteers who received H10407 had serum immunoglobulin A (IgA) and IgG responses, and all but one volunteer had antibody-secreting cell (ASC) responses. One-half the volunteers who received B7A had an ASC response to CS6, and about one-third had serum IgA or IgG responses. Despite the differences in clinical illness and immune responses to colonization factors, the immune responses to LT were similar in all groups and were intermediate between the CFA/I and CS6 responses. These results provide standards for immune responses after ETEC vaccination.

Infection and cross-protection studies of winter dysentery and calf diarrhea bovine coronavirus strains in colostrum-deprived and gnotobiotic calves.

OBJECTIVE: To investigate in vitro antigenic relations, in vivo cross-protection, and isotype antibody responses to a winter dysentery (WD) and calf diarrhea strain of bovine coronavirus (BCV). DESIGN AND ANIMALS: Gnotobiotic and colostrum-deprived calves were inoculated oronasally with a WD (DBA) or a calf diarrhea (DB2) BCV, and were challenge exposed with the heterologous BCV. PROCEDURE: Nasal swab and feces specimens and blood samples were collected. Fecal and nasal specimens were assayed for BCV shedding by antigen-capture ELISA or immune electron microscopy. Bovine coronavirus antigens were detected in nasal epithelial cells by immunofluorescence. Antibody titers to BCV in serum were assayed by virus neutralization (VN), and BCV antibody isotype titers in feces and sera were quantitated by ELISA. RESULTS: All calves developed diarrhea and shed BCV nasally and in feces, then recovered and were protected from BCV-associated diarrhea after challenge exposure with the heterologous BCV. After challenge exposure with either strain, fecal shedding of DBA was detected in 1 of 4 calves and nasal shedding of DB2 was detected in 2 of 4 calves. Immunoglobulin M was the principal coproantibody to BCV early, followed predominantly by IgA. Immunoglobulin G1 coproantibody titers to BCV were low, but increased after challenge exposure. Immunoglobulin G1 antibodies were predominant in serum. After challenge exposure, all serum antibody isotype titers increased except IgG2. The VN antibody responses paralleled serum IgG1 antibody responses. CONCLUSIONS AND CLINICAL RELEVANCE: Immunoglobulin A coproantibodies at challenge exposure were associated with protection against diarrhea. Nasal shedding of BCV after challenge exposure confirmed field data documenting reinfection of the respiratory tract of cattle, suggesting that, in closed herds, respiratory tract infections constitute a source of BCV transmission to cows (WD) or young calves.

Tiamulin in drinking water for treatment and development of immunity to swine dysentery.

The diarrhea of swine dysentery receded in swine treated with 60 or 45 mg of tiamulin/L of drinking water (60 or 45 ppm). However, within 2 to 10 days (average 4.1 days) after drug withdrawal, diarrhea recurred. Tiamulin (22.5 mg/L in drinking water) did not markedly reduce the diarrhea during medication, and tylosin (66 mg/L in the drinking water) was not effective. In swine treated with 120 mg of dimetridazole/L of drinking water, there was no recurrence of diarrhea. After the recurrence of diarrhea in swine, repeated medication with tiamulin in drinking water reduced the severity of diarrhea and prevented deaths. After 1 to 3 retreatments, swine were immune to exposure with swine dysentery inoculum, and there was a significant (P less than 0.05) increase in their serum anti-Treponema hyodysenteriae antibodies. Seemingly, drug withdrawal permitted the occurrence and recurrence of diarrhea that was necessary to stimulate immunity.