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

Abstract

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.

Introduction

S higa toxin–producing Escherichia coli O157:H7 (STEC O157) is a human pathogen that may lead to diarrhea, hemorrhagic uremic syndrome, or death (Griffin et al., 1988). Ruminants serve as a reservoir for STEC O157 exposure of humans via direct contact or indirect contact with contaminated food, water, or other environmental sources (Sargeant et al., 2003). The probability of detecting STEC O157 in the feces of cattle is variable by season, with higher pathogen levels found in the summer months (Hancock et al., 1997; Chapman et al., 1997; Heuvelink et al., 1998; Van Donkersgoed et al., 1999; Smith et al., 2005). Cattle hides contaminated with STEC O157 have been correlated with STEC O157 carcass contamination in packing facilities (Elder et al., 2000; Arthur et al., 2004). A recent study has shown that the seasonal peak in STEC O157 fecal shedding in beef cattle precedes the peak of both the prevalence of STEC O157 contaminated beef, and incidence of STEC O157 human illness (Williams et al., 2010). Collectively, these findings suggest that reducing STEC O157 fecal shedding in beef cattle might result in less frequent human illness.

Interventions against STEC O157 carriage in live cattle may aid in reducing STEC O157 throughout the beef production chain. Several studies have demonstrated that vaccinating cattle using type III secreted proteins (TTSP) decreases the probability of detecting STEC O157 from cattle feces (Potter et al., 2004; Peterson et al., 2007a; Peterson et al., 2007b; Moxley et al., 2009; Smith et al., 2009a,b; Vogstad et al., unpublished). Risk modelers have also predicted that a STEC O157 vaccine administered to live cattle might have the greatest potential impact at reducing STEC O157 carcass contamination (Jordan et al., 1999). A systematic review on commercially available vaccines concluded that vaccination of cattle has efficacy as a preharvest intervention (Snedeker et al., 2012). In this review, the odds of detecting STEC O157 in the feces of cattle vaccinated with TTSP were reduced by 62% compared to control cattle. Another important finding from this study was that the measure of efficacy for the TTSP vaccine product demonstrated statistically significant heterogeneity. Factors accounting for the heterogeneity of vaccine efficacy between studies were left unaccounted for in this report (Snedeker et al., 2012). Vaccine efficacy is the percent reduction in the proportion of culture-positive animals in a pen attributable to vaccination. Factors that lead to heterogeneity (variability in the effect of the vaccine) could be important if vaccination is adopted widely as a preharvest intervention. Heterogeneity of vaccine efficacy could be a result of (1) testing a product that varied in efficacy in different studies; (2) the relative environmental conditions favoring bacterial survival and transmission, as evidenced by test-period within block fecal prevalence of nonvaccinated cattle; or (3) waxing or waning immunity occurring over time from administration of the last dose of the vaccine. Since we possessed the complete datasets for these TTSP vaccine trials, our objectives were (1) to determine the efficacy of a three-dose regimen of a TTSP vaccine product at reducing the probability to detect STEC O157 in the feces of feedlot cattle; and (2) to test factors that may modify the overall efficacy of the STEC O157 TTSP vaccine in vaccinated pens of cattle.

Materials and Methods

Data selection and coding

Eight randomized controlled TTSP vaccine studies were screened for possible use in this study. Trials were performed at the University of Nebraska–Lincoln within the years 2002–2008. Studies selected to test for heterogeneity in the measure of efficacy of a TTSP vaccine product had a dose-regimen according to the vaccine label, and a comparable study design, and study outcome. Regional vaccination and herd immunity studies were excluded (Peterson et al., 2007b; Smith et al., 2009a), since we were only interested in studies comparing pens of vaccinated and nonvaccinated cattle (Table 1). Studies where the outcome was a measure of STEC O157 fecal shedding were selected: Potter et al., 2004; Peterson et al., 2007a; Moxley et al., 2009; Vogstad et al., unpublished. In the Peterson et al., 2007a study, the terminal rectal mucosa outcome was excluded. The vaccine dose–regimen for all studies selected was three doses. Vaccinated cattle received a commercial TTSP vaccine product provided by Bioniche Life Sciences, Belleville, Ontario, Canada as previously described (Potter et al., 2004; Peterson et al., 2007a; Moxley et al., 2009; Vogstad et al., unpublished). Animals in the control treatment were given either a placebo vaccination or no placebo. Vaccination and control treatments were administered at the pen-level, with all animals within a pen receiving the treatment. Fecal samples were collected longitudinally from cattle following administration of the vaccination treatment. For the analysis, we were left with four studies with four vaccinated versus nonvaccinated treatment comparisons. Variables included in our dataset were block, test-period, vaccination treatment, study, test-period within block fecal prevalence of nonvaccinated cattle, and days from vaccination (Table 2). Test-period within block fecal prevalence and days from vaccination were calculated from the raw data.

Table 1.

Studies and/or Treatment Comparisons Excluded in the Assessment of Heterogeneity of Efficacy of a Three-Dose Regimen of a Type III Secreted Protein Vaccine for Reducing Shiga Toxin–Producing Escherichia coli O157:H7 in Feces of Feedlot Cattle

Study	Reason for excluding study or treatment comparison
Moxley et al., 2009	Two-dose regimen vaccine treatment
Peterson et al., 2007b	Herd immunity outcome
Smith et al., 2009a	Regional vaccination
Smith et al., 2009b	Terminal rectal mucosa outcome and two-dose regimen vaccine treatment

Table 2.

Factors Included in the Assessment of Heterogeneity of Efficacy of a Three-Dose Regimen of a Type III Secreted Protein Vaccine for Reducing Shiga Toxin–Producing Escherichia coli O157:H7 (STEC O157) in Feces of Feedlot Cattle

Factor	Definition
Block	Corresponds to feedlots, regions within a feedlot, and feedlot arrival dates
Test period	The number of post-treatment rectal fecal sampling events, where each animal in a pen is sampled and cultured for STEC O157
Vaccination treatment	(1) Three doses of a type III secreted proteins vaccine, (2) Adjuvant or no adjuvant
Study	Potter et al., 2004; Peterson et al., 2007a; Moxley et al., 2009; Vogstad et al., unpublished
Test period within block fecal prevalence of nonvaccinated animals	STEC O157–positive animals in a nonvaccinate pen over the number of animals in a nonvaccinate pen averaged over each test period within a block
Days from vaccination	Days from the date of administration of the third dose of the vaccine/control treatment to the test period sampling date

Statistical analysis

A generalized estimating equations logistic regression model (Proc Genmod, SAS Institute, Cary, NC) was used to test the null hypothesis that there was no difference in the probability for a positive STEC O157 fecal sample between pens of vaccinated and nonvaccinated cattle. The generalized estimating equations model specified a logit link function for a binomial response, which was the number of culture-positive animals in a pen divided by the total number of animals in that pen (SAS, 2009). An autoregressive correlation structure was defined to account for clustering of repeated test-periods within study blocks. Potential confounding and clustering by study was accounted for by treating study as a fixed effect. Fixed effects tested to explain the probability for a positive fecal sample were (1) vaccination, (2) study, (3) test-period within block fecal prevalence, and (4) days from vaccination. Two-way interactions tested to assess heterogeneity in the effect of the vaccine were vaccination and the factors (1) study; (2) test-period within block fecal prevalence; and (3) days from vaccination. The final multivariable model was determined using a manual forward selection process based on (1) significance and (2) model fit. Significance level was set at α≤0.05 and p-values were obtained from the Type III Score statistic. Model fit was assessed using the quasi-likelihood independence criterion, with the better-fitting model possessing a lower value (Pan, 2001).

A corresponding log-binomial model was specified to obtain model adjusted–probabilities and relative risk (McNutt et al., 2003). Explanatory variables represented in the final logistic regression model were specified in the log-binomial model. Model-adjusted probabilities were calculated for each level of categorical variables explaining the probability to detect STEC O157 in the feces of cattle using least-squares means. Model-adjusted relative risk estimates and 95% confidence intervals were obtained from the contrast estimate results. Vaccine efficacy represents the proportion of cases prevented by vaccination. Efficacy of the vaccine treatment was then derived as 1 minus the relative risk.

Results

Features of the four trials included in the analysis are presented in Table 3 (Potter et al., 2004; Peterson et al., 2007a; Moxley et al., 2009; Vogstad et al., unpublished). One hundred eighty-four pens were represented by the analysis. Overall STEC O157 was detected from 661/5451 (12%) of postvaccination fecal samples. The probability of detecting STEC O157 in the feces of cattle over all studies and postvaccination time periods was 8.4% (231/2734) and 15.8% (430/2717) in the vaccination and control treatments, respectively.

Table 3.

Descriptive Statistics for Four Natural Exposure Randomized Controlled Trials Used in the Assessment of Heterogeneity of Efficacy of a Three-Dose Regimen of a Type III Secreted Protein Vaccine for Reducing Shiga Toxin–Producing Escherichia coli O157:H7 (STEC O157) in Feces of Feedlot Cattle

Study	Year conducted	Blocks	Pens/treatment	Animals/pen	Sample size	Control type	Test- periods	Days post-vaccination	Positive samples	Odds ratio	p-Value	Result
Moxley et al., 2009	2006	4	20	8	320	Placebo	4	21, 35, 49, 70	79/1273	0.34	0.002	Vaccine reduced shedding of STEC O157
Peterson et al., 2007a	2003	1	18	8	288	Placebo	4	14, 28, 42, 56	79/1127	0.81	0.57	No difference between vaccine and control
Potter et al., 2004	2002	3	24	8	384	Placebo	3	21, 42, 62/64	134/1152	0.36	0.04	Vaccine reduced shedding of STEC O157
Vogstad et al., unpublished	2008	3	30	8	480	No placebo	4	21/22, 42/43, 63/64, 84/85	369/1899	0.5	<0.0001	Vaccine reduced shedding of STEC O157

The initial variable included in the logistic regression model was study (p<0.01). The only other main effect variable that improved model fit with study was vaccination (p<0.0001). All interactions were evaluated while keeping study and vaccination treatment as fixed effects. Interactions between study and vaccination (p=0.32), and test-period within block fecal prevalence and vaccination (p=0.21) were not significant (see Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/fpd).

An interaction between days from vaccination and vaccination treatment was significant (p=0.05); however, the interaction reduced model fit in the logistic regression model and caused the log-binomial model to fail to converge. Further evaluation of the interaction showed that significance was dependent on a single fecal collection day in the final test-period of the Peterson et al., 2007a study. On the day cattle were transported to harvest, a major rain event had occurred, possibly resulting in intestinal pass-through shedding of the organism because at harvest, colonization at the rectal–anal junction was 98% less for vaccinated compared to nonvaccinated cattle (Peterson et al., 2007a). When this single date was removed, model fit improved, but the interaction was not significant (p=0.08; Supplementary Table S1). Therefore, the interaction between days from vaccination by vaccination treatment was not included in the final model.

In the final model, adjusting for study, vaccination treatment reduced the probability of cattle to shed STEC O157 in the feces. The final logistic and log-binomial regression models are summarized in Tables 4 and 5, respectively. Vaccinated cattle had a 54% lowered odds of shedding STEC O157 in the feces than nonvaccinated cattle did (odds ratio=0.46; 95% confidence interval=0.37–0.58; p<0.0001). The model-adjusted probabilities of recovering STEC O157 from the feces of immunized and non-immunized cattle were 0.068 and 0.131, respectively. Model-adjusted vaccine efficacy was 48% (95% confidence interval, 0.37–0.57; p<0.0001).

Table 4.

Multivariable Logistic Regression Model for the Probability of Recovering Shiga Toxin–Producing Escherichia coli O157:H7 from the Feces of Feedlot Cattle (n=5451) Sampled from Four Natural Exposure Studies from Within 92 Pens of Vaccinated Cattle and 92 Pens of Nonvaccinated Cattle, While Accounting for Clustering of Repeated Test-Periods Within Block and Study as a Fixed Effect

Variable	Unit	Parameter estimate	Odds ratio	95% Confidence interval	p-Value
Intercept		−1.8555			<0.0001
Vaccination	Vaccine	−0.7704	0.463	0.369–0.580	<0.0001
	Control	0	1	1
Study	Moxley	−1.3090	0.27	0.14–0.52	0.0043
	Peterson	−1.1822	0.31	0.18–0.53
	Potter	−0.6117	0.54	0.29–1.01
	Vogstad	0	1	1

Table 5.

Multivariable Log-Binomial Model for the Probability of Recovering Shiga Toxin–Producing Escherichia coli O157:H7 from the Feces of Feedlot Cattle (n=5451) Sampled from Four Natural Exposure Studies from Within 92 Pens of Vaccinated Cattle and 92 Pens of Nonvaccinated Cattle, While Accounting for Clustering of Repeated Test-Periods Within Block and Study as a Fixed Effect

Variable	Unit	Parameter estimate	Relative risk	95% Confidence interval	p-Value
Intercept		−2.0250			<0.0001
Vaccination	Vaccine	−0.6573	0.518	0.427–0.629	<0.0001
	Control	0	1	1
Study	Moxley	−1.1332	0.32	0.18–0.58	0.0042
	Peterson	−1.0237	0.36	0.22–0.58
	Potter	−0.4992	0.61	0.36–1.03
	Vogstad	0	1	1

Discussion

Two major findings of this study were as follows: (1) a three-dose regimen of TTSP vaccine significantly reduced fecal shedding of STEC O157 in cattle by 48% compared to nonvaccinated cattle under conditions of natural exposure; and (2) study and test-period within block fecal prevalence did not modify the overall efficacy of the vaccine.

Our findings are consistent with two recently conducted systematic reviews and meta-analyses that concluded that vaccine efficacy of TTSP vaccines was significant (Varela et al., 2012; Snedeker et al., 2012). However, we did not find an explanation for heterogeneity in vaccine efficacy. Understanding factors that modify vaccine efficacy is important to the practical application of a preharvest vaccine. Dose regimen, type of control treatment used, season, farm type, and animal type are all variables that have been previously tested to explain variation in efficacy of a TTSP vaccine against STEC O157 in cattle (Snedeker et al., 2012; Varela et al., 2012). In an assessment of vaccine efficacy of both siderophore receptor and porin protein (SRP) and TTSP vaccines, heterogeneity across the studies was investigated and attributed to the commingling of vaccinates and non-vaccinates within a pen (Varela et al, 2012). Other researchers have hypothesized that significant heterogeneity was due to individual animal variation, challenge load, and number of animals in a pen, although these variables have not previously been tested (Snedeker et al., 2012).

In our final model, study significantly explained the probability of recovering STEC O157 from the feces of cattle, meaning that STEC O157 fecal shedding prevalence differed by study. For example, fecal prevalence was three times greater for the Vogstad et al. unpublished study versus the Moxley et al., 2009 study. This was to be expected since exposure of cattle to STEC O157 in the pen environment has been related to both time and place-dependent factors (Smith et al., 2001; Smith et al., 2005). We also tested for an interaction of vaccination by study, to determine whether vaccine efficacy differed from study to study (e.g., due to differences in the potency of different vaccine lots). We found no evidence that vaccine efficacy differed across the studies tested in this analysis.

In this analysis, test period within block fecal prevalence was tested as a correlate for pathogen load in the environment. The probability of detecting STEC O157 in the feces of cattle is highly variable (Smith et al., 2001), partly due to environmental factors that influence the survival and transmission of the pathogen (Smith et al., 2005). Season has been repeatedly shown to influence STEC O157 fecal shedding in cattle, with a greater proportion of cattle testing positive to STEC O157 in the summer (Hancock et al., 1997; Chapman et al., 1997; Heuvelink et al., 1998; Van Donkersgoed et al., 1999). Condition of the pen floor may also influence STEC O157 transmission. Cattle housed on feedlot pen surfaces characterized as muddy compared to normal are more likely to shed STEC O157 in the feces (Smith et al., 2001). Similarly, cattle in close contact with a high shedder are at a greater risk of shedding STEC O157 in the feces (Cobbold et al., 2007). Pathogen load of oral exposure, measured using rope devices to detect STEC O157–culture positive animals, has been previously shown to correlate with fecal prevalence (Irwin et al., 2002; Smith et al., 2004). Our hypothesis was that an increase in STEC O157 in the feedlot environment (pathogen load) could overwhelm the beneficial effect of the TTSP vaccine, or conversely, that the beneficial effect of the vaccine would be more observable during periods of high prevalence. We found no evidence that the within test-period and block fecal-prevalence affected vaccine efficacy.

We cannot draw strong conclusions about the effect of days elapsing from administering the last dose of the vaccine and efficacy of the TTSP vaccine product. We tested this interaction because it is of practical importance to food safety that a vaccine product offer effective immunity in cattle until shipment for slaughter. In the full dataset, inclusion of the interaction term caused poor model fit in the logistic regression model and the log-binomial model failed to find a solution. With the removal of a problematic test-period the logistic regression model fit improved, but the variable was not significant. Even so, the interaction term approached significance and we may have lacked adequate power to conclude that vaccine efficacy is not affected over time. We have not seen significant difference in the efficacy of the vaccine over time in the studies individually, and the direction of efficacy over time has both waxed and waned (Potter et al., 2004; Peterson et al., 2007a; Moxley et al., 2009). These studies may not be ideal for testing the question of length of immunity because the postvaccination period of evaluation has been relatively short, from 14 to 85 days.

Conclusions

We conclude that the estimate for the efficacy of a three-dose TTSP vaccine regimen for reducing STEC O157 in the feces of cattle was not affected by study and test-period within block fecal prevalence. Duration of immunity requires future study.

Footnotes

Acknowledgments

This study was supported by a contribution of the University of Nebraska Agricultural Research Division, supported in part by Animal Health and Hatch Act funds. This project was funded through a grant from the Agriculture and Food Research Initiative (Grant No. 2009-04248) of the Cooperative State Research, Education and Extension Service, U.S. Department of Agriculture.

Disclosure Statement

Neither the authors nor the University of Nebraska–Lincoln has direct financial interest in the commercialization of this vaccine product.

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