Evaluating Use Cases for Human Challenge Trials in Accelerating SARS-CoV-2 Vaccine Development.

Human challenge trials (HCTs) have been proposed as a means to accelerate SARS-CoV-2 vaccine development. We identify and discuss 3 potential use cases of HCTs in the current pandemic: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We outline the limitations of HCTs and find that HCTs are likely to be most useful for vaccine candidates currently in preclinical stages of development. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be extremely beneficial. Therefore, the option of conducting HCTs to accelerate SARS-CoV-2 vaccine development should be preserved. As HCTs require many months of preparation, we recommend an immediate effort to (1) establish guidelines for HCTs for COVID-19; (2) take the first steps toward HCTs, including preparing challenge virus and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs.

Evaluation of an Immersive Farm Experience to Teach and Attract Veterinary Students to Food-Animal Medicine.

The Bovine Educational Symposium (BES) is a unique opportunity for North Carolina State University (NCSU) veterinary students to visit dairy farms, feedlots, cow-calf operations, and processing facilities, and to meet local bovine veterinarians. We hypothesized that this active learning opportunity would increase knowledge, change perceptions of animal agriculture and food-animal medicine, and provide skills that persist beyond graduation. Pre- and post-trip surveys were administered to 124 first-, second-, and third-year veterinary students attending BES over 3 years. The surveys assessed students' perceived competence with regard to 12 key areas of bovine practice, attitudes toward segments of the cattle industry, attitudes to veterinarians' role in these segments, and interest in a career in bovine practice. Content knowledge was assessed using a multiple-choice test for comparison to self-assessments. A control group of 10 fourth-year students was administered the same tests before and after a 2-week food-animal clinical rotation. A convenience sample of nine BES alumni were interviewed to assess their opinion on the educational impact of BES. BES participants exhibited significant gains in perceived competence and actual knowledge in all 12 areas, and they also had improved perceptions of animal agriculture and increased interest in food-animal careers. Benefits noted by alumni ranged from improved knowledge of basic concepts of biosecurity and population medicine to greater appreciation for professional skills, including client communication. Immersing pre-clinical veterinary students in an active learning environment can have a significant impact on their knowledge and perception of food-animal medicine, irrespective of students' ultimate career goals.

Short communication: Apparent efficiency of colostral immunoglobulin G absorption in Holstein heifers.

Adequate absorption of bovine colostrum correlates with improved neonatal health. The apparent efficiency of absorption (AEA) of immunoglobulins can be measured using a mathematical equation based on serum and colostral IgG concentration levels, as well as calf body weight and the volume of colostrum being fed. Although commonly measured in research projects, little information is available on the normal AEA across a large group of healthy calves on multiple farms. The purpose of this study was to observe how contributing factors (volume of feeding, birth weight, and time of feeding) can alter AEA and establish a reference range for AEA in healthy calves. Study subjects were 100 Holstein heifer calves from 5 different dairies in North Carolina and Colorado. After a normal calving, the heifer received either 4 or 5.6 L of colostrum within 4 h of birth, an aliquot of the fed colostrum was saved, and a blood sample was collected between 24 and 36 h after birth. Birth weights were measured using the same weight tape on each farm. Radial immunodiffusion assay was performed to obtain IgG concentrations in the colostrum and serum samples. From this data, the AEA was calculated. The AEA ranged from 7.7 to 59.9% with mean of 28.1 ± 9.5% and median of 27.5%. The AEA of 69% of the calves fell between 21 and 40%. The AEA varied widely between calves, even when feeding was standardized. Results suggest that serum IgG concentration may potentially be increased by feeding increased volumes of colostrum or genetic selection, given the wide range of AEA values obtained.

Efficacy of an Escherichia coli O157:H7 SRP Vaccine in Orally Challenged Goats and Strain Persistence Over Time.

Small ruminants have been implicated in outbreaks of Escherichia coli O157:H7 at livestock exhibitions throughout the United States. Additionally, goat meat or milk may serve as a reservoir for foodborne transmission of the organism. These associations highlight the public health importance of an effective strategy to reduce E. coli O157:H7 shedding in goats. We examined the efficacy of the SRP® vaccine in goats orally challenged with E. coli O157:H7. Mixed-breed goats (n = 14) were randomly allocated into vaccinated and unvaccinated treatments (n = 7 per treatment). Goats were housed with a vaccinated and unvaccinated animal in each pen. Feces were collected for 3 weeks, then at necropsy, gastrointestinal contents were collected to determine the concentration of E. coli O157:H7. Three isolates per positive sample were saved and evaluated by pulsed-field gel electrophoresis (PFGE) to assess strain persistence over time. The mean concentration of E. coli O157:H7 in the feces of goats was numerically reduced in the vaccinated treatment; however, it was not statistically significant. In addition, the total number of days goats were fecal positive for E. coli O157:H7 were not different between vaccinated and unvaccinated treatments. Pulsotypes of isolates revealed that goats initially shed two of the four challenge strains of E. coli O157:H7, after which there was a distinct shift to two different strains. Further work is needed to evaluate cost-effective intervention strategies that reliably reduce E. coli O157:H7 shedding in goats, particularly those that may reduce the risk of transmission at public events, including petting zoos and fairs.

Effect of high-pressure processing of bovine colostrum on immunoglobulin G concentration, pathogens, viscosity, and transfer of passive immunity to calves.

This study aimed to determine the effects of high-pressure processing on the immunoglobulin concentration, microbial load, viscosity, and transfer of passive immunity to calves when applied to bovine colostrum as an alternative to thermal pasteurization. A pilot study using Staphylococcus aureus was conducted to determine which pressure-time treatments are most appropriate for use with bovine colostrum, with the goals of maximizing bacterial inactivation while minimizing IgG content and viscosity changes. Following the pilot study, an inoculation study was conducted in which first-milking colostrum samples from Holstein-Friesian cows were inoculated with known concentrations of various bacteria or viruses and pressure processed at either 300 MPa for up to 60min or at 400MPa for up to 30min. The recovery of total native aerobic bacteria, Escherichia coli, Salmonella enterica ssp. enterica serovar Dublin, Mycobacterium avium ssp. paratuberculosis, bovine herpesvirus type 1, and feline calicivirus were determined after processing. Colostrum IgG content was measured before and after pressure processing. Shear stress and viscosity for each treatment was determined over shear rates encompassing those found during calf feeding and at normal bovine body temperature (37.8°C). Following a calf trial, serum IgG concentration was measured in 14 calves fed 4 L of colostrum pressure processed at 400MPa for 15min. In the pilot study, S. aureus was effectively reduced with pressure treatment at 300 and 400MPa (0, 5, 10, 15, 30, and 45min), with 2 treatments at 400MPa (30, 45min) determined to be inappropriate for use with bovine colostrum due to viscosity and IgG changes. High-pressure processing at 300MPa (30, 45, and 60min) and 400MPa (10, 15, and 20min) was shown to effectively reduce total native aerobic bacteria, E. coli, Salmonella Dublin, bovine herpesvirus type 1, and feline calicivirus populations in bovine colostrum, but no decrease occurred in Mycobacterium avium ssp. paratuberculosis. All inoculation study pressure treatments insignificantly decreased IgG content of colostrum. Treatment of colostrum at 400MPa for 15min during the calf trial decreased IgG content of colostrum. Treatment at 400MPa for 15min increased colostrum viscosity, with 2 of 14 samples requiring dilution with water for calf feeding. Calves fed pressure-processed colostrum had similar serum IgG but lower efficiency of absorption than calves fed heat-treated colostrum. The results of this study suggest that high-pressure processing of bovine colostrum maintains an acceptable IgG level while decreasing bacterial and viral counts. Changes in viscosity sometimes made calf feeding more difficult, but still feasible. Additional research to optimize this technology for on-farm use is necessary.

Short communication: Characterization of the serologic response induced by vaccination of late-gestation cows with a Salmonella Dublin vaccine.

Diarrhea due to Salmonella infection is an important cause of neonatal calf diarrhea. The acquisition of passive immunity in the calf by vaccinating the dam has shown some success in previous studies; however, no data exists on the use of currently licensed vaccines in the United States. Therefore, the purpose of this study was to determine whether vaccinating cows in late gestation with a commercially available Salmonella Dublin vaccine would stimulate Salmonella-specific antibodies in the colostrum of cows at calving and whether these antibodies would be transferred to the calf. Thirty Holstein cows were vaccinated 3 wk before the end of lactation with a Salmonella enterica serovar Dublin vaccine, with a second dose given at dry-off. An additional 30 cows received only saline. Calves had a blood sample collected immediately after birth and were then fed fresh colostrum from their dam within 2 h of calving. A postcolostrum blood sample was collected 24 to 48 h later. Salmonella Dublin antibodies in colostrum as well as serum from the cows and calves were measured using an ELISA technique. Results of this study showed that vaccinated cattle had elevated Salmonella Dublin antibody titers at the time of calving (40.3 ± 9.1) as compared with control cows (-9.4 ± 1.1). Calves that received colostrum from vaccinated cattle also had a significant increase in Salmonella Dublin antibodies (88.5 ± 8.9) as compared with calves born to unvaccinated cows (-3.2 ± 1.2). This study demonstrated that the use of a commercially available Salmonella Dublin vaccine can stimulate antibodies that are passed on to the calf via colostral transfer. Further studies need to be done to determine whether these antibodies will offer protection against Salmonella challenge.

Impact of florfenicol dosing regimen on the phenotypic and genotypic resistance of enteric bacteria in steers.

The food animal sector's use of antimicrobials is heavily critiqued for its role in allowing resistance to develop against critically important antimicrobials in human health. The WHO recommends using lower tier antimicrobials such as florfenicol for disease treatment. The primary objective of this study was to assess the differences in resistance profiles of enteric microbes following administration of florfenicol to steers using both FDA-approved dosing regimens and two different detection methods. Our hypothesis was that we would identify an increased prevalence of resistance in the steers administered the repeated, lower dose of florfenicol; additionally, we hypothesized resistance profiles would be similar between both detection methods. Twelve steers were administered either two intramuscular (20 mg/kg q 48 h; n = 6) or a single subcutaneous dose (40 mg/kg, n = 6). Fecal samples were collected for 38 days, and E. coli and Enterococcus were isolated and tested for resistance. Fecal samples were submitted for metagenomic sequencing analysis. Metagenomics revealed genes conferring resistance to aminoglycosides as the most abundant drug class. Most multidrug resistance genes contained phenicols. The genotypic and phenotypic patterns of resistance were not similar between drug classes. Observed increases in resistant isolates and relative abundance of resistance genes peaked after drug administration and returned to baseline by the end of the sampling period. The use of a "lower tier" antimicrobial, such as florfenicol, may cause an increased amount of resistance to critically important antimicrobials for a brief period, but these changes largely resolve by the end of the drug withdrawal period.

Quantifying trade-offs between therapeutic efficacy and resistance dissemination for enrofloxacin dose regimens in cattle.

The use of antimicrobial drugs in food-producing animals increases the selection pressure on pathogenic and commensal bacteria to become resistant. This study aims to evaluate the existence of trade-offs between treatment effectiveness, cost, and the dissemination of resistance in gut commensal bacteria. We developed a within-host ordinary differential equation model to track the dynamics of antimicrobial drug concentrations and bacterial populations in the site of infection (lung) and the gut. The model was parameterized to represent enrofloxacin treatment for bovine respiratory disease (BRD) caused by Pastereulla multocida in cattle. Three approved enrofloxacin dosing regimens were compared for their effects on resistance on P. multocida and commensal E. coli: 12.5 mg/kg and 7.5 mg/kg as a single dose, and 5 mg/kg as three doses. Additionally, we explored non-approved regimes. Our results indicated that both 12.5 mg/kg and 7.5 mg/kg as a single dose scenario increased the most the treatment costs and prevalence of P. multocida resistance in the lungs, while 5 mg/kg as three doses increased resistance in commensal E. coli bacteria in the gut the most out of the approved scenarios. A proposed scenario (7.5 mg/kg, two doses 24 hours apart) showed low economic costs, minimal P. multocida, and moderate effects on resistant E. coli. Overall, the scenarios that decrease P. multocida, including resistant P. multocida did not coincide with the scenarios that decrease resistant E. coli the most, suggesting a trade-off between both outcomes. The sensitivity analysis indicates that bacterial populations were the most sensitive to drug conversion factors into plasma (ß), elimination of the drug from the colon (υ), fifty percent sensitive bacteria (P. multocida) killing effect (Ls50), fifty percent of bacteria (E. coli) above ECOFF killing effect (Cr50), and net drug transfer rate in the lung (γ) parameters.

Proteasome inhibition of pathologic shedding of enterocytes to defend barrier function requires X-linked inhibitor of apoptosis protein and nuclear factor κB.

BACKGROUND & AIMS: Although we are beginning to understand where, when, and how intestinal epithelial cells are shed, physiologically, less is understood about alterations in cell fate during minimally invasive epithelial infections. We used a piglet model of Cryptosporidium parvum infection to determine how elimination of infected enterocytes is balanced with the need to maintain barrier function. METHODS: We studied the effects of enterocyte shedding by C parvum-infected ileum on barrier function ex vivo with Ussing chambers. The locations and activities of caspase-3, nuclear factor κB (NF-κB), and inhibitor of apoptosis proteins (IAP) were assayed by enzyme-linked immunosorbent assay, immunoblot, and tissue immunoreactivity analyses and using specific pharmacologic inhibitors. The location, specificity, and magnitude of enterocyte shedding were quantified using special stains and light microscopy. RESULTS: Infection with C parvum activated apoptotic signaling pathways in enterocytes that resulted in cleavage of caspase-3. Despite caspase-3 cleavage, enterocyte shedding was confined to villus tips, coincident with apoptosis, and observed more frequently in infected cells. Epithelial expression of X-linked inhibitor of apoptosis protein (XIAP), activation of NF-κB, and proteasome activity were required for control of cell shedding and barrier function. The proteasome blocked activity of caspase-3; this process was mediated by expression of XIAP, which bound to cleaved caspase-3. CONCLUSIONS: We have identified a pathway by which villus epithelial cells are maintained during C parvum infection. Loss of barrier function is reduced by active retention of infected enterocytes until they reach the villus tip. These findings might be used to promote clearance of minimally invasive enteropathogens, such as by increasing the rate of migration of epithelial cells from the crypt to the villus tip.

Wintersweet (Chimonanthus praecox) toxicity in 5 sheep.

Two sheep presented with acute tonic-clonic seizures, opisthotonos, absent pupillary light reflexes and abnormal vital signs within 18 hours after observed consumption of leaves from an ornamental shrub later identified as wintersweet (Chimonanthus praecox). Despite symptomatic treatment, both sheep died. Three other sheep that consumed the plant died after displaying similar clinical signs, resulting in 2 deaths the prior evening and 1 recovery the next morning. Gross necropsy and histologic findings were diagnostically inconclusive. Rumen contents tested positive for the alkaloid calycanthine, a centrally-acting convulsant known to be present in wintersweet. Case reports of calycanthine toxicity in ruminants are limited, with no detailed reports published in the United States. Calycanthine has been isolated from the seeds, flowers, and leaves of the plant. Wintersweet is part of the family Calycanthaceae that including 3 species native to North America, all of which pose a neurologic risk to ruminants if consumed.

Genomic Analysis Reveals That Isolation Temperature on Selective Media Introduces Genetic Variation in Campylobacter jejuni from Bovine Feces.

Campylobacter jejuni is commonly isolated on selective media following incubation at 37 °C or 42 °C, but the impact of these temperatures on genome variation remains unclear. Previously, Campylobacter selective enrichments from the feces of steers before and after ceftiofur treatment were plated on selective agar media and incubated at either 37 °C or 42 °C. Here, we analyzed the whole genome sequence of C. jejuni strains of the same multilocus sequence typing (MLST)-based sequence type (ST) and isolated from the same sample upon incubation at both temperatures. Four such strain pairs (one ST8221 and three ST8567) were analyzed using core genome and whole genome MLST (cgMLST, wgMLST). Among the 1970 wgMLST loci, 7-25 varied within each pair. In all but one of the pairs more (1.7-8.5 fold) new alleles were found at 42 °C. Most frameshift, nonsense, or start-loss mutations were also found at 42 °C. Variable loci CAMP0575, CAMP0912, and CAMP0913 in both STs may regularly respond to different temperatures. Furthermore, frameshifts in four variable loci in ST8567 occurred at multiple time points, suggesting a persistent impact of temperature. These findings suggest that the temperature of isolation may impact the sequence of several loci in C. jejuni from cattle.

Retrospective study on the use of lidocaine constant rate infusions for the treatment of ileus in ruminants and camelids.

Limited knowledge exists regarding the use of lidocaine as a prokinetic in ruminants and camelids to treat gastrointestinal ileus. In this retrospective study, ruminant and camelid cases diagnosed with ileus and treated with a lidocaine constant rate of infusion were assessed for adverse reactions and medical outcomes. A review of medical records was performed to identify cases in which lidocaine was administered as a prokinetic. Ten cases were identified consisting of 8 cattle, 1 goat, and 1 alpaca. Nine animals improved with a lidocaine treatment. No adverse effects were reported during lidocaine administration. Nine animals were discharged, and 1 was euthanized.

Mycobacterial Cell Wall Stimulant in the Treatment of Squamous Cell Carcinoma: A Case Series Regarding Treatment in Equine, Bovine and Caprine Patients.

Squamous cell carcinoma (SCC) is a common dermatological neoplasia found in large animal species. Treatment options, such as surgery and cryotherapy may be difficult or not feasible. Alternative therapies, such as immunomodulating drugs, can potentially be used for companion large animals. The hypothesis of the following retrospective study is: following multiple intravenous and intralesional injections of a mycobacterial cell wall stimulant (MCW) regression of SCC in equine, bovine and caprine patients will be observed. In this observational-retrospective case series, patients included are 2 bovine, 2 caprine and 3 equine patients. The medical records at two different teaching veterinary hospitals were searched for cases with a positive histopathological diagnosis of squamous cell carcinoma that were subsequently treated with MCW, as either the sole therapy, or in conjunction with other therapies. Seven cases were included in this retrospective study. The median duration of therapy was 56.5 days, with 3 of the 7 patients being euthanized. Significant complications were seen in 3/7 patients. Repeated injections of a MCW may lead to reduction in lesion size of SCC in some cases, but long-term resolution is unlikely and the risk of significant complications is high; due to limited sample size and the variety in species, it is difficult to conclude if MCW is an effective therapy for SCC.

Impact of Ceftiofur Administration in Steers on the Prevalence and Antimicrobial Resistance of Campylobacter spp.

Bacterial resistance to ceftiofur raises health concerns due to ceftiofur's extensive veterinary usage and structural similarity with the human antibiotic ceftriaxone. Ceftiofur crystalline-free acid (CCFA) and ceftiofur hydrochloride (CHCL) are ceftiofur types used therapeutically in cattle, but their potential impacts on Campylobacter prevalence and antimicrobial resistance remain unclear. In this study two groups of steers were each treated with CCFA or CHCL. In vivo active drug concentrations were measured and fecal samples were analyzed for Campylobacter for up to 42 days post-treatment. Following administration, the colonic concentration of ceftiofur initially increased then dropped to pre-treatment levels by day 8. The estimated prevalence of Campylobacter spp. was significantly (p = 0.0009) higher during the first week after CCFA treatment than after CHCL treatment (81.3% vs. 45.2%). Campylobacter jejuni predominated overall, with other Campylobacter spp. mainly identified in the first week after CCFA treatment. No treatment impacts were noted on ceftiofur minimum inhibitory concentration (MIC) for C. jejuni (10-20 µg/mL). More C. jejuni genotypes were detected in CCFA-treated than CHCL-treated steers. These findings suggest that ceftiofur did not significantly impact Campylobacter prevalence or ceftiofur MIC. However, CHCL may be preferable due to the lower likelihood of temporary increases in Campylobacter prevalence.

Concurrent Clostridial Enteritis and Oviductal Adenocarcinoma with Carcinomatosis in an Adult Alpaca (Vicugna pacos).

An adult alpaca (Vicugna pacos) with a history of colic and anorexia was euthanized because of failure to respond to treatment. Macroscopically, pale-tan, multifocal to coalescing, firm nodules and plaques markedly expanded the omentum, mesentery and the parietal and visceral peritoneum of multiple abdominal organs, especially the right oviduct and associated mesosalpinx. Abundant dark-red watery digesta were present in the duodenum and jejunum. Histological evaluation of the right oviduct, abdominal visceral nodules and plaques and mesenteric lymph nodes revealed transmural expansion and replacement by an epithelial malignant neoplasm, comprised of tubules and acini of ciliated columnar cells supported by abundant fibrous connective tissue. Both ovaries were histologically normal. On the basis of the ciliated morphology of the neoplastic cells, the focus on the proximal reproductive tract and the unremarkable ovaries, a reproductive tubal adenocarcinoma with carcinomatosis was diagnosed, with both the endometrium and oviduct considered as the tissues of origin. The prominent ciliated morphology of the neoplastic cells and the classification of human fallopian tube (oviduct) neoplasia lead us to propose oviductal adenocarcinoma with widespread carcinomatosis as the definitive diagnosis. The lamina propria of the small intestine was infiltrated segmentally by lymphocytes, plasma cells and neutrophils, and Clostridium perfringens with beta2 toxin production was identified by polymerase chain reaction in the small intestinal contents. To our knowledge, this is the first report of these two distinct diseases in an alpaca.

Comparison of the Intestinal Pharmacokinetics of Two Different Florfenicol Dosing Regimens and Its Impact on the Prevalence and Phenotypic Resistance of E. coli and Enterococcus over Time.

In order to mitigate the food animal sector's role in the growing threat of antimicrobial resistance (AMR), the World Health Organization (WHO) suggests the use of lower tier antimicrobials, such as florfenicol. Florfenicol has two dosing schemes used to treat primarily bovine respiratory disease. In this study, the objective was to characterize the plasma and gastrointestinal pharmacokinetics of each dosing regimen and assess the effect of these dosing regimens on the prevalence of resistant indicator bacteria over time. Twelve steers underwent abdominal surgery to facilitate the placement of ultrafiltration probes within the lumen of the ileum and colon, as well as placement of an interstitial probe. Following surgery, cattle were dosed with either 20 mg/kg IM every 48 h of florfenicol given twice (n = 6) or a single, subcutaneous dose (40 mg/kg, n = 6). Plasma, interstitial fluid, gastrointestinal ultrafiltrate, and feces were collected. Pharmacokinetic analysis demonstrated high penetration of florfenicol within the gastrointestinal tract for both the high and low dose group (300%, 97%, respectively). There was no significant difference noted between dosing groups in proportion or persistence of phenotypically resistant bacterial isolates; however, the percent of resistant isolates was high throughout the study period. The recommendation for the use of a lower tier antimicrobial, such as florfenicol, may allow for the persistence of co-resistance for antibiotics of high regulatory concern.

Identification of CTX-M Type ESBL E. coli from Sheep and Their Abattoir Environment Using Whole-Genome Sequencing.

Widespread dissemination of extended-spectrum beta-lactamase (ESBL) Escherichia coli (E. coli) in animals, retail meats, and patients has been reported worldwide except for limited information on small ruminants. Our study focused on the genotypic characterization of ESBL E. coli from healthy sheep and their abattoir environment in North Carolina, USA. A total of 113 ESBL E. coli isolates from sheep (n = 65) and their abattoir environment (n = 48) were subjected to whole-genome sequencing (WGS). Bioinformatics tools were used to analyze the WGS data. Multiple CTX-M-type beta-lactamase genes were detected, namely blaCTX-M-1, blaCTX-M-14, blaCTX-M-15, blaCTX-M-27, blaCTX-M-32, blaCTX-M-55, and blaCTX-M-65. Other beta-lactamase genes detected included blaCMY-2, blaTEM-1A/B/C, and blaCARB-2. In addition, antimicrobial resistance (AMR) genes and/or point mutations that confer resistance to quinolones, aminoglycosides, phenicols, tetracyclines, macrolides, lincosamides, and folate-pathway antagonists were identified. The majority of the detected plasmids were shared between isolates from sheep and the abattoir environment. Sequence types were more clustered around seasonal sampling but dispersed across sample types. In conclusion, our study reported wide dissemination of ESBL E. coli in sheep and the abattoir environment and associated AMR genes, point mutations, and plasmids. This is the first comprehensive AMR and WGS report on ESBL E. coli from sheep and abattoir environments in the United States.

Option-based guarantees to accelerate urgent, high-risk vaccines: a new market-shaping approach.

Accelerating the availability of COVID-19 vaccines is critical to preventing further waves and mitigating the impact on society. However, preparations for large-scale manufacturing, such as building production facilities, are typically delayed until a vaccine is proven safe and effective. This makes sense from a commercial perspective, but incurs great costs in terms of lives lost and damage to the economy. Several policy options are available to reduce this delay, all of which involve incentives or subsidies to invest in production facilities. We review existing approaches, then propose a novel alternative using "option-based guarantees" in which the government commits to paying a proportion of the manufacturer's preparation costs should the product turn out not to be viable. Counterintuitively, this "payment for failure" is appropriate because in the case of success, a company makes a profit from the product itself, and does not need additional money from the government. While other approaches have critical roles, we argue that option-based guarantees are the most promising approach to ensuring a rapid vaccine for COVID-19. Compared to the alternative approaches, they reduce both costs to the government and risk to the companies, while maintaining an incentive to produce a high-quality product quickly and at scale.

The effect of enrofloxacin on enteric Escherichia coli: Fitting a mathematical model to in vivo data.

Antimicrobial drugs administered systemically may cause the emergence and dissemination of antimicrobial resistance among enteric bacteria. To develop logical, research-based recommendations for food animal veterinarians, we must understand how to maximize antimicrobial drug efficacy while minimizing risk of antimicrobial resistance. Our objective is to evaluate the effect of two approved dosing regimens of enrofloxacin (a single high dose or three low doses) on Escherichia coli in cattle. We look specifically at bacteria above and below the epidemiological cutoff (ECOFF), above which the bacteria are likely to have an acquired or mutational resistance to enrofloxacin. We developed a differential equation model for the antimicrobial drug concentrations in plasma and colon, and bacteria populations in the feces. The model was fit to animal data of drug concentrations in the plasma and colon obtained using ultrafiltration probes. Fecal E. coli counts and minimum inhibitory concentrations were measured for the week after receiving the antimicrobial drug. We predict that the antimicrobial susceptibility of the bacteria above the ECOFF pre-treatment strongly affects the composition of the bacteria following treatment. Faster removal of the antimicrobial drugs from the colon throughout the study leads to improved clearance of bacteria above the ECOFF in the low dose regimen. If we assume a fitness cost is associated with bacteria above the ECOFF, the increased fitness costs leads to reduction of bacteria above the ECOFF in the low dose study. These results suggest the initial E. coli susceptibility is a strong indicator of how steers respond to antimicrobial drug treatment.