Are Rabies Vaccines Measured By Animal Weight

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Am J Vet Res. Author manuscript; available in PMC 2018 Jun 1.

Published in last edited form every bit:

PMCID: PMC5520579

NIHMSID: NIHMS880605

Assessment of the immunogenicity of rabies vaccine preserved by vaporization and delivered to the duodenal mucosa of gray foxes (Urocyon cinereoargenteus)

Todd G. Smith, PhD, Xianfu Wu, DVM, PhD, James A. Ellison, PhD, Ashutosh Wadhwa, PhD, Richard Franka, DVM, PhD, Gregory L. Langham, DVM, MPH, Brianna L. Skinner, DVM, MPH, Cathleen A. Hanlon, VMD, PhD, and Victor 50. Bronshtein, PhD

Abstract

OBJECTIVE

To assess the immunogenicity of thermostable live-attenuated rabies virus (RABV) preserved by vaporization (PBV) and delivered to the duodenal mucosa of a wildlife species targeted past an oral vaccination program.

ANIMALS

8 grayness foxes (Urocyon cinereoargenteus).

PROCEDURES

Endoscopy was used to place RABV PBV, alginate-encapsulated RABV PBV, or nonpreserved RABV into the duodenum of each play a joke on. Blood samples were collected weekly to monitor the immune response. Saliva samples were collected weekly and tested for virus shedding by use of a conventional reverse-transcriptase PCR analysis. Foxes were euthanized 28 days later on vaccine assistants, and relevant tissues were nerveless and tested for presence of RABV.

RESULTS

2 of 3 foxes that received RABV PBV and 1 of ii foxes that received nonpreserved RABV seroconverted by twenty-four hour period 28. None of the iii foxes receiving alginate-encapsulated RABV PBV seroconverted. No RABV RNA was detected in saliva at any of the time points, and RABV antigen or RNA was not detected in any of the tissues obtained on twenty-four hours 28. None of the foxes displayed whatever clinical signs of rabies.

CONCLUSIONS AND CLINICAL RELEVANCE

Results for this written report indicated that a live-attenuated RABV vaccine delivered to the duodenal mucosa tin can induce an immune response in gray foxes. A safe, potent, thermostable RABV vaccine that could exist delivered orally to wildlife or domestic animals would raise current rabies control and prevention efforts.

Nearly of the rabies cases in humans occur in developing countries where canine rabies is enzootic and access to rabies biologics is express.^ane,2 The cost associated with canine rabies is estimated at $124 billion annually^three, and information technology is estimated that at that place are 26,000 to 86,000 cases of rabies in humans annually every bit a result of exposure to canine rabies.^four,five Information technology is believed that virtually all of these cases could be prevented by elimination of canine rabies and proper administration of postexposure prophylaxis.^6,7 Poor veterinary health infrastructure in countries with enzootic canine rabies has led to proposals to vaccinate children against rabies prior to exposure.⁸

In countries in which canine rabies has been eliminated, wildlife serve every bit a dominant reservoir. Oral vaccination confronting rabies is a proven strategy to prevent rabies in wildlife and thus spillover to domestic animals or humans.^9–11 Rabies vaccines for oral assistants must be stored cold (5° ± iii°C) earlier distribution to the environment.^12–xvi Stability of electric current vaccines differs, with some vaccines stable up to 12 months at 45°C¹⁵ and others stable up to iii months at 37°C¹⁷; still, no industry recommends vaccine be stored at ambient temperature considering of the risk for loss of authorisation.

The foam drying technique PBV finer stabilizes RABV at ambience temperatures (30° ± seven°C) for at least 15 months.¹⁸ The RABV PBV vaccine can induce RABV-neutralizing antibodies when delivered IM and protects mice from claiming exposure.¹⁸ Ane advantage of PBV is the ability to micronize biologics, which allows for needle-gratis and traditional pharmaceutical delivery (eg, intradermal microneedle patches, intranasal inhaler, dissolvable oral gels, or gastric capsules).^19,20 Investigators who attempted abdominal delivery of rabies vaccine found a limited response for multiple doses of an inactivated vaccine administered by this route to red foxes (Vulpes vulpes)²¹ and raccoons (Procyon lotor).²²

In the study reported hither, endoscopy was used to identify live-attenuated nonencapsulated RABV PBV vaccine, alginate-encapsulated RABV PBV vaccine, or non-PBV RABV vaccine into the duodenum of gray foxes (Urocyon cinereoargenteus). Endoscopy was used to ensure delivery of vaccines to the abdominal mucosa. The study was required as a proof-of-concept for development of future vaccines designed for intestinal delivery. Alginate encapsulation was used for vaccine formulation on the basis of results of a study²³ that indicated increased protection and persistence of the antigen. Grayness foxes were selected for use because these mesocarnivores are the most abundant and widely distributed species of fox in the southeastern Us and are a target for oral vaccination campaigns in Texas.^24–26

Materials and Methods

Animals

Grey foxes were purchased from a vendor. ^a Claret samples were collected by veterinary staff at the vendor and used to decide that all foxes had negative results for rVNA before shipment to our facility. Foxes were housed for 120 days in an animal biosafety level-2 facility at the investigator's facility. Foxes were housed in indoor-outdoor runs (1.1 m in length × 0.8 m in width) with a climate-controlled cake wall pens (iv.9 m in length × 0.viii m in width) with a heated floor (used in winter) with a concatenation link door and chain link roof. Gray foxes were fed a 1:1 mix of diets formulated for omnivores ^b and dogs. ^c Methods were used to enrich the diet and promote consumption. Foxes received peeled hard boiled eggs twice weekly, which were alternated with ane/3 can of a beef or a chicken dog nutrient that was mixed with the regular nutrition. Animal use protocols were approved by the Centers for Disease Control and Prevention Institutional Animal Care and Use Commission.

RABV vaccine

The RABV PBV vaccine was produced every bit described elsewhere.¹⁸ Briefly, RABV strain ERA was adulterate by use of a opposite genetics system.^27,28 Amino acid 333 in the glycoprotein was altered at the corresponding nucleotide positions in the glycoprotein cistron past use of site-directed mutagenesis.^29–31 The recovered virus, ERAG333, was mixed with preservation solution (formulated with or without alginate) and dried via the PBV process. Vaccines were suspended in sterile mineral oil and stored with a desiccant for up to 65 days at 22° ± iv°C in the night.

Experimental procedures

Foxes were arbitrarily allocated into 3 groups, and vaccine was endoscopically placed in the duodenum of all groups (day 0). Group 1 (2 males and 1 female) received i mL of nonencapsulated RABV PBV (mean ± SD; 5.2 ± 0.09 log_ten ffu/mL), group 2 (three females) received 1 mL of alginate-encapsulated RABV PBV (4.3 ± 0.2 log_ten ffu/mL), and group three (2 males) received 1 mL of RABV ERAG333 (from stock stored at −80°C; 8.0 ± 0.ii log₁₀ ffu/mL).

Food and water was withheld from all foxes for 24 hours prior to endoscopy to permit ingesta to pass from the stomach and proximal portions of the intestines, minimize the potential of regurgitation during anesthesia, reduce the potential for impeding visual video monitoring, and reduce the potential of obstruction of the endoscope and thus placement of the vaccine. Nutrient and h2o were withheld for 24 hours prior to scheduled endoscopy for 1 fox in group iii; however, endoscopy could not exist performed at that time. Considering the period for withholding of food and water from animals should not exceed 24 hours, this play a joke on received food and afterwards had ingesta in its tummy and duodenum at the time of vaccine placement (24 hours later the originally scheduled endoscopy).

Each fox was restrained with a catchpole, and anesthesia was induced by administration of a combination product ^d that contained tiletamine HCl–zolazepam HCl (9 mg/kg, IM). Once anesthetic induction was confirmed, each fox received atropine (0.04 mg/kg, IM) to reduce salivation, and an appropriately sized endotracheal tube with inflatable cuff ^e was placed and secured. Isoflurane (2% to four%) was administered to establish a surgical plane of anesthesia. Foxes were positioned in left lateral recumbency to promote passage of the endoscope into the duodenum. A flexible endoscope ^f was passed through the rima oris and into the esophagus. Video monitoring confirmed cardinal anatomic landmarks from the rima oris into the esophagus, stomach, pylorus, and opening of the proximal portion of the duodenum. Approximately 1 mL of vaccine was placed in the biopsy channel. The vaccine was delivered through the aqueduct by the use of air, and the aqueduct then was flushed with sterile water. Once placement of the vaccine was confirmed, the endoscope was slowly removed. Foxes were monitored constantly until they had recovered from anesthesia. The endoscope was done and disinfected before use in the subsequent fox.

Drove of data and samples

Foxes were purchased and arrived at our facility (solar day −ninety). After a 14-day acclimation period was completed, a health examination was performed on each fox (twenty-four hours −76). Body weight was measured on days −90, −76, 0, 7, 14, 21, and 28. A blood sample (2 mL) was collected from each fox immediately before vaccine placement on day 0 and on days, 7, 14, 21, and 28 after vaccination. Samples were used to make up one's mind the rVNA titer by use of a rapid fluorescent focus inhibition test.³² Food and water were withheld from the foxes for 24 hours prior to sedation to avoid regurgitation and possible aspiration. Foxes were restrained with a catchpole and sedated by administration of a combination product that independent tiletamine HCl–zolazepam HCl (< 9 mg/kg, IM). An area on the ventral aspect of the neck or forelimb of the sedated foxes was shaved and scrubbed with alcohol, and blood samples were collected from a jugular or cephalic vein past utilize of a 21-gauge (or smaller approximate) needle. Saliva samples were obtained from the sedated foxes at the same time as collection of the claret samples. A sterile cotton swab was inserted into the oral cavity, and oral swab specimens were used for virus detection with a standard RT-PCR assay for RABV nucleocapsid protein gene.^33,34 Foxes were monitored constantly until they had recovered from sedation.

Necropsy

On day 28, foxes were restrained with a catchpole, anesthetized by administration of tiletamine HCl–zolazepam HCl (ix mg/kg, IM), and euthanized by intracardiac administration of 2 mL of pentobarbital sodium–phenytoin sodium. ^g Euthanasia was confirmed every bit a lack of respiratory and cardiac function via stethoscopic auscultation, and 1 mL of CSF was so collected. Necropsy was performed on each trick, and samples of the duodenum, salivary glands, heart, lungs, liver, kidneys, spleen, lumbar spinal cord, and brain stem were nerveless. The RABV antigen was detected past utilise of directly fluorescent antibody testing or immunohistochemical staining, and RABV RNA was detected by use of an RT-PCR assay.^33–35

Statistical assay

Seroconversion was designated equally increase in rVNA titers to > 0.1 U/mL. Two-way Anova (alpha = 0.05) with Tukey correction for multiple comparisons (alpha = 0.05, CI = 95%) was performed to compare results for hateful rVNA over fourth dimension, among the 3 groups. Values were considered meaning at P < 0.05.

Results

Animals

All foxes were in good status and remained healthy throughout the experimental period. Overall, the mean trunk weight of all the groups increased; nonetheless, males gained more weight than did females (Figure i). All foxes recovered well from endoscopic placement of the vaccine, and the procedures did not result in inappetence. Foxes were observed daily, and no clinical signs of rabies were observed in any fauna.

Hateful ± SD percentage change in body weight of greyness foxes (Urocyon cinereoargenteus) administered RABV vaccine on the basis of group (A) and on the basis of sexual activity (B). Trunk weight was obtained at the time of inflow at our facility (day −90), at a wellness exam performed after a fourteen-day acclimation flow (twenty-four hours −76), before endoscopic delivery of vaccine (day 0), and at the time of claret collection on days vii, 14, 21, and 28. Mean and SD were calculated for each group by the percentage change for each trick calculated by employ of the body weight obtained on 24-hour interval −76 as the denominator. In panel A, results are reported for all eight foxes (black circles), 3 foxes (2 males and 1 female) that received ane mL of nonencapsulated RABV PBV (hateful ± SD; 5.2 ± 0.09 log_x ffu/mL; grouping 1 [black squares]), 3 foxes (three females) that received 1 mL of alginate-encapsulated RABV PBV (iv.3 ± 0.2 log₁₀ ffu/mL; group 2 [black triangles]), and 2 foxes (2 males) that received 1 mL of RABV ERAG333 (eight.0 ± 0.2 log₁₀ ffu/mL; group three [inverted black triangles]). In panel B, results are reported for all viii foxes (black circles), the 4 female person foxes (white circles), and the 4 male foxes (white squares).

Vaccination response

Values for rVNA did not differ significantly among the groups. Two of 3 foxes of group 1 (received nonencapsulated RABV PBV) seroconverted (titer > 0.ane U/mL) by day 14, and titers continued to increment until the end of the written report. The titer of both animals on day 28 was 1.two U/ml. One of 2 foxes of group 3 (received RABV ERAG333) seroconverted by day 14, and the titer of that animal connected to increase until the terminate of the study (titer on day 28 was 1.vi U/ml). Administration of both nonencapsulated RABV PBV and ERAG333 induced similar titers on day 28. The other trick of group iii may have failed to seroconvert because of bile inactivation of the live RABV because this fox had nutrient in its tum at the time of endoscopy (come across Experimental procedures in Textile and Methods). None of the foxes of grouping 2 (alginate-encapsulated RABV PBV) seroconverted. Some weak virus neutralization was observed in 1 flim-flam of group 2. The titer on days, 7, 14, 21 and 28 was 0.07, 0.06, < 0.05, and 0.i U/ml, respectively.

Examination of oral swab specimens obtained during the study was performed. No RABV RNA was detected on whatsoever day of the study.

Necropsy

None of the foxes had evidence of rVNA in the CSF on day 28. None of the foxes had evidence of RABV infection in the lumbar spinal cord or brain stalk on day 28, every bit determined past employ of direct fluorescent antibody staining. Finally, RABV RNA was not detected in any tissues obtained from whatever of the foxes on twenty-four hour period 28.

Discussion

Results for the study reported here indicated that the response to vaccination was owing to commitment of live RABV vaccine to the duodenal mucosa of gray foxes. On the footing of results for the 3 foxes that seroconverted, geometric mean ± SD titer increased from 0.28 ± 0.03 U/mL on day 14 to 1.3 ± 0.2 U/mL on day 28. The rVNA did not differ significantly among the groups. However, the results were clinically relevant because RABV PBV vaccine placed endoscopically in the duodenum induced rabies virus neutralizing antibiotic titers greater than the Globe System for Animal Wellness recommended value of 0.5 U/mL.³⁶ On the basis of the present proof-of-concept report, thermostable RABV PBV may accept use every bit part of oral vaccination programs in the future.

The RABV PBV vaccines were suspended in sterile mineral oil, whereas, the control RABV was delivered in an aqueous solution. Mineral oil may have protected the nonencapsulated RABV PBV from bile or acted equally an adjuvant to allow the virus to persist at the target site and increase the chances of activating an allowed response. Future formulations should include bile inhibitors, mineral oil, or both.

The alginate-encapsulated vaccine failed to stimulate an allowed response. This formulation of the vaccine resulted in a lower mean ± SD RABV titer, compared with the mean titer for the nonencapsulated vaccine and control RABV, which may not have been sufficient to stimulate an immune response. By comparison, other studies^18,30,37 with live-attenuated RABV vaccines involved formulations at 4.4 log_x ffu/mL to ix.three log₁₀ ffu/mL. Because the vaccine was a alive-attenuated virus, viral replication should have negated any differences in the initial titer. Previous attempts^23,28 to target the intestinal mucosa by use of alginate-encapsulated vaccines have been successful. Delivery of the alginate-encapsulated vaccine through the biopsy channel may have been hindered considering the encapsulated vaccine was more viscous than the nonencapsulated vaccine. Concerns virtually dose and the problem of inactivation by bile could be resolved by use of a capsulated vaccine that is designed to target the abdominal mucosa and is delivered orally to animals in their regular diet.

Although the present study was non designed to find viral shedding, which may occur within the start 48 hours subsequently oral vaccination,^39,40 nosotros did non discover viral shedding in saliva samples obtained at the times of blood collection. Whatever localized viral replication was cleared past day 28 such that no testify of infection could be detected in the tissue samples collected during necropsy. None of the foxes adult rabies, and all nerve tissue and CSF obtained on solar day 28 had negative results when tested for RABV. Future studies to examine possible viral shedding in feces and to evaluate oral delivery methods could exist completed in ruddy foxes because this is an established and more accessible animal used for rabies research. Overall, the results of the study reported here added to the show that RABV PBV may be formulated into a vaccine for domestic or wildlife and supported future testing of the desired method of commitment in target species.

Acknowledgments

The authors thank Dr. Cynthia Cary, Dr. Nicole Lukovsky Akhsanov, and Ryan Johnson for technical assistance.

Supported in part past the National Institutes of Health (grant No. R44AI080035-three awarded to Dr. Bronshtein).

Supported in part by a contract between Solution One Industries, Inc. and CDC.

Supported in part past an appointment to the Inquiry Participation Plan at CDC administered by the Oak Ridge Found for Scientific discipline and Education through an interagency understanding betwixt the U.S. Department of Energy and CDC.

ABBREVIATIONS

ERA	Evelyn-Rokitnicki-Abelseth
ERAG	Evelyn-Rokitnicki-Abelseth glycoprotein
ffu	Focus-forming unit
PBV	Preservation past vaporization
RABV	Rabies virus
RT	Reverse transcriptase
rVNA	Rabies virus neutralizing antibodies

Footnotes

Presented in part in abstract form at the 25th International Conference on Rabies in the Americas, Cancún, México, Oct, 2014.

Use of merchandise names and commercial sources are for identification only and do not imply endorsement past the Us government. The findings and conclusions in this report are those of the authors and exercise non necessarily correspond the views of their institutions.

^aCherry's Farm, New Sharon, Iowa.

^bMazuri Omnivore-Zoo Feed 'A' 5635, Purina Mills International, St Louis, Mo.

^cLab Diet Laboratory Canine Nutrition 5006, Purina Mills International, St Louis, Mo.

^dZoetis, Florham Park, NJ.

^eastVedco, St Joseph, Mo.

^fOlympus America, Middle Valley, Pa.

^kMerck & Co, Kenilworth, NJ.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520579/

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