Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease
Mucosal immunization with an attenuated Salmonella vaccine partially
protects white-tailed deer from chronic wasting disease
Fernando Goñia, Candace K. Mathiasone, Lucia Yimf, Kinlung Wonga, Jeanette
Hayes-Kluge, Amy Nallse, Daniel Peysera, Veronica Estevezf, Nathaniel Denkerse,
Jinfeng Xuc, David A. Osbornh, Karl V. Millerh, Robert J. Warrenh, David R.
Browng, Jose A. Chabalgoityf, Edward A. Hoovere, Thomas Wisniewskia, b, d, , a
Department of Neurology, New York University School of Medicine, 550 First
Avenue, New York, NY 10016, United States b Department of Pathology, New York
University School of Medicine, 550 First Avenue, New York, NY 10016, United
States c Department of Population Health, New York University School of
Medicine, 550 First Avenue, New York, NY 10016, United States d Department of
Psychiatry, New York University School of Medicine, 550 First Avenue, New York,
NY 10016, United States e College of Veterinary Medicine and Biomedical
Sciences, Colorado State University, Fort Collins, CO, United States f
Laboratory for Vaccine Research, Department of Biotechnology, Instituto de
Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
g Department of Biology and Biochemistry, University of Bath, UK h Warnell
School of Forestry and Natural Resources, University of Georgia, United States
Received 20 August 2014, Revised 13 November 2014, Accepted 19 November 2014,
Available online 21 December 2014
Abstract
Prion disease is a unique category of illness, affecting both animals and
humans, in which the underlying pathogenesis is related to a conformational
change of a normal, self-protein called PrPC (C for cellular) to a pathological
and infectious conformer known as PrPSc (Sc for scrapie). Bovine spongiform
encephalopathy (BSE), a prion disease believed to have arisen from feeding
cattle with prion contaminated meat and bone meal products, crossed the species
barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of
deer and elk, with the potential to infect humans. Currently no prionosis has an
effective treatment. Previously, we have demonstrated we could prevent
transmission of prions in a proportion of susceptible mice with a mucosal
vaccine. In the current study, white-tailed deer were orally inoculated with
attenuated Salmonella expressing PrP, while control deer were orally inoculated
with vehicle attenuated Salmonella. Once a mucosal response was established, the
vaccinated animals were boosted orally and locally by application of polymerized
recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control
animals were then challenged orally with CWD-infected brain homogenate. Three
years post CWD oral challenge all control deer developed clinical CWD (median
survival 602 days), while among the vaccinated there was a significant
prolongation of the incubation period (median survival 909 days; p = 0.012 by
Weibull regression analysis) and one deer has remained CWD free both clinically
and by RAMALT and tonsil biopsies. This negative vaccinate has the highest
titers of IgA in saliva and systemic IgG against PrP. Western blots showed that
immunoglobulins from this vaccinate react to PrPCWD. We document the first
partially successful vaccination for a prion disease in a species naturally at
risk.
--------------------------------------------------------------------------------
Graphical abstract Illustrates the study design of the CWD vaccination
experiment. There were five vaccinated white-tailed deer and 6 vehicle controls.
Deer were matched for Prnp genotype (95Q/96G/116A/138S/226Q), except two deer in
both the control and vaccinated group had the most common polymorphism (∼26% of
deer) that confers partial resistance to CWD infection, codon 96 G/S instead of
96 G/G.
Friday, December 19, 2014
Pan-Provincial Vaccine Enterprise Inc. (PREVENT) Conducting a Chronic
Wasting Disease (CWD) Vaccine Efficacy Trial in Elk
PrionImmunity
Immunotherapy of familial prion diseases
Project Coordinator
Adriano Aguzzi
University of Zurich
Zurich
Switzerland
Partners
Ehud Cohen The Hebrew University of Jerusalem Jerusalem, Israel Luca
Berdondini Istituto Italiano di Tecnologia Genova, Italy Holger Wille University
of Alberta Edmonton, Canada Thorsten Lührs Medizinische Hochschule Hannover
Hannover, Germany
Familial prion diseases are rare neurodegenerative disorders affecting
individuals in the prime of their life, with no known therapy apart from
palliation. Aguzzi showed that passive immunoprophylaxis can afford protection
from prions in vivo (Heppner et al., Science 294, 2001). Aguzzi then discovered
that monoclonal antibodies targeting the flexible tail of the cellular prion
protein (PrPC) are protective, whereas those against its globular domain can be
neurotoxic (Sonati et al., Nature 501, 2013), suggesting that the flexible tail
mediates toxicity. Here we propose to translate the above discoveries into a
preclinical pipeline for discovering immunotherapeutics against familial prion
diseases. Aguzzi will execute a high-throughput screen aimed at saturation
coverage of the human PrP surface, using a novel methodology combining phage
display with next-generation sequencing and allowing for the discovery of rare
non-immunodominant epitopes. High-affinity phages will be tested for prion
neutralization using a robotized high-throughput cell-based assay. Neutralizing
phages will be converted into monovalent recombinant miniantibodies and
epitope-mapped by Wille, Lührs, and Aguzzi. Miniantibodies will then be tested
by Berdondini for their capacity to combat prion toxicity using high-density
multielectrode arrays. Cohen will test the capability of select antibodies to
counteract mutant PrP toxicity in C. elegans. Complexes of the most promising
antibodies with PrP will be analyzed by X-ray crystallography, nuclear magnetic
resonance spectroscopy, and cryo-electron microscopy.
Singeltary submission ;
Program Standards: Chronic Wasting Disease Herd Certification Program and
Interstate Movement of Farmed or Captive Deer, Elk, and Moose
DOCUMENT ID: APHIS-2006-0118-0411
***Singeltary submission
Docket No. 00-108-10 Chronic Wasting Disease Herd Certification Program and
Interstate Movement of Farmed or Captive Deer, Elk, and Moose; Program
Standards
>>>The CWD herd certification program is a voluntary, cooperative
program that establishes minimum requirements for the interstate movement of
farmed or captive cervids, provisions for participating States to administer
Approved State CWD Herd Certification Programs, and provisions for participating
herds to become certified as having a low risk of being infected with
CWD<<<
Greetings USDA/APHIS et al,
I kindly would like to comment on Docket No. 00-108-10 Chronic Wasting
Disease Herd Certification Program and Interstate Movement of Farmed or Captive
Deer, Elk, and Moose; Program Standards.
I believe, and in my opinion, and this has been proven by scientific facts,
that without a validated and certified test for chronic wasting disease cwd,
that is 100% sensitive, and in use, any voluntary effort will be futile. the
voluntary ban on mad cow feed and SRMs have failed terribly, the bse mad cow
surveillance program has failed terribly, as well as the testing for bse tse
prion in cattle, this too has failed terrible. all this has been proven time and
time again via OIG reports and GOA reports.
I believe that until this happens, 100% cwd testing with validated test,
ALL MOVEMENT OF CERVIDS BETWEEN STATES MUST BE BANNED, AND THE BORDERS CLOSED TO
INTERSTATE MOVEMENT OF CERVIDS. there is simply to much at risk.
In my opinion, and the opinions of many scientists and DNR officials, that
these so called game farms are the cause of the spreading of chronic wasting
disease cwd through much negligence. the game farms in my opinion are not the
only cause, but a big factor. I kindly wish to submit the following to show what
these factors are, and why interstate movement of cervids must be banned.
...
snip...see full text and PDF ATTACHMENT HERE ;
Sunday, July 07, 2013
*** Could avian scavengers translocate infectious prions to disease-free
areas initiating new foci of chronic wasting disease? Prion. 2013 Jul 3;7(4).
[Epub ahead of print]
Monday, February 14, 2011
*** THE ROLE OF PREDATION IN DISEASE CONTROL: A COMPARISON OF SELECTIVE AND
NONSELECTIVE REMOVAL ON PRION DISEASE DYNAMICS IN DEER
NO, NO, NOT NO, BUT HELL NO !
Journal of Wildlife Diseases, 47(1), 2011, pp. 78-93 © Wildlife Disease
Association 2011
DEFRA U.K. What is the risk of Chronic Wasting Disease CWD being introduced
into Great Britain? A Qualitative Risk Assessment October 2012
snip...
In the USA, under the Food and Drug Administration’s BSE Feed Regulation
(21 CFR 589.2000) most material (exceptions include milk, tallow, and gelatin)
from deer and elk is prohibited for use in feed for ruminant animals. With
regards to feed for non-ruminant animals, under FDA law, CWD positive deer may
not be used for any animal feed or feed ingredients. For elk and deer considered
at high risk for CWD, the FDA recommends that these animals do not enter the
animal feed system. However, this recommendation is guidance and not a
requirement by law.
Animals considered at high risk for CWD include:
1) animals from areas declared to be endemic for CWD and/or to be CWD
eradication zones and
2) deer and elk that at some time during the 60-month period prior to
slaughter were in a captive herd that contained a CWD-positive animal.
Therefore, in the USA, materials from cervids other than CWD positive
animals may be used in animal feed and feed ingredients for non-ruminants.
The amount of animal PAP that is of deer and/or elk origin imported from
the USA to GB can not be determined, however, as it is not specified in TRACES.
It may constitute a small percentage of the 8412 kilos of non-fish origin
processed animal proteins that were imported from US into GB in 2011.
Overall, therefore, it is considered there is a __greater than negligible
risk___ that (nonruminant) animal feed and pet food containing deer and/or elk
protein is imported into GB.
There is uncertainty associated with this estimate given the lack of data
on the amount of deer and/or elk protein possibly being imported in these
products.
snip...
36% in 2007 (Almberg et al., 2011). In such areas, population declines of
deer of up to 30 to 50% have been observed (Almberg et al., 2011). In areas of
Colorado, the prevalence can be as high as 30% (EFSA, 2011).
The clinical signs of CWD in affected adults are weight loss and
behavioural changes that can span weeks or months (Williams, 2005). In addition,
signs might include excessive salivation, behavioural alterations including a
fixed stare and changes in interaction with other animals in the herd, and an
altered stance (Williams, 2005). These signs are indistinguishable from cervids
experimentally infected with bovine spongiform encephalopathy (BSE).
Given this, if CWD was to be introduced into countries with BSE such as GB,
for example, infected deer populations would need to be tested to differentiate
if they were infected with CWD or BSE to minimise the risk of BSE entering the
human food-chain via affected venison.
snip...
The rate of transmission of CWD has been reported to be as high as 30% and
can approach 100% among captive animals in endemic areas (Safar et al., 2008).
snip...
In summary, in endemic areas, there is a medium probability that the soil
and surrounding environment is contaminated with CWD prions and in a
bioavailable form. In rural areas where CWD has not been reported and deer are
present, there is a greater than negligible risk the soil is contaminated with
CWD prion.
snip...
In summary, given the volume of tourists, hunters and servicemen moving
between GB and North America, the probability of at least one person travelling
to/from a CWD affected area and, in doing so, contaminating their clothing,
footwear and/or equipment prior to arriving in GB is greater than negligible.
For deer hunters, specifically, the risk is likely to be greater given the
increased contact with deer and their environment. However, there is significant
uncertainty associated with these estimates.
snip...
Therefore, it is considered that farmed and park deer may have a higher
probability of exposure to CWD transferred to the environment than wild deer
given the restricted habitat range and higher frequency of contact with tourists
and returning GB residents.
snip...
NEW URL LINK ;
Friday, December 14, 2012
DEFRA U.K. What is the risk of Chronic Wasting Disease CWD being introduced
into Great Britain? A Qualitative Risk Assessment October 2012
*** The potential impact of prion diseases on human health was greatly
magnified by the recognition that interspecies transfer of BSE to humans by beef
ingestion resulted in vCJD. While changes in animal feed constituents and
slaughter practices appear to have curtailed vCJD, there is concern that CWD of
free-ranging deer and elk in the U.S. might also cross the species barrier.
Thus, consuming venison could be a source of human prion disease. Whether BSE
and CWD represent interspecies scrapie transfer or are newly arisen prion
diseases is unknown. Therefore, the possibility of transmission of prion disease
through other food animals cannot be ruled out. There is evidence that vCJD can
be transmitted through blood transfusion. There is likely a pool of unknown size
of asymptomatic individuals infected with vCJD, and there may be asymptomatic
individuals infected with the CWD equivalent. These circumstances represent a
potential threat to blood, blood products, and plasma supplies.
cwd exposure, and iatrogenic CJD, what if ???
*** our results raise the possibility that CJD cases classified as VV1 may
include cases caused by iatrogenic transmission of sCJD-MM1 prions or food-borne
infection by type 1 prions from animals, e.g., chronic wasting disease prions in
cervid. In fact, two CJD-VV1 patients who hunted deer or consumed venison have
been reported (40, 41). The results of the present study emphasize the need for
traceback studies and careful re-examination of the biochemical properties of
sCJD-VV1 prions. ***
snip...see full text ;
Thursday, January 2, 2014
*** CWD TSE Prion in cervids to hTGmice, Heidenhain Variant
Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ??? ***
*** We hypothesize that both BSE prions and CWD prions passaged through
felines will seed human recPrP more efficiently than BSE or CWD from the
original hosts, evidence that the new host will dampen the species barrier
between humans and BSE or CWD. The new host effect is particularly relevant as
we investigate potential means of trans-species transmission of prion disease.
Tuesday, November 04, 2014
*** Six-year follow-up of a point-source exposure to CWD contaminated
venison in an Upstate New York community: risk behaviours and health outcomes
2005–2011
Thursday, March 20, 2014
CHRONIC WASTING DISEASE CWD TSE PRION OF CERVID AND THE POTENTIAL FOR HUMAN
TRANSMISSION THEREFROM 2014
Tuesday, July 01, 2014
*** CHRONIC WASTING DISEASE CWD TSE PRION DISEASE, GAME FARMS, AND
POTENTIAL RISK FACTORS THERE FROM ***
Thursday, July 03, 2014
*** How Chronic Wasting Disease is affecting deer population and what’s the
risk to humans and pets? ***
Thursday, October 23, 2014
*** FIRST CASE OF CHRONIC WASTING DISEASE CONFIRMED IN OHIO ON PRIVATE
PRESERVE
Tuesday, October 21, 2014
*** Pennsylvania Department of Agriculture Tenth Pennsylvania Captive Deer
Tests Positive for Chronic Wasting Disease CWD TSE PRION DISEASE
”The occurrence of CWD must be viewed against the contest of the locations
in which it occurred. It was an incidental and unwelcome complication of the
respective wildlife research programmes. Despite it’s subsequent recognition as
a new disease of cervids, therefore justifying direct investigation, no specific
research funding was forthcoming. The USDA veiwed it as a wildlife problem and
consequently not their province!” ...page 26.
Sunday, January 06, 2013
USDA TO PGC ONCE CAPTIVES ESCAPE
*** "it‘s no longer its business.”
Sunday, July 13, 2014
Louisiana deer mystery unleashes litigation 6 does still missing from CWD
index herd in Pennsylvania Great Escape
Saturday, June 29, 2013
PENNSYLVANIA CAPTIVE CWD INDEX HERD MATE YELLOW *47 STILL RUNNING LOOSE IN
INDIANA, YELLOW NUMBER 2 STILL MISSING, AND OTHERS ON THE RUN STILL IN LOUISIANA
Tuesday, June 11, 2013
*** CWD GONE WILD, More cervid escapees from more shooting pens on the
loose in Pennsylvania
Wednesday, September 04, 2013
***cwd - cervid captive livestock escapes, loose and on the run in the
wild...
Tuesday, October 07, 2014
*** Wisconsin white-tailed deer tested positive for CWD on a Richland
County breeding farm, and a case of CWD has been discovered on a Marathon County
hunting preserve
Thursday, October 02, 2014
*** IOWA TEST RESULTS FROM CAPTIVE DEER HERD WITH CHRONIC WASTING DISEASE
RELEASED 79.8 percent of the deer tested positive for the disease
Tuesday, April 29, 2014
CWD Herd Certification Program and Interstate Movement of Farmed or Captive
Deer, Elk, and Moose FR Doc No: 2014-09714 April 29, 2014 UPDATE
*** We conclude that TSE infectivity is likely to survive burial for long
time periods with minimal loss of infectivity and limited movement from the
original burial site. However PMCA results have shown that there is the
potential for rainwater to elute TSE related material from soil which could lead
to the contamination of a wider area. These experiments reinforce the importance
of risk assessment when disposing of TSE risk materials.
*** The results show that even highly diluted PrPSc can bind efficiently to
polypropylene, stainless steel, glass, wood and stone and propagate the
conversion of normal prion protein. For in vivo experiments, hamsters were ic
injected with implants incubated in 1% 263K-infected brain homogenate. Hamsters,
inoculated with 263K-contaminated implants of all groups, developed typical
signs of prion disease, whereas control animals inoculated with non-contaminated
materials did not.
PRION 2014 CONFERENCE
CHRONIC WASTING DISEASE CWD
A FEW FINDINGS ;
Conclusions. To our knowledge, this is the first established experimental
model of CWD in TgSB3985. We found evidence for co-existence or divergence of
two CWD strains adapted to Tga20 mice and their replication in TgSB3985 mice.
Finally, we observed phenotypic differences between cervid-derived CWD and
CWD/Tg20 strains upon propagation in TgSB3985 mice. Further studies are underway
to characterize these strains.
We conclude that TSE infectivity is likely to survive burial for long time
periods with minimal loss of infectivity and limited movement from the original
burial site. However PMCA results have shown that there is the potential for
rainwater to elute TSE related material from soil which could lead to the
contamination of a wider area. These experiments reinforce the importance of
risk assessment when disposing of TSE risk materials.
The results show that even highly diluted PrPSc can bind efficiently to
polypropylene, stainless steel, glass, wood and stone and propagate the
conversion of normal prion protein. For in vivo experiments, hamsters were ic
injected with implants incubated in 1% 263K-infected brain homogenate. Hamsters,
inoculated with 263K-contaminated implants of all groups, developed typical
signs of prion disease, whereas control animals inoculated with non-contaminated
materials did not.
Our data establish that meadow voles are permissive to CWD via peripheral
exposure route, suggesting they could serve as an environmental reservoir for
CWD. Additionally, our data are consistent with the hypothesis that at least two
strains of CWD circulate in naturally-infected cervid populations and provide
evidence that meadow voles are a useful tool for CWD strain typing.
Conclusion. CWD prions are shed in saliva and urine of infected deer as
early as 3 months post infection and throughout the subsequent >1.5 year
course of infection. In current work we are examining the relationship of
prionemia to excretion and the impact of excreted prion binding to surfaces and
particulates in the environment.
Conclusion. CWD prions (as inferred by prion seeding activity by RT-QuIC)
are shed in urine of infected deer as early as 6 months post inoculation and
throughout the subsequent disease course. Further studies are in progress
refining the real-time urinary prion assay sensitivity and we are examining more
closely the excretion time frame, magnitude, and sample variables in
relationship to inoculation route and prionemia in naturally and experimentally
CWD-infected cervids.
Conclusions. Our results suggested that the odds of infection for CWD is
likely controlled by areas that congregate deer thus increasing direct
transmission (deer-to-deer interactions) or indirect transmission
(deer-to-environment) by sharing or depositing infectious prion proteins in
these preferred habitats. Epidemiology of CWD in the eastern U.S. is likely
controlled by separate factors than found in the Midwestern and endemic areas
for CWD and can assist in performing more efficient surveillance efforts for the
region.
Conclusions. During the pre-symptomatic stage of CWD infection and
throughout the course of disease deer may be shedding multiple LD50 doses per
day in their saliva. CWD prion shedding through saliva and excreta may account
for the unprecedented spread of this prion disease in nature.
see full text and more ;
Monday, June 23, 2014
*** PRION 2014 CONFERENCE CHRONIC WASTING DISEASE CWD
*** Infectious agent of sheep scrapie may persist in the environment for at
least 16 years***
Gudmundur Georgsson1, Sigurdur Sigurdarson2 and Paul Brown3
New studies on the heat resistance of hamster-adapted scrapie agent:
Threshold survival after ashing at 600°C suggests an inorganic template of
replication
Prion Infected Meat-and-Bone Meal Is Still Infectious after Biodiesel
Production
Detection of protease-resistant cervid prion protein in water from a
CWD-endemic area
A Quantitative Assessment of the Amount of Prion Diverted to Category 1
Materials and Wastewater During Processing
Rapid assessment of bovine spongiform encephalopathy prion inactivation by
heat treatment in yellow grease produced in the industrial manufacturing process
of meat and bone meals
Survival and Limited Spread of TSE Infectivity after Burial
Karen Fernie, Allister Smith and Robert A. Somerville The Roslin Institute
and R(D)SVS; University of Edinburgh; Roslin, Scotland UK
Scrapie and chronic wasting disease probably spread via environmental
routes, and there are also concerns about BSE infection remaining in the
environment after carcass burial or waste 3disposal. In two demonstration
experiments we are determining survival and migration of TSE infectivity when
buried for up to five years, as an uncontained point source or within bovine
heads. Firstly boluses of TSE infected mouse brain were buried in lysimeters
containing either sandy or clay soil. Migration from the boluses is being
assessed from soil cores taken over time. With the exception of a very small
amount of infectivity found 25 cm from the bolus in sandy soil after 12 months,
no other infectivity has been detected up to three years. Secondly, ten bovine
heads were spiked with TSE infected mouse brain and buried in the two soil
types. Pairs of heads have been exhumed annually and assessed for infectivity
within and around them. After one year and after two years, infectivity was
detected in most intracranial samples and in some of the soil samples taken from
immediately surrounding the heads. The infectivity assays for the samples in and
around the heads exhumed at years three and four are underway. These data show
that TSE infectivity can survive burial for long periods but migrates slowly.
Risk assessments should take into account the likely long survival rate when
infected material has been buried.
The authors gratefully acknowledge funding from DEFRA.
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
9:41 AM
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