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#Post#: 944--------------------------------------------------
Vaccination against PML on the horizon
By: agate Date: September 25, 2015, 6:36 pm
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From Medical News Today, September 24, 2015:
[quote]Vaccination on the horizon for severe viral infection of
the brain
Researchers from the University of Zurich and the University
Hospital Zurich reveal possible new treatment methods for a
rare, usually fatal brain disease. Thanks to their discovery
that specific antibodies play a key role in combating the viral
infection, a vaccine against the disease "progressive multifocal
leukoencephalopathy" could now be developed.
Humans carry a multitude of viruses and bacteria in their gut,
on their skin and in other organs. Often, these are involved in
important bodily functions. Under certain conditions, however,
some can also cause diseases. The JC virus, a member of the
polyoma tumor virus family, is a prime example. This pathogen
was first isolated from the brain of a patient who was suffering
from a rare brain disease known as progressive multifocal
leukoencephalopathy (PML). The virus, which more than 60 percent
of the global population are infected with, normally resides in
the kidneys and certain other organs. JC virus can trigger the
PML infection in the brain, which, in most cases, is fatal.
Weak immune system facilitates brain infection
Two studies conducted by an international team of researchers
from the University of Zurich, the University Hospital Zurich,
the National Institutes of Health in the USA, San Raffaele
Hospital in Milan, the University of Tübingen, and the UZH
spin-off Neurimmune now reveal that the antibodies in PML
patients often fail to recognize the JC virus they are infected
with. "In healthy people, the disease never breaks out as the
immune system keeps it well under control. Once the immune
system is compromised, however, such as in patients with tumors,
leukemia, AIDS, autoimmune diseases and certain
immunosuppressive treatments, the JC virus is able to alter its
genetic information and infect the brain," explains Roland
Martin, professor of neurology at the University of Zurich.
In multiple sclerosis (MS) patients, for instance, the treatment
with a particular antibody, TysabriTM, prevents immune cells
from reaching the brain - but at the same time, also inhibits
the brain's immunosurveillance. If JC viruses enter the brain
during the treatment, they go undetected, which can cause PML,
the most significant side effect of the highly effective
TysabriTM.
Over 560 MS patients worldwide have already developed the PML
brain infection. Over 20 percent of them died from the disease
as there is no effective treatment to date. Only if the immune
system function is completely restored can the JC virus be
removed from the brain.
Active vaccination method and ther[ape]utic antibodies developed
in Zurich
The researchers now reveal potential ways to vaccinate against
PML preventatively or, if the brain has already been infected,
treat it with virus-specific human antibodies. By vaccinating
mice and a PML patient with the virus' coating protein, the
international groups were able to demonstrate that the antibody
response was so strong that the patient was soon able to
eliminate the JC virus. The so-called active vaccination method
was developed at the University of Zurich and the University
Hospital Zurich, and has already been used successfully on two
more patients. The JC-virus-specific antibodies that are of
interest for the treatment of the existing brain infection were
developed by the group at the University of Zurich and the
University Hospital Zurich together with colleagues from the
University of Tübingen and the biotechnology company Neurimmune
in Schlieren.
"We made a major breakthrough", says Martin. We managed to
isolate antibody-producing cells from a patient who survived PML
and use them to produce neutralizing antibodies against the JC
virus. These human antibodies have a major advantage: they
recognize the most important mutants of the JC virus that can
cause PML. They now make promising candidates for the
development of a treatment for PML."[/quote]
The article, which includes a photo, can be seen here
HTML http://www.medicalnewstoday.com/releases/300010.php?tw.
#Post#: 946--------------------------------------------------
Two abstracts about PML vaccination possibility
By: agate Date: September 27, 2015, 11:13 am
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Abstracts about this research from PubMed, September 25, 2015:
[quote]Sci Transl Med. 2015 Sep 23;7(306):306ra151. doi:
10.1126/scitranslmed.aab1720.
JC polyomavirus mutants escape antibody-mediated neutralization
Ray U1, Cinque P2, Gerevini S3, Longo V2, Lazzarin A4,
Schippling S5, Martin R5, Buck CB6, Pastrana DV6.
Author information
1Lab of Cellular Oncology, Center for Cancer Research, National
Cancer Institute, Bethesda, MD 20892, USA.
2Department of Infectious Diseases, San Raffaele Scientific
Institute, 20132 Milan, Italy.
3Neuroradiology Unit, Head and Neck Department, San Raffaele
Scientific Institute, 20132 Milan, Italy.
4Department of Infectious Diseases, San Raffaele Scientific
Institute, 20132 Milan, Italy. San Raffaele University, 20132
Milan, Italy.
5Neuroimmunology and Multiple Sclerosis Research Section,
Department of Neurology, University Hospital Zurich, University
Zurich, 8091 Zurich, Switzerland.
6Lab of Cellular Oncology, Center for Cancer Research, National
Cancer Institute, Bethesda, MD 20892, USA. buckc@mail.nih.gov
pastrand@mail.nih.gov.
JC polyomavirus (JCV) persistently infects the urinary tract of
most adults. Under conditions of immune impairment, JCV causes
an opportunistic brain disease, progressive multifocal
leukoencephalopathy (PML). JCV strains found in the
cerebrospinal fluid of PML patients contain distinctive
mutations in surface loops of the major capsid protein, VP1.
We hypothesized that VP1 mutations might allow the virus to
evade antibody-mediated neutralization. Consistent with this
hypothesis, neutralization serology revealed that plasma samples
from PML patients neutralized wild-type JCV strains but failed
to neutralize patient-cognate PML-mutant JCV strains. This
contrasted with serological results for healthy individuals,
most of whom robustly cross-neutralized all tested JCV variants.
Mice administered a JCV virus-like particle (VLP) vaccine
initially showed neutralizing "blind spots" (akin to those
observed in PML patients) that closed after booster
immunization. A PML patient administered an experimental JCV VLP
vaccine likewise showed markedly increased neutralizing titer
against her cognate PML-mutant JCV. The results indicate that
deficient humoral immunity is a common aspect of PML
pathogenesis and that vaccination may overcome this humoral
deficiency. Thus, vaccination with JCV VLPs might prevent the
development of PML.[/quote]
The abstract can be seen here
HTML http://www.ncbi.nlm.nih.gov/pubmed/26400912.
And:
[quote]Sci Transl Med. 2015 Sep 23;7(306):306ra150.
Broadly neutralizing human monoclonal JC polyomavirus
VP1-specific antibodies as candidate therapeutics for
progressive multifocal leukoencephalopathy.
Jelcic I1, Combaluzier B2, Jelcic I1, Faigle W1, Senn L2,
Reinhart BJ1, Ströh L3, Nitsch RM4, Stehle T5, Sospedra M1,
Grimm J6, Martin R7.
Author information
1Neuroimmunology and Multiple Sclerosis Research Section,
Department of Neurology, University of Zurich, University
Hospital Zurich, 8091 Zurich, Switzerland.
2Neurimmune Holding AG, 8952 Schlieren, Switzerland.
3Interfaculty Institute of Biochemistry, University of Tübingen,
72076 Tübingen, Germany.
4Neurimmune Holding AG, 8952 Schlieren, Switzerland. Division of
Psychiatry Research, University of Zurich, 8952 Schlieren,
Switzerland.
5Interfaculty Institute of Biochemistry, University of Tübingen,
72076 Tübingen, Germany. Vanderbilt University School of
Medicine, Nashville, TN 37232, USA.
6Neurimmune Holding AG, 8952 Schlieren, Switzerland.
roland.martin@usz.ch jan.grimm@neurimmune.com.
7Neuroimmunology and Multiple Sclerosis Research Section,
Department of Neurology, University of Zurich, University
Hospital Zurich, 8091 Zurich, Switzerland. roland.martin@usz.ch
jan.grimm@neurimmune.com.
In immunocompromised individuals, JC polyomavirus (JCPyV) may
mutate and gain access to the central nervous system resulting
in progressive multifocal leukoencephalopathy (PML), an often
fatal opportunistic infection for which no treatments are
currently available.
Despite recent progress, the contribution of JCPyV-specific
humoral immunity to controlling asymptomatic infection
throughout life and to eliminating JCPyV from the brain is
poorly understood.
We examined antibody responses against JCPyV major capsid
protein VP1 (viral protein 1) variants in the serum and
cerebrospinal fluid (CSF) of healthy donors (HDs),
JCPyV-positive multiple sclerosis patients treated with the
anti-VLA-4 monoclonal antibody natalizumab (NAT), and patients
with NAT-associated PML.
Before and during PML, CSF antibody responses against JCPyV VP1
variants show "recognition holes"; however, upon immune
reconstitution, CSF antibody titers rise, then recognize
PML-associated JCPyV VP1 variants, and may be involved in
elimination of the virus. We therefore reasoned that the memory
B cell repertoire of individuals who recovered from PML could be
a source for the molecular cloning of broadly neutralizing
antibodies for passive immunization.
We generated a series of memory B cell-derived JCPyV
VP1-specific human monoclonal antibodies from HDs and a patient
with NAT-associated PML-immune reconstitution inflammatory
syndrome (IRIS). These antibodies exhibited diverse binding
affinity, cross-reactivity with the closely related BK
polyomavirus, recognition of PML-causing VP1 variants, and JCPyV
neutralization. Almost all antibodies with exquisite specificity
for JCPyV, neutralizing activity, recognition of all tested
JCPyV PML variants, and high affinity were derived from one
patient who had recovered from PML.
These antibodies are promising drug candidates for the
development of a treatment of PML.[/quote]
The abstract can be seen here
HTML http://www.ncbi.nlm.nih.gov/pubmed/26400911.
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