Author Topic: Vaccination against PML on the horizon  (Read 184 times)

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Offline agate

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Vaccination against PML on the horizon
« on: September 25, 2015, 02:36:03 pm »
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."

The article, which includes a photo, can be seen here.
« Last Edit: September 27, 2015, 06:08:57 am by agate »
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Offline agate

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Two abstracts about PML vaccination possibility
« Reply #1 on: September 27, 2015, 07:13:25 am »
Abstracts about this research from PubMed, September 25, 2015:

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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.

The abstract can be seen here.

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.

The abstract can be seen here.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.