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Can We Vaccinate Against PML in MS?

The JC polyomavirus is reported to be a persistent but otherwise asymptomatic kidney infection in a large portion of healthy people. However, in those with hereditary or acquired immune deficiency, a mutated form of the JC polyomavirus may lead to progressive multifocal leukoencephalopathy (PML), a central nervous system (CNS) infection characterized by progressive inflammation of the white matter of the brain. This is of particular interest in the treatment of multiple sclerosis (MS) with natalizumab (Tysabri), which has been associated with an increased risk for the development of PML.

Antiviral agents do not seem to be effective in treating the JC virus disease, leaving reconstitution of the immune system the only current approach for PML treatment. However, this is associated with possible development of a potentially lethal immune reconstitution inflammatory syndrome.

Now, two studies are laying the foundation for a possible PML vaccine with neutralizing antibodies.

“MS patients with PML under natalizumab treatment are special in that their immune system is not compromised, but the anti-VLA-4 antibody natalizumab prevents access of immune cells to the CNS compartment. As a result, PML may develop since physiological immune surveillance of the CNS is not functioning,” study author Roland Martin, MD, of the Neuroimmunology and Multiple Sclerosis Research Section at the Department of Neurology, University of Zurich in Switzerland, told Neurology Advisor. “As soon as PML is diagnosed and the treatment with Tysabri stopped, the immune cells gain access to the CNS again and mount an efficient immune response in most cases. From these reasons, MS patients with PML were a particularly good source for antibody-producing cells and generation of the broadly neutralizing antibodies.”

Dr Martin and colleagues looked at the antibody response of JC virus major capsid protein VP1 variants in the cerebrospinal fluid (CSF) and sera of healthy patients, MS patients treated with natalizumab, and MS patients treated with natalizumab who developed PML. They found that prior to and during PML, antibodies in the CSF demonstrate “recognition holes” in the ability to recognize JC polyomavirus VP1 variants. However, the investigators reported that once the immune system was reconstituted, the CSF antibodies increased and recognized the VP1 variants, suggesting they may also be involved in elimination. The authors also suggested that memory B cells from a patient who has recovered from PML may be a source for passive immunization with neutralizing antibodies.

“Both active vaccination/treatment with major capsid protein VP1 of JC polyoma virus and passive vaccination/treatment with broadly neutralizing antibodies are in principle feasible and ready for clinical development. Hence, one could develop a treatment and prophylaxis for this devastating disease that is so far not treatable,” Dr Martin said.

In another study, Christopher Buck, PhD, senior investigator at the Center for Cancer Research at the National Cancer Institute in Bethesda, MD, and colleagues were able to demonstrate that plasma samples from patients with PML were not able to neutralize PML mutant JC polyomavirus strains, whereas healthy subjects' serological results indicated that most were able to neutralize all of the tested JC polyomavirus variants. Further, they demonstrated that mice given a JC polyomavirus virus-like particle vaccine too showed “blind spots” in their ability to neutralize similarly to patients with PML. Buck and colleagues go on to report on a patient with PML who received an experimental JC polyomavirus virus-like particle vaccine and demonstrated an increase in the neutralizing titer.

“A virus-like particle (VLP) vaccine against JCV seems very likely to prevent PML. All available evidence indicates that the JCV VLP vaccine will be at least as safe and effective as current VLP vaccines against HPVs,” Dr Buck told Neurology Advisor. “At this point, the goal of our work is to elicit industry interest in developing and marketing a JCV vaccine.”

Story Source: The above story is based on materials provided by NEUROLOGYADVISOR
Note: Materials may be edited for content and length

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