Will we be able to prevent PML with a JCV vaccine? #ResearchSpeak #MSBlog #MSResearch
"Can you imagine a world in where the risk of PML did not exist? This would allow us to offer natalizumab as first-line therapy to all people with MS. It would allow us to flip-the-pyramid and with the development of a subcutaneous formulation of natalizumab free-up patients from having to come for monthly infusions. Eliminating the risk of PML and making natalizumab easier, and cheaper, to administer would transform the treatment of MS."
"How do we de-risk natalizumab in JCV-seropositive individuals? The two studies below are a start."
"To cause PML, the JC virus has to mutate and be able to infect the brain of MSers. It is of interest that the antibody against JCV that found in blood of MSers with PML does not recognise the JC virus in their brains; this indicates that the PML mutant has escaped recognition by the immune system. In comparison, healthy people reacted to all JCV variants. When you immunise mice with mutant JCV they make antibodies that are capable of neutralizing JCV-PML variants. This experiment was then tried in someone with PML; they were given an experimental vaccine made from the coat protein from a JCV-PML variant. When their immune system saw this mutant variant they were able to make a neutralizing antibody to the virus. I suspect that in MSers on natalizumab who have PML the virus is able to hide from the immune system in the brain; essentially hidden behind a blood-brain-barrier that is sealed off from immune cells that would normally find the virus and destroy it."
"The first study opens up the possibility of creating a vaccine to neutralise JCV mutants capable of causing PML."
"In the second study the researchers' clone an antibody from someone who had IRIS, which is the immune reconstitution syndrome that occurs when natalizumab is stopped. The cloned antibody was capable of recognising and neutralizing the mutated JC virus."
"So what next? Maybe we can develop a vaccine that can be given before someone starts taking natalizumab, or other immunosuppressive drug, to try and protect them from getting PML in the future. I personally think this strategy is flawed as it may not be possible to make a vaccine that is capable of neutralising all potential JCV-mutants capable of causing PML. We know nature always fights back; this is what happens with other viruses and microbes and is best studied with the flu and HIV viruses. As you mount an immune response to one strain, or mutant, the flu and HIV viruses evolve to escape immune detection and a new mutant emerges. This is what we call the red queen effect and is what underpins evolution. In short it is an evolutionary arms race. Therefore a much better option will be to develop drugs to interfere with the biology of the JCV in the hope of clearing the virus from the body. A good analogy is hepatitis C; the new hepatitis C protease inhibitors are so effective at blocking viral replication that the majority of people treated with the new generation of drugs are cured."
"I therefore envisage a future in which all JCV positive individuals simply take a course of treatment that will eliminate the JCV from their body before they start immunosuppressive treatments, or natalizumab, or natalizumab-like drugs."
"I am clearly an optimist and don't think PML is an intractable problem. All we need is the investment in the necessary R&D and I suspect we will be able to solve the problem."
Background: 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.
Hypothesis: 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.
Results: A PML patient administered an experimental JCV VLP vaccine likewise showed markedly increased neutralizing titre against her cognate PML-mutant JCV.
Conclusion: 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.
Methods: 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.
Results: Before and during PML, CSF antibody responses against JCPyV VP1 variants show "recognition holes"; however, upon immune reconstitution, CSF antibody titres 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.
Conclusions: These antibodies are promising drug candidates for the development of a treatment of PML.