Immunogenic JC polyomavirus compositions and methods of use
Inventors
Buck, Christopher B. • Ray, Upasana • Pastrana, Diana V.
Assignees
US Department of Health and Human Services
Publication Number
US-9931393-B2
Publication Date
2018-04-03
Expiration Date
2034-12-19
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Methods of eliciting an immune response to a JC polyomavirus (JCV) by administering an effective amount of an immunogenic composition including an isolated JCV VP1 polypeptide or a nucleic acid encoding the VP1 polypeptide to a subject are provided. VP1 polypeptides and immunogenic compositions suitable for use in the methods are provided, including JCV genotype 2 VP1 polypeptides and/or JCV genotype 3 polypeptides. Methods of identifying a subject at risk of developing progressive multifocal leukoencephalopathy (PML) are also provided. In some embodiments, the methods include obtaining a biological sample from a subject, detecting presence or absence of JCV neutralizing antibodies in the sample from the subject, and identifying that the subject is at risk of developing PML if there is an absence of detectable JCV neutralizing antibodies in the sample from the subject.
Core Innovation
The invention provides methods and compositions for eliciting an immune response against JC polyomavirus (JCV), specifically by administering an effective amount of an immunogenic composition that includes an isolated JCV VP1 polypeptide or a nucleic acid encoding the VP1 polypeptide to a subject. The disclosed compositions include monovalent immunogenic compositions based on wild type (WT) JCV VP1 polypeptides from genotypes such as genotype 2 (e.g., 2A, 2B, or 2C) and genotype 3 (e.g., 3A or 3B), which unexpectedly elicit an immune response capable of neutralizing multiple JCV genotypes, including those with VP1 mutations associated with progressive multifocal leukoencephalopathy (PML). It is disclosed that immunogenic compositions containing VP1 polypeptides derived from PML-associated mutants are less effective than those based on WT VP1 polypeptides for eliciting broadly neutralizing antibodies.
The problem addressed by this invention is the lack of effective compositions and methods to prevent or inhibit JCV infection or the development of PML in vulnerable subjects. JCV chronically infects most adults but can cause the lethal CNS disease PML in immunosuppressed individuals. The incidence of PML has increased with the use of immunosuppressive therapies and remains a significant risk, as no effective antiviral treatments are available and damage caused by PML is often irreversible. The need exists for compositions that can elicit neutralizing immune responses capable of preventing infection by multiple JCV genotypes and VP1 variants, including PML-associated mutants that escape neutralization by some naturally occurring antibodies.
The invention further provides methods of identifying subjects at risk of developing PML by detecting the presence or absence of JCV neutralizing antibodies in biological samples. Subjects lacking detectable neutralizing antibodies are identified as at risk. These subjects can then be administered the disclosed immunogenic compositions to elicit an immune response against JCV. Additionally, the invention discloses virus-like particles (VLPs) and pentameric VP1 capsomers comprising isolated VP1 polypeptides suitable for use in these methods. The compositions can induce broadly cross-neutralizing antibody responses, even against JCV VP1 variants associated with PML, thereby offering a strategy for prophylaxis and treatment in at-risk immunocompromised populations.
Claims Coverage
The patent discloses 31 inventive features primarily related to methods of eliciting immune responses to JCV, methods of identifying subjects at risk of PML, and immunogenic compositions containing JCV VP1 polypeptides or encoding nucleic acids.
Methods of eliciting immune response using isolated JCV genotype 2 and/or 3 VP1 polypeptides or nucleic acids
Administering an effective amount of an immunogenic composition comprising isolated JCV genotype 2 VP1 polypeptide, genotype 3 VP1 polypeptide, or a combination thereof, or isolated nucleic acids encoding these polypeptides, to a subject to elicit an immune response against JCV.
Compositions consisting essentially of isolated VP1 polypeptides or nucleic acids
Using immunogenic compositions that consist essentially of isolated JCV genotype 2 VP1 polypeptide, genotype 3 VP1 polypeptide, or combinations thereof, or isolated nucleic acids encoding these polypeptides.
Methods employing monovalent immunogenic compositions
Administering a monovalent immunogenic composition comprising isolated JCV genotype 2 or genotype 3 VP1 polypeptide or nucleic acid encoding such polypeptides to elicit an immune response.
Methods specifying specific JCV VP1 genotypes
Employing VP1 polypeptides comprising JCV genotype 2A VP1 or JCV genotype 3B VP1 polypeptides in immunogenic compositions and methods to elicit immune responses.
Methods specifying VP1 polypeptides with at least 99% sequence identity or exact sequences
Using VP1 polypeptides comprising amino acid sequences with at least 99% identity to SEQ ID NOs: 1, 2, or 9, or consisting of these exact sequences in immunogenic compositions to elicit immune responses.
Use of specific nucleic acid sequences encoding VP1 polypeptides
Using isolated nucleic acids encoding VP1 polypeptides with sequences as set forth in SEQ ID NOs: 16-18, 25, or 26 in immunogenic compositions and methods.
Administering virus-like particles comprising VP1 polypeptides
Administration of immunogenic compositions comprising virus-like particles including the isolated JCV genotype 2 VP1 polypeptide, genotype 3 VP1 polypeptide, or both to elicit immune responses.
Eliciting neutralizing antibody responses
Eliciting immune responses that include neutralizing antibody responses capable of neutralizing multiple JCV genotypes, including both WT and variant VP1 polypeptides, including PML-associated variants.
Adjuvant inclusion in immunogenic compositions
Inclusion of an adjuvant such as alum in the immunogenic composition to enhance immune responses.
Target subject populations for administration
Subjects include immunocompromised individuals, those treated with or candidates for immunosuppressants, organ transplant recipients, bone marrow transplant recipients, or subjects diagnosed with PML.
Methods of identifying subjects at risk of PML
Obtaining a biological sample from a subject, detecting the presence or absence of JCV neutralizing antibodies, identifying subjects as at risk if neutralizing antibodies are absent, and administering an immunogenic composition comprising isolated VP1 polypeptides or encoding nucleic acid to those subjects.
Specific features of samples and polypeptides for PML risk methods
Biological samples comprise blood or serum; VP1 polypeptides comprise JCV genotype 2, genotype 3, or combinations thereof.
Immunogenic composition components
Immunogenic compositions include isolated JCV genotype 2 VP1 polypeptide, genotype 3 VP1 polypeptide, or combinations/nucleic acids thereof, combined with adjuvants and possibly pharmaceutically acceptable carriers.
Immunogenic compositions containing specific genotypes and adjuvants
Immunogenic compositions wherein VP1 polypeptides include genotype 2A or 3B and adjuvants include aluminum hydroxide or phosphate.
Use of VP1 polypeptides of defined sequences in compositions
Employing isolated VP1 polypeptides with at least 99% identity or consisting of sequences SEQ ID NOs: 1, 2, or 9 in compositions.
Use of nucleic acids encoding VP1 polypeptides of defined sequences in compositions
Employing isolated nucleic acids encoding VP1 polypeptides with sequences per SEQ ID NOs: 16-18, 25, or 26 in compositions.
Methods eliciting neutralizing antibodies to VP1 variant polypeptides via WT immunogens
Administering immunogenic compositions comprising isolated wild type genotype 1A, 2A, or 3B VP1 polypeptides or nucleic acids encoding these to elicit neutralizing antibody responses to VP1 variant polypeptides.
VLP administration for eliciting neutralizing antibodies
Administering immunogenic compositions comprising virus-like particles including wild type JCV genotype 1A, 2A, or 3B VP1 polypeptides.
The claims cover methods of eliciting immune responses to JCV by administering immunogenic compositions comprising isolated VP1 polypeptides or encoding nucleic acids from specific JCV genotypes, especially genotype 2 and 3. The claims also encompass methods for identifying subjects at risk for PML based on neutralizing antibody presence and providing such subjects treatment with these immunogenic compositions. Additionally, immunogenic compositions containing these VP1 polypeptides or nucleic acids with adjuvants are claimed, particularly compositions including virus-like particles for eliciting broadly neutralizing antibody responses.
Stated Advantages
Administration of WT JCV VP1 polypeptide immunogenic compositions elicits broadly cross-neutralizing antibody responses effective against multiple JCV genotypes, including PML-associated VP1 variants.
Vaccination with PML-mutant VP1 polypeptides is less effective than WT-based compositions for eliciting neutralizing antibodies.
Identification of subjects lacking neutralizing antibodies allows targeted vaccination to reduce PML risk.
The immunogenic compositions enable closing of neutralization blind spots, enhancing antibody breadth.
Use of monovalent WT VP1 immunogens simplifies vaccine formulation despite diverse PML-associated mutations.
Documented Applications
Eliciting neutralizing immune responses to JC polyomavirus infection in subjects, including immunocompromised individuals or those at risk of PML.
Identifying subjects at risk for developing PML through detection of JCV neutralizing antibody absence.
Administering immunogenic compositions to subjects identified as at risk of PML to prevent or treat PML.
Using virus-like particles or nucleic acid-based vaccines to induce immunity to JCV genotypes in subjects.
Treating PML patients by enhancing their JCV-neutralizing antibody titers through vaccination with JCV VP1 VLPs.
Interested in licensing this patent?