Papillomavirus L2 N-terminal peptides for the induction of broadly cross-neutralizing antibodies
Inventors
Schiller, John T. • Pastrana, Diana V. • Roden, Richard B. S. • Gambhira, Ratish • Lowy, Douglas R.
Assignees
Johns Hopkins University • US Department of Health and Human Services
Publication Number
US-8404244-B2
Publication Date
2013-03-26
Expiration Date
2026-02-01
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Abstract
The invention comprises a method for inducing broadly cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types or against heterologous papillomavirus types in humans comprising administering to a human in need thereof an immunogenic peptide or protein (or polynucleotide encoding therefor), where the immunogenic peptide or protein is: (a) a peptide or protein of at least 10 amino acid residues in length having a sequence corresponding to either a sequence from the N terminal amino acids 1-200 of papillomavirus L2 protein (for cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types) or a sequence from the N terminal amino acids 1-88 of papillomavirus L2 protein (for cross-neutralizing antibodies against heterologous papillomavirus types), (b) a peptide or protein of at least 10 amino acid residues in length with at least 55% identity with the sequence from (a), or (c) a peptide or protein as defined in either (a) or (b) which is conjugated or fused to a protein or peptide other than a papillomavirus L2 protein or peptide.
Core Innovation
The invention relates to the use of papillomavirus L2 protein fragments, specifically peptides or proteins derived from the N-terminal region of the L2 protein, for inducing broadly cross-neutralizing antibodies against both cutaneous and mucosal papillomavirus types in humans. This method involves administering an immunogenic peptide or protein of at least 10 amino acid residues in length, corresponding to sequences from the N-terminal amino acids 1-200 of L2 (for cross-neutralizing antibodies against cutaneous and mucosal types) or from the N-terminal amino acids 1-88 of L2 (for cross-neutralizing antibodies against heterologous papillomavirus types). The immunogenic peptide or protein can be isolated, recombinant, or synthetic, and may be conjugated or fused to a protein or peptide other than papillomavirus L2.
The problem addressed by the invention arises from the need for broad protection against the numerous oncogenic and non-oncogenic papillomavirus types, which cause a variety of diseases including cervical cancer and warts. Existing vaccines based on L1 virus-like particles tend to induce primarily type-specific neutralizing antibodies, requiring multivalent vaccines targeting many HPV types, which is complex and costly. Although vaccination with L2 proteins can provide homologous immunity and show some limited cross-neutralization, the neutralizing antibody titers are low and cross-protection to distantly related types is uncertain.
The invention demonstrates that peptides corresponding to the N-terminal region of L2, especially amino acids 1-88, and particularly from bovine papillomavirus type 1 (BPV1) L2, induce robust and broadly cross-neutralizing antibodies effective against a wide range of human papillomavirus types as well as animal papillomaviruses. Antisera raised against BPV1 L2 1-88 neutralized diverse papillomavirus types including HPV16, HPV18, HPV31, HPV6, cottontail rabbit papillomavirus (CRPV), and native HPV11 virions. This N-terminal region includes highly conserved residues critical for viral infection and is immunogenic, providing an antigen basis for broadly protective vaccines.
Claims Coverage
The patent contains one independent claim focused on a method for inducing broadly cross-neutralizing antibodies using immunogenic peptides or proteins derived from the N-terminal region of papillomavirus L2 protein.
Use of immunogenic peptides or proteins from the N-terminal 1-88 amino acids of papillomavirus L2
A method of administering an immunogenic peptide or protein containing at least 10 and up to 88 amino acid residues from the N-terminal amino acids 1-88 of papillomavirus L2 protein to induce broadly cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types in humans.
Inclusion of sequences corresponding to HPV16 L2 N-terminal region
The immunogenic peptide or protein used can have a sequence corresponding specifically to the N-terminal amino acids 1-88 of HPV16 L2 protein to induce the antibody response.
Use of immunogenic peptides or proteins corresponding to N-terminal amino acids 17-36 of HPV16 L2
The method includes immunogenic peptides or proteins comprising the sequence corresponding to amino acids 17-36 of HPV16 L2 as effective antigens.
Fusion or conjugation with non-L2 proteins or peptides
The immunogenic peptide or protein can be conjugated or fused to an amino acid, protein, or peptide other than a papillomavirus L2 protein or peptide to enhance immunogenicity or application.
Overall, the claims cover methods of immunizing humans to induce broad cross-neutralizing antibody responses against papillomaviruses through administration of immunogenic peptides or proteins derived from specific conserved N-terminal segments of papillomavirus L2 protein, including modifications by conjugation or fusion to other proteins or peptides.
Stated Advantages
Induces broadly cross-neutralizing antibodies effective against multiple cutaneous and mucosal papillomavirus types, including heterologous types.
Focuses vaccination strategies on a single conserved region (L2 N-terminal 1-88 amino acids) to reduce the complexity and cost compared to multivalent L1 VLP vaccines.
The BPV1 L2 1-88 peptide is an exceptionally effective immunogen for eliciting cross-neutralizing antibodies across divergent papillomavirus types.
Potential to provide prophylactic as well as therapeutic protection, reducing morbidity and mortality associated with papillomavirus infections.
Documented Applications
Vaccines for immunization against papillomavirus and papillomavirus-related diseases in mammals, particularly humans.
Use as prophylactic vaccine compositions to minimize or prevent papillomavirus infection prior to exposure.
Use as therapeutic vaccines to treat existing papillomavirus infections and reduce disease severity or progression.
Diagnostic and research tools involving detection and quantification of antibodies or antigens related to papillomavirus infection.
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