The minor capsid protein L2 is a promising candidate for the construction of an anti-human papillomavirus (HPV) broadly protective vaccine for the prophylaxis of cervical cancer. However, L2-derived peptides are usually poorly immunogenic and extensive knowledge on the most relevant (cross)neutralizing epitope(s) is still needed. We systematically examined the immunogenicity and virus neutralization potential of six peptides encompassing the N-terminal (amino acids 1 -- 120) region of HPV16 L2 (20 -- 38; 28 -- 42; 56 -- 75; 64 -- 81; 96 -- 115; 108 -- 120) using bacterial thioredoxin (Trx) as a novel peptide scaffold. Mice antisera generated by 19 different Trx-L2 peptide fusions bearing one or multiple copies of each peptide were analyzed. Internal fusion to thioredoxin conferred strong immunogenicity to all the tested peptides, with a trend toward an increased immunogenicity for the multipeptide vs. the monopeptide forms of the various antigens. All Trx-L2 peptides induced HPV16 neutralizing antibodies in some of the immunized mice, but neutralization titers differed by more than two orders of magnitude. Trx-L2(20 -- 38) antisera were by far the most effective in HPV16 neutralization and did not differ significantly from those induced by a reference polypeptide covering the entire L2 (1 -- 120) region. The same antisera were also the most effective when challenged against the non-cognate HPV 18, 58, 45 and 31 pseudovirions. The data identify L2(20 -- 38) as the best (cross)neutralizing epitope among the six that were examined, and point to thioredoxin fusion derivatives of this peptide as excellent candidates for the formulation of a low-cost, broadly protective HPV vaccine
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