Long-peptide therapeutic vaccination against CRPV-induced papillomas in HLA-A2.1 transgenic rabbits

Abstract

Long peptide immunization is a promising strategy to clear established tumors. In the current study, we investigated the therapeutic effect of a naturally existing long peptide that contained two HLA-A2.1 restricted epitopes (CRPVE1/149-157 and CRPVE1/161-169) from cottontail rabbit papillomavirus (CRPV) E1 using our CRPV/HLA-A2.1 transgenic rabbit model. A universal Tetanus Toxin helper motif (TT helper) was tagged at either the N-terminus or the carboxyl-terminus of this long peptide and designated as TT-E1 peptide and E1 peptide-TT respectively. Four groups of HLA-A2.1 transgenic rabbits were infected with wild type CRPV DNA. Three weeks post-infection, the rabbits were immunized four times with TT-E1 peptide, E1peptide only, E1 peptide -TT or TT-control peptide with two-week intervals between immunizations. Tumor outgrowth was monitored and recorded weekly. After the third booster immunization, tumors on two of the four E1 peptide-TT immunized rabbits began to shrink. One animal from this group was free of tumors at the termination of the study. The mean papilloma size of E1 peptide-TT immunized rabbits was significantly smaller when compared with that of the three other groups (P<0.05, one way ANOVA analysis). It is interesting that E1 peptide-TT vaccination not only stimulated stronger T cell mediate immune responses but also stronger antibody generations. We conclude that the location of a TT helper motif tagged at the long peptide vaccine is critical for the outcome of therapeutic responses to persistent tumors in our HLA-A2.1 transgenic rabbit model.

Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

“…CRPV infectious virions used in the current study were from a viral stock previously 483 reported (Hu et al, 2014). CRPV DNA was cloned into a pUC19 vector as described in our 484 previous publications (Hu et al, 2009).…”

“…Anti-CRPV 613 monoclonal antibody (CRPV.1A) or anti-MmuPV1 monoclonal antibody (MPV.A4) was used as 614 positive control and the sera of non-infected animals as negative control for the corresponding 615 antigens. The ELISA was conducted as previously reported (Hu et al, 2014). 616 617…”

Recent advances in preclinical model systems for papillomaviruses

“…Considerable studies have also been conducted to test therapeutic T-cell based vaccines including recombinant viruses and bacteria (Jensen, Selvakumar et al, 1997; Brandsma, Shlyankevich et al, 2004), DNA-based vectors (Han, Cladel et al, 1999; Han, Cladel et al, 2000; Sundaram, Tigelaar et al, 1996), and synthetic long peptides (Vambutas, DeVoti et al, 2005; Hu, Budgeon et al, 2014). These studies have collectively shown that vaccines that induce T-cell responses to E1, E2, E6, E7, E10 and L1 show strong to intermediate protection against subsequent infection (Han, Cladel et al, 1999; Hu, Cladel et al, 2006; Hu, Han et al, 2002; Leachman, Shylankevich et al, 2002).…”

The rabbit papillomavirus model: a valuable tool to study viral–host interactions

“…Recent promising studies used long peptides of E6 and E7 proteins as immunogens [72,94]. This immunization strategy showed a strong therapeutic effect in the SfPV1/rabbit model as well as in human clinical trials [94,[97][98][99]].…”