Route of administration of chimeric BPV1 VLP determines the character of the induced immune responses

Abstract

SummaryTo examine the mucosal immune response to papillomavirus virus-like particles (PV-VLP), mice were immunized with VLP intrarectally (i.r.), intravaginally (i.va.) or intramuscularly (i.m.) without adjuvant. PV-VLP were assembled with chimeric BPV-1 L1 proteins incorporating sequence from HIV-1 gp120, either the V3 loop or a shorter peptide incorporating a known CTL epitope (HIVP18I10). Antibody specific for BPV-1 VLP and P18 peptide was detected in serum following i.m., but not i.r. or i.va. immunization. Denatured VLP induced a much reduced immune response when compared with native VLP. Immune responses following mucosal administration of VLP were generally weaker than following systemic administration. VLP specific IgA was higher in intestine washes following i.r. than i.va. immunization, and higher in vaginal washes following i.m. than i.r. or i.va. immunization. No differences in specific antibody responses were seen between animals immunized with BPV-1 P18 VLP or with BPV-1 V3 VLP. Cytotoxic T lymphocyte precursors specific for the P18 CTL epitope were recovered from the spleen following i.m., i.va. or i.r. immunization with P18 VLP, and were similarly detected in Peyer's patches following i.m. or i.r. immunization. Thus, mucosal or systemic immunization with PV VLP induces mucosal CTL responses and this may be important for vaccines for mucosal infection with human papillomaviruses and for other viruses.

Human Papillomavirus Type 16 L1 Capsomeres Induce L1-Specific Cytotoxic T Lymphocytes and Tumor Regression in C57BL/6 Mice

“…In fact, this mechanism was confirmed in two independent studies demonstrating that VLPs activate dendritic cells and trigger the presentation of CTL epitopes, thus leading to the activation of CD8 ϩ cells (21,39). Since immunogenicity was also demonstrated for other VLP-linked antigens (24,32), papillomavirus particles are considered suitable carriers for alien proteins, which by themselves are unable to induce an MHC-I-restricted immune response. The restrictions of the CVLPs available at this time are the small number of heterologous molecules per particle in the case of L2 fusions (at full occupancy yielding 1/30 of the molarity of the L1 molecules [15]) or the limited size of acceptable heterologous sequences in the case of the L1 fusions (up to 60 aa of the HPV16 E7 protein [30]).…”

Chimeric Human Papillomavirus Type 16 (HPV-16) L1 Particles Presenting the Common Neutralizing Epitope for the L2 Minor Capsid Protein of HPV-6 and HPV-16

“…There are a number of studies describing the use of PV VLPs to deliver and/or display foreign epitopes (11,22,23,25,27,37). L1 C-terminal fusion chimeras have worked well in presenting the epitopes of the HPV-16 E7 protein (15,25), human immunodeficiency virus type 1 (HIV-1) p18 cytotoxic T lymphocyte epitopes, and HIV-1 gp120 (22,23) and HIV-1 gp41 epitopes (37), in HPV-11, HPV-16, and bovine PV-1.…”

“…L1 C-terminal fusion chimeras have worked well in presenting the epitopes of the HPV-16 E7 protein (15,25), human immunodeficiency virus type 1 (HIV-1) p18 cytotoxic T lymphocyte epitopes, and HIV-1 gp120 (22,23) and HIV-1 gp41 epitopes (37), in HPV-11, HPV-16, and bovine PV-1. Attempts have been made to insert epitopes into the core sequences of the PV L1, with the result of capsomers rather than VLPs being formed (37).…”

“…Based on the reports of cross-reactivity of the neutralizing L2 epitope characterized by and the evidence that VLPs can be used to deliver foreign epitopes (14,15,22,23,25,26,28,32,34,37), we decided to investigate the possibility of making chimeric vaccine candidates with the L2 epitope displayed on HPV-16 L1 particles, which hopefully maintained the neutralizing MAb H16:V5 and H16:E70-binding epitopes. We constructed five HPV-16 L1 chimeras that displayed the L2 epitope as replacement sequences, expressed them in insect cells using a baculovirus expression system, and characterized the chimeric products with a panel of MAbs.…”

A virus-based vaccine may prevent cervical cancer

“…It is widely expected that a vaccine that generates cytotoxic CD8+ T cells directed against these oncoproteins may have therapeutic effect against established disease. Chimeric VLPs that have both L1 and E7 proteins have been constructed, in the hope that they may have preventive and therapeutic effects [29][30][31].…”