In Vivo Mechanisms of Vaccine-Induced Protection against HPV Infection

Laboratory of Cellular Oncology, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892, USA.
Cell host & microbe (Impact Factor: 12.33). 09/2010; 8(3):260-70. DOI: 10.1016/j.chom.2010.08.003
Source: PubMed


Using a human papillomavirus (HPV) cervicovaginal murine challenge model, we microscopically examined the in vivo mechanisms of L1 virus-like particle (VLP) and L2 vaccine-induced inhibition of infection. In vivo HPV infection requires an initial association with the acellular basement membrane (BM) to induce conformational changes in the virion that permit its association with the keratinocyte cell surface. By passive transfer of immune serum, we determined that anti-L1 antibodies can interfere with infection at two stages. Similarly to active VLP immunization, transfer of high L1 antibody concentrations prevented BM binding. However, in the presence of low concentrations of anti-L1, virions associated with the BM, but to the epithelial cell surface was not detected. Regardless of the concentration, L2 vaccine-induced antibodies allow BM association but prevent association with the cell surface. Thus, we have revealed distinct mechanisms of vaccine-induced inhibition of virus infection in vivo.


Available from: Patricia M Day
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    • "These studies showed that protection from oral canine papillomavirus infection was provided by passive transfer of hyperimmune IgG collected from regressor animals, supporting a role for systemic humoral immunity in healing from oral papillomas (Ghim et al., 2000; Suzich et al., 1995). Furthermore recent data from mammalian models, assessing passive immunization with sera from animals immunized with the commercially available vaccines, showed that anti- HPV antibodies are protective even at low titres (Day et al., 2010). This evidence is of particular importance, accounting for the efficiency of cross-protecting anti-HPV antibodies toward non-vaccine types, despite they are generally under-represented compared to vaccine type ones. "
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    ABSTRACT: Background: Semen represents a reservoir for human papillomavirus (HPV), rising concern in couples eligible for assisted reproduction techniques (ART). Humoral immunity against HPV is considered to protect from reinfec-tion. We investigated the impact of vaccination on virus clearance in a cohort of infertile male patients showing HPV semen infection. Methods: 179 out of 619 infertile patients, showing HPV-DNA detection in semen by FISH analysis, were enrolled. Subjects were split into 91 vaccine-sensitive (VSPs) and 88 nonvaccine-sensitive patients (NVSPs) by INNO-LiPA. 19 VSPs showed vaccine-type specific seroconvesion at recruitment. All patients underwent specific counselling. 42 seronegative VSPs were randomly assigned to receive quadrivalent vaccination in 6 months, whilst 49 VSPs, 19 seroconverted and 30 seronegative, served as controls. The prevalence of HPV-DNA semen infection and se-rology was studied in a follow-up of 24 months. Results: Compared to seronegative patients, VSP seroconverted at recruitment showed absence of multiple infections and reduced prevalence of HPV semen infection at 12 (P = 0.039), 18 (P = 0.034) and 24 months (P = 0.034) of follow-up. Vaccinated VSP showed improved healing (P = 0.001 at 6 months and P b 0.001 at 12 months vs seroconverted VSP), achieving clearance in 12 months. Discussion: Humoral immunity has a major role in healing from HPV infection. Elder ART patients with HPV semen infection may benefit by the union of both specific counselling and available prophylactic vaccination.
    10/2015; DOI:10.1016/j.ebiom.2015.09.005
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    • "Day et al identified spatio-temporal differences during the early events of HPV infection in vivo versus the in vitro infection of 293TT cells resulting in an abbreviated opportunity for furin cleavage of L2, exposure of its neutralization epitopes on the virus surface and thus for L2-mediated neutralization to occur in the L1-PBNA [33], [34], [35]. To enhance the sensitivity for L2-specific neutralizing antibodies, improved neutralization assays have been developed recently [36], [37], [38]. "
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    ABSTRACT: Antibodies specific for neutralizing epitopes in either Human papillomavirus (HPV) capsid protein L1 or L2 can mediate protection from viral challenge and thus their accurate and sensitive measurement at high throughput is likely informative for monitoring response to prophylactic vaccination. Here we compare measurement of L1 and L2-specific neutralizing antibodies in human sera using the standard Pseudovirion-Based Neutralization Assay (L1-PBNA) with the newer Furin-Cleaved Pseudovirion-Based Neutralization Assay (FC-PBNA), a modification of the L1-PBNA intended to improve sensitivity towards L2-specific neutralizing antibodies without compromising assay of L1-specific responses. For detection of L1-specific neutralizing antibodies in human sera, the FC- PBNA and L1-PBNA assays showed similar sensitivity and a high level of correlation using WHO standard sera (n = 2), and sera from patients vaccinated with Gardasil (n = 30) or an experimental human papillomavirus type 16 (HPV16) L1 VLP vaccine (n = 70). The detection of L1-specific cross-neutralizing antibodies in these sera using pseudovirions of types phylogenetically-related to those targeted by the L1 virus-like particle (VLP) vaccines was also consistent between the two assays. However, for sera from patients (n = 17) vaccinated with an L2-based immunogen (TA-CIN), the FC-PBNA was more sensitive than the L1-PBNA in detecting L2-specific neutralizing antibodies. Further, the neutralizing antibody titers measured with the FC-PBNA correlated with those determined with the L2-PBNA, another modification of the L1-PBNA that spacio-temporally separates primary and secondary receptor engagement, as well as the protective titers measured using passive transfer studies in the murine genital-challenge model. In sum, the FC-PBNA provided sensitive measurement for both L1 VLP and L2-specific neutralizing antibody in human sera. Vaccination with TA-CIN elicits weak cross-protective antibody in a subset of patients, suggesting the need for an adjuvant.
    PLoS ONE 07/2014; 9(7):e101576. DOI:10.1371/journal.pone.0101576 · 3.23 Impact Factor
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    • "More significantly , vaccination studies with L2 in animal challenge models showed the production of antibodies neutralizing for a wide spectrum of PV types, and similarly broad protection from experimental viral challenges (Campo et al., 1997; Embers et al., 2002; Gambhira et al., 2007a; Jagu et al., 2009; Kawana et al., 2001a, 2001b; Lin et al., 1992). Passive transfer of L2-specific neutralizing antibodies is sufficient to mediate protection of mice from cutaneous or vaginal challenge with HPV pseudovirions (Day et al., 2010; Gambhira et al., 2007a, 2007b; Jagu et al., 2013). While some variation in these neutralizing epitopes is apparent (Seitz et al., 2013), sequence comparison at the N-terminus of L2 reveals high conservation across PV types (Fig. 5), including Table 2 Published list of known protein interactions with PV L2. "
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    ABSTRACT: The capsid protein L2 plays major roles in both papillomavirus assembly and the infectious process. While L1 forms the majority of the capsid and can self-assemble into empty virus-like particles (VLPs), L2 is a minor capsid component and lacks the capacity to form VLPs. However, L2 co-assembles with L1 into VLPs, enhancing their assembly. L2 also facilitates encapsidation of the ∼8kbp circular and nucleosome-bound viral genome during assembly of the non-enveloped T=7d virions in the nucleus of terminally differentiated epithelial cells, although, like L1, L2 is not detectably expressed in infected basal cells. With respect to infection, L2 is not required for particles to bind to and enter cells. However L2 must be cleaved by furin for endosome escape. L2 then travels with the viral genome to the nucleus, wherein it accumulates at ND-10 domains. Here, we provide an overview of the biology of L2.
    Virology 05/2013; 445(1-2). DOI:10.1016/j.virol.2013.04.017 · 3.32 Impact Factor
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