A papillomavirus-like particle (VLP) vaccine displaying HPV16 L2 epitopes induces cross-neutralizing antibodies to HPV11

Slupetzky, Katharina; Gambhira, Ratish; Culp, Timothy D.; Shafti-Keramat, Saeed; Schellenbacher, Christina; Christensen, Neil D.; Roden, Richard B.S.; Kirnbauer, Reinhard

doi:10.1016/j.vaccine.2006.11.049

Cited by 96 publications

(91 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our data are consistent with the finding that targeting the N terminus is neutralizing at a stage after binding and entry. The role of L2 during early entry has been shown to be primarily after virus binding and has been attributed to the findings that parts of the N terminus of L2 seem to loop out of the viral capsid in the fully formed particle or are exposed after a conformational change that occurs after the virus binds to the target cells (29,30,32,36,41,43,46,48,52). It was previously suggested that the L2 region encompassing residues 41 to 44 was exposed on the outside of pseudoviral particles using an enzyme-linked immunosorbent trap assay (30), but this has not been confirmed by EM.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been suggested by enzyme-linked pseudovirion capture assay using an L2 antibody that HPV type 16 residues 14 to 144 and in particular residues 32 to 81 are likely to reside on the surface of the viral capsid (30). These EM and neutralization data have led to several studies addressing the use of papillomavirus L2 sequences as vaccine targets for specific and multiple PV genotypes since the regions of L2 shown to be exposed on the capsid surface are more conserved than the loops of the L1 protein (29,30,36,43,48). In addition, there is evidence that upon cell binding, a conformational change allows for the exposure of hidden L2 residues that can serve as neutralizing epitopes (41,46,52).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Bovine Papillomavirus Type 1 Infection Is Mediated by SNARE Syntaxin 18

Laniosz¹,

Nguyen

Meneses

2007

J Virol

View full text Add to dashboard Cite

Events that lead to viral infections include the binding of the virus to the target cells, internalization of the virus into the cells, and the ability of the viral genome to be expressed. These steps are mediated by cellular and viral proteins and are temporally regulated. The papillomavirus capsid consists of two virally encoded capsid proteins, L1 and L2. Much is known about the role of the major capsid protein L1 compared to what is known of the role of the L2 protein. We identified the interaction of the L2 protein with SNARE protein syntaxin 18, which mediates the trafficking of vesicles and their cargo between the endoplasmic reticulum, the cis-Golgi compartment, and possibly the plasma membrane. Mutations of L2 residues 41 to 44 prevented the interaction of L2 protein with syntaxin 18 in cotransfection experiments and resulted in noninfectious pseudovirions. In this paper, we describe that syntaxin 18 colocalizes with infectious bovine papillomavirus type 1 (BPV1) pseudovirions during infection but does not colocalize with the noninfectious BPV1 pseudovirions made with an L2 mutant at residues 41 to 44. We show that an antibody against BPV1 L2 residues 36 to 49 (␣L2 36-49) binds to in vitro-generated BPV1 pseudoviral capsids and does not coimmunoprecipitate syntaxin 18-and BPV1 L2-transfected proteins. ␣L2 36-49 was able to partially or completely neutralize infection of BPV1 pseudovirions and genuine virions. These results support the dependence of syntaxin 18 during BPV1 infection and the ability to interfere with infection by targeting the L2-syntaxin 18 interaction and further define the infectious route of BPV1 mediated by the L2 protein.Papillomaviruses (PVs) induce a variety of lesions such as cutaneous or genital warts in humans and exophytic papillomas of cutaneous or mucosal epithelia in animals. Human PV (HPV) infection is the most common sexually transmitted disease in the United States (approximately 5.5 million cases per annum) (31), and specific HPV genotypes (high risk) are the etiologic agents of cervical carcinoma, a major killer of women worldwide (23,(37)(38)(39). Bovine PV (BPV) infection causes benign tumors, which can result in squamous cell carcinoma in the presence of environmental factors such as bracken (7).The PV capsids consist primarily of two virally encoded proteins, L1 and L2, at an estimated ratio of 30:1 (17, 49). The L1/L2 ratio suggests that there is one L2 at each of 12 capsid vertices (49). Each viral particle contains a single doublestranded circular DNA genome of about 8 kb bound by histone proteins (15, 24), and the virus is assembled in the nucleus of squamous epithelial cells into particles that are 52 to 55 nm in diameter (9).The expression of the viral L1 protein in the absence of other viral proteins results in the packaging of viral DNA at inefficient levels (5, 50). The addition of L2 to viral particle production increases DNA packaging into virions (28, 53) and contributes to the infectious process of the virus (2, 18). Antibodies to L2 have proven to be ...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Bovine Papillomavirus Type 1 Infection Is Mediated by SNARE Syntaxin 18

Laniosz¹,

Nguyen

Meneses

2007

J Virol

View full text Add to dashboard Cite

show abstract

“…An alternative strategy to broaden the protection of HPV vaccines that is also being considered is to use conserved epitopes from the L2 minor capsid protein incorporated into HPV L1 VLPs (22)(23)(24)(25)(26)(27)(28)(29). This strategy is supported by evidence that vaccines based on L2 peptides can confer broad protection in mouse or rabbit HPV challenge models and elicit neutralizing antibodies against a wide range of HPVs (27,(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles

Boxus

Fochesato

Miseur

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

At least 15 high-risk human papillomaviruses (HPVs) are linked to anogenital preneoplastic lesions and cancer. Currently, there are three licensed prophylactic HPV vaccines based on virus-like particles (VLPs) of the L1 major capsid protein from HPV-2, -4, or -9, including the AS04-adjuvanted HPV-16/18 L1 vaccine. The L2 minor capsid protein contains HPV-neutralizing epitopes that are well conserved across numerous high-risk HPVs. Therefore, the objective of our study was to assess the capacity to broaden vaccine-mediated protection using AS04-adjuvanted vaccines based on VLP chimeras of L1 with one or two L2 epitopes. Several chimeric VLPs were constructed by inserting L2 epitopes within the DE loop and/or C terminus of L1. Based on the shape, yield, size, and immunogenicity, one of seven chimeras was selected for further evaluation in mouse and rabbit challenge models. The chimeric VLP consisted of HPV-18 L1 with insertions of HPV-33 L2 (amino acid residues 17 to 36; L1 DE loop) and HPV-58 L2 (amino acid residues 56 to 75; L1 C terminus). This chimeric L1/L2 VLP vaccine induced persistent immune responses and protected against all of the different HPVs evaluated (HPV-6, -11, -16, -31, -35, -39, -45, -58, and -59 as pseudovirions or quasivirions) in both mouse and rabbit challenge models. The degree and breadth of protection in the rabbit were further enhanced when the chimeric L1/L2 VLP was formulated with the L1 VLPs from the HPV-16/18 L1 vaccine. Therefore, the novel HPV-18 L1/L2 chimeric VLP (alone or in combination with HPV-16 and HPV-18 L1 VLPs) formulated with AS04 has the potential to provide broad protective efficacy in human subjects. IMPORTANCEFrom evaluations in human papillomavirus (HPV) protection models in rabbits and mice, our study has identified a prophylactic vaccine with the potential to target a wide range of HPVs linked to anogenital cancer. The three currently licensed vaccines contain virus-like particles (VLPs) of the L1 major capsid protein from two, four, or nine different HPVs. Rather than increasing the diversity of L1 VLPs, this vaccine contains VLPs based on a recombinant chimera of two highly conserved neutralizing epitopes from the L2 capsid protein inserted into L1. Our study demonstrated that the chimeric L1/L2 VLP is an effective vehicle for displaying two different L2 epitopes and can be used in a quantity equivalent to what is used in the licensed vaccines. Hence, using the chimeric L1/L2 VLP may be a more cost-effective approach for vaccine formulation than adding different VLPs for each HPV. O ncogenic human papillomaviruses (HPVs) cause cervical cancer (1), and it is widely considered that all cervical cancers are linked to at least one HPV (2-5). The oncogenic HPV-16 and HPV-18 are detected in approximately 70% of HPV-positive cervical cancers and represent the two HPVs most frequently detected in these cancers (3,(6)(7)(8). Other high-risk oncogenic HPVs also detected in cervical cancer include 7,8). In addition to cervical cancer, other HPVs, such as HPV-5, ha...

show abstract

“…A number of different VLPs were shown to be highly immunogenic antigen carriers capable of inducing humoral immune responses. For example, VLPs expressing proteins from influenza virus, papillomavirus, and rotavirus all induce high titers of neutralizing or protective antibodies (25,28,35). Some VLPs were also shown to induce CTL responses.…”

mentioning

confidence: 99%