scholarly journals Chimeric L1-L2 Virus-Like Particles as Potential Broad-Spectrum Human Papillomavirus Vaccines

2009 ◽  
Vol 83 (19) ◽  
pp. 10085-10095 ◽  
Author(s):  
Christina Schellenbacher ◽  
Richard Roden ◽  
Reinhard Kirnbauer
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Capsid Protein ◽  
Broad Spectrum ◽  
Neutralizing Antibodies ◽  
Low Risk ◽  
Virus Like Particles ◽  
Monophosphoryl Lipid A ◽  
Hpv Types ◽  
Cross Neutralization

ABSTRACT The amino (N) terminus of the human papillomavirus (HPV) minor capsid protein L2 can induce low-titer, cross-neutralizing antibodies. The aim of this study was to improve immunogenicity of L2 peptides by surface display on highly ordered, self-assembled virus-like particles (VLP) of major capsid protein L1, and to more completely characterize neutralization epitopes of L2. Overlapping peptides comprising amino acids (aa) 2 to 22 (hereafter, chimera or peptide 2-22), 13 to 107, 18 to 31, 17 to 36, 35 to 75, 75 to 112, 115 to 154, 149 to 175, and 172 to 200 of HPV type 16 (HPV16) L2 were genetically engineered into the DE surface loop of bovine papillomavirus type 1 L1 VLP. Except for chimeras 35-75 and 13-107, recombinant fusion proteins assembled into VLP. Vaccination of rabbits with Freund's adjuvanted native VLP induced higher L2-specific antibody titers than vaccination with corresponding sodium dodecyl sulfate-denatured proteins. Immune sera to epitopes within residues 13 to 154 neutralized HPV16 in pseudovirion neutralization assays, whereas chimera 17-36 induced additional cross-neutralization to divergent high-risk HPV18, -31, -45, -52, and -58; low-risk HPV11; and beta-type HPV5 (titers of 50 to 10,000). Aluminum hydroxide-monophosphoryl lipid A (Alum-MPL)-adjuvanted VLP induced similar patterns of neutralization in both rabbits and mice, albeit with 100-fold-lower titers than Freund's adjuvant. Importantly, Alum-MPL-adjuvanted immunization with chimeric HPV16L1-HPV16L2 (peptide 17-36) VLP induced neutralization or cross-neutralization of HPV16, -18, -31, -45, -52, and -58; HPV6 and -11; and HPV5 (titers of 50 to 100,000). Immunization with HPV16 L1-HPV16 L2 (chimera 17-36) VLP in adjuvant applicable for human use induces broad-spectrum neutralizing antibodies against HPV types evolutionarily divergent to HPV16 and thus may protect against infection with mucosal high-risk, low-risk, and beta HPV types and associated disease.

scholarly journals Type-specific and cross-reactive antibodies induced by human papillomavirus 31 L1/L2 virus-like particles

2007 ◽  
Vol 56 (7) ◽  
pp. 907-913 ◽  
Author(s):  
Yufei Xu ◽  
Qingyong Wang ◽  
Yehua Han ◽  
Guoxing Song ◽  
Xuemei Xu
Keyword(s):  
Human Papillomavirus ◽  
Western Blotting ◽  
Neutralizing Antibodies ◽  
Cross Reaction ◽  
Hpv 16 ◽  
Virus Like Particles ◽  
Hpv Types ◽  
Cross Neutralization ◽  
The Cross ◽  
L1 Protein

The aim of this study was to determine whether antibodies induced by human papillomavirus (HPV) type 31 L1/L2 virus-like particles (VLPs) could cross-react with VLPs of the closely related HPV-16 and distantly related HPV-11, and to investigate the potential role of the L2 protein in L1/L2 VLPs in inducing cross-neutralizing antibodies. Antisera were prepared from rabbits immunized with intact or denatured HPV-31 L1/L2 VLPs. Cross-reaction and cross-neutralization were analysed by Western blotting and ELISA, and by haemagglutination inhibition, respectively. Western blotting results showed that H31 L1/L2 (D) antiserum (antiserum from a rabbit immunized with denatured HPV-31 L1/L2 VLPs) could cross-react with the L1 protein of HPV-11 and -16. HPV-31 L1/L2 VLP antiserum showed strong cross-reaction with and cross-neutralization of HPV-16 VLPs, but this was significantly less with HPV-11 VLPs. In addition, the cross-neutralizing activity against HPV-16 L1/L2 VLPs was slightly higher than that against HPV-16 L1 VLPs, although the difference was not statistically significant. Epitope-blocking ELISA showed that mAb H16.V5 could partially inhibit the cross-reaction of HPV-31 L1/L2 VLP antiserum with HPV-16 L1/L2 VLPs. These results suggested that (i) H31 L1/L2 (D) antiserum could cross-react with L1 protein from both closely related and distantly related HPV types, but HPV-31 L1/L2 VLP antiserum could only cross-neutralize closely related HPV types, (ii) surface-exposed epitopes of the L2 protein in L1/L2 VLPs may induce only low titres of cross-neutralizing antibodies and (iii) certain epitopes that cross-reacted with HPV-31 L1/L2 VLP antiserum are located close to the epitopes recognized by mAb H16.V5. These findings may provide suggestions for the design of multivalent VLP vaccines.

scholarly journals Skin and Mucosal Human Papillomavirus Seroprevalence in Persons with Fanconi Anemia

2015 ◽  
Vol 22 (4) ◽  
pp. 413-420 ◽  
Author(s):  
Rachel A. Katzenellenbogen ◽  
Joseph J. Carter ◽  
Joshua E. Stern ◽  
Melinda S. Butsch Kovacic ◽  
Parinda A. Mehta ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Fanconi Anemia ◽  
Hpv Vaccine ◽  
Hpv Vaccination ◽  
Low Risk ◽  
Luminex Assay ◽  
History Of ◽  
Hpv Types ◽  
And Behavior

ABSTRACTPersons with Fanconi anemia (FA) are at risk for human papillomavirus (HPV)-associated cancers; however, their natural HPV exposure and infection rates are unknown as is the adequacy with which they mount antibodies to HPV vaccination. This study aimed to determine, in 62 persons with FA, the seroprevalence of skin and mucosal HPV types, the seroprevalence in individuals self-reporting a history of HPV vaccination, and the factors associated with HPV seropositivity. A bead Luminex assay was used to determine seropositivity for HPV1, -2, and -4 (low-risk skin), -6 and -11 (low-risk mucosal, included in one HPV vaccine), -16 and -18 (high-risk mucosal, included in both HPV vaccines), and -52 and -58 (high-risk mucosal). Health- and behavior-related questionnaires were completed. Type-specific seroprevalence estimates and participant characteristics associated with seroprevalence were calculated; 48% reported HPV vaccination. Type-specific seropositivity in unvaccinated persons ranged from 7 to 21% for skin HPV types and 7 to 38% for mucosal HPV types. Among the unvaccinated participants, adults versus children demonstrated increased HPV1, -6, -16, and -58 seroprevalence of 45% versus 6%, 64% versus 22%, 64% versus 17%, and 36% versus 0%, respectively (allP< 0.05). The vaccinated participants versus the nonvaccinated participants demonstrated increased seroprevalence of HPV6, -11, -16, and -18 of 92% versus 38%, 92% versus 24%, 96% versus 34%, and 75% versus 7%, respectively (allP< 0.0001). Our data demonstrate that the unvaccinated participants had serologic evidence of prior skin and mucosal HPV infections and that seroprevalence increased among adults; in self-reported vaccinees, seroprevalence of HPV vaccine types was 75 to 96%.

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

2016 ◽  
Vol 90 (14) ◽  
pp. 6314-6325 ◽  
Author(s):  
Mathieu Boxus ◽  
Michel Fochesato ◽  
Agnès Miseur ◽  
Emmanuel Mertens ◽  
Najoua Dendouga ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Capsid Protein ◽  
Major Capsid Protein ◽  
Amino Acid Residues ◽  
Hpv 16 ◽  
Virus Like Particles ◽  
C Terminus ◽  
Hpv 18 ◽  
Neutralizing Epitopes

ABSTRACTAt 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.

scholarly journals Additional Human Papillomavirus Types Detected by the Hybrid Capture Tube Test among Samples from Women with Cytological and Colposcopical Atypia

2000 ◽  
Vol 38 (1) ◽  
pp. 408-411
Author(s):  
József Kónya ◽  
György Veress ◽  
Attila Juhász ◽  
Krisztina Szarka ◽  
Tamás Sápy ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Fragment Length Polymorphism ◽  
Low Risk ◽  
Double Positive ◽  
Detection Range ◽  
Hybrid Capture ◽  
Pcr Rflp ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACT The type specificity of the human papillomavirus (HPV) Hybrid Capture Tube (HCT) test was evaluated by using typing with PCR (MY09-MY11)-restriction fragment length polymorphism (RFLP) and sequencing. All samples HCT test positive for only low-risk HPV ( n = 15) or only high-risk HPV ( n = 102) were confirmed, whereas 9 of 12 HCT test double-positive samples contained only high-risk HPV types as determined by PCR-RFLP. Several high-risk HPV types (HPV-53, -58, -62, -66, -CP8304, and -MM4) not included in the HCT test were indeed detected, indicating a broader detection range with retained distinction between low-risk and high-risk HPV types.

scholarly journals Cellular Changes Induced by Low-Risk Human Papillomavirus Type 11 in Keratinocytes That Stably Maintain Viral Episomes

2001 ◽  
Vol 75 (16) ◽  
pp. 7564-7571 ◽  
Author(s):  
Jennifer T. Thomas ◽  
Stephen T. Oh ◽  
Scott S. Terhune ◽  
Laimonis A. Laimins
Keyword(s):  
Human Papillomavirus ◽  
Life Cycle ◽  
High Risk ◽  
Life Cycles ◽  
Low Risk ◽  
Global Changes ◽  
Culture Methods ◽  
Transfected Cells ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACT Infections by low-risk papillomavirus types, such as human papillomavirus (HPV) type 6 (HPV-6) and HPV-11, induce benign genital warts that rarely progress to malignancy. In contrast, lesions induced by high-risk HPV types have the potential to progress to cancer. Considerable information is available concerning the pathogenesis of high-risk HPV types, but little is known about the life cycle of low-risk HPV types. Although functionally distinct, both high- and low-risk virus types infect keratinocytes and induce virion production upon differentiation. This information suggests that they may share common mechanisms for regulating their productive life cycles. Using tissue culture methods developed to study high-risk HPV types, we examined the ability of HPV-11 to be stably maintained as episomes following transfection of normal human keratinocytes with cloned viral DNA. HPV-11 genomes were found to be maintained in keratinocytes for extended passages in cultures in 14 independent experiments involving transfection of cloned HPV-11 DNA. Interestingly, the HPV-11-positive cells exhibited an extended life span that averaged approximately twofold longer than that of control neomycin-transfected cells. In organotypic cultures, HPV-11-positive cells exhibited altered differentiation patterns, but the extent of disruption was less severe than that seen with high-risk HPV types. In addition, the amplification of HPV-11 DNA, as well as the induction of several viral messages, was observed following differentiation of transfected cells in semisolid media. To determine whether global changes in cellular gene expression induced by HPV-11 were similar to those observed with high-risk HPV-31 (Y. E. Chang and L. A. Laimins, J. Virol. 74:4174–4182, 2000), microarray analysis of 7,075 expressed sequences was performed. A spectrum of cellular genes different from that previously reported for HPV-31 was found to be activated or repressed by HPV-11. The expression of only a small set of genes was similarly altered by both high- and low-risk HPV types. This result suggests that different classes of HPVs have distinct effects on global cellular transcription patterns during infection. The methods described allow for a genetic analysis of HPV-11 in the context of its differentiation-dependent life cycle.

scholarly journals Human papillomavirus infection prevalence in female university students in Novi Sad, Serbia

2016 ◽  
Vol 144 (5-6) ◽  
pp. 300-306 ◽  
Author(s):  
Gordana Kovacevic ◽  
Aleksandra Jovanovic-Galovic ◽  
Vladimir Petrovic ◽  
Zeljka Vinarz ◽  
Gordana Marinkovic ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
University Students ◽  
Statistical Significance ◽  
Hpv Infection ◽  
Low Risk ◽  
Infection Prevalence ◽  
Gynecological Examination ◽  
Hpv Types ◽  
Novi Sad

Introduction. Cervical cancer, attributed to human papillomavirus (HPV) infection, represents the fourth most common and lethal cancer in Serbian women, and the second most common cancer in women aged 15-44. Objective. The aim of the study was to determine the presence of high-risk and low-risk HPV types in population of unvaccinated female university students in Novi Sad, Serbia, and to evaluate possible risk factors for HPV infection. Methods. Sample consisted of 250 young women (19-26 years of age) attending outpatient clinics for screening gynecological examination. All participants in the study completed a specially designed anonymous questionnaire. For the detection of HPV DNA, two commercial kits - High Risk HPV Real-TM and Low Risk HPV 6/11 Real-TM (Sacace Biotechnologies, Como, Italy) were used. Thirty positive samples were retested by GenoFlow HPV Array Test (DiagCor Bioscience Incorporation Limited, Hong Kong, China). Results. The overall prevalence rate of HPV was 61.6%. The most common HPV types in the present study were as follows: HPV 16, 31, 51, 52, and 18. Female students with only one sexual partner had significantly lower chance of having HPV infection. Other variables describing lifestyle did not show statistical significance. Conclusion. The present paper provides data on the prevalence of high- and low-risk HPV genotypes among university students in Novi Sad. Obtained results indicate the need for educational activities on sexually transmitted infections, including HPV, together with promotion of healthy lifestyles. According to our results, bivalent and quadrivalent prophylactic vaccines have the potential to prevent over 50% of infections. Percentage of protection with a second-generation prophylactic nonavalent vaccine would be more than 80%.

scholarly journals HPV-Impfstoffe – zugelassene Vakzinen und experimenteller RG1-VLP-Impfstoff der nächsten Generation

hautnah ◽  
2021 ◽  
Author(s):  
Christina Schellenbacher ◽  
Bettina Huber ◽  
Saeed Shafti-Keramat ◽  
Reinhard Kirnbauer
Keyword(s):  
High Risk ◽  
Phase I ◽  
Low Risk ◽  
Next Generation ◽  
Virus Like Particles

ZusammenfassungInfektionen mit >12 sexuell übertragbaren genitalen „high-risk“ (hr) humanen Papillomviren (HPV) sind hauptverantwortlich für anogenitale Karzinome, insbesondere Zervix- und Analkarzinome sowie oropharyngeale Karzinome, insgesamt für 5 % der Karzinome weltweit. Genitale „low-risk“ (lr) HPV und kutane HPV verursachen Anogenitalwarzen (Kondylome) bzw. Hautwarzen, kutane Genus β‑HPV sind ein potenzieller Kofaktor für die Entwicklung nichtmelanozytärer Hautkarzinome in Immunsupprimierten. Die zugelassenen HPV-Vakzinen sind Spaltimpfstoffe bestehend aus leeren Hauptkapsidproteinhüllen (L1-virus-like particles, VLP). Die prophylaktische Impfung mit dem modernen nonavalenten Impfstoff Gardasil‑9 (HPV6/11/16/18/31/33/45/52/58) verhindert persistierende Infektionen mit Typen, die bis zu 90 % der Zervixkarzinome und Kondylome verursachen. Der Impfschutz ist vorwiegend typenspezifisch, daher besteht kein Schutz gegen Infektionen mit den übrigen genitalen hrHPV oder Hauttypen. RG1-VLP ist ein experimenteller „next generation“-Impfstoff, bestehend aus HPV16L1-VLP, welche ein Kreuzneutralisierungs-Epitop des HPV16 Nebenkapsidproteins L2 („RG1“; Aminosäuren 17–36) repetitiv (360×) an der Oberfläche tragen. Eine Vakzinierung mit RG1-VLP schützt im Tierversuch gegen experimentelle Infektionen mit allen relevanten genitalen hrHPV (~96 % aller Zervixkarzinome), lrHPV (~90 % der Kondylome) sowie gegen einige kutane und β‑HPV. Präklinische Daten zeigen langanhaltende Protektion ohne Boosterimmunisierung ein Jahr nach der Impfung sowie Wirksamkeit nach nur 2 Dosen. Auch in lyophilisierter, thermostabiler Form bleibt die Immunogenität der RG1-VLP erhalten. Eine Phase-I-Studie ist mit Unterstützung des US NCI/NIH in Vorbereitung. Der vorliegende Artikel diskutiert Fragestellungen zur HPV-Impfstoffoptimierung und präsentiert den pan-HPV-Impfstoffkandidat RG1-VLP.

scholarly journals Development of Neutralizing Monoclonal Antibodies for Oncogenic Human Papillomavirus Types 31, 33, 45, 52, and 58

2014 ◽  
Vol 21 (4) ◽  
pp. 587-593 ◽  
Author(s):  
Martha J. Brown ◽  
Hanna Seitz ◽  
Victoria Towne ◽  
Martin Müller ◽  
Adam C. Finnefrock
Keyword(s):  
Monoclonal Antibodies ◽  
Human Papillomavirus ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Cervical Cancers ◽  
Hpv Types ◽  
Oncogenic Hpv ◽  
Neutralizing Epitopes ◽  
Selection Of

ABSTRACTHuman papillomavirus (HPV) is the etiological agent for all cervical cancers, a significant number of other anogenital cancers, and a growing number of head and neck cancers. Two licensed vaccines offer protection against the most prevalent oncogenic types, 16 and 18, responsible for approximately 70% of cervical cancer cases worldwide and one of these also offers protection against types 6 and 11, responsible for 90% of genital warts. The vaccines are comprised of recombinantly expressed major capsid proteins that self-assemble into virus-like particles (VLPs) and prevent infection by eliciting neutralizing antibodies. Adding the other frequently identified oncogenic types 31, 33, 45, 52, and 58 to a vaccine would increase the coverage against HPV-induced cancers to approximately 90%. We describe the generation and characterization of panels of monoclonal antibodies to these five additional oncogenic HPV types, and the selection of antibody pairs that were high affinity and type specific and recognized conformation-dependent neutralizing epitopes. Such characteristics make these antibodies useful tools for monitoring the production and potency of a prototype vaccine as well as monitoring vaccine-induced immune responses in the clinic.

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