scholarly journals Virus-like Particle-Based L2 Vaccines against HPVs: Where Are We Today?

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 18 ◽  
Author(s):  
Rashi Yadav ◽  
Lukai Zhai ◽  
Ebenezer Tumban
Keyword(s):  
Amino Acids ◽  
Capsid Protein ◽  
Hpv Vaccine ◽  
Genital Warts ◽  
Human Papillomaviruses ◽  
Target Antigen ◽  
Sexually Transmitted ◽  
Virus Like Particle ◽  
Protective Antibodies ◽  
Hpv Types

Human papillomaviruses (HPVs) are the most common sexually transmitted infections worldwide. Ninety percent of infected individuals clear the infection within two years; however, in the remaining 10% of infected individuals, the infection(s) persists and ultimately leads to cancers (anogenital cancers and head and neck cancers) and genital warts. Fortunately, three prophylactic vaccines have been approved to protect against HPV infections. The most recent HPV vaccine, Gardasil-9 (a nonavalent vaccine), protects against seven HPV types associated with ~90% of cervical cancer and against two HPV types associated with ~90% genital warts with little cross-protection against non-vaccine HPV types. The current vaccines are based on virus-like particles (VLPs) derived from the major capsid protein, L1. The L1 protein is not conserved among HPV types. The minor capsid protein, L2, on the other hand, is highly conserved among HPV types and has been an alternative target antigen, for over two decades, to develop a broadly protective HPV vaccine. The L2 protein, unlike the L1, cannot form VLPs and as such, it is less immunogenic. This review summarizes current studies aimed at developing HPV L2 vaccines by multivalently displaying L2 peptides on VLPs derived from bacteriophages and eukaryotic viruses. Recent data show that a monovalent HPV L1 VLP as well as bivalent MS2 VLPs displaying HPV L2 peptides (representing amino acids 17–36 and/or consensus amino acids 69–86) elicit robust broadly protective antibodies against diverse HPV types (6/11/16/18/26/31/33/34/35/39/43/44/45/51/52/53/56/58/59/66/68/73) associated with cancers and genital warts. Thus, VLP-based L2 vaccines look promising and may be favorable, in the near future, over current L1-based HPV vaccines and should be explored further.

scholarly journals The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

2015 ◽  
Vol 59 (9) ◽  
pp. 5250-5259 ◽  
Author(s):  
Valeria Cagno ◽  
Manuela Donalisio ◽  
Antonella Bugatti ◽  
Andrea Civra ◽  
Roberta Cavalli ◽  
...  
Keyword(s):  
Cell Surface ◽  
Viral Infections ◽  
Human Papillomaviruses ◽  
Sexually Transmitted ◽  
Human Papillomavirus 16 ◽  
Virus Attachment ◽  
Hpv Types ◽  
Heparan Sulfates ◽  
Further Development ◽  
Topical Microbicide

ABSTRACTThe agmatine-containing poly(amidoamine) polymer AGMA1 was recently shown to inhibit the infectivity of several viruses, including human papillomavirus 16 (HPV-16), that exploit cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The aim of this work was to assess the antiviral activity of AGMA1 and its spectrum of activity against a panel of low-risk and high-risk HPVs and to elucidate its mechanism of action. AGMA1 was found to be a potent inhibitor of mucosal HPV types (i.e., types 16, 31, 45, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 0.34 μg/ml and 0.73 μg/ml, and no evidence of cytotoxicity was observed. AGMA1 interacted with immobilized heparin and with cellular heparan sulfates, exerting its antiviral action by preventing virus attachment to the cell surface. The findings from this study indicate that AGMA1 is a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections.

scholarly journals Broad Neutralization Responses Against Oncogenic Human Papillomaviruses Induced by a Minor Capsid L2 Polytope Genetically Incorporated Into Bacterial Ferritin Nanoparticles

2020 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Filipe C. Mariz ◽  
Xueer Zhao ◽  
Gloria Spagnoli ◽  
Simone Ottonello ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Capsid Protein ◽  
Pyrococcus Furiosus ◽  
Neutralizing Antibody ◽  
Hpv Infection ◽  
Cross Reactivity ◽  
Human Papillomaviruses ◽  
Promising Alternative ◽  
Peptide Epitope ◽  
Hpv Types

Cervical cancer remains a global health burden despite the introduction of highly effective vaccines for the prophylaxis of causative human papillomavirus infection (HPV). Current efforts to eradicate cervical cancer focus on the development of broadly protective, cost-effective approaches. HPV minor capsid protein L2 is being recognized as a promising alternative to the major capsid protein L1 because of its ability to induce responses against a wider range of different HPV types. However, a major limitation of L2 as a source of cross-neutralizing epitopes is its lower immunogenicity compared to L1 when assembled into VLPs. Various approaches have been proposed to overcome this limitation, we developed and tested ferritin-based bio-nanoparticles displaying tandemly repeated L2 epitopes from eight different HPV types grafted onto the surface of Pyrococcus furiosus thioredoxin (Pf Trx). Genetic fusion of the Pf Trx-L2(8x) module to P. furiosus ferritin (Pf Fe) did not interfere with ferritin self-assembly into an octahedral structure composed by 24 protomers. In guinea pigs and mice, the ferritin super-scaffolded, L2 antigen induced a broadly neutralizing antibody response covering 14 oncogenic and two non-oncogenic HPV types. Immune-responsiveness lasted for at least one year and the resulting antibodies also conferred protection in a cervico-vaginal mouse model of HPV infection. Given the broad organism distribution of thioredoxin and ferritin, we also verified the lack of cross-reactivity of the antibodies elicited against the scaffolds with human thioredoxin or ferritin. Altogether, the results of this study point to P. furiosus ferritin nanoparticles as a robust platform for the construction of peptide-epitope-based HPV vaccines.

scholarly journals Minor capsid protein L2 polytope induces broad protection against oncogenic and mucosal human papillomaviruses

2017 ◽  
pp. JVI.01930-17 ◽  
Author(s):  
Somayeh Pouyanfard ◽  
Gloria Spagnoli ◽  
Lorenzo Bulli ◽  
Kathrin Balz ◽  
Fan Yang ◽  
...  
Keyword(s):  
Capsid Protein ◽  
Vaccine Design ◽  
Neutralizing Antibody ◽  
Human Papillomaviruses ◽  
Minor Capsid Protein ◽  
Wide Range ◽  
Hpv Types ◽  
Prophylactic Vaccines ◽  
Oncogenic Hpv ◽  
Single Peptide

The amino terminus of the human papillomavirus minor capsid protein L2 contains a major cross-neutralization epitope which provides the basis for the development of a broadly protecting HPV vaccine. Wide range of protection against different HPV types would eliminate one of the major drawbacks of the commercial, L1 based prophylactic vaccines. Previously, we have reported that insertion of the L2 epitope into a scaffold composed of bacterial thioredoxin protein generates a potent antigen inducing comprehensive protection against different animal and human papillomaviruses. We also reported, however, that although protection is broad, some oncogenic HPV types escape the neutralizing antibody response, if L2 epitopes from single HPV types are used as immunogen. We were able to compensate for this by applying a mix of thioredoxin proteins carrying L2 epitopes from HPV types 16, 31, and 51. As the development of a cost-efficient HPV prophylactic vaccines is one of our objectives, this approach is not feasible as it requires the development of multiple good manufacturing production processes in combination with a complex vaccine formulation. Here we report the development of a thermostable thioredoxin based single peptide vaccine carrying an L2 polytope of up to 11 different HPV types. The L2 polytope antigens have excellent abilities in respect to broadness of protection and robustness of induced immune responses. To further increase immunogenicity, we fused the thioredoxin L2 polytope antigen with a heptamerization domain. In the final vaccine design, we achieve protective responses against all 14 oncogenic HPV types we have analyzed plus the low risk HPV types 6 and 11 and a number of cutaneous HPVs.ImportanceInfections by a large number of human papillomaviruses lead to malignant and non-malignant disease. Current commercial vaccines based on virus-like particles effectively protect against some HPV types but fail to do so for most others. Further, only about a third of all countries have access to the VLP vaccines. The minor capsid protein L2 has been shown to contain so called neutralization epitopes within its N-terminus. We designed polytopes comprising the L2 epitope amino acids 20-38 of up to 11 different mucosal HPV types and inserted them into the scaffold of thioredoxin derived from a thermophile achaebacterium. The antigen induced neutralizing antibody responses in mice and guinea pigs against 26 mucosal and cutaneous HPV types. Further, addition of a heptamerization domain significantly increased the immunogenicity. The final vaccine design comprising an heptamerized L2 8mer thioredoxin single peptide antigen with excellent thermal stability might overcome some of the limitations of the current VLP vaccines.

scholarly journals Mixed Bacteriophage MS2-L2 VLPs Elicit Long-Lasting Protective Antibodies against HPV Pseudovirus 51

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1113
Author(s):  
Rashi Yadav ◽  
Lukai Zhai ◽  
Nitesh K. Kunda ◽  
Pavan Muttil ◽  
Ebenezer Tumban
Keyword(s):  
Cervical Cancer ◽  
Genital Warts ◽  
Recurrent Respiratory Papillomatosis ◽  
Bacteriophage Ms2 ◽  
Skin Cancers ◽  
Current Vaccine ◽  
Freeze Dried ◽  
Protective Antibodies ◽  
Hpv Types ◽  
High Risk Hpv

Three prophylactic vaccines are approved to protect against HPV infections. These vaccines are highly immunogenic. The most recent HPV vaccine, Gardasil-9, protects against HPV types associated with ~90% of cervical cancer (worldwide). Thus, ~10% of HPV-associated cancers are not protected by Gardasil-9. Although this is not a large percentage overall, the HPV types associated with 10% of cervical cancer not protected by the current vaccine are significantly important, especially in HIV/AIDS patients who are infected with multiple HPV types. To broaden the spectrum of protection against HPV infections, we developed mixed MS2-L2 VLPs (MS2-31L2/16L2 VLPs and MS2-consL2 (69-86) VLPs) in a previous study. Immunization with the VLPs neutralized/protected mice against infection with eleven high-risk HPV types associated with ~95% of cervical cancer and against one low-risk HPV type associated with ~36% of genital warts & up to 32% of recurrent respiratory papillomatosis. Here, we report that the mixed MS2-L2 VLPs can protect mice from three additional HPV types: HPV51, which is associated with ~0.8% of cervical cancer; HPV6, which is associated with up to 60% of genital warts; HPV5, which is associated with skin cancers in patients with epidermodysplasia verruciformis (EV). Overall, mixed MS2-L2 VLPs can protect against twelve HPV types associated with ~95.8% of cervical cancers and against two HPV types associated with ~90% of genital warts and >90% recurrent respiratory papillomatosis. Additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with EV. More importantly, we observed that mixed MS2-L2 VLPs elicit protective antibodies that last over 9 months. Furthermore, a spray-freeze-dried formulation of the VLPs is stable, immunogenic, and protective at room temperature and 37 °C.

Evaluation of antibodies induced by an HPV vaccine to cross-neutralize pseudovirions of vaccine-related HPV types

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15008-15008 ◽  
Author(s):  
J. T. Bryan ◽  
J. F. Smith ◽  
W. Ruiz ◽  
M. K. Brownlow ◽  
M. J. Brown ◽  
...  
Keyword(s):  
Hpv Vaccine ◽  
Neutralizing Antibodies ◽  
Neutralization Titer ◽  
Indirect Measure ◽  
Virus Like Particle ◽  
Vaccine Type ◽  
Antibody Titers ◽  
Hpv Types ◽  
L1 And L2

15008 Background: Human papillomavirus (HPV) is the causative agent of cervical cancer. The HPV types 6, 11, 16 and 18 quadrivalent L1 virus-like particle (VLP) vaccine has been shown to be highly efficacious in preventing HPV vaccine type-related disease. The HPV A7 species contains types 18, 45 and 59. The A9 species include types 16, 31, 33, 35, 52 and 58. The potential of the vaccine induced antibodies to cross-neutralize infection of pseudovirions (PsV) of HPV types within the A9 and A7 species was evaluated. Methods: Sera from quadrivalent, monovalent HPV 16, or monovalent HPV 18 vaccinees were evaluated. Sera were tested in a multiplexed competitive Luminex Immunoassay (cLIA) against vaccine types to demonstrate HPV type-specific seroconversion. A9 and A7 VLP type cross-reactive binding ability was assessed by a total IgG LIA. HPV L1 and L2 PsV containing secreted alkaline-phosphatase (SEAP) sequences were constructed using native HPV sequences for 16 and 31 and with mammalian codon-optimized sequences for 18 and 45. Demonstrated expression of SEAP was used as an indirect measure of PsV infection of 293TT cells. Results: All subjects seroconverted to high titers against the vaccine HPV types. Cross-reactive antibodies were generated. Quadrivalent vaccinee sera bound to HPV 31, 45, 52 and 58 VLPs. These total IgG titers were 1.5–2 logs lower than the titers to the vaccine types. PsV types 18 and 45 were neutralized using the 18 monovalent and the quadrivalent sera. At month 7, the PsV 18 neutralization titer was ∼1–1.5 logs less than that required for PsV 45 cross-neutralization. Neutralization studies using PsV of the A9 species are in progress. Conclusions: High titers of anti-HPV antibodies are elicited by vaccination with HPV VLP vaccines. These antibodies can prevent in vitro PsV infection of vaccine-HPV types. Cross-reactive, cross-neutralizing antibodies are generated, however at reduced titers compared to the vaccine-specific types. Antibody titers required for cross-protection against non-vaccine types are not known. [Table: see text]

HPV Vaccine: Updates and Highlights

2019 ◽  
Vol 63 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Cristina Mendes de Oliveira ◽  
José Humberto T.G. Fregnani ◽  
Luisa Lina Villa
Keyword(s):  
Hpv Vaccine ◽  
Recombinant Dna ◽  
Vaccine Development ◽  
Recombinant Dna Technology ◽  
Men And Women ◽  
Sexually Transmitted ◽  
Hpv Types ◽  
Dna Technology ◽  
L1 Protein ◽  
High Risk Hpv

HPV is the most common sexually transmitted biological agent and is the cause of many conditions in men and women, including precancer lesions and cancer. Three prophylactic HPV vaccines targeting high-risk HPV types are available in many countries worldwide: 2-, 4- and 9-valent vaccines. All the 3 vaccines use recombinant DNA technology and are prepared from the purified L1 protein that self-assembles to form HPV type-specific empty shells. This non-systematic review aims to summarize the HPV epidemiology and the vaccine development to review the landmark trials of HPV vaccine, to present to most remarkable results from clinical trials and the real world, and to stress the challenges and the barriers for HPV vaccine implementation.

Potential Barriers to HPV Immunization: From Public Health to Personal Choice

2009 ◽  
Vol 35 (2-3) ◽  
pp. 389-399 ◽  
Author(s):  
Gregory D. Zimet
Keyword(s):  
High Risk ◽  
Genital Warts ◽  
Hpv Infection ◽  
Low Risk ◽  
Surgical Interventions ◽  
Sexually Transmitted ◽  
Potential Barriers ◽  
Cervical Cancers ◽  
Hpv Types ◽  
Serious Disease

Of the over 100 types of human papillomavirus (HPV), more than 40 can be sexually transmitted. Genital HPV infection is very common, with a point prevalence among women worldwide of approximately 10 percent. In most cases, HPV infection is either cleared or becomes undetectable and causes no disease; however, persistent HPV infection is causally related to all cervical cancers and genital warts. In addition, a large proportion of other cancers, such as vaginal, vulvar, anal, and penile cancers as well as many cancers of the head and neck, are associated with HPV infection. Moreover, recurrent respiratory papillomatosis (RRP) is a potentially serious disease caused by HPV types typically responsible for genital warts. RRP can lead to severe airways obstructions and may require repeated surgical interventions. HPV types are typically divided into high-risk types, most often associated with cancers, and low-risk types, typically associated with warts. High-risk types 16 and 18 are responsible for approximately 70 percent of cervical cancers worldwide, whereas low-risk types 6 and 11 are responsible for approximately 90 percent of genital warts.

scholarly journals Detection of Human Papillomaviruses DNA in paired peripheral blood and cervix samples patients with cervical lesions and healthy individuals

2021 ◽  
Author(s):  
Kamylla Conceicao Gomes Nascimento ◽  
Elyda Goncalves Lima ◽  
Barbara Simas Chagas ◽  
Zhilbelly Mota Nunes ◽  
Marconi Rego Barros Junior ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Intraepithelial Neoplasia ◽  
Human Papillomaviruses ◽  
Healthy Individuals ◽  
Cervical Lesions ◽  
Hpv16 E6 ◽  
Hpv Dna ◽  
Sexually Transmitted ◽  
Standard Procedures ◽  
Hpv Types

This study evaluated the presence of HPV DNA in the cervix and peripheral blood of women with cervical intraepithelial neoplasia (CIN I, II, and III) and healthy individuals. Overall, 139 paired peripheral blood and cervix samples of healthy women and women with CIN I, II, and III (n= 68) were tested for HPV DNA by using standard procedures. PCR-sequencing determined HPV types. Quantification of HPV16 E6 and E2 genes was performed to determine viral load and physical state. HPV DNA was detected in the cervix (21.1% in healthy individuals; 48.8-55.5% in CIN patients), blood (46.4% in healthy individuals; 44.1-77.7% in CIN patients), and paired peripheral blood and cervix samples (24% in healthy individuals; 32.5-44.4% in CIN patients). The most frequent types found in the cervix were HPV16, 18, 31, 33, 58, and 70, while HPV16, 18, 33, 58, and 66 were the most frequent types found in the blood. HPV DNA in the cervix was associated with previous sexually transmitted infections (STIs) (P=0.023; OR: 2.978; CI:1.34-7.821), HPV DNA in the blood (P=0.000; OR: 3.369; CI:3.700-18.540), and cervical lesions (CIN I/II or III) (P=0.001; OR: 3.369; CI:1.634-6.945). Binomial Logistic regression showed that HPV DNA in the blood (P=0.000; OR: 9.324; CI:3.612-24.072) and cervical lesions (P=0.011; OR: 3.622; CI:1.338-9.806) were associated with HPV DNA in the cervix. However, we did not find an association between HPV DNA in blood and cervical lesions (P=0.385). Our results showed that, although there is an association between HPV DNA in the cervix with HPV DNA in blood, only HPV DNA found in the cervix was associated with cervical lesions.

scholarly journals Identification of B-Cell Epitopes on Virus-Like Particles of Cutaneous Alpha-Human Papillomaviruses

2009 ◽  
Vol 83 (24) ◽  
pp. 12692-12701 ◽  
Author(s):  
Tilo Senger ◽  
Maria R. Becker ◽  
Lysann Schädlich ◽  
Tim Waterboer ◽  
Lutz Gissmann
Keyword(s):  
B Cell ◽  
Large Fraction ◽  
Human Papillomaviruses ◽  
B Cell Epitopes ◽  
Virus Like Particle ◽  
Linear Epitopes ◽  
Hpv Types ◽  
First Time

ABSTRACT Human papillomavirus (PV) (HPV) types 2, 27, and 57 are closely related and, hence, represent a promising model system to study the correlation of phylogenetic relationship and immunological distinctiveness of PVs. These HPV types cause a large fraction of cutaneous warts occurring in immunocompromised patients. Therefore, they constitute a target for the development of virus-like particle (VLP)-based vaccines. However, the immunogenic structure of HPV type 2, 27, and 57 capsids has not been studied yet. Here we provide, for the first time, a characterization of the B-cell epitopes on VLPs of cutaneous alpha-HPVs using a panel of 94 monoclonal antibodies (MAbs) generated upon immunization with capsids from HPV types 2, 27, and 57. The MAbs generated were characterized regarding their reactivities with glutathione S-transferase-L1 fusion proteins from 18 different PV types, the nature of their recognized epitopes, their isotypes, and their ability to neutralize HPV type 2, 27, 57, or 16. In total, 33 of the 94 MAbs (35%) showed type-specific reactivity. All type-specific MAbs recognize linear epitopes, most of which map to the hypervariable surface loop regions of the L1 amino acid sequence. Four of the generated MAbs neutralized pseudovirions of the inoculated HPV type efficiently. All four MAbs recognized epitopes within the BC loop, which is required and sufficient for their neutralizing activity. Our data highlight the immunological distinctiveness of individual HPV types, even in comparison to their closest relatives, and they provide a basis for the development of VLP-based vaccines against cutaneous alpha-HPVs.

scholarly journals Noninferiority of Antibody Response to Human Papillomavirus Type 16 in Subjects Vaccinated with Monovalent and Quadrivalent L1 Virus-Like Particle Vaccines

2007 ◽  
Vol 14 (6) ◽  
pp. 792-795 ◽  
Author(s):  
Suzanne M. Garland ◽  
Marc Steben ◽  
Mauricio Hernandez-Avila ◽  
Laura A. Koutsky ◽  
Cosette M. Wheeler ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Antibody Response ◽  
Hpv Vaccine ◽  
Multivalent Vaccine ◽  
Virus Like Particles ◽  
Human Papillomavirus Type 16 ◽  
Virus Like Particle ◽  
Hpv Types ◽  
Immune Interference

ABSTRACT The incorporation of multiple antigens into a single human papillomavirus (HPV) vaccine may induce immune interference. To evaluate whether interference occurs when HPV type 16 (HPV16) virus-like particles are combined in a multivalent vaccine, we conducted a study to evaluate anti-HPV16 responses among subjects receiving three-dose regimens of either a monovalent HPV16 vaccine or a quadrivalent HPV (types 6, 11, 16, and 18) vaccine.

Sign in / Sign up

Export Citation Format

Share Document