A three component mix of thioredoxin-L2 antigens elicits broadly neutralizing responses against oncogenic human papillomaviruses

Seitz, Hanna; Canali, Elena; Ribeiro-Müller, Lis; Pálfí, Anikó; Bolchi, Angelo; Tommasino, Massimo; Ottonello, Simone; Müller, Martin

doi:10.1016/j.vaccine.2014.03.033

Cited by 30 publications

(37 citation statements)

References 25 publications

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“…2). Consistent with our previous results (19), the PfTrx-L2 mix elicited comparable HPV16 type-specific responses ( Fig. 2A) in addition to significantly broader cross-reactivity ( Fig.…”

Section: Superior In Vitro Cross-neutralization Capacity Of the Pftrxsupporting

confidence: 92%

“…mice (19), PfTrx-16L2 extended neutralization to HPV51 in guinea pigs as effectively as PfTrx-51L2. However, fairly low anti-HPV31 neutralization titers were induced in guinea pigs by PfTrx-L2 mix, whereas the opposite was observed with HPV16-L1-VLPs.…”

Section: Discussionmentioning

confidence: 96%

“…We recently demonstrated the superior cross-neutralization responses elicited by a trivalent mixture of E. coli thioredoxin-L2 immunogens bearing L2 sequences from HPV16, 31, and 51 compared with the corresponding monovalent antigens (19). Because the latter study only measured in vitro neutralization, we wished to further investigate the immune performance of the Trx-L2 mix via a comprehensive set of in vivo (vaginal challenge and passive transfer) and in vitro (L1-and L2-PBNA) assays, using monovalent Trx-16L2 and HPV16-L1-VLPs as reference immunogens.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cross-neutralization was not extended to notable high-risk HPV types, including HPV31. We recently showed that a trivalent mixture of monovalent E. coli thioredoxin-L2 antigens bearing L2 (20-38) epitopes from HPV16, HPV31, and HPV51 elicits a broader and more robust neutralization than individual monovalent antigens (19). We also showed that Trx-HPV16-L2 based on a far-divergent and hyperthermostable thioredoxin from Pyrococcus furiosus is as immunogenic as E. coli Trx-L2, but comes with the added benefits of (i) reduced cross-reactivity with human thioredoxin; (ii) a simplified purification; and (iii) a strikingly increased thermal stability (>12 h at 100 C, apparent Tm > 95 C; ref.…”

Section: Introductionmentioning

confidence: 99%

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Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine

Seitz

Ribeiro-Müller

Canali

et al. 2015

Cancer Prevention Research

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Current prophylactic virus-like particle (VLP) human papillomavirus (HPV) vaccines are based on the L1 major capsid protein and provide robust but virus type-restricted protection. Moreover, VLP vaccines have a high production cost, require cold-chain storage, and are thus not readily implementable in developing countries, which endure 85% of the cervical cancer-related death burden worldwide. In contrast with L1, immunization with minor capsid protein L2 elicits broad cross-neutralization, and we previously showed that insertion of a peptide spanning amino acids 20-38 of L2 into bacterial thioredoxin (Trx) greatly enhances its immunogenicity. Building on this finding, we use, here, four different neutralization assays to demonstrate that low doses of a trivalent Trx-L2 vaccine, incorporating L2(20-38) epitopes from HPV16, HPV31 and HPV51, and formulated in a human-compatible adjuvant, induce broadly protective responses. Specifically, we show that this vaccine, which uses a far-divergent archaebacterial thioredoxin as scaffold and is amenable to an easy onestep thermal purification, induces robust cross-neutralization against 12 of the 13 known oncogenic HPV types. Immune performance measured with two different in vitro neutralization assays was corroborated by the results of mouse cervico-vaginal challenge and passive transfer experiments indicating robust cross-protection also in vivo. Altogether, our results attest to the potential of Trx-L2 as a thermostable second-generation HPV vaccine particularly well suited for low-resource countries. Cancer Prev Res; 8(10); 932-41. Ó2015 AACR.

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“…2). Consistent with our previous results (19), the PfTrx-L2 mix elicited comparable HPV16 type-specific responses ( Fig. 2A) in addition to significantly broader cross-reactivity ( Fig.…”

Section: Superior In Vitro Cross-neutralization Capacity Of the Pftrxsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine

Seitz

Ribeiro-Müller

Canali

et al. 2015

Cancer Prevention Research

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“…Recently, the thioredoxin-L2 design was modified to include L2 sequence information from the highly divergent HPV-31 and HPV-51 types in addition to HPV-16, with the aim of extending cross-neutralization. A mixture of monovalent antigens comprising L2(20-38) peptides from all three HPV types conferred broadly crossneutralizing responses against ten prominent oncogenic HPV types [147].…”

Section: L2 Vaccine Developmentmentioning

confidence: 99%

Current Perspectives on HPV Vaccination: A Focus on Targeting the L2 Protein

Seitz

Müller

2014

Future Virol.

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Thirty years ago, human papillomavirus types 16 and 18 were isolated from cervical carcinomas, and it has been almost 10 years since the introduction of the first prophylactic virus-like particle (VLP) vaccine. The VLP vaccines have already impacted the reduction of pre-malignant lesions and genital warts, and it is expected that vaccination efforts will successfully lower the incidence of cervical cancer before the end of the decade. Here we summarize the historical developments leading to the prophylactic HPV vaccines and discuss current advances of next-generation vaccines that aim to overcome certain limitations of the VLP vaccines, including their intrinsic narrow range of protection, stability and production/distribution costs. KEYWORDS• cervical cancer • emerging HPV-associated diseases • human papillomavirus • major capsid protein L1-based virus-like particle vaccines • markers for protection • minor capsid protein L2-based crossprotective vaccines • neutralizing antibodies • nonavalent VLP vaccine • second-generation HPV vaccine • vaccine accessibility and production/ distribution costs Introduction & historyOver the last 150 years the recognition of papillomaviruses as causative agents for a number of malignancies in both animals and humans has evolved. In the 1960s sufficient evidence began accumulating demonstrating a causative role of certain human papillomaviruses (HPVs) in the development of cervical cancer beyond reasonable doubt [1]. Numerous investigations, among them a large number of epidemiological studies, were required to reach this point. As of 2007 we stand with two successful commercial prophylactic vaccines that efficiently protect against the most prevalent oncogenic HPV types.Early observations reported by the Italian physician Rigoni-Stern already hinted at the involvement of infectious agents in the development of cervical cancer when he suggested behavioral risks for this type of tumor [2]. These investigations were eventually resumed in the second half of the 20th century. Not only was the risk for cervical cancer attributed to genital infection, those studies eventually acquitted some of the suspects; for example, an involvement of herpes simplex virus 2 could be ruled out [3].In the 1970s HPV-6 and HPV-11 were isolated and cloned from condylomas and laryngeal papillomas, respectively. At this time, Harald zur Hausen had noted that condylomas and cervical carcinomas share a similar epidemiological pattern and this initiated the systematic hunt for novel papillomaviruses. The strategy at the time utilized Southern blot hybridization techniques under low stringency conditions using the DNA of already isolated HPV types as molecular probes. Within a few years a large number of human and animal papillomavirus genomes had been isolated [4][5][6][7]. Of the more than 200 papillomaviruses known today, many are infecting the genital epithelium and approximately 13 of them are recognized as human oncogenic viruses [8].In the following years it became evident that most if not all cases of ...

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Vaccine escape challenges virus prevention: The example of two vaccine‐preventable oncogenic viruses

Qu,

Sui,

2023

Journal of Medical Virology

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Over the years, the pace of developing vaccines for HBV and HPV has never stopped. After more than 30 years of application, the HBV vaccine has reduced 80% of hepatocellular carcinoma (HCC). However, vaccine escape variants occur under selective pressure induced by widespread vaccination and antiviral therapy, which results in fulminant infection and horizontal transmission. Several mechanisms have been studied to explain HBV vaccine escape, including vaccine escape mutations (VEMs) in the major hydrophilic region, which leads to a decrease in the binding ability to neutralize antibodies and is the primary escape mechanism, protein conformational and N‐linked glycosylation sites changes caused by VEMs, differences in genotype distribution, gene recombination, and some temporarily unknown reasons. However, effective solutions are still being explored. The HPV vaccine has also been proven to prevent 70%–90% of cervical cancer worldwide. Cases of HPV infection after being vaccinated have been observed in clinical practice. However, few researchers have paid attention to the mechanism of HPV vaccine escape. Thus, we reviewed the literature on vaccine escape of both HBV and HPV to discuss the mechanism of the virus escaping from vaccine protection and possible solutions to this problem. We analyzed the gap between studies of HPV and HBV and made prospects for further research in HPV vaccine escape.

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A three component mix of thioredoxin-L2 antigens elicits broadly neutralizing responses against oncogenic human papillomaviruses

Cited by 30 publications

References 25 publications

Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine

Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine

Current Perspectives on HPV Vaccination: A Focus on Targeting the L2 Protein

Vaccine escape challenges virus prevention: The example of two vaccine‐preventable oncogenic viruses

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