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Martin F. Bachmann - One of the best experts on this subject based on the ideXlab platform.
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major findings and recent advances in virus like Particle vlp based vaccines
Seminars in Immunology, 2017Co-Authors: Gustavo Cabralmiranda, Mona O Mohsen, Martin F. BachmannAbstract:Virus-Like Particles (VLPs) have made giant strides in the field of vaccinology over the last three decades. VLPs constitute versatile tools in vaccine development due to their favourable immunological characteristics such as their size, repetitive surface geometry, ability to induce both innate and adaptive immune responses as well as being safe templates with favourable economics. Several VLP-based vaccines are commercially available including vaccines against Human Papilloma Virus (HPV) such as Cervarix®, Gardasil® & Gardasil9® and Hepatitis B Virus (HBV) including the 3rd generation Sci-B-Vac™. In addition, the first licensed malaria-VLP-based vaccine Mosquirix™ has been recently approved by the European regulators. Several other VLP-based vaccines are currently undergoing preclinical and clinical development. This review summarizes some of the major findings and recent advances in VLP-based vaccine development and technologies and outlines general principles that may be harnessed for induction of targeted immune responses.
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versatile virus like Particle carrier for epitope based vaccines
PLOS ONE, 2010Co-Authors: Alain C Tissot, Regina Renhofa, Indulis Cielens, Edwin Meijerink, Gary T Jennings, Nicole Schmitz, Paul Pumpens, Philippe Saudan, Martin F. BachmannAbstract:Background Recombinant proteins and in particular single domains or peptides are often poorly immunogenic unless conjugated to a carrier protein. Virus-Like-Particles are a very efficient means to confer high immunogenicity to antigens. We report here the development of Virus-Like-Particles (VLPs) derived from the RNA bacteriophage AP205 for epitope-based vaccines. Methodology/Principal Findings Peptides of angiotensin II, S.typhi outer membrane protein (D2), CXCR4 receptor, HIV1 Nef, gonadotropin releasing hormone (GnRH), Influenza A M2-protein were fused to either N- or C-terminus of AP205 coat protein. The A205-peptide fusions assembled into VLPs, and peptides displayed on the VLP were highly immunogenic in mice. GnRH fused to the C-terminus of AP205 induced a strong antibody response that inhibited GnRH function in vivo. Exposure of the M2-protein peptide at the N-terminus of AP205 resulted in a strong M2-specific antibody response upon immunization, protecting 100% of mice from a lethal influenza infection. Conclusions/Significance AP205 VLPs are therefore a very efficient and new vaccine system, suitable for complex and long epitopes, of up to at least 55 amino acid residues in length. AP205 VLPs confer a high immunogenicity to displayed epitopes, as shown by inhibition of endogenous GnRH and protective immunity against influenza infection.
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Versatile Virus-Like Particle carrier for epitope based vaccines
PLoS ONE, 2010Co-Authors: Alain C Tissot, Regina Renhofa, Indulis Cielens, Edwin Meijerink, Velta Ose, Gary T Jennings, Nicole Schmitz, Paul Pumpens, Philippe Saudan, Martin F. BachmannAbstract:Recombinant proteins and in particular single domains or peptides are often poorly immunogenic unless conjugated to a carrier protein. Virus-Like-Particles are a very efficient means to confer high immunogenicity to antigens. We report here the development of Virus-Like-Particles (VLPs) derived from the RNA bacteriophage AP205 for epitope-based vaccines.
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the coming of age of virus like Particle vaccines
Biological Chemistry, 2008Co-Authors: Gary T Jennings, Martin F. BachmannAbstract:Abstract Virus-Like Particles are supra-molecular assemblages, usually icosahedral or rod-like structures. They incorporate key immunologic features of viruses which include repetitive surfaces, particulate structures and induction of innate immunity through activation of pathogen-associated molecular-pattern recognition receptors. They carry no replicative genetic information and can be produced recombinantly in large scale. Virus-Like Particles thus represent a safe and effective vaccine platform for inducing potent B- and T-cell responses. In addition to being effective vaccines against the corresponding virus from which they are derived, Virus-Like Particles can also be used to present foreign epitopes to the immune system. This can be achieved by genetic fusion or chemical conjugation. This technological innovation has greatly broadened the scope of their use, from immunizing against microbial pathogens to immunotherapy for chronic diseases. Towards this end, Virus-Like Particles have been used to induce autoantibodies to disease-associated self-molecules involved in chronic diseases, such as hypertension and Alzheimer's disease. The recognition of the potent immunogenicity and commercial potential for Virus-Like Particles has greatly accelerated research and development activities. During the last decade, two prophylactic Virus-Like Particle vaccines have been registered for human use, while another 12 vaccines entered clinical development.
Sina Bavari - One of the best experts on this subject based on the ideXlab platform.
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monovalent virus like Particle vaccine protects guinea pigs and nonhuman primates against infection with multiple marburg viruses
Expert Review of Vaccines, 2008Co-Authors: Dana L Swenson, KELLY LYN WARFIELD, Tom Larsen, Derron A Alves, Sadie S Coberley, Sina BavariAbstract:Background: Virus-Like Particle (VLP)-based vaccines have the advantage of being morphologically and antigenically similar to the live virus from which they are derived. Expression of the glycoprotein and VP40 matrix protein from Lake Victoria marburgvirus (MARV) results in spontaneous production of VLPs in mammalian cells. Guinea pigs vaccinated with Marburg virus VLPs (mVLPs) or inactivated MARV (iMARV) develop homologous humoral and T-cell responses and are completely protected from a lethal homologous MARV challenge. Aims & methods: To determine whether mVLPs based on the Musoke (aka Lake Victoria) isolate of MARV could broadly protect against diverse isolates of MARV, guinea pigs were vaccinated with mVLPs or iMARV-Musoke and challenged with MARV-Musoke, -Ravn or -Ci67. Results: Prior to challenge, the mVLP- and iMARV-vaccinated guinea pigs had high levels of homologous MARV-Musoke and heterologous MARV-Ravn and -Ci67 antibodies. The Musoke-based mVLPs and iMARV vaccines provided complete protection ...
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ebola virus like Particle based vaccine protects nonhuman primates against lethal ebola virus challenge
The Journal of Infectious Diseases, 2007Co-Authors: KELLY LYN WARFIELD, Dana L Swenson, Warren V Kalina, Gene G Olinger, Javad M Aman, Sina BavariAbstract:Background. Currently, there are no licensed vaccines or therapeutics for the prevention or treatment of infection by the highly lethal filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), in humans. We previously had demonstrated the protective efficacy of Virus-Like Particle (VLP)-based vaccines against EBOV and MARV infection in rodents. Methods. To determine the efficacy of vaccination with Ebola VLPs (eVLPs) in nonhuman primates, we vaccinated cynomolgus macaques with eVLPs containing EBOV glycoprotein (GP), nucleoprotein (NP), and VP40 matrix protein and challenged the macaques with 1000 pfu of EBOV. Results. Serum samples from the eVLP-vaccinated nonhuman primates demonstrated EBOV-specific antibody titers, as measured by enzyme-linked immunosorbent assay, complement-mediated lysis assay, and antibody-dependent cell-mediated cytotoxicity assay. CD44 + T cells from eVLP-vaccinated macaques but not from a naive macaque responded with vigorous production of tumor necrosis factor-a after EBOV-peptide stimulation. All 5 eVLP-vaccinated monkeys survived challenge without clinical or laboratory signs of EBOV infection, whereas the control animal died of infection. Conclusion. On the basis of safety and efficacy, eVLPs represent a promising filovirus vaccine for use in humans.
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Ebola Virus-Like Particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge.
The Journal of infectious diseases, 2007Co-Authors: KELLY LYN WARFIELD, M. Javad Aman, Dana L Swenson, Warren V Kalina, Gene G Olinger, Sina BavariAbstract:BACKGROUND: Currently, there are no licensed vaccines or therapeutics for the prevention or treatment of infection by the highly lethal filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), in humans. We previously had demonstrated the protective efficacy of Virus-Like Particle (VLP)-based vaccines against EBOV and MARV infection in rodents. METHODS: To determine the efficacy of vaccination with Ebola VLPs (eVLPs) in nonhuman primates, we vaccinated cynomolgus macaques with eVLPs containing EBOV glycoprotein (GP), nucleoprotein (NP), and VP40 matrix protein and challenged the macaques with 1000 pfu of EBOV. RESULTS: Serum samples from the eVLP-vaccinated nonhuman primates demonstrated EBOV-specific antibody titers, as measured by enzyme-linked immunosorbent assay, complement-mediated lysis assay, and antibody-dependent cell-mediated cytotoxicity assay. CD44+ T cells from eVLP-vaccinated macaques but not from a naive macaque responded with vigorous production of tumor necrosis factor- alpha after EBOV-peptide stimulation. All 5 eVLP-vaccinated monkeys survived challenge without clinical or laboratory signs of EBOV infection, whereas the control animal died of infection. CONCLUSION: On the basis of safety and efficacy, eVLPs represent a promising filovirus vaccine for use in humans.
KELLY LYN WARFIELD - One of the best experts on this subject based on the ideXlab platform.
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Advances in Virus-Like Particle vaccines for filoviruses
Journal of Infectious Diseases, 2011Co-Authors: KELLY LYN WARFIELD, M. Javad AmanAbstract:Ebola virus (EBOV) and Marburg virus (MARV) are among the deadliest human pathogens, with no vaccines or therapeutics available. Multiple vaccine platforms have been tested for efficacy as prophylactic pretreatments or therapeutics for prevention of filovirus hemorrhagic fever. Most successful vaccines are based on a virus-vectored approach expressing the protective glycoprotein (GP); protein-based subunit and DNA vaccines have been tested with moderate success. Virus-Like Particle (VLP) vaccines have realized promising results when tested in both rodents and nonhuman primates. VLPs rely on the natural properties of the viral matrix protein (VP) 40 to drive budding of filamentous Particles that can also incorporate ? 1 other filovirus protein, including GP, VP24, and nucleoprotein (NP). Filovirus VLP vaccines have used Particles containing 2 or 3 (GP and VP40, with or without NP) viral proteins generated in either mammalian or insect cells. Early studies successfully demonstrated efficacy of bivalent VLP vaccines in rodents; more recent studies have shown the ability of the VLP vaccines containing GP, NP, and VP40 to confer complete homologous protection against Ebola virus and Marburg virus in a prophylactic setting against in macaques. This review will discuss published work to date regarding development of the VLP vaccines for prevention of lethal filovirus hemorrhagic fever.
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monovalent virus like Particle vaccine protects guinea pigs and nonhuman primates against infection with multiple marburg viruses
Expert Review of Vaccines, 2008Co-Authors: Dana L Swenson, KELLY LYN WARFIELD, Tom Larsen, Derron A Alves, Sadie S Coberley, Sina BavariAbstract:Background: Virus-Like Particle (VLP)-based vaccines have the advantage of being morphologically and antigenically similar to the live virus from which they are derived. Expression of the glycoprotein and VP40 matrix protein from Lake Victoria marburgvirus (MARV) results in spontaneous production of VLPs in mammalian cells. Guinea pigs vaccinated with Marburg virus VLPs (mVLPs) or inactivated MARV (iMARV) develop homologous humoral and T-cell responses and are completely protected from a lethal homologous MARV challenge. Aims & methods: To determine whether mVLPs based on the Musoke (aka Lake Victoria) isolate of MARV could broadly protect against diverse isolates of MARV, guinea pigs were vaccinated with mVLPs or iMARV-Musoke and challenged with MARV-Musoke, -Ravn or -Ci67. Results: Prior to challenge, the mVLP- and iMARV-vaccinated guinea pigs had high levels of homologous MARV-Musoke and heterologous MARV-Ravn and -Ci67 antibodies. The Musoke-based mVLPs and iMARV vaccines provided complete protection ...
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ebola virus like Particle based vaccine protects nonhuman primates against lethal ebola virus challenge
The Journal of Infectious Diseases, 2007Co-Authors: KELLY LYN WARFIELD, Dana L Swenson, Warren V Kalina, Gene G Olinger, Javad M Aman, Sina BavariAbstract:Background. Currently, there are no licensed vaccines or therapeutics for the prevention or treatment of infection by the highly lethal filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), in humans. We previously had demonstrated the protective efficacy of Virus-Like Particle (VLP)-based vaccines against EBOV and MARV infection in rodents. Methods. To determine the efficacy of vaccination with Ebola VLPs (eVLPs) in nonhuman primates, we vaccinated cynomolgus macaques with eVLPs containing EBOV glycoprotein (GP), nucleoprotein (NP), and VP40 matrix protein and challenged the macaques with 1000 pfu of EBOV. Results. Serum samples from the eVLP-vaccinated nonhuman primates demonstrated EBOV-specific antibody titers, as measured by enzyme-linked immunosorbent assay, complement-mediated lysis assay, and antibody-dependent cell-mediated cytotoxicity assay. CD44 + T cells from eVLP-vaccinated macaques but not from a naive macaque responded with vigorous production of tumor necrosis factor-a after EBOV-peptide stimulation. All 5 eVLP-vaccinated monkeys survived challenge without clinical or laboratory signs of EBOV infection, whereas the control animal died of infection. Conclusion. On the basis of safety and efficacy, eVLPs represent a promising filovirus vaccine for use in humans.
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Ebola Virus-Like Particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge.
The Journal of infectious diseases, 2007Co-Authors: KELLY LYN WARFIELD, M. Javad Aman, Dana L Swenson, Warren V Kalina, Gene G Olinger, Sina BavariAbstract:BACKGROUND: Currently, there are no licensed vaccines or therapeutics for the prevention or treatment of infection by the highly lethal filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), in humans. We previously had demonstrated the protective efficacy of Virus-Like Particle (VLP)-based vaccines against EBOV and MARV infection in rodents. METHODS: To determine the efficacy of vaccination with Ebola VLPs (eVLPs) in nonhuman primates, we vaccinated cynomolgus macaques with eVLPs containing EBOV glycoprotein (GP), nucleoprotein (NP), and VP40 matrix protein and challenged the macaques with 1000 pfu of EBOV. RESULTS: Serum samples from the eVLP-vaccinated nonhuman primates demonstrated EBOV-specific antibody titers, as measured by enzyme-linked immunosorbent assay, complement-mediated lysis assay, and antibody-dependent cell-mediated cytotoxicity assay. CD44+ T cells from eVLP-vaccinated macaques but not from a naive macaque responded with vigorous production of tumor necrosis factor- alpha after EBOV-peptide stimulation. All 5 eVLP-vaccinated monkeys survived challenge without clinical or laboratory signs of EBOV infection, whereas the control animal died of infection. CONCLUSION: On the basis of safety and efficacy, eVLPs represent a promising filovirus vaccine for use in humans.
Terrence M Tumpey - One of the best experts on this subject based on the ideXlab platform.
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influenza virus like Particle can accommodate multiple subtypes of hemagglutinin and protect from multiple influenza types and subtypes
Vaccine, 2011Co-Authors: Peter Pushko, Gale Smith, Melissa B Pearce, Attiya Ahmad, Irina Tretyakova, Jessica A Belser, Terrence M TumpeyAbstract:Abstract Despite existing vaccines and specific therapies, epidemics of seasonal influenza annually claim 200,000–500,000 lives worldwide. Pandemic influenza represents an even greater threat, with numerous potentially pandemic viruses circulating in nature. Development of multi-specific vaccines against multiple pandemic or seasonal strains is important for human health and the global economy. Here we report a novel Virus-Like Particle (VLP) platform that contains three hemagglutinin (HA) subtypes. This recombinant vaccine design resulted in the expression of three HA subtypes co-localized within a VLP. Experimental triple-HA VLPs containing HA proteins derived from H5N1, H7N2, and H2N3 viruses were immunogenic and protected ferrets from challenge from all three potentially pandemic viruses. Similarly, VLPs containing HA subtypes derived from seasonal H1N1, H3N2, and type B influenza viruses protected ferrets from three seasonal influenza viruses. We conclude that this technology may represent a novel strategy for rapid development of trivalent seasonal and pandemic vaccines.
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recombinant h1n1 virus like Particle vaccine elicits protective immunity in ferrets against the 2009 pandemic h1n1 influenza virus
Vaccine, 2010Co-Authors: Peter Pushko, Gale Smith, Melissa B Pearce, Thomas Kort, Margret Nathan, Terrence M TumpeyAbstract:Abstract The pandemic virus of 2009 (2009 H1N1) continues to cause illness worldwide, especially in younger age groups. The widespread H1N1 virus infection further emphasizes the need for vaccine strategies that are effective against emerging pandemic viruses and are not dependent on the limitations of traditional egg-based technology. This report describes a recombinant influenza Virus-Like Particle (VLP) vaccine consisting of hemagglutinin (HA), neuraminidase (NA), and matrix (M1) proteins of influenza A/California/04/2009 (H1N1) virus. Influenza H1N1 VLPs with a diameter of approximately 120 nm were released into the culture medium from Sf9 insect cells infected with recombinant baculovirus coexpressing HA, NA, and M1 proteins. Purified recombinant H1N1 VLPs morphologically resembled influenza virions and exhibited biological characteristics of influenza virus, including HA and NA activities. In the ferret challenge model, 2009 influenza H1N1 VLPs elicited high-titer serum hemagglutination inhibition (HI) antibodies specific for the 2009 H1N1 virus and inhibited replication of the influenza virus in the upper and lower respiratory tract tissues following A/Mexico/4482/09 (H1N1) virus challenge. Moreover, a single 15 μg dose of H1N1 VLPs resulted in complete virus clearance in the ferret lung. These results provide support for the use of recombinant influenza VLP vaccine as an effective strategy against pandemic H1N1 virus.
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cross clade protective immune responses to influenza viruses with h5n1 ha and na elicited by an influenza virus like Particle
PLOS ONE, 2008Co-Authors: Rick A Bright, Peter Pushko, Donald M Carter, Corey J Crevar, Franklin R Toapanta, Jonathan D Steckbeck, Kelly Stefano Cole, Niranjan M Kumar, Gale Smith, Terrence M TumpeyAbstract:Background. Vaccination is a cost-effective counter-measure to the threat of seasonal or pandemic outbreaks of influenza. To address the need for improved influenza vaccines and alternatives to egg-based manufacturing, we have engineered an influenza Virus-Like Particle (VLP) as a new generation of non-egg or non-mammalian cell culture-based candidate vaccine. Methodology/Principal Findings. We generated from a baculovirus expression system using insect cells, a non-infectious recombinant VLP vaccine from both influenza A H5N1 clade 1 and clade 2 isolates with pandemic potential. VLPs were administered to mice in either a one-dose or two-dose regimen and the immune responses were compared to those induced by recombinant hemagglutinin (rHA). Both humoral and cellular responses were analyzed. Mice vaccinated with VLPs were protected against challenge with lethal reassortant viruses expressing the H5N1 HA and NA, regardless if the H5N1 clade was homologous or heterologous to the vaccine. However, rHA-vaccinated mice showed considerable weight loss and death following challenge with the heterovariant clade virus. Protection against death induced by VLPs was independent of the prechallenge HAI titer or cell-mediated responses to HA or M1 since vaccinated mice, with low to undetectable cross-clade HAI antibodies or cellular responses to influenza antigens, were still protected from a lethal viral challenge. However, an apparent association rate of antibody binding to HA correlated with protection and was enhanced using VLPs, particularly when delivered intranasally, compared to rHA vaccines. Conclusion/Significance. This is the first report describing the use of an H5N1 VLP vaccine created from a clade 2 isolate. The results show that a non-replicating Virus-Like Particle is effective at eliciting a broadened, cross-clade protective immune response to proteins from emerging H5N1 influenza isolates giving rise to a potential pandemic influenza vaccine candidate for humans that can be stockpiled for use in the event of an outbreak of H5N1 influenza.
Cosette M Wheeler - One of the best experts on this subject based on the ideXlab platform.
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efficacy of a prophylactic adjuvanted bivalent l1 virus like Particle vaccine against infection with human papillomavirus types 16 and 18 in young women an interim analysis of a phase iii double blind randomised controlled trial
The Lancet, 2007Co-Authors: Jorma Paavonen, Cosette M Wheeler, Paulo Naud, David Jenkins, Xavier F Bosch, Jorge Salmeron, Song Nan Chow, Dan Apter, Henry C Kitchener, Xavier CastellsagueAbstract:Summary Background The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 Virus-Like-Particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women. Methods 18 644 women aged 15–25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint—vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18—was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681. Findings Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14·8 (SD 4·9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90·4% (97·9% CI 53·4–99·3; p Interpretation The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.
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efficacy of a quadrivalent prophylactic human papillomavirus types 6 11 16 and 18 l1 virus like Particle vaccine against high grade vulval and vaginal lesions a combined analysis of three randomised clinical trials
The Lancet, 2007Co-Authors: Elmar A Joura, Cosette M Wheeler, Laura A Koutsky, Diane M Harper, S Leodolter, Mauricio Hernandezavila, Gonzalo Perez, Suzanne M Garland, Grace W K Tang, Daron Gale FerrisAbstract:Summary Background Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus (HPV). These cancers are preceded by high-grade vulval intraepithelial neoplasia (VIN2–3) and vaginal intraepithelial neoplasia (VaIN2–3). Our aim was to do a combined analysis of three randomised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases. Methods 18 174 women (16–26 years) were enrolled and randomised to receive either quadrivalent HPV6/11/16/18 L1 Virus-Like-Particle vaccine or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after dose three, and at 6–12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary endpoint was the combined incidence of VIN2–3 or VaIN2–3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population. Findings The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n=7811; placebo n=7785), the vaccine was 100% effective (95% CI 72–100) against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18 174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18 was 71% (37–88). The vaccine was 49% (18–69) effective against all VIN2–3 or VaIN2–3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain. Interpretation Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high-grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination. With time, such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers.
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sustained efficacy up to 4 5 years of a bivalent l1 virus like Particle vaccine against human papillomavirus types 16 and 18 follow up from a randomised control trial
The Lancet, 2006Co-Authors: Diane M Harper, Cosette M Wheeler, Eduardo L Franco, Annabarbara Moscicki, Barbara Romanowski, Cecilia Rotelimartins, D G Jenkins, Anne Schuind, Sue Ann Costa Clemens, Gary DubinAbstract:Summary Background Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 Virus-Like Particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. Methods We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 Virus-Like Particle AS04 vaccine (0·5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. Findings More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96·9% (95% CI 81·3–99·9); persistent infection: 6 month definition, 94·3 (63·2–99·9); 12 month definition, 100% (33·6–100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42·4–100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. Interpretation Up to 4·5 years, the HPV-16/18 L1 Virus-Like Particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.
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prophylactic quadrivalent human papillomavirus types 6 11 16 and 18 l1 virus like Particle vaccine in young women a randomised double blind placebo controlled multicentre phase ii efficacy trial
Lancet Oncology, 2005Co-Authors: Luisa L Villa, Cosette M Wheeler, Laura A Koutsky, Anna R Giuliano, Ronaldo L R Costa, Carlos Alberto Petta, Rosires Pereira De Andrade, Kevin A Ault, Christian Malm, Matti LehtinenAbstract:Summary Background A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). Methods 277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 Virus-Like-Particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Findings Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p Interpretation A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7
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efficacy of a bivalent l1 virus like Particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women a randomized controlled trial
Obstetrical & Gynecological Survey, 2005Co-Authors: Diane M Harper, Cosette M Wheeler, Eduardo L Franco, D G Jenkins, Anne Schuind, Daron Gale Ferris, Toufik Zahaf, Bruce L Innis, Paulo Naud, Newton S DecarvalhoAbstract:This double-blind, multicenter, randomized, placebo-controlled study was conducted to assess the efficacy of a bivalent human papillomavirus (HPV)-16/18 L1 Virus-Like Particle vaccine in preventing cervical infection withHPV-16/18. The study participants were recruited among healthy women aged 15 to 25 years from 32 healthcare facilities in Brazil, Canada, and the United States. A total of 1113 women enrolled in the study. Enrollees had 6 or fewer lifetime sexual partners, no history of cervical abnormality, and were negative for high-risk HPV types. The subjects were randomized to receive placebo injections or the vaccine that contained 20 μg each of HPV-16 and HPV-18 Virus-Like Particles. Women received 1 0.5-mL dose of vaccine or placebo at enrollment, 1 month, and 6 months. Cervical smears were taken at 6, 12, and 18 months. In addition, participants collected self-administered cervicovaginal samples at enrollment, 6 months, and every 3 months thereafter. Serologic testing for immunogenicity was performed at 0, 1, 6, 12, and 18 months. The women kept a diary of symptoms for 1 week after each injection, and symptoms were evaluated by telephone interview 1 month after each injection. Outcome results at 27 months were available for 81 women in the vaccine group and 59 in the placebo group. Study subject data were analyzed in two different cohorts. One analysis was performed including women who received all 3 injections and who had complete follow-up data. They comprised the 'according-to-protocol' cohort (ATP). Another analysis was performed using data from the 'intention-to-treat' cohort (ITT), which consisted of all enrolled participants who had at least one dose of vaccine or placebo and had any data available for analysis. There were 560 subjects randomized to receive vaccine and 553 randomized to receive placebo. The average age was 20 years. The two groups had similar patterns of risk factors for HPV infection. There were no cases of persistent HPV-16/18 among ATP women who received the vaccine. The vaccine was 100% effective against HPV-16, HPV-18, and HPV-16/18 (P < 0.0001). The effectiveness against HPV-18 infection was not significant until 27 months. In comparison, 13 (2.1%) women in the ATP group who received placebo developed a persistent HPV-16 infection, 4 (0.6%) had persistent HPV-18, and 16 (2.6%) had persistent HPV-16/18. In the ITT cohort, there were 4 women in the vaccine group who were positive for persistent HPV-16 (0.5%: efficacy 84.5%, P < 0.0001), 1 positive for persistent HPV-18 (0.1%: efficacy 91.1%, P = 0.003) and 4 with HPV-16/18 (0.5%: efficacy 87.5%, P <.0001). In the ITT placebo group, 25 women (3.2%) were positive for persistent HPV-16, 11 (1.4%) had persistent HPV-18, and 31 (4.0%) persistent HPV-16/18. Among the 560 women who received the vaccine, 2 developed cervical abnormalities associated with HPV types 16 or 18. One had atypical squamous cells of unknown significance (ASGUS) and 1 had a low-grade squamous intraepithelial lesion (LSIL). Of the 553 women who received placebo, 27 developed cervical abnormalities, including 15 ASCUS, 14 LSIL, and 1 high-grade squamous intraepithelial lesion (HSIL). The vaccine had an efficacy of 95.2% against HPV-16 (P < 0.0001), 91.2% against HPV-18 (P = 0.003), and 92.9% against HPV-16/18 (P < 0.0001). Cervical intraepithelial neoplasia (CIN) 1 or 2 was seen in 7 women, including 1 CIN 1 in the vaccine group, and 3 each CIN 1 and CIN 2 in the placebo group.
