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  • 1
  • 2
    Language: English
    In: PLoS ONE, Sept 18, 2015, Vol.10(9)
    Description: Persistent infection with high-risk human papillomavirus (HPV) types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs)-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-[gamma] ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c.) prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease.
    Keywords: Papillomavirus Infections – Prevention ; Papillomavirus Infections – Research ; Cervical Cancer – Causes of ; Cervical Cancer – Prevention ; Cervical Cancer – Research ; Influenza Viruses – Physiological Aspects ; Influenza Viruses – Research
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: Vaccine, 16 December 2013, Vol.31(52), pp.6194-6200
    Description: The non-structural protein NS1 of the influenza virus counteracts the interferon-mediated immune response of the host. We investigated the safety and immunogenicity of a trivalent formulation containing influenza H1N1, H3N2 and B strains lacking NS1 (delNS1-trivalent). Healthy adult study participants who were seronegative for at least one strain present in the vaccine formulation were randomized to receive a single intranasal dose of delNS1-trivalent vaccine at 7.0 log10 TCID50/subject ( = 39) or placebo ( = 41). Intranasal vaccination with the live replication-deficient delNS1-trivalent vaccine was well tolerated with no treatment-related serious adverse events. The most common adverse events identified, i.e. headache, oropharyngeal pain and rhinitis-like symptoms, were mainly mild and transient and distributed similarly in the treatment and placebo groups. Significant vaccine-specific immune responses were induced. Pre-existing low antibody titers or seronegativity for the corresponding vaccine strain yielded better response rates. We show that vaccination with a replication-deficient trivalent influenza vaccine containing H1N1, H3N2 and B strains lacking NS1 is safe and induces significant levels of antibodies (ClinicalTrials.gov identifier ).
    Keywords: Influenza ; Ns1 ; Intranasal ; Trivalent ; Live-Attenuated ; Reverse Genetics ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 4
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e36506
    Description: Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Infectious Diseases ; Molecular Biology ; Oncology ; Dermatology
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: The Journal of Virology, 2011, Vol. 85(5), p.2469
    Description: Segment 8 of the influenza A virus codes for two proteins (NS1 and NS2/NEP) via splicing. Here, we developed a viral vector expressing a cytokine or chemokine instead of the interferon antagonist NS1. To achieve both the desired genetic stability and high transgene expression levels, NS2/NEP mRNA splicing efficacy had to be fine-tuned by modification of splicing elements. Expression levels of secreted foreign proteins could be further enhanced by fusing the N-terminal 13 amino acids of NS1 with an IgK-derived secretion signal peptide. Thus, the first start codon was used for translation initiation of both NS2/NEP and the foreign protein.
    Keywords: Interferon ; Chemokines ; Splicing ; Amino Acids ; Secretion Signals ; Translation Initiation ; Transgenes ; Codons ; Influenza A Virus ; Genetics, Taxonomy & Structure ; Methods;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 6
    In: PLoS ONE, 2015, Vol.10(9)
    Description: Persistent infection with high-risk human papillomavirus (HPV) types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs)-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-γ ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c.) prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, 2012, Vol.7(6), p.e39921
    Description: The nonstructural protein 1 (NS1) of influenza A virus (IAV) enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL) immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1) induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN) immunization and was associated with high levels of virus-specific antibodies (Abs). SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymphoid organs. Thus, SL immunization with DeltaNS1 offers a novel potential vaccination strategy for the control of influenza outbreaks including pandemics.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Virology ; Infectious Diseases ; Microbiology
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: PLoS ONE, 2011, Vol.6(4), p.e18577
    Description: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. ; We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH≤5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K→I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose. Moreover, the reassortants keeping 58K→I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. ; Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Immunology ; Infectious Diseases
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: The Journal of infectious diseases, 01 February 2010, Vol.201(3), pp.354-62
    Description: BACKGROUND. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (DeltaNS1-H1N1) in healthy volunteers. METHODS. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the DeltaNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log(10) median tissue culture infective dose) (n = 36 recipients) or placebo (n = 12 recipients). RESULTS. Intranasal vaccination with the replication-deficient DeltaNS1-H1N1 vaccine was well tolerated. Rhinitis-like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants. CONCLUSIONS. We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. TRIAL REGISTRATION. ClinicalTrials.gov identifier: NCT00724997 .
    Keywords: Influenza A Virus, H1n1 Subtype -- Immunology ; Influenza Vaccines -- Immunology ; Influenza, Human -- Prevention & Control ; Vaccines, Attenuated -- Immunology ; Viral Nonstructural Proteins -- Genetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 11 April 2000, Vol.97(8), pp.4309-4314
    Description: We propose a rational approach to the generation of live viral vaccines: alteration of virally encoded type I IFN antagonists to attenuate virulence while retaining immunogenicity. We have explored this concept by using the influenza virus. Previously we have shown that the NS1 protein of influenza A virus possesses anti-IFN activity. We now present evidence that influenza A and B viruses encoding altered viral NS1 proteins are highly attenuated in the mouse host, yet provide protection from challenge with wild-type viruses.
    Keywords: Biological sciences -- Biology -- Microbiology ; Biological sciences -- Biology -- Zoology ; Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical treatment -- Biological therapy ; Health sciences -- Medical treatment -- Biological therapy ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Anatomy ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Microbiology ; Biological sciences -- Biology -- Cytology
    ISSN: 00278424
    E-ISSN: 10916490
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