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      Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines

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          Abstract

          Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow for stringent, deliberate spatial and temporal control of virus replication. The resulting replication-competent controlled viruses (RCCVs) can be activated to undergo one or, if desired, several rounds of efficient replication at the inoculation site, but are nonreplicating in the absence of activation. Extrapolating from observations that attenuated replicating viruses are better immunogens than replication-defective or inactivated viruses, it was hypothesized that RCCVs that replicate with wild-type-like efficiency when activated will be even better immunogens. The vigorous replication of the RCCVs should also render heterologous antigens expressed from them highly immunogenic. RCCVs for administration to skin sites or mucosal membranes were constructed using a virulent wild-type HSV-1 strain as the backbone. The recombinants are activated by a localized heat treatment to the inoculation site in the presence of a small-molecule regulator (SMR). Derivatives expressing influenza virus antigens were also prepared. Immunization/challenge experiments in mouse models revealed that the activated RCCVs induced far better protective immune responses against themselves as well as against the heterologous antigens they express than unactivated RCCVs or a replication-defective HSV-1 strain. Neutralizing antibody and proliferation responses mirrored these findings. We believe that the data obtained so far warrant further research to explore the possibility of developing effective RCCV-based vaccines directed to herpetic diseases and/or diseases caused by other pathogens.

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          Most cited references54

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          Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs

          Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer’s disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects.
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            A viral inhibitor of peptide transporters for antigen presentation.

            Cytotoxic T lymphocytes lyse target cells after T-cell-receptor-mediated recognition of class I major histocompatibility complex molecules presenting peptides. Antigenic peptides are generated in the cytoplasm by proteasomes and translocated into the lumen of the endoplasmic reticulum (ER) by peptide transporters (TAP). Herpes simplex virus (HSV) expresses a cytoplasmic protein, ICP47, which seems to interfere with such immune surveillance by mediating retention of 'empty' class I molecules in the ER. By expressing ICP47 in HeLa cells under an inducible promoter, we show that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides. This inhibition was overcome by transfecting murine TAP. Further, we demonstrate that ICP47 colocalizes and physically associates with TAP within the cell. Inhibition of peptide translocation by a viral protein indicates a previously undocumented potential mechanism for viral immune evasion.
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              Evasion of host antiviral innate immunity by HSV-1, an update

              Herpes simplex virus type 1 (HSV-1) infection triggers a rapid induction of host innate immune responses. The type I interferon (IFN) signal pathway is a central aspect of host defense which induces a wide range of antiviral proteins to control infection of incoming pathogens. In some cases, viral invasion also induces DNA damage response, autophagy, endoplasmic reticulum stress, cytoplasmic stress granules and other innate immune responses, which in turn affect viral infection. However, HSV-1 has evolved multiple strategies to evade host innate responses and facilitate its infection. In this review, we summarize the most recent findings on the molecular mechanisms utilized by HSV-1 to counteract host antiviral innate immune responses with specific focus on the type I IFN signal pathway.
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                Author and article information

                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                18 May 2020
                June 2020
                : 8
                : 2
                : 230
                Affiliations
                [1 ]HSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, Switzerland
                [2 ]Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA; dbloom@ 123456ufl.edu
                [3 ]Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; nuria.vilaboa@ 123456salud.madrid.org
                [4 ]CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, 28046 Madrid, Spain
                Author notes
                [* ]Correspondence: rvoellmy@ 123456hsfpharma.com ; Tel.: +41-21-534-0260
                Author information
                https://orcid.org/0000-0003-4183-0871
                https://orcid.org/0000-0003-4473-4498
                Article
                vaccines-08-00230
                10.3390/vaccines8020230
                7349925
                32443425
                9f497ff4-686a-4649-a3ef-9f5a537dbb4a
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 April 2020
                : 13 May 2020
                Categories
                Review

                herpesvirus,hsv-1,candidate vaccine,vaccine vector,live vaccine,replication-competent controlled

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