Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus as a Vector for Immunotherapy of Cancer

Boursnell, Mike; Entwisle, Claire; Ali, Selman A.; Sivasubramaniam, Shiva; Reeder, Stephen; McLean, C. S.; Blakeley, D M; Miller, Judith Kelvin; Hill, Samuel L.; Shields, John G.; Inglis, Stephen; Rees, Robert C.

doi:10.1007/978-1-4615-5357-1_59

Cited by 11 publications

(5 citation statements)

References 10 publications

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“…Subsequent vaccines strategies changed from inactivated to replication-defective HSV strains such as virulent type HSV mutants (i.e., lacking ICP8, ICP10, dl5-29, or VHS), discontinuously replicating virus known as “disabled infectious single cycle” or “DISC”, and a virus with a deletion of UL22, the late gene encoding glycoprotein H (gH) [40]. A DISC HSV-2 vaccine has entered clinical trials and has been found relatively safe with no serious adverse effects [41, 42]. Among HSV-seronegative subjects, dose-dependent induction of T-cell proliferation was noted four weeks after a single DISC HSV-2 immunization and continued for sixteen weeks after the second immunization.…”

Section: Past and Current Herpes Vaccinesmentioning

confidence: 99%

Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown

Chentoufi

Kritzer

et al. 2012

Clinical and Developmental Immunology

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The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally “protected” exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4+and CD8+T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation “asymptomatic” clinical herpes vaccines, and discuss future mucosal “asymptomatic” prime-boost vaccines that could optimize local protective immunity.

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Section: Past and Current Herpes Vaccinesmentioning

confidence: 99%

Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown

Chentoufi

Kritzer

et al. 2012

Clinical and Developmental Immunology

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“…DISC-HSV-2 has been shown to be an efficient vector for cytokine gene delivery into tumour cells, and that the expression of mGM-CSF or hIL-2 enhances the immunogenicity of whole-cell vaccines [108, 109]. …”

Section: Hsv-based Vectors For Vaccinationmentioning

confidence: 99%

HSV Recombinant Vectors for Gene Therapy~!2009-12-17~!2010-13-31~!2010-06-17~!

Manservigi¹,

Argnani²,

Marconi³

2010

TOVJ

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Abstract:The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges.Keywords: HSV, viral vectors, oncolytic vectors, gene therapy, neurodegenerative disorders, cancer, targeting, vaccines. THE HERPES SIMPLEX VIRUS LIFE CYCLEHerpes simplex virus (HSV) is an enveloped, doublestranded (ds) DNA virus [1]. The mature virion consists of different components: an external envelope containing about 13 glycoproteins involved in different functions, among which the first steps of binding and entry into the host cell; an amorphous layer known as the tegument, containing some 20 different proteins with structural and regulatory roles; and an icosadeltahedral capsid containing a toroidal dsDNA. The HSV-1 genome consists of 152 kb of linear, dsDNA arranged as long and short unique segments (UL and US) flanked by inverted repeated sequences (TRL/IRL and IRS/TRS, respectively) (Fig. 1). The repeated regions of the viral genome contain two immediate-early (IE) genes [infected cell protein (ICP) 4 and ICP0], a late (L) gene (ICP34.5) and the latency associated transcripts (LAT) that are each present in two copies. Thus, the repeated region located between the long and short segments of the genome (the joint repeat region) contains a single copy of each gene. HSV genome encodes approximately 90 genes that can be classified as essential or nonessential based on their requirement for virus replication in tissue culture. Essential genes are required for virus growth such that viral mutants lacking these genes can only establish a lytic infection if the missing genes are supplied in trans by an engineered c...

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“…Mutants of HSV are possible candidates for experimental gene therapy (Boursnell et al 1998;Weir 2001) or vaccination against infection with the wild-type virus (Boursnell et al 1997;Dennehy 2001). However, the use of "disabled infectious single cycle" HSV (Boursnell et al 1997) for gene therapy or as a viral vaccine is limited by the low viral stability under conditions commonly encountered during the storage of pharmaceutical products.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Inactivation of HSV-2 during Storage in Frozen and Lyophilized Forms

Hansen

Zhai

Skepper

et al. 2008

Biotechnol Progress

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The structural integrity of herpes simplex virus 2 (HSV-2) during freezing, thawing, and lyophilization has been studied using scanning and transmission electron microscopy. Viral particles should be thawed quickly from -80 to 37 degrees C to avoid artifacts of thawing. To avoid freezing damage, the virus should be rapidly frozen (>20 K s(-1)) rather than slowly frozen as occurs on the shelf of a lyophilizer (<1 K s(-1)). Fast freezing and thawing allows six cycles of freeze thaw with no loss of viral titer TCID50. Viral particles were characterized using immunogold labeling methods. Freshly thawed virus had 19 +/- 4 polyclonal immunogold particles virus(-1); virus stored at -80 degrees C for at least 4 months had 17 +/- 3 particles virus(-1); virus stored for 1 week at 4 degrees C had 8 +/- 4 particles virus(-1). By bulk lyophilization the number of particles was 4 +/- 4, but by fast freezing and lyophilization the number of gold particles improved to 12 +/- 5. The loss of viral membrane was directly observed, and the in vitro loss was demonstrated to occur through three possible pathways, including (i) simultaneous release of tegument and membrane, (ii) sequential release of membrane and then tegument, and (iii) release like by in vivo infection. The capsids were not further degraded as indicated by the lack of free DNA, which was only released by boiling the viral samples with 1% SDS, followed by a dilution to 0.001% w/v SDS for the real-time PCR reaction.

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Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus as a Vector for Immunotherapy of Cancer

Cited by 11 publications

References 10 publications

Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown

Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown

HSV Recombinant Vectors for Gene Therapy~!2009-12-17~!2010-13-31~!2010-06-17~!

Mechanisms of Inactivation of HSV-2 during Storage in Frozen and Lyophilized Forms

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