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Article ; Online: Some independence results related to finite trees.

Friedman, Harvey M / Weiermann, Andreas

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences

2023 Volume 381, Issue 2248, Page(s) 20220017

Abstract: We investigate some concrete independence results for systems of reverse mathematics which emerge from monotonicity properties of number-theoretic functions. Natural properties of the less than or equal to relation with respect to sums of natural numbers ...

Abstract	We investigate some concrete independence results for systems of reverse mathematics which emerge from monotonicity properties of number-theoretic functions. Natural properties of the less than or equal to relation with respect to sums of natural numbers lead to independence results for first-order Peano arithmetic. Natural properties of the less than or equal to relation with respect to sums and products of natural numbers lead to independence results for arithmetical transfinite recursion. By considering number-theoretic functions of arbitrary arities, we obtain independence results for systems beyond arithmetical transfinite recursion. We discuss how these embeddability relations are related to tree embeddability relations and we consider variants where the tree embeddability relation is not assumed to preserve infima. The findings of this paper are complementary to results on Kruskal-like theorems proved earlier by the first author. This article is part of the theme issue 'Modern perspectives in Proof Theory'.
Language	English
Publishing date	2023-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	208381-4
ISSN	1471-2962 ; 0080-4614 ; 0264-3820 ; 0264-3952 ; 1364-503X
ISSN (online)	1471-2962
ISSN	0080-4614 ; 0264-3820 ; 0264-3952 ; 1364-503X
DOI	10.1098/rsta.2022.0017
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Article ; Online: An mRNA vaccine to prevent genital herpes.

Awasthi, Sita / Friedman, Harvey M

Translational research : the journal of laboratory and clinical medicine

2021 Volume 242, Page(s) 56–65

Abstract: The rapid development of two nucleoside-modified mRNA vaccines that are safe and highly effective against coronavirus disease 2019 has transformed the vaccine field. The mRNA technology has the advantage of accelerated immunogen discovery, induction of ... ...

Abstract	The rapid development of two nucleoside-modified mRNA vaccines that are safe and highly effective against coronavirus disease 2019 has transformed the vaccine field. The mRNA technology has the advantage of accelerated immunogen discovery, induction of robust immune responses, and rapid scale up of manufacturing. Efforts to develop genital herpes vaccines have been ongoing for 8 decades without success. The advent of mRNA technology has the potential to change that narrative. Developing a genital herpes vaccine is a high public health priority. A prophylactic genital herpes vaccine should prevent HSV-1 and HSV-2 genital lesions and infection of dorsal root ganglia, the site of latency. Vaccine immunity should be durable for decades, perhaps with the assistance of booster doses. While these goals have been elusive, new efforts with nucleoside-modified mRNA-lipid nanoparticle vaccines show great promise. We review past approaches to vaccine development that were unsuccessful or partially successful in large phase 3 trials, and describe lessons learned from these trials. We discuss our trivalent mRNA-lipid nanoparticle approach for a prophylactic genital herpes vaccine and the ability of the vaccine to induce higher titers of neutralizing antibodies and more durable CD4
MeSH term(s)	Antibodies, Viral ; COVID-19 ; Herpes Genitalis/prevention & control ; Humans ; Liposomes ; Nanoparticles ; SARS-CoV-2 ; Vaccines, Synthetic ; Viral Envelope Proteins/genetics ; mRNA Vaccines
Chemical Substances	Antibodies, Viral ; Lipid Nanoparticles ; Liposomes ; Vaccines, Synthetic ; Viral Envelope Proteins ; mRNA Vaccines
Language	English
Publishing date	2021-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2021.12.006
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Article ; Online: Guinea Pig and Mouse Models for Genital Herpes Infection.

Hook, Lauren M / Friedman, Harvey M / Awasthi, Sita

Current protocols

2021 Volume 1, Issue 12, Page(s) e332

Abstract: This article describes procedures for two preclinical animal models for genital herpes infection. The guinea pig model shares many features of genital herpes in humans, including a natural route of inoculation, self-limiting primary vulvovaginitis, ... ...

Abstract	This article describes procedures for two preclinical animal models for genital herpes infection. The guinea pig model shares many features of genital herpes in humans, including a natural route of inoculation, self-limiting primary vulvovaginitis, spontaneous recurrences, symptomatic and subclinical shedding of HSV-2, and latent infection of the associated sensory ganglia (lumbosacral dorsal root ganglia, DRG). Many humoral and cytokine responses to HSV-2 infection in the guinea pig have been characterized; however, due to the limited availability of immunological reagents, assessments of cellular immune responses are lacking. In contrast, the mouse model has been important in assessing cellular immune responses to herpes infection. Both the mouse and guinea pig models have been extremely useful for evaluating preventative and immunotherapeutic approaches for controlling HSV infection and recurrent disease. In this article, we describe procedures for infecting guinea pigs and mice with HSV-2, scoring subsequent genital disease, and measuring replicating virus to confirm infection. We also provide detailed protocols for dissecting and isolating DRG (the site of HSV-2 latency), quantifying HSV-2 genomic copies in DRG, and assessing symptomatic and subclinical shedding of HSV-2 in the vagina. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Primary and recurrent genital herpes infection in the guinea pig model Support Protocol 1: Blood collection via lateral saphenous vein or by cardiac puncture after euthanasia Support Protocol 2: Dissection and isolation of dorsal root ganglia from guinea pigs Support Protocol 3: PCR amplification and quantification of HSV-2 genomic DNA from samples Basic Protocol 2: Primary genital herpes infection in the mouse model Alternate Protocol: Flank infection with HSV-2 in the mouse model Support Protocol 4: Dissection and isolation of mouse dorsal root ganglia.
MeSH term(s)	Animals ; Disease Models, Animal ; Female ; Genital Diseases ; Guinea Pigs ; Herpes Genitalis ; Herpesvirus 2, Human ; Immunity, Cellular ; Mice
Language	English
Publishing date	2021-12-21
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.332
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Article ; Online: Receptor Binding-Induced Conformational Changes in Herpes Simplex Virus Glycoprotein D Permit Interaction with the gH/gL Complex to Activate Fusion.

Atanasiu, Doina / Saw, Wan Ting / Cairns, Tina M / Friedman, Harvey M / Eisenberg, Roselyn J / Cohen, Gary H

Viruses

2023 Volume 15, Issue 4

Abstract: Herpes simplex virus (HSV) requires four essential virion glycoproteins-gD, gH, gL, and gB-for virus entry and cell fusion. To initiate fusion, the receptor binding protein gD interacts with one of two major cell receptors, HVEM or nectin-1. Once gD ... ...

Abstract	Herpes simplex virus (HSV) requires four essential virion glycoproteins-gD, gH, gL, and gB-for virus entry and cell fusion. To initiate fusion, the receptor binding protein gD interacts with one of two major cell receptors, HVEM or nectin-1. Once gD binds to a receptor, fusion is carried out by the gH/gL heterodimer and gB. A comparison of free and receptor-bound gD crystal structures revealed that receptor binding domains are located within residues in the N-terminus and core of gD. Problematically, the C-terminus lies across and occludes these binding sites. Consequentially, the C-terminus must relocate to allow for both receptor binding and the subsequent gD interaction with the regulatory complex gH/gL. We previously constructed a disulfide bonded (K190C/A277C) protein that locked the C-terminus to the gD core. Importantly, this mutant protein bound receptor but failed to trigger fusion, effectively separating receptor binding and gH/gL interaction. Here, we show that "unlocking" gD by reducing the disulfide bond restored not only gH/gL interaction but fusion activity as well, confirming the importance of C-terminal movement in triggering the fusion cascade. We characterize these changes, showing that the C-terminus region exposed by unlocking is: (1) a gH/gL binding site; (2) contains epitopes for a group (competition community) of monoclonal antibodies (Mabs) that block gH/gL binding to gD and cell-cell fusion. Here, we generated 14 mutations within the gD C-terminus to identify residues important for the interaction with gH/gL and the key conformational changes involved in fusion. As one example, we found that gD L268N was antigenically correct in that it bound most Mabs but was impaired in fusion, exhibited compromised binding of MC14 (a Mab that blocks both gD-gH/gL interaction and fusion), and failed to bind truncated gH/gL, all events that are associated with the inhibition of C-terminus movement. We conclude that, within the C-terminus, residue 268 is essential for gH/gL binding and induction of conformational changes and serves as a flexible inflection point in the critical movement of the gD C-terminus.
MeSH term(s)	Simplexvirus/genetics ; Viral Envelope Proteins/metabolism ; Protein Binding ; Glycoproteins/metabolism ; Disulfides ; Virus Internalization
Chemical Substances	Viral Envelope Proteins ; Glycoproteins ; Disulfides
Language	English
Publishing date	2023-03-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15040895
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Article ; Online: Molecular association of herpes simplex virus type 1 glycoprotein E with membrane protein Us9.

Awasthi, Sita / Friedman, Harvey M

Archives of virology

2016 Volume 161, Issue 11, Page(s) 3203–3213

Abstract: Herpes simplex virus type 1 (HSV-1) glycoprotein E (gE), glycoprotein I (gI), and Us9 promote efficient anterograde axonal transport of virus from the neuron cytoplasm to the axon terminus. HSV-1 and PRV gE and gI form a heterodimer that is required for ... ...

Abstract	Herpes simplex virus type 1 (HSV-1) glycoprotein E (gE), glycoprotein I (gI), and Us9 promote efficient anterograde axonal transport of virus from the neuron cytoplasm to the axon terminus. HSV-1 and PRV gE and gI form a heterodimer that is required for anterograde transport, but an association that includes Us9 has not been demonstrated. NS-gE380 is an HSV-1 mutant that has five amino acids inserted after gE residue 380, rendering it defective in anterograde axonal transport. We demonstrated that gE, gI and Us9 form a trimolecular complex in Vero cells infected with NS-gE380 virus in which gE binds to both Us9 and gI. We detected the complex using immunoprecipitation with anti-gE or anti-gI monoclonal antibodies in the presence of ionic detergents. Under these conditions, Us9 did not associate with gE in cells infected with wild-type HSV-1; however, using a nonionic detergent, TritonX-100, an association between Us9 and gE was detected in immunoprecipitates of both wild-type and NS-gE380-infected cells. The results suggest that the interaction between Us9 and gE is weak and disrupted by ionic detergents in wild-type infected cells. We postulate that the tight interaction between Us9 and gE leads to the anterograde spread defect in the NS-gE380 virus.
MeSH term(s)	Animals ; Cercopithecus aethiops ; Herpesvirus 1, Human/physiology ; Immunoprecipitation ; Lipoproteins/metabolism ; Phosphoproteins/metabolism ; Protein Binding ; Protein Interaction Mapping ; Vero Cells ; Viral Envelope Proteins/metabolism ; Viral Proteins/metabolism
Chemical Substances	Lipoproteins ; Phosphoproteins ; US9 protein, Human herpesvirus 1 ; Viral Envelope Proteins ; Viral Proteins ; glycoprotein E, herpes simplex virus type 1 ; glycoprotein I, herpes simplex virus type 1
Language	English
Publishing date	2016-11
Publishing country	Austria
Document type	Journal Article
ZDB-ID	7491-3
ISSN	1432-8798 ; 0304-8608
ISSN (online)	1432-8798
ISSN	0304-8608
DOI	10.1007/s00705-016-3028-z
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Article ; Online: Trivalent Glycoprotein Subunit Vaccine Prevents Neonatal Herpes Simplex Virus Mortality and Morbidity.

Patel, Chaya D / Taylor, Sean A / Mehrbach, Jesse / Awasthi, Sita / Friedman, Harvey M / Leib, David A

Journal of virology

2020 Volume 94, Issue 11

Abstract: Herpes simplex virus (HSV) can cause severe infection in neonates leading to mortality and lifelong morbidity. Prophylactic approaches, such as maternal immunization, could prevent neonatal HSV (nHSV) infection by providing protective immunity and ... ...

Abstract	Herpes simplex virus (HSV) can cause severe infection in neonates leading to mortality and lifelong morbidity. Prophylactic approaches, such as maternal immunization, could prevent neonatal HSV (nHSV) infection by providing protective immunity and preventing perinatal transmission. We previously showed that maternal immunization with a replication-defective HSV vaccine candidate,
MeSH term(s)	Animals ; Animals, Newborn ; Cell Line ; Child ; Herpes Simplex/immunology ; Herpes Simplex/prevention & control ; Herpesvirus 1, Human/immunology ; Humans ; Infant, Newborn ; Mice ; Pregnancy Complications, Infectious/immunology ; Pregnancy Complications, Infectious/prevention & control ; Vaccines, Subunit/immunology ; Vaccines, Subunit/pharmacology
Chemical Substances	Vaccines, Subunit
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.02163-19
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Article ; Online: Herpes simplex virus type 2 trivalent protein vaccine containing glycoproteins C, D and E protects guinea pigs against HSV-1 genital infection.

Egan, Kevin / Hook, Lauren M / Naughton, Alexis / Friedman, Harvey M / Awasthi, Sita

Human vaccines & immunotherapeutics

2020 Volume 16, Issue 9, Page(s) 2109–2113

Abstract: A vaccine to prevent genital herpes is an unmet public health need. We previously reported that a trivalent vaccine containing herpes simplex virus type 2 (HSV-2) glycoproteins C, D, and E (gC2, gD2, gE2) produced in baculovirus and administered with CpG/ ...

Abstract	A vaccine to prevent genital herpes is an unmet public health need. We previously reported that a trivalent vaccine containing herpes simplex virus type 2 (HSV-2) glycoproteins C, D, and E (gC2, gD2, gE2) produced in baculovirus and administered with CpG/alum as adjuvants blocks immune evasion mediated by gC2 and gE2 and virus entry by gD2. The vaccine protected guinea pigs against HSV-2 vaginal infection. We evaluated whether the HSV-2 vaccine cross-protects against HSV-1 because many first-time genital herpes infections are now caused by HSV-1. Guinea pigs were mock immunized or immunized with the trivalent vaccine and challenged intravaginally with a different HSV-1 isolate in two experiments. Guinea pigs immunized with the trivalent vaccine developed genital lesions on fewer days than the mock group: 2/477 (0.4%) days compared to 15/424 (3.5%) in experiment one, and 0/135 days compared to 17/135 (12.6%) in experiment two (both
MeSH term(s)	Animals ; Female ; Genitalia ; Guinea Pigs ; Herpes Genitalis/prevention & control ; Herpes Simplex ; Herpesvirus 1, Human ; Herpesvirus 2, Human ; Vaccines ; Viral Envelope Proteins
Chemical Substances	Vaccines ; Viral Envelope Proteins
Language	English
Publishing date	2020-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2664176-8
ISSN	2164-554X ; 2164-5515
ISSN (online)	2164-554X
ISSN	2164-5515
DOI	10.1080/21645515.2020.1749509
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Article ; Online: Vaccines to prevent genital herpes.

Egan, Kevin / Hook, Lauren M / LaTourette, Philip / Desmond, Angela / Awasthi, Sita / Friedman, Harvey M

Translational research : the journal of laboratory and clinical medicine

2020 Volume 220, Page(s) 138–152

Abstract: Genital herpes increases the risk of acquiring and transmitting Human Immunodeficiency Virus (HIV), is a source of anxiety for many about transmitting infection to intimate partners, and is life-threatening to newborns. A vaccine that prevents genital ... ...

Abstract	Genital herpes increases the risk of acquiring and transmitting Human Immunodeficiency Virus (HIV), is a source of anxiety for many about transmitting infection to intimate partners, and is life-threatening to newborns. A vaccine that prevents genital herpes infection is a high public health priority. An ideal vaccine will prevent both genital lesions and asymptomatic subclinical infection to reduce the risk of inadvertent transmission to partners, will be effective against genital herpes caused by herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and will protect against neonatal herpes. Three phase 3 human trials were performed over the past 20 years that used HSV-2 glycoproteins essential for virus entry as immunogens. None achieved its primary endpoint, although each was partially successful in either delaying onset of infection or protecting a subset of female subjects that were HSV-1 and HSV-2 uninfected against HSV-1 genital infection. The success of future vaccine candidates may depend on improving the predictive value of animal models by requiring vaccines to achieve near-perfect protection in these models and by using the models to better define immune correlates of protection. Many vaccine candidates are under development, including DNA, modified mRNA, protein subunit, killed virus, and attenuated live virus vaccines. Lessons learned from prior vaccine studies and select candidate vaccines are discussed, including a trivalent nucleoside-modified mRNA vaccine that our laboratory is pursuing. We are optimistic that an effective vaccine for prevention of genital herpes will emerge in this decade.
MeSH term(s)	Animals ; Antibodies, Viral/blood ; Clinical Trials as Topic ; Disease Models, Animal ; Herpes Genitalis/immunology ; Herpes Genitalis/prevention & control ; Humans ; Immune Evasion ; Viral Vaccines/immunology
Chemical Substances	Antibodies, Viral ; Viral Vaccines
Language	English
Publishing date	2020-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2020.03.004
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Article ; Online: A Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Provides Outstanding Protection in Mice against Genital and Non-Genital HSV-1 Infection, Comparable to the Same Antigens Derived from HSV-1.

Egan, Kevin P / Awasthi, Sita / Tebaldi, Giulia / Hook, Lauren M / Naughton, Alexis M / Fowler, Bernard T / Beattie, Mitchell / Alameh, Mohamad-Gabriel / Weissman, Drew / Cohen, Gary H / Friedman, Harvey M

Viruses

2023 Volume 15, Issue 7

Abstract: HSV-1 disease is a significant public health burden causing orofacial, genital, cornea, and brain infection. We previously reported that a trivalent HSV-2 gC2, gD2, gE2 nucleoside-modified mRNA-lipid nanoparticle (LNP) vaccine provides excellent ... ...

Abstract	HSV-1 disease is a significant public health burden causing orofacial, genital, cornea, and brain infection. We previously reported that a trivalent HSV-2 gC2, gD2, gE2 nucleoside-modified mRNA-lipid nanoparticle (LNP) vaccine provides excellent protection against vaginal HSV-1 infection in mice. Here, we evaluated whether this HSV-2 gC2, gD2, gE2 vaccine is as effective as a similar HSV-1 mRNA LNP vaccine containing gC1, gD1, and gE1 in the murine lip and genital infection models. Mice were immunized twice with a total mRNA dose of 1 or 10 µg. The two vaccines produced comparable HSV-1 neutralizing antibody titers, and surprisingly, the HSV-2 vaccine stimulated more potent CD8
MeSH term(s)	Female ; Animals ; Mice ; Herpesvirus 2, Human/genetics ; Herpesvirus 1, Human/genetics ; Herpes Genitalis/prevention & control ; Nucleosides ; Antibodies, Neutralizing ; Viral Envelope Proteins ; Antibodies, Viral ; RNA, Messenger/genetics
Chemical Substances	Nucleosides ; Antibodies, Neutralizing ; Viral Envelope Proteins ; Antibodies, Viral ; RNA, Messenger
Language	English
Publishing date	2023-06-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15071483
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Article ; Online: Status of prophylactic and therapeutic genital herpes vaccines.

Awasthi, Sita / Friedman, Harvey M

Current opinion in virology

2014 Volume 6, Page(s) 6–12

Abstract: A half billion people have genital herpes infections worldwide. Approximately one-fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the ... ...

Abstract	A half billion people have genital herpes infections worldwide. Approximately one-fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the mental anguish genital herpes causes for some individuals, the fact that pregnant women with genital herpes risk transmitting infection to their newborn children, and the observation that HSV-2 infection is associated with a 3-fold to 4-fold increased probability of HIV acquisition. We review the strengths and limitations of preclinical animal models used to assess genital herpes vaccine candidates and the goals of prophylactic and therapeutic vaccines. We also discuss the current pipeline of vaccine candidates and lessons learned from past clinical trials that serve as a stimulus for new strategies, study designs and endpoint determinations.
MeSH term(s)	Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Female ; Herpes Genitalis/prevention & control ; Herpes Genitalis/therapy ; Herpes Simplex Virus Vaccines/administration & dosage ; Herpes Simplex Virus Vaccines/immunology ; Humans ; Male ; Simplexvirus/immunology
Chemical Substances	Herpes Simplex Virus Vaccines
Language	English
Publishing date	2014-03-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2014.02.006
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