scholarly journals Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

2014 ◽  
Vol 88 (14) ◽  
pp. 7786-7795 ◽  
Author(s):  
J. Charles Whitbeck ◽  
Zhen-Yu Huang ◽  
Tina M. Cairns ◽  
John R. Gallagher ◽  
Huan Lou ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Subunit Vaccine ◽  
Humoral Response ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glycoprotein D ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Neutralizing Epitopes

ABSTRACTThe results of a clinical trial of a subunit vaccine against genital herpes were recently reported (R. B. Belshe, P. A. Leone, D. I. Bernstein, A. Wald, M. J. Levin, J. T. Stapleton, I. Gorfinkel, R. L. Morrow, M. G. Ewell, A. Stokes-Riner, G. Dubin, T. C. Heineman, J. M. Schulte, C. D. Deal, N. Engl. J. Med.366:34–43, 2012, doi:10.1056/NEJMoa1103151). The vaccine consisted of a soluble form of herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative enzyme-linked immunosorbent assay (ELISA) titers against gD2; 10 samples had high titers, 10 had medium titers, and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb)-blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized MAbs. Importantly, IgGs from the majority of gD2-immunized subjects competed for gD binding with four antigenically distinct virus-neutralizing MAbs (MC2, MC5, MC23, and DL11). Screening of patient IgGs against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N and C termini of gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs against the epitopes of MAbs MC2, MC5, MC23, and DL11. This suggests that optimal virus-neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2.IMPORTANCESeveral herpes simplex virus 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2). Although several distinct, well-characterized virus-neutralizing epitopes on gD2 are targeted by murine monoclonal antibodies, it is not known whether the same epitopes are targeted by the humoral response to gD2 in humans. We have developed a novel, biosensor-based competition assay to directly address this important question. Using this approach, we identified epitopes that elicit strong humoral responses in humans, as well as other epitopes that elicit much weaker responses. These data provide new insight into the human response to known neutralizing gD2 epitopes and reveal characteristics of this response that may guide future vaccine development.

An Interleukin 12 Adjuvanted Herpes Simplex Virus 2 DNA Vaccine Is More Protective Than a Glycoprotein D Subunit Vaccine in a High-Dose Murine Challenge Model

2017 ◽  
Vol 30 (3) ◽  
pp. 178-195 ◽  
Author(s):  
Kenneth C. Bagley ◽  
Jennifer A. Schwartz ◽  
Hanne Andersen ◽  
John H. Eldridge ◽  
Rong Xu ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dna Vaccine ◽  
Subunit Vaccine ◽  
Interleukin 12 ◽  
High Dose ◽  
Glycoprotein D ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
D Subunit

scholarly journals The Major Neutralizing Antigenic Site on Herpes Simplex Virus Glycoprotein D Overlaps a Receptor-Binding Domain

1999 ◽  
Vol 73 (12) ◽  
pp. 9879-9890 ◽  
Author(s):  
J. Charles Whitbeck ◽  
Martin I. Muggeridge ◽  
Ann H. Rux ◽  
Wangfang Hou ◽  
Claude Krummenacher ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Amino Acid ◽  
Herpes Simplex ◽  
Receptor Binding ◽  
Binding Domain ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Receptor Binding Domain ◽  
Glycoprotein D ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) entry is dependent on the interaction of virion glycoprotein D (gD) with one of several cellular receptors. We previously showed that gD binds specifically to two structurally dissimilar receptors, HveA and HveC. We have continued our studies by using (i) a panel of baculovirus-produced gD molecules with various C-terminal truncations and (ii) a series of gD mutants with nonoverlapping 3-amino-acid deletions between residues 222 and 254. Binding of the potent neutralizing monoclonal antibody (MAb) DL11 (group Ib) was unaffected in forms of gD containing residues 1 to 250 but was greatly diminished in molecules truncated at residue 240 or 234. Both receptor binding and blocking of HSV infection were also affected by these C-terminal truncations. gD-1(234t) bound weakly to both HveA and HveC as determined by enzyme-linked immunosorbent assay (ELISA) and failed to block infection. Interestingly, gD-1(240t) bound well to both receptors but blocked infection poorly, indicating that receptor binding as measured by ELISA is not the only gD function required for blocking. Optical biosensor studies showed that while gD-1(240t) bound HveC with an affinity similar to that of gD-1(306t), the rates of complex formation and dissociation were significantly faster than for gD-1(306t). Complementation analysis showed that any 3-amino-acid deletion between residues 222 and 251 of gD resulted in a nonfunctional protein. Among this set of proteins, three had lost DL11 reactivity (those with deletions between residues 222 and 230). One of these proteins (deletion 222–224) was expressed as a soluble form in the baculovirus system. This protein did not react with DL11, bound to both HveA and HveC poorly as shown by ELISA, and failed to block HSV infection. Since this protein was bound by several other MAbs that recognize discontinuous epitopes, we conclude that residues 222 to 224 are critical for gD function. We propose that the potent virus-neutralizing activity of DL11 (and other group Ib MAbs) likely reflects an overlap between its epitope and a receptor-binding domain of gD.

scholarly journals Antiviral Activity of a Single-Domain Antibody Immunotoxin Binding to Glycoprotein D of Herpes Simplex Virus 2

2014 ◽  
Vol 59 (1) ◽  
pp. 527-535 ◽  
Author(s):  
Eileen M. Geoghegan ◽  
Hong Zhang ◽  
Prashant J. Desai ◽  
Arya Biragyn ◽  
Richard B. Markham
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Single Domain ◽  
Surface Glycoprotein ◽  
Glycoprotein D ◽  
Single Domain Antibody ◽  
Domain Antibody ◽  
Infected Cells ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACTDespite years of research dedicated to preventing the sexual transmission of herpes simplex virus 2 (HSV-2), there is still no protective vaccine or microbicide against one of the most common sexually transmitted infections in the world. Using a phage display library constructed from a llama immunized with recombinant HSV-2 glycoprotein D, we identified a single-domain antibody VHH, R33, which binds to the viral surface glycoprotein D. Although R33 does not demonstrate any HSV-2 neutralization activityin vitro, when expressed with the cytotoxic domain of exotoxin A, the resulting immunotoxin (R33ExoA) specifically and potently kills HSV-2-infected cells, with a 50% neutralizing dilution (IC50) of 6.7 nM. We propose that R33ExoA could be used clinically to prevent transmission of HSV-2 through killing of virus-producing epithelial cells during virus reactivation. R33 could also potentially be used to deliver other cytotoxic effectors to HSV-2-infected cells.

scholarly journals Performance of Kalon herpes simplex virus 2 assay using dried blood spots among young women in Uganda

2016 ◽  
Vol 5 (1) ◽  
Author(s):  
Sam L. Nsobya ◽  
Paul C. Hewett ◽  
Sam Kalibala ◽  
Barbara S. Mensch
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Young Women ◽  
Herpes Simplex Virus Type ◽  
Dried Blood Spots ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Spots ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

This study evaluated the performance of the Kalon Biological HSV2 IgG enzyme-linked immunosorbent assay (Kalon Biological Ltd, Surrey, United Kingdom) on dried blood spots (DBS) of various dilutions compared with plasma from young women aged 18–24 years in Uganda. We estimated the sensitivity and specificity of three DBS dilutions using plasma as the reference. All three evaluated DBS dilutions yielded low sensitivities and specificities, with DBS 1:2 yielding the highest concurrence. Other herpes simplex virus type 2 assays should be examined with regard to their utility for testing DBS.

scholarly journals A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

2015 ◽  
Vol 90 (1) ◽  
pp. 562-574 ◽  
Author(s):  
Kening Wang ◽  
Kyle N. Goodman ◽  
Daniel Y. Li ◽  
Mark Raffeld ◽  
Mayra Chavez ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Genital Herpes ◽  
Virus Replication ◽  
Dorsal Root ◽  
Subunit Vaccine ◽  
Challenge Virus ◽  
A Subunit ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACTA recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells,in vitroand is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891–12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2-gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum.IMPORTANCEGenital herpes simplex is one of the most prevalent sexually transmitted diseases. Though HSV-2 disease is usually mild, it can be life threatening in neonates and immunocompromised persons. In addition, genital herpes increases the frequency of HIV infection and transmission. HSV-2 maintains a latent infection in sensory neurons and cannot be cleared with antiviral drugs. The virus frequently reactivates, resulting in virus shedding in the genital area, which serves as a source for transmission. A prophylactic vaccine is needed to prevent disease and to control the spread of the virus. Previous human trials of subunit vaccines have been unsuccessful. Here we report the results of vaccinating mice with a new type of live attenuated HSV-2 vaccine that is impaired for infection of neurons and provides better protection of mice than that obtained with a subunit vaccine. The strategy of altering the cell tropism of a virus is a new approach for a live attenuated vaccine.

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