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An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection
HSV-1 causes 50% of first-time genital herpes infections in resource-rich countries and affects 190 million people worldwide. A prophylactic herpes vaccine is needed to protect against genital infections by both HSV-1 and HSV-2. Previously our laboratory developed a trivalent vaccine that targets glycoproteins C, D, and E present on the HSV-2 virion. We reported that this vaccine protects animals from genital disease and recurrent virus shedding following lethal HSV-2 challenge. Importantly the vaccine also generates cross-reactive antibodies that neutralize HSV-1, suggesting it may provide protection against HSV-1 infection. Here we compared the efficacy of this vaccine delivered as protein or nucleoside-modified mRNA immunogens against vaginal HSV-1 infection in mice. Both the protein and mRNA vaccines protected mice from HSV-1 disease; however, the mRNA vaccine provided better protection as measured by lower vaginal virus titers post-infection. In a second experiment, we compared protection provided by the mRNA vaccine against intravaginal challenge with HSV-1 or HSV-2. Vaccinated mice were totally protected against death, genital disease and infection of dorsal root ganglia caused by both viruses, but somewhat better protected against vaginal titers after HSV-2 infection. Overall, in the two experiments, the mRNA vaccine prevented death and genital disease in 54/54 (100%) mice infected with HSV-1 and 20/20 (100%) with HSV-2, and prevented HSV DNA from reaching the dorsal root ganglia, the site of virus latency, in 29/30 (97%) mice infected with HSV-1 and 10/10 (100%) with HSV-2. We consider the HSV-2 trivalent mRNA vaccine to be a promising candidate for clinical trials for prevention of both HSV-1 and HSV-2 genital herpes.
Journal Article
HSV-2 gC2 mRNA immunization in mice protects by producing antibodies that bind immune evasion epitopes
Our vaccine candidate for genital herpes includes three immunogens involved in virus entry and immune evasion. HSV-2 glycoprotein C (gC2) is one of the immune evasion molecules that inhibits complement activation by binding C3b, and is the focus of this manuscript. Mice were immunized with 0.25, 0.5, 1, 10, or 30 µg of gC2 lipid nano particle (LNP)-encapsulated nucleoside-modified mRNA and challenged intravaginally with HSV-2. The gC2 mRNA-LNP, even at the lowest dose, was highly protective as a single immunogen. We measured antibody responses to six gC2 epitopes. Both neutralizing and C3b binding epitopes on gC2 were targeted. We passively immunized mice with monoclonal antibodies (mAbs) to gC2 and determined that the mAbs that enhance complement activation by blocking C3b binding were protective, while the mAb that neutralizes the virus, but does not block C3b binding, failed to protect. These results highlight the importance of a vaccine immunogen that induces antibodies that block the ability of gC to inhibit complement activation.
Journal Article
Untraceable
Jennifer Marsh is an FBI secret service agent who gets caught up in a very personal and deadly cat-and-mouse game with a serial killer. The killer knows that people are drawn to the curious and the dark side of things. They will log onto an 'untraceable' website where the killer conducts violent and painful murders live on the internet. The more people who log on and enter the website, the quicker and more violently the victim dies.
DVD
Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs
Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.
Journal Article
Structure of Herpes Simplex Virus Glycoprotein D Bound to the Human Receptor Nectin-1
Binding of herpes simplex virus (HSV) glycoprotein D (gD) to a cell surface receptor is required to trigger membrane fusion during entry into host cells. Nectin-1 is a cell adhesion molecule and the main HSV receptor in neurons and epithelial cells. We report the structure of gD bound to nectin-1 determined by x-ray crystallography to 4.0 Å resolution. The structure reveals that the nectin-1 binding site on gD differs from the binding site of the HVEM receptor. A surface on the first Ig-domain of nectin-1, which mediates homophilic interactions of Ig-like cell adhesion molecules, buries an area composed by residues from both the gD N- and C-terminal extensions. Phenylalanine 129, at the tip of the loop connecting β-strands F and G of nectin-1, protrudes into a groove on gD, which is otherwise occupied by C-terminal residues in the unliganded gD and by N-terminal residues in the gD/HVEM complex. Notably, mutation of Phe129 to alanine prevents nectin-1 binding to gD and HSV entry. Together these data are consistent with previous studies showing that gD disrupts the normal nectin-1 homophilic interactions. Furthermore, the structure of the complex supports a model in which gD-receptor binding triggers HSV entry through receptor-mediated displacement of the gD C-terminal region.
Journal Article
Practical Suggestions for Reducing Burnout in US Medical Students
Burnout is common in physicians and medical students in the United States and other countries. This commentary defines burnout in physicians and medical students. A literature review and my own outline will provide a partial list of its many causes of burnout through the four years of medical school. Current recommendations for reducing medical student burnout are more theoretical than practical in many cases. This review consists of my original suggestions for limiting burnout in medical students, including careful listening to the expected concerns and anxieties of beginning students, and support groups throughout the four years. I propose a reduction in the academic workload, more flexible scheduling of licensing examinations, and ways of lowering student educational debt. Reducing the duration of medical school to three years can also be helpful. Finally, a new beginning of the school day during the first two years is proposed.
Journal Article
Dynamic organization of Herpesvirus glycoproteins on the viral envelope revealed by super-resolution microscopy
The processes of cell attachment and membrane fusion of Herpes Simplex Virus 1 involve many different envelope glycoproteins. Viral proteins gC and gD bind to cellular receptors. Upon binding, gD activates the gH/gL complex which in turn activates gB to trigger membrane fusion. Thus, these proteins must be located at the point of contact between cellular and viral envelopes to interact and allow fusion. Using super-resolution microscopy, we show that gB, gH/gL and most of gC are distributed evenly round purified virions. In contrast, gD localizes essentially as clusters which are distinct from gB and gH/gL. Upon cell binding, we observe that all glycoproteins, including gD, have a similar ring-like pattern, but the diameter of these rings was significantly smaller than those observed on cell-free viruses. We also observe that contrary to cell-free particles, gD mostly colocalizes with other glycoproteins on cell-bound particles. The differing patterns of localization of gD between cell-free and cell-bound viruses indicates that gD can be reorganized on the viral envelope following either a possible maturation of the viral particle or its adsorption to the cell. This redistribution of glycoproteins upon cell attachment could contribute to initiate the cascade of activations leading to membrane fusion.
Journal Article
Bispecific antibodies targeting herpes simplex virus glycoproteins B and D
Herpes simplex viruses (HSV-1 and HSV-2) can be transmitted both orally and sexually and cause lifelong morbidity and, in some cases, meningitis and encephalitis. Although several clinical trials using subunit antigens have been conducted, no vaccine exists. One problem in viral treatment is the emergence of drug resistance through mutations, thereby conferring resistance. Treatment with antibodies targeting multiple epitopes, such as antibody cocktails or bispecific antibodies (BsAbs), should reduce the likelihood of viral escape.
We screened pairs of antibodies targeting key functional sites on glycoproteins B (gB) and D (gD), which are crucial for HSV entry. Murine hybridoma cells expressing anti-gD and anti-gB Mabs were sequenced. Recombinant antibodies, mono- and bispecific, were purified from supernatants of 293T transfected cells.
From a panel of gD-gB monoclonal antibodies (Mabs), we selected MC2 (anti-gD) and C226 (anti-gB) for the design of BsAbs: MC2/C226sc and a simpler version in which the C226scFv was cloned at the C-terminus of MC2 Fc, which we termed BD Tetra. Notably, both MC2/C226sc and BD Tetra BsAbs simultaneously recognized and bound gB and gD and had a marked synergistic effect on inhibiting cell-cell fusion, virus entry, and plaque formation. Although MC2 is HSV-2 specific, both MC2/C226sc and BD Tetra showed activity against HSV-1. The Fc domains of these two BsAbs were equally effective at binding to mouse Fcγ receptors RI or RIV
.
The data presented here demonstrate the generation, characterization, and potential of bispecific antibodies targeting two distinct glycoproteins to enhance neutralization of herpes simplex virus compared with monoclonal antibodies. BsAbs offer a potential avenue for herpes therapeutics, but their design and mechanism of action require careful consideration for optimal efficacy. Engineering different formats of BsAbs will not only enable optimal protective and therapeutic outcomes but also aid in the study of the spatial relationships between key glycoproteins involved in HSV infection. We propose that targeting distinct steps of the fusion cascade will yield a BsAb that is highly effective.
Journal Article