Better neutralization of HSV-1 than HSV-2 by antibody from subjects immunized with the GlaxoSmithKline gD2 vaccine.
ABSTRACT The Herpevac Trial evaluated an HSV-2 glycoprotein D (gD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 but not HSV-2. We evaluated sera from 30 HSV-1 and HSV-2 seronegative women immunized with gD2 in the Herpevac Trial. Neutralizing antibody titers were 3.5-fold higher to HSV-1 than HSV-2 (P<0.001). HSV-2 glycoproteins C (gC2) and E (gE2) on the virus blocked neutralization of gD2, while HSV-1 gC1 and gE1 did not block neutralization of HSV-1. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results and shielding neutralizing domains provides a potential mechanism.
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ABSTRACT: We investigated the role of antibodies against the mature portion of glycoprotein G (mgG-2) of herpes simplex virus 2 (HSV-2) in protective immunity after vaccination. Mice were immunized intramuscularly with mgG-2 and oligodeoxynucleotides containing two CpG motifs plus alum as adjuvant. All C57BL/6 mice survived and presented no genital or systemic disease. High levels of immunoglobulin G subclass 1 (IgG1) and IgG2 antibodies were detected and re-stimulated splenic CD4+ T cells proliferated and produced IFN-γ. None of the sera from immunized mice exhibited neutralization, while all sera exerted antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis (ACMC) activity. Passive transfer of anti-mgG-2 monoclonal antibodies, or immune serum, to naive C57BL/6 mice did not limit disease progression. Immunized B‑cell KO mice presented lower survival rate and higher vaginal viral titers, as compared with vaccinated B-cell KO mice after passive transfer of immune serum and vaccinated C57BL/6 mice. Sera from mice that were vaccinated subcutaneously and intranasally with mgG-2 presented significantly lower titers of IgG antibodies and lower ADCC and ACMC activity. We conclude that anti-mgG-2 antibodies were of importance to limit genital HSV‑2 infection. ADCC and ACMC activity are potentially important mechanisms in protective immunity, and could tentatively be evaluated in future animal vaccine studies and in clinical trials.Viruses 11/2014; 6(11):4358-4372. DOI:10.3390/v6114358 · 3.28 Impact Factor
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ABSTRACT: No vaccines are approved for prevention or treatment of genital herpes. The focus of genital herpes vaccine trials has been on prevention using herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) alone or combined with glycoprotein B. These prevention trials did not achieve their primary end points. However, subset analyses reported some positive outcomes in each study. The most recent trial was the Herpevac Trial for Women that used gD2 with monophosphoryl lipid A and alum as adjuvants in herpes simplex virus type 1 (HSV-1) and HSV-2 seronegative women. Unexpectedly, the vaccine prevented genital disease by HSV-1 but not HSV-2. Currently, HSV-1 causes more first episodes of genital herpes than HSV-2, highlighting the importance of protecting against HSV-1. The scientific community is conflicted between abandoning vaccine efforts that include gD2 and building upon the partial successes of previous trials. We favor building upon success and present approaches to improve outcomes of gD2-based subunit antigen vaccines.Expert Review of Vaccines 08/2014; 13(12):1-14. DOI:10.1586/14760584.2014.951336 · 4.22 Impact Factor
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ABSTRACT: eLife digest Herpes simplex virus 2 (or HSV-2) infects millions of people worldwide and is the leading cause of genital diseases. The virus initially infects skin cells, but then spreads to nerve cells where it persists for life. Often, the virus remains in a dormant state for long periods of time and does not cause any symptoms. However, HSV-2 can periodically re-activate, leading to repeated infections; this can be life-threatening in patients who suffer from a weak immune system. There is no cure for Herpes simplex virus infection, and there are currently no vaccines that would prevent the virus from infecting humans. HSV-2 contains a protein on its surface known as ‘glycoprotein D’ which it needs to enter host cells. The interaction between glycoprotein D and the host is also essential for cell-to-cell spread of the virus. Vaccines that contain glycoprotein D trigger the production of antibodies that bind to this viral protein. These vaccines have been tested in several large clinical trials, but the results have so far been disappointing. As such, new vaccines that provide effective protection against HSV-2 are urgently needed. Live attenuated vaccines are commonly used to prevent diseases such as measles mumps and chicken pox or shingles. These vaccines contain a harmless or weakened version of the disease-causing virus. Petro, González et al. have now developed a new potential vaccine that contains live attenuated HSV-2, which completely lacks glycoprotein D and thus cannot spread from cell-to-cell. When this weakened virus was administered to mice that have a poor immune system, the mice remained healthy. On the other hand, when Petro, González et al. treated similar mice with the wild-type HSV-2 virus instead, many mice died within a few days. Petro, González et al. then went on to show that mice that had been treated with the weakened virus as a vaccine were completely protected from a later infection with wild-type HSV-2 and did not develop any symptoms of the disease. Furthermore, no virus was detected in the nerve cells of these mice—which is where the virus would normally persist in its dormant state. Finally, Petro, González et al. showed that blood serum from immunized mice could be used to completely protect other mice from exposure to wild-type virus. These results demonstrate that a live attenuated HSV-2 virus that lacks glycoprotein D (the main component of other failed vaccines) elicits a different type of immune response and is a safe and effective vaccine in mouse models of virus infection. With further work, these findings may eventually lead to a preventative treatment to combat HSV-2 infections in humans. DOI: http://dx.doi.org/10.7554/eLife.06054.002eLife Sciences 03/2015; 4. DOI:10.7554/eLife.06054 · 8.52 Impact Factor