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dc.contributor.authorSiddall, Nicolle M.
dc.date.accessioned2018-12-20T11:44:51Z
dash.embargo.terms2020-05-01
dc.date.created2018-05
dc.date.issued2018-04-16
dc.date.submitted2018
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:37945098*
dc.description.abstractOral and genital herpes diseases are major global health problems, infecting approximately 90% of the world’s population. Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes worldwide; however, herpes simplex virus type 1 (HSV-1), usually associated with oral disease, has become an increasing cause of genital infections. While antiviral therapies are available that reduce virus-related symptoms, they are imperfect. Improved treatment options such as a vaccines are believed to be the answer to control this public health problem, however despite many years of research and development an effective vaccine has not yet reached the market. Subunit vaccines have centered on the use of HSV surface glycoprotein D (gD), an antigen required for viral infection and a dominant target for neutralizing antibody production against both HSV-1 and HSV-2. A subunit vaccine candidate developed by Genocea Biosciences, GEN-003, containing the HSV-2 antigens gD2TMR (a deletion mutant of gD2), Infected Cell Protein-4 (ICP4), and Matrix-M2 adjuvant, induces neutralizing antibodies (NAb) against HSV-2 in seropositive subjects (HSV-2pos and HSV-2pos/HSV-1pos). In addition, the vaccine was effective, reducing both viral shedding and genital lesion recurrence in treated subjects. I have hypothesized that GEN-003 vaccination in the same population will elicit a NAb response against HSV-1 that can also serve as a correlate of protection. To address immune correlates of disease, serum samples from subjects’ enrolled in Genocea’s GEN-003-003 Phase 2 clinical trial were evaluated to quantitate HSV-1 NAb responses and these results were used to correlate a relationship with viral shedding and lesion outcomes. These studies indicate that: 1) the GEN-003 vaccine elicited HSV-1 NAb titer fold-changes from baseline in seropositive individuals that were equivalent or better than the induction of HSV-2 NAb titer fold-changes, 2) significantly higher HSV-1 NAb titer fold-change from baseline were reached in double seropositive (HSV-1pos/HSV-2pos) individuals compared to single seropositive (HSV-1neg/HSV-2pos) individuals after the 3rd dose of vaccine, 3) a weak Spearman correlation (r = - 0.350, p = 0.037) between HSV-1 NAb titers after the 3rd dose of vaccine and viral shedding rate was present, and 4) no significant Spearman correlation was calculated between HSV-1 NAb titers and time to first lesion appearance. In addition, the results show that HSV-1 NAbs induced by GEN-003 vaccination are long lasting and durable. Although the correlations are significant but weak, this work suggests that HSV-1 NAbs may have a role in protecting infected persons against viral reactivation and shedding. Finally, the potential benefit of a strong HSV-1 NAb response to the GEN-003 vaccines is that it could provide protection against HSV-1 genital and oral disease.
dc.format.mimetypeapplication/pdf
dash.licenseLAA
dc.subjectHealth Sciences, Immunology
dc.titleEvaluation of a HSV-2 Therapeutic Candidate Vaccine, GEN-003, for the Production of Herpes Simplex Virus Type 1 (HSV-1) Neutralizing Antibodies in Seropositive Individuals
dc.typeThesis or Dissertation
dash.depositing.authorSiddall, Nicolle M.
dash.embargo.until2020-05-01
dc.date.available2018-12-20T11:44:51Z
thesis.degree.date2018
thesis.degree.grantorHarvard Extension School
thesis.degree.levelMasters
thesis.degree.nameALM
dc.contributor.committeeMemberDenkin, Steven
dc.contributor.committeeMemberLong, Deborah
dc.type.materialtext
thesis.degree.departmentBiotechnology
dash.identifier.vireohttp://etds.lib.harvard.edu/dce/admin/view/668
dc.description.keywordsGenital Hereps, HSV-1 Neutralizing Antibodies
dash.author.emailnicollemsiddall@gmail.com


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