1022. Establishing Models of Herpes Simplex Virus Type 2 Superinfection of Herpes Simplex Virus Type 1 Seropositive Mice to Test The Efficacy of a Novel Vaccine
Session: Poster Abstract Session: Adult Immunization - Miscellaneous
Friday, October 6, 2017
Room: Poster Hall CD
Posters
  • posterramsey.jpg (2.0 MB)
  • Background: Multiple subunit vaccines that elicit neutralizing antibodies (nAbs) against the immunodominant HSV-2 glycoproteins D and/or B (gD and gB) were advanced into the clinic after demonstrating protection against disease in animal models. However, although the vaccines elicited nAbs in seronegative and boosted nAb titers in HSV-1 seropositive (HSV-1+) participants, none prevented HSV-2 infection suggesting that nAbs alone are not sufficient. The results also indicate that current animal models are not predictive of clinical trial outcomes. We recently engineered a candidate single cycle vaccine strain deleted in gD (ΔgD-2) and showed that it elicits high titer non-neutralizing Abs that provide complete protection against HSV-1 or HSV-2. The Abs passively protect naïve mice and activate the Fc receptor to induce antibody dependent cell mediated cytotoxicity (ADCC). We hypothesize that ΔgD-2 will protect HSV-1+ individuals from HSV-2 because it elicits a different type of immune response. To test this hypothesis, we established a model of HSV-2 superinfection in HSV-1+ mice.

    Methods: We infected mice by corneal scarification with serial dilutions of a clinical strain of HSV-1 (Bx31.1) to identify a sublethal dose associated with seroconversion. We then superinfected mice on the skin with HSV-2 and monitored for disease. Presence of virus in dorsal root ganglia (DRG), the site of HSV latency, was determined by quantitative PCR.

    Results: Corneal infection with 10^4 PFU of HSV-1 resulted in disease in 18/29 (62%) mice and 13/18 survived. Seroconversion was documented in 9/13 survivors. Surviving mice were superinfected 2 weeks post-recovery with HSV-2. All of the mice developed signs of disease, but only 2/9 who were HSV-1+ died compared to 4/4 seronegative mice (p=0.02, Fisher exact test). HSV-2 DNA was detected in the DRG of 12/13 mice.

    Conclusion: Sublethal HSV-1 corneal disease provides partial protection against HSV-2 superinfection and provides a model to test vaccine efficacy. We speculate that superinfection boosts preexisting nAb titers, a response consistent with immune repertoire freeze, but that ΔgD-2, because it elicits ADCC Abs, will overcome repertoire freeze and provide greater protection against HSV-2 superinfection.

    Natalie Ramsey, B.S.1, William Jacobs, PhD1 and Betsy C. Herold, MD, FIDSA, FPIDS2, (1)Albert Einstein College of Medicine, Bronx, NY, (2)Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY

    Disclosures:

    N. Ramsey, None

    W. Jacobs, X-vax: Grant Investigator , Research grant and Research support

    B. C. Herold, X-vax: Grant Investigator , Research grant and Research support

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