Reply to “Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth?”

Abstract

S cientific rigor is essential for the advancement of biomedical knowledge and human health (1). However, rigor must be applied to scientific research and scholarly review alike (2). We acknowledge Homayon Ghiasi for this opportunity to underscore the importance of scholarly rigor in scientific review. Alas, his letter is fraught with duplicitous misapprehensions and logical fallacies. This letter aims to substantiate "reality" and rebut "myth" concerning our recent publications characterizing a prophylactic live attenuated herpes simplex virus 1 (HSV-1) vaccine (3-5). Ghiasi erroneously pigeonholes the HSV-1 vaccine utilized in our research as a poorly immunogenic, nonreplicating virus altogether lacking the viral protein ICP0. As consistently reported (3-5), our novel live attenuated vaccine designated "HSV-1 0ΔNLS" encodes the entire ICP0 protein, except for its nuclear localization sequence (NLS). This mutation renders the virus highly susceptible to type 1 interferon in vitro and in vivo (3, 4). While the attenuated HSV-1 0ΔNLS vaccine strain lacks neurovirulence and pathogenicity, it replicates in mucosal tissue for up to 7 days in vivo and was found to be as immunogenic as a fully virulent parental strain in C57BL/6 mice (4). Epistemological concern was raised regarding the control vaccine and challenge inocula employed in efficacy testing for the HSV-1 0ΔNLS vaccine in mice. An HSV-2 glycoprotein D subunit vaccine (gD-2) was utilized as a control in our studies (3, 5), as it is the only prophylactic HSV vaccine reported to date in masked phase III clinical trials to demonstrate efficacy against HSV-1 infection (35%) or HSV-1 genital disease (58%) in humans-albeit unexpectedly (6). Ghiasi fallaciously misquotes this report from Belshe et al. (6) to indicate otherwise. Furthermore, Ghiasi inexplicably alleges a lack of stringency in our ocular HSV-1 challenge inocula. The 50% lethal dose (LD 50) challenge inoculum is classically appropriate for assessing vaccine efficacy in preclinical animal studies. We have reported the efficacy of the HSV-1 0ΔNLS vaccine in outbred CD-1 mice using postvaccination ocular HSV-1 challenge inocula equal to and 100 times the LD 50 for naive animals (3). Ghiasi's arguments also contain two logical fallacies that overlook the pathophysiology of HSV-1. He first includes a faulty generalization in which no distinction is made between prophylactic and therapeutic vaccines. This equivocation transitions into a secondary false dichotomy between cell-mediated and humoral immunity. However, the immunologic correlates of protection essential for prophylactic protection against mucosal infection and establishment of neuronal latency during primary HSV-1 infection are not necessarily identical to the immune mechanisms that govern reactivation in latently infected individuals (7). Prophylactic and therapeutic vaccines intrinsically target different phases of the virus life cycle. As Ghiasi outlines above, cell-mediated immunity is important for protection against HSV-1 reactivation. Conve...