Passive immune protection by herpes simplex virus-specific monoclonal antibodies and monoclonal antibody-resistant mutants altered in pathogenicity

Abstract

Virus-neutralizing monoclonal antibodies specific for 13 different genetically defined epitopes of glycoproteins gC, gB, and gD of herpes simplex virus type 1, strain KOS-321, were compared for their ability to provide passive immunity to DBA-2 mice challenged intracranially. Protection was highly specific, since individual monoclonal antibodies failed to protect against infection with monoclonal antibody-resistant (mar) mutants altered in the single epitope recognized by the injected antibody. The dose-response kinetics of passive immunity paralleled the in vitro neutralization titers for each antibody. No correlation was observed between immune protection and antibody isotype or complement-dependent in vitro neutralization titers. This suggests that virus neutralization was not the protective mechanism. In general, antibodies reactive with epitopes of gC were protective at the lowest antibody doses, antibodies specific for gB were less efficient in providing immunity, and antibodies against gD were the least effective. mar mutants with single epitope changes in gC and multiple epitope changes in gB showed highly reduced pathogenicity, requiring up to 5 x 106 PFU to kill * Corresponding author.

Molecular basis of the glycoprotein C-negative phenotypes of herpes simplex virus type 1 mutants selected with a virus-neutralizing monoclonal antibody

“…However, this glycoprotein may play an important role in natural infection because nearly all clinical isolates of HSV-1 express gC (25,32). Indeed, a gCmutant of HSV-1 (strain KOS) is less pathogenic than wild-type virus following intracranial inoculation of mice (17).…”

Vaccine induced HSV 1 antibodies fail to correlate with protection against HSV 2 in guinea pigs

“…A consistent positive correlation was found between ELISA antibody titres to gD-1, and titre in all the other assays. Monoclonal antibodies to gD are capable of neutralizing virus in the absence of complement, and of mediating CMC and ADCC [3,4]. Western blots probed with sera from our vaccinated guinea pigs have shown that there is a more pronounced response to gD than to the other virion glycoproteins (data not shown).…”

“…Attempts have been made to correlate the ability to protect with activity and in vitro functional assays, i.e., antibody and complement-mediated cytotoxicity (CMC), antibody-dependent cellular cytotoxicity (ADCC), and neutralization with or without complement. However, such associations have not been conclusively demonstrated [3][4][5]. In the present study we vaccinated guinea pigs with a HSV 1 subunit vaccine [6], and subsequently challenged them intravaginally with HSV 2.…”

“…Protection can be achieved with both polyclonal antiviral sera [1] and monoclonal antibodies raised to the major virion glycoproteins (gB, gC and gD, see [2]). No clear relationships have emerged linking function in vitro (neutralization, CMC, ADCC) with ability to protect [3,4]. Monoclonal antibodies inactive in all of these assays may nevertheless protect against virus challenge [5].…”

Recombinant simian varicella viruses induce immune responses to simian immunodeficiency virus (SIV) antigens in immunized vervet monkeys

“…The SVV gC is nonessential for viral replication in cell culture, but may be important in viral pathogenesis (Gray and Byrne, 2003). HSV-1, bovine herpesvirus type 1 (BHV-1), and equine herpesvirus type 1 (EHV-1) gC mutants are attenuated (Kumel et al, 1985;Kúdelová et al, 1991;Kaashoek et al, 1998;Osterrieder, 1999). The VZV gC is associated with virion morphogenesis in the skin and VZV gC mutants have restricted ability to replicate in skin tissue in SCIDhu mice (Moffat et al, 1998,Storlie et al, 2006) and a defective gC has been proposed as the basis of attenuation for the VZV Oka vaccine (Kinchington et al, 1990).…”