Acute and latent herpes simplex virus neurological disease in mice immunized with purified virus‐specific glycoproteins gB or gD

Abstract

Groups of 5-week-old BALB/c mice were immunized intraperitoneally with approximately 10 micrograms of purified alum-precipitated glycoprotein gB or gD of either herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) origin. Control mice received injections of alum-precipitated 1% bovine serum albumin (BSA). Following a second immunization 4 weeks later, seroconversion was confirmed by demonstrating the presence of glycoprotein-specific antibody by immune precipitation. All animals were challenged with lethal doses of either HSV-1 or HSV-2 by footpad inoculation and assessed for acute virus-induced neurological disease and the development of ganglionic latency. Whereas 70% of control (BSA-immunized) HSV-1-infected animals developed ascending myelitis and died, 100% of mice immunized with either gB-1, gB-2, gD-1, or gD-2 antigens remained free of clinical illness and survived HSV-1 challenge. In contrast, gB-1-or gB-2-immunized mice were not protected against acute HSV-2-induced neurological disease and showed a mortality rate of 60-90% (equivalent to that seen in controls), although mean survival times were prolonged. However, significant protection against HSV-2 challenge was observed with gD-1 or gD-2 immunization. When sacral ganglia were removed from surviving mice 9-12 months after virus challenge, latent virus was detected in all gB- or gD-immunized animals, although the extent of latent infection was restricted. These results provide evidence that glycoprotein gD might be superior to glycoprotein gB as an immunogen for the control of acute HSV-1 and HSV-2 neurological disease in mice. However, neither glycoprotein prevents ganglionic latency, the source of virus for recurrent herpesvirus infections.

Single and Combination Herpes Simplex Virus Type 2 Glycoprotein Vaccines Adjuvanted with CpG Oligodeoxynucleotides or Monophosphoryl Lipid A Exhibit Differential Immunity That Is Not Correlated to Protection in Animal Models

“…In light of the immunogenicity data generated with gB, these efficacy results were surprising and represent a novel finding, as they suggest that superior immunogenicity does not correlate to superior protection. A difference in the protective abilities of gB and gD has been reported previously, using a mouse model of HSV-2-induced neurological disease (7). In this case, gB (plus alum only)-immunized mice were not protected and showed a mor- b Mean estimated slope of the weight loss between days 5 and 14 postchallenge.…”

“…CPG is a highly active TLR9 agonist capable of generating higher levels of neutralizing antibody and superior T cell responses in mice compared to MPL, which is a TLR4 agonist (4,7,32). TLRs link innate and adaptive immunity; after recognition of their ligands, all TLRs (except TLR3) signal through the adaptor protein MyD88, leading to the activation of NF-B and consequently the induction of many genes involved in immunity (17).…”

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

“…Preinfection immunization with subunit glycoprotein immunogens can reduce symptomatic clinical disease in animals challenged with HSV, although the effect is adjuvant-dependent (Chan, 1983;Schrier et al, 1983;Long et al, 1984;Dix & Mills, 1985;Roberts et al, 1985;Berman et al, 1985Berman et al, , 1988Dix, 1987;Meignier et al, 1987;Stanberry et al, 1987). We report here that alum enhances the efficacy of HSV glycoprotein immunogens but is a less potent adjuvant than CFA in providing protection against primary disease.…”

Mutations within the Pathogenic Region of Herpes Simplex Virus 1 gK Signal Sequences Alter Cell Surface Expression and Neurovirulence

“…The finding that HSV-1 glycoproteins are the major inducers and targets of humoral and cell-mediated immune responses after infection (12)(13)(14)(15)(16) suggest that they may play a major role in the development of the immune responses that cause CS in infected individuals. We have investigated the role of the HSV-1 glycoproteins in protection from eye disease and have shown that immunization with glycoprotein B (gB), gC, gD, gE, or gI completely protected mice against lethal challenge with HSV-1 and eye disease, whereas no significant protection is seen on immunization with gG, gH, gL, or gJ (17)(18)(19)(20)(21).…”