The role of neutralizing antibody and T‐helper subtypes in protection and pathogenesis of vaccinated mice following ocular HSV‐1 challenge

Abstract

In order to determine the possible correlation of specific immune responses with protection against mortality and ocular disease following ocular herpes simplex virus type 1 (HSV-1) challenge, BALB/c mice were vaccinated with different doses and regimens of baculovirus-expressed gD. Neutralizing antibody, virus titres in the eyes, corneal scarring, and survival were measured. In addition, infiltration into the cornea of CD4+ T cells and cells containing the lymphokines interleukin-2 (IL-2), IL-4, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were monitored on days 3, 7, 10, 14 and 21 post-challenge by immunocytochemistry. The vaccination regimens used induced varying degrees of immune responses and protection upon ocular challenge with HSV-1. Our results suggest that neutralizing antibody was the most important immune response in protecting mice against lethal ocular challenge and corneal scarring. TNF-alpha and IL-2 were not crucial in terms of survival and corneal scarring, since gD1 (one vaccination with 1 microg of gD) and gD0.1 (one vaccination with 0.1 microg of gD), both of which provided high levels of protection, showed no TNF-alpha or IL-2 expression. However, TNF-alpha and IL-2 were crucial in terms of virus clearance from the eyes, since gD3 (three vaccinations with 1 microg of gD), which had less virus in their eyes, had high numbers of TNF-alpha and IL-2 infiltrates. Finally, mock-vaccinated mice were not protected from death and corneal disease following HSV-1 challenge. Eyes of mock-vaccinated mice had little or no TNF-alpha or IL-2 responses and the strongest IL-4 and IL-6 responses.

Overexpression of Interleukin-2 by a Recombinant Herpes Simplex Virus Type 1 Attenuates Pathogenicity and Enhances Antiviral Immunity

“…This finding extends our previously published results and further supports the concept that there is a correlation between IL-2 levels and reduced viral replication in the eye (13,17). Since the expressed IL-2 also appeared to decrease viral replication in tissue culture, it is possible that some of the decreased replication in the eye is due to direct effects of IL-2 on the infected cells in the eye and not simply due to an immune cell response.…”

“…The replication of virus subsequent to a primary HSV-1 infection of the eye can cause eye disease (17). Both the duration of the infection and the titer of virus in the eye affect the severity of eye disease (13).…”

Recombinant Herpes Simplex Virus Type 1 (HSV-1) Codelivering Interleukin-12p35 as a Molecular Adjuvant Enhances the Protective Immune Response against Ocular HSV-1 Challenge

“…Herpetic blepharitis is an inflammation of the lid margin that occurs after intraocular HSV-1 infection, and increased blepharitis correlates with increased HSV-1 replication in the mouse (22,23). Therefore, to determine the efficacy of recombinant viruses in preventing or reducing blepharitis, the eyes of the above groups of mice, infected with 2 ϫ 10 5 PFU of HSV-1 strain McKrae/eye, were examined on day 7 postinfection.…”

“…Therefore, an important goal to overcome this problem involves design of vaccine regimens that elicit the most appropriate responses, namely, to elicit cell-mediated responses in addition to antibody-mediated responses. Previously, we showed that a successful and efficacious vaccine against ocular HSV-1 infection should induce a potent T H 1-mediated immune response in addition to neutralizing antibody (17,(21)(22)(23). Such protective immune responses can be further enhanced or altered by using cytokine genes as genetic adjuvants (40,45).…”

“…Previously, we have shown that improved vaccine efficacy against ocular HSV-1 infection correlates with increased T H 1 cytokine responses (17,22,23,44,46). Various cytokines have been used as genetic adjuvants to direct immune responses toward a T H 1 response and away from a T H 2 response (32,40,45,46,52).…”