Vaccine-Induced Serum Immunoglobin Contributes to Protection from Herpes Simplex Virus Type 2 Genital Infection in the Presence of Immune T Cells

Abstract

Herpes simplex type virus 2 (HSV-2) is a sexually transmitted pathogen that causes genital lesions and spreads to the nervous system to establish acute and latent infections. Systemic but not mucosal cellular and humoral immune responses are elicited by immunization of mice with a replication-defective mutant of HSV-2, yet the mice are protected against disease caused by subsequent challenge of the genital mucosa with virulent HSV-2. In this study, we investigated the role of immune serum antibody generated by immunization with a replication-defective HSV-2 vaccine prototype strain in protection of the genital mucosa and the nervous system from HSV-2 infection. Passive transfer of replication-defective virus-immune serum at physiologic concentrations to SCID or B-cell-deficient mice had no effect on replication of challenge virus in the genital mucosa but did significantly reduce the incidence and severity of genital and neurologic disease. In contrast, B-cell-deficient mice immunized with replication-defective HSV-2 were able to control replication of challenge virus in the genital mucosa, but not until 3 days postchallenge, and were not completely protected against genital and neurologic disease. Passive transfer of physiologic amounts of immune serum to immunized, B-cell-deficient mice completely restored their capacity to limit replication of challenge virus in the genital mucosa and prevented signs of genital and systemic disease. In addition, the numbers of viral genomes in the lumbosacral dorsal root ganglia of immunized, B-cell-deficient mice were dramatically reduced by transfer of immune serum prior to challenge. These results suggest that there is an apparent synergism between immune serum antibody and immune T cells in achieving protection and that serum antibody induced by vaccination with replication-defective virus aids in reducing establishment of latent infection after genital infection with HSV-2.Mucosal surfaces are a favored entry site for numerous pathogenic microorganisms. Infections with some of these organisms remain localized to the mucosal epithelium, while others spread systemically. The mucosal entry points are thought to be guarded by local mucosal immune responses, but systemic immune protection also can extend into the mucosa. This is particularly true of humoral immunity; antibody bathes interstitial spaces and can pass through the mucosa as a transudate from serum. Herpes simplex virus type 2 (HSV-2) is a common human pathogen that enters the body primarily via the genital mucosa. HSV-2 replicates in the genital epithelium and spreads to lumbosacral sensory ganglia, where latent infection is maintained for the life of the individual. Periodic reactivation results in reinfection of the genital epithelium innervated by the infected dorsal root ganglia (DRG). Prophylactic immunization ideally would reduce infection of the genital epithelium and prevent latent infection of the ganglia, thereby eliminating the recurrent HSV-2 infections that provide opportunities for transmission to s...

Novel Recombinant Parapoxvirus Vectors Induce Protective Humoral and Cellular Immunity against Lethal Herpesvirus Challenge Infection in Mice

“…However, as discussed above, transfer of the induced gC antibodies alone was not sufficient for solid protection, and, therefore, the presence of immune T cells seems to be required for full protective capacity of immune serum antibodies, as also reported for herpes simplex virus type 2 (HSV-2) infection (36).…”

Virus-Encoded B7-2 Costimulation Molecules Enhance the Protective Capacity of a Replication-Defective Herpes Simplex Virus Type 2 Vaccine in Immunocompetent Mice

“…The capacity to protect the nervous system is most noteworthy as a desirable characteristic of vaccine-mediated protection against sexually transmitted herpesviral disease, and we observed nearly complete protection of the CNS from acute infection after genital challenge of immunized mice. We were unable to accurately assess latent genome loads in dorsal root ganglia, but genome loads of challenge virus in immunized immunodeficient mice are very low (24) and may be even lower in the fully immunocompetent mice used in this study.…”

“…The greatest impact on the replication of HSV-2 in the vaginal mucosa, particularly over the first 2 days postchallenge, was observed in mice receiving the high immunizing dose of 5B86. Previous work with replication-defective HSV-2 indicated that immune antibody and CD4 T cells work synergistically to protect the genital tract from HSV-2 replication during this period but are not independently effective (21,24). Thus, improved CD4 Tcell responses in 5B86-immunized mice may assist antibody to better control early replication of challenge virus in the vaginal mucosa.…”

“…Thus, improved CD4 Tcell responses in 5B86-immunized mice may assist antibody to better control early replication of challenge virus in the vaginal mucosa. CD4 T cells and antibody stimulated by replicationdefective virus also work cooperatively to ameliorate genital and neurological disease (24). The lowest immunizing dose of 5B86 stimulated an immune response that did not reduce challenge virus replication in the mucosa significantly more than did that of 5BlacZ but, nonetheless, greatly limited genital and neurological disease compared with 5BlacZ.…”

Immunological aspects of herpesvirus infections

“…В интерфероновом и цитокиновом статусе при рецидивирующей герпетической инфекции реги-стрируют снижение продукции стимулированного ИФН-γ, что свидетельствует об истощении меха-низмов противовирусной защиты, и тенденцию к гиперпродукции ИЛ-4, свидетельствующую о нали-чии Th 2 -иммунного ответа, который при ГВИ явля-ется неполноценным [25]. Гиперпродукция стиму-лированного ИФН-γ при атипичной герпетической инфекции может быть следствием незначительной, но постоянной антигенной стимуляции [26].…”