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The innate and acquired immune response induced by a commercial inactivated vaccine against Bovine Herpesvirus-1 (BoHV-1) and protection conferred against the virus were analyzed in cattle. Vaccination induced high levels of BoHV-1 antibodies at 30, 60, and 90 days post-vaccination (dpv). IgG1 and IgG2 isotypes were detected at 90 dpv, as well as virus-neutralizing antibodies. An increase of anti-BoHV-1 IgG1 in nasal swabs was detected 6 days post-challenge in vaccinated animals. After viral challenge, lower virus excretion and lower clinical score were observed in vaccinated as compared to unvaccinated animals, as well as BoHV-1-specific proliferation of lymphocytes and production of IFNγ, TNFα, and IL-4. Downregulation of the expression of endosome Toll-like receptors 8-9 was detected after booster vaccination. This is the first thorough study of the immunity generated by a commercial vaccine against BoHV-1 in cattle.

Equid herpesvirus-1 (EHV-1) outbreaks continue despite widely used vaccination. We demonstrated previously that an ORF1/ORF71 gene deletion mutant of the EHV-1 strain Ab4 (Ab4ΔORF1/71) is less virulent than its parent Ab4 virus. Here, we describe the Ab4 challenge infection evaluating protection induced by the Ab4ΔORF1/71 vaccine candidate. Susceptible control horses developed respiratory disease, fever, nasal shedding, and viremia. Full protection after challenge infection was observed in 5/5 previously Ab4 infected horses and 3/5 Ab4ΔORF1/71 horses. Two Ab4ΔORF1/71 horses developed short-lasting viremia and/or virus shedding. Protective immunity in the respiratory tract was characterized by pre-existing EHV-1-specific IgG4/7 antibodies, the absence of IFN-α secretion and rapidly increasing IgG4/7 upon challenge infection. Pre-existing systemic EHV-1-specific IgG4/7 highly correlated with protection. T-cell immunity was overall low. In conclusion, protective immunity against EHV-1 infection including prevention of viremia was associated with robust systemic and intranasal IgG4/7 antibodies suggesting immediate virus neutralization at the local site.

Viral vaccines have traditionally protected against disease, but for viruses that establish latent infection, it is desirable for the vaccine to reduce infection to reduce latent infection and reactivation. While seroconversion has been used in clinical trials of herpes simplex virus (HSV) vaccines to measure protection from infection, this has not been modeled in animal infection systems. To measure the ability of a genital herpes vaccine candidate to protect against various aspects of infection, we established a non-lethal murine model of genital HSV-2 infection, an ELISA assay to measure antibodies specific for infected cell protein 8 (ICP8), and a very sensitive qPCR assay. Using these assays, we observed that immunization with HSV-2 dl5-29 virus reduced disease, viral shedding, seroconversion, and latent infection by the HSV-2 challenge virus. Therefore, it may be feasible to obtain protection against genital disease, seroconversion and latent infection by immunization, even if sterilizing immunity is not achieved.

Replication-defective herpes simplex virus 2 (HSV-2), used as an immunization strategy, protects against HSV-2 challenge in animal models. The roles of replication-defective virus-induced T cell subsets in control of HSV-2 infection have not been established. Mice lacking B cells (microMT) were immunized, depleted of CD4 or CD8 T cells, and then challenged intravaginally with HSV-2 to elucidate T cell subset contributions in the absence of virus-specific antibody. Immunized, CD4-depleted microMT mice developed severe infection of the genital tract and nervous system. In contrast, depletion of CD8 T cells from microMT mice did not attenuate protection. Immunized wild-type mice depleted of CD4 T cells also developed more severe HSV-2 infection than mice from which CD8 T cells were depleted. Thus, immunization with replication-defective virus induces T cell responses that effectively control HSV-2 infection in the absence of HSV-immune antibody, and CD4 T cells play the predominant role in this protective effect.

Vaccination is the most effective medical intervention against diseases caused by human viral pathogens. Viral vaccines prevent or modify the severity of illness in the individual and interrupt or reduce the transmission of the pathogens to other susceptible people. Through these mechanisms, vaccines against smallpox, polio, measles and hepatitis B have had an enormous impact on world health over the last 50 years. Advances in basic virology and understanding of human immunity promise more progress in the control of human viral diseases as the 21st century begins. Some important targets, including human immunodeficiency virus, respiratory syncytial virus and hepatitis C virus present challenges that require more basic research. The purpose of this review is to highlight four new viral vaccines that have recently, or will soon demonstrate the effective translation of basic investigations into clinical benefits for disease control in healthy and high-risk populations. These vaccines include the live attenuated vaccines against the RNA viruses, rotavirus and influenza A and B, and vaccines against human papilloma virus and varicella-zoster virus, which are DNA viruses that cause morbidity and mortality through their capacity to establish persistent infection. Although only the influenza vaccine has been licensed in the United States, these other new tools for disease prevention are likely to be introduced within the next few years, with profound effects on the diseases that they cause. Hence, as Virology celebrates its 50th anniversary, it is appropriate to examine these examples of recent advances in viral vaccines.

Rabbits latently infected with herpes simplex virus type 1 (HSV-1) were vaccinated either periocularly or systemically with a subunit vaccine (gB2 + gD2) plus adjuvant or adjuvant alone. Tear films were collected daily to measure recurrent infectious HSV-1 shedding. After systemic vaccination, the latently infected rabbits were not protected against recurrent ocular viral shedding (HSV-1-positive tear film cultures/total cultures) compared with either the systemic or periocular adjuvant controls (systemic vaccination = 49 of 972, 5.0%; systemic control = 46 of 972, 4.7%; periocular control = 43 of 930, 4.6%;P> 0.8). In contrast, latently infected rabbits vaccinated periocularly with the same vaccine had significantly reduced recurrent shedding (20 of 1026, 2.0%) compared with controls (P< 0.001) or systemic vaccination (P= 0.0002). Thus, recurrent HSV-1 shedding was significantly reduced by therapeutic local periocular subunit vaccination but not by therapeutic systemic subunit vaccination. Neutralizing antibody titers in the serum of systemically and ocularly vaccinated rabbits was similar. In contrast, HSV-specific tear secretory immunoglobulin A was significantly higher in the ocularly vaccinated group (P< 0.01). These results strongly suggest that in the rabbit, and presumably in humans, the local ocular (mucosal) immune response is much more important than the systemic immune response for therapeutic protection against recurrent ocular HSV-1. Thus development of a therapeutic vaccine against recurrent ocular HSV-1 should be directed at enhancing the local ocular (mucosal) immune response.

As an approach to create a divalent DNA vaccine, a truncated secreted version of bovine herpesvirus-1 (BHV-1) glycoprotein D (tgD) and the amino-terminal subunit of glycoprotein B (gBb) were expressed from a dicistronic plasmid, designated pSLIAtgD-IRES-gBb. Intradermal immunization of mice with pSLIAtgD-IRES-gBb or a mixture of plasmids encoding tgD (pSLIAtgD) and gBb (pSLIAgBb) by needle injection or gene gun elicited strong tgD-specific immune responses. However, a significant reduction in gBb-specific immune responses was observed upon immunization of mice with pSLIAtgD-IRES-gBb or a mixture of pSLIAtgD and pSLIAgBb in comparison to immunization with pSLIAgBb alone. This reduction in gBb-specific immune responses induced by pSLIAtgD-IRES-gBb was due to production of low amounts of gBb from pSLIAtgD-IRES-gBb, inefficient processing and transport of gBb, and possibly competition for antigen-presenting cells by tgD and gBb. These results indicate that, although divalent plasmids may be used to express different antigens, the efficacy of vaccination with such plasmids may be influenced by the plasmid design and the characteristics of the expressed antigens.

STAT6 (signal transducers and activators of transcription 6)-deficient (STAT6 −/− ) mice have defects in IL-4- and IL-13-mediated functions and thus have a reduced T H 2-mediated immune response. Conversely, they have elevated levels of IL-2 and thus an increased T H 1-mediated immune response. To assess the relative impact of reduced T H 2- and elevated T H 1-dependent immune responses on HSV-1 infection, vaccinated and mock-vaccinated STAT6 −/− mice were challenged ocularly with HSV-1. Mock-vaccinated STAT6 −/− mice were as susceptible to lethal HSV-1 infection as parental BALB/c mice. Mock-vaccinated STAT6 −/− mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Furthermore, mock-vaccinated STAT6 −/− mice had significantly less corneal scarring than their BALB/c counterparts. Vaccination induced significantly higher serum-neutralizing antibody titers in STAT6 −/− mice compared to BALB/c mice, while completely protecting both types of mice against HSV-1-induced death and corneal scarring. Vaccinated STAT6 −/− mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Lymphocytes from both vaccinated and mock-vaccinated STAT6 −/− mice secreted higher amounts of IL-2 than lymphocytes from BALB/c mice, in the presence or absence of stimulation with UV-inactivated HSV-1. Finally, depletion of IL-2 increased ocular virus replication in STAT6 −/− mice to levels similar to that measured in BALB/c mice. Our results suggest that in the absence of the STAT6 pathway, IL-2-mediated immune responses are up-regulated. This, in turn, leads to faster viral clearance and, consequently, lower levels of eye disease.

Ocular infections with herpes simplex virus 1 can lead to corneal scarring and blindness, with herpes keratitis being the major infectious cause of blindness. There is currently no clinically approved vaccine and nearly all developmental vaccines are targeted against HSV-2 and genital herpes. We tested the ability of an HSV-2 replication-defective virus, a genital herpes vaccine candidate, to protect against HSV-1 corneal infection. Immunization with HSV-2 dl5-29 reduced viral replication in the cornea, prevented ocular disease and reduced latent infection by the HSV-1 strain. Therefore, this HSV-2 replication-defective mutant strain may have applications for prevention of herpes keratitis and genital herpes due to HSV-1 infection.