In two recent clinical trials, a vaccine containing herpes simplex virus (HSV) type 2 glycoprotein D (gD2) and a novel adjuvant AS04 comprising alum (Al) and 3-deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women significant protection against HSV-2 genital disease (vaccine efficacy, 73% in study 1 and 74% in study 2) and limited protection against infection (46% in study 1 and 39% in study 2). In the present report, studies in the guinea pig model investigated the protection afforded by gD2/AS04 against HSV-1 and HSV-2 genital herpes and investigated whether immunization could prevent or reduce recurrent disease in guinea pigs that developed mucosal infection. Immunization with gD2/AS04 conveyed nearly complete protection against primary disease with either virus but did not prevent mucosal infection. Guinea pigs immunized with gD2/AS04 were significantly better protected against recurrent disease than were guinea pigs immunized with a gD2/Al vaccine, which suggests that inclusion of 3-dMPL improved protection against latent infection.

Glycoprotein B (gB) has emerged as a subunit-vaccine candidate for congenital cytomegalovirus (CMV) infection, a major public health problem. The present study evaluated a cloned, recombinant gB vaccine in the guinea pig cytomegalovirus (GPCMV) model of congenital infection. Guinea pigs were immunized with gB, which was coadministered with either Freund's adjuvant or alum. All gB-immunized dams had enzyme-linked immunosorbent-assay and neutralizing-antibody responses, with significantly higher titers in the gB/Freund's group. Pregnant dams were challenged with GPCMV subcutaneously during the 3rd trimester. Maternal DNAemia on day 10 after infection trended lower in gB-immunized dams than in control animals, with significant reductions in the gB/Freund's group. Vaccination resulted in a highly significant reduction in pup mortality. For the gB-vaccine groups, pup mortality was significantly lower, and reduced rates of GPCMV transmission were noted, for dams immunized with gB and Freund's adjuvant, compared with dams immunized with gB and alum. These are the first data indicating that a recombinant gB vaccine protects against congenital CMV infection and disease.

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.

The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro. Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo. Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.

bImmunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2⌬TMR 340-363 ) and a truncated form of infected cell polypeptide 4 (ICP4 383-766 ), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4؉ and CD8 ؉ T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003-or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease. H erpes simplex virus 2 (HSV-2) is one of the most prevalent sexually transmitted diseases, having infected more than 500 million people worldwide, with an estimated 23 million new infections occurring annually (1). HSV-2 infects epithelial cells of the genital mucosa during primary infection, followed by the establishment of latency in neuronal dorsal root ganglia via retrograde transport along nerve axons. Throughout latency, virus can reactivate, causing genital lesions and/or asymptomatic shedding of virus. Although suppressive antiviral therapy has shown promise in reducing both symptomatic recurrent lesions and overall viral shedding, subclinical HSV reactivation persists, likely contributing significantly to the observed continued transmission (2). The development of an efficacious immunotherapeutic vaccine targeting HSV-2 likely represents the best strategy for preventing both lesion outbreaks and the continued spread of virus.Despite considerable effort, all vaccine candidates to date have failed to meet their defined endpoints in clinical trials. The majority of clinical trials to date have focused on prophylactic subunit vaccines, largely using the HSV-2 surface glycoproteins as immunogens. The viral envelope glycoproteins gD and gB are the dominant targets for neutralizing antibody production (3, 4), making them logical candidates for vaccine devel...

Cytomegalovirus (CMV) is the most common congenital viral infection, but little is known about the protective immune mechanisms. The guinea pig (gp) model of congenital CMV was used to evaluate the effects of passive antibody given to pregnant dams on pup survival. Dams received three doses of high-titer gpCMV or control antibody on days -3, -1, and +7, or +1, +3, and +7, in relation to gpCMV challenge. gpCMV was inoculated in the late second to early third trimester at three different doses. Compared with controls, gpCMV antibody begun before gpCMV challenge significantly increased pup survival from 14% to 52%, 21% to 84%, and 51% to 77%, respectively, for the three challenge doses. gpCMV antibody started after viral challenge increased pup survival after only the lowest challenge dose (51% to 81%). Antibody did not protect against CMV infection of the pups. CMV antibody appeared to improve survival in congenital CMV infection but did not affect vertical transmission.

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[reaction: see text] The stereoselectivity of Lewis acid-induced endo-regioselective oxacyclizations of 1,4-diepoxides is dependent upon the nature of the terminating nucleophile. For instance, the tert-butyl carbonate-substituted diepoxide of 3,6-dimethylhepta-2,5-dien-1-ol provides a cis-fused bicyclic product, whereas the N,N-dimethylcarbamate derivative affords the trans-fused diastereomer. Stereospecific and regioselective conversion of the tertiary carbamate-terminated 1,4,7-triepoxide (I) to tricyclic all-trans-fused polypyran (II) is also demonstrated.