lipid-a and Herpes-Genitalis

The primary objective of this investigation was to assess whether the AS04-adjuvanted herpes simplex virus (HSV) glycoprotein D candidate prophylactic vaccine against genital herpes disease increases the risk of spontaneous abortion associated with pregnancy conceived within the vaccination exposure window (vaccine dose received within the period starting 60 days before and ending 20 weeks post-conception day). We performed a meta-analysis of studies designed as part of the clinical development program for this vaccine, to examine the relative risk of abortion (spontaneous or elective) associated with unintended vaccination exposure during pregnancy. Nineteen studies, completed before September 2010, were eligible; 5 matched the inclusion criteria for this analysis (presence of a control arm and at least one adverse pregnancy outcome reported). All vaccinated women (N=19,727) were included, of whom 660 reported a pregnancy during the study period. Overall, 13.3% of pregnancies in the HSV vaccine group and 11.0% in the control group resulted in spontaneous abortion; 24.2% and 20.0% resulted in elective abortion. Among 180 women with a first pregnancy conceived in the vaccination exposure window, 16.7% (HSV vaccine) and 9.5% (control) had a spontaneous abortion and 38.5% and 33.3%, elective abortion. The relative risk for spontaneous abortion associated with vaccine exposure during the risk period for abortion in the course of pregnancy was 1.7 (95% CI: 0.7-4.6). For all women receiving HSV vaccine, this relative risk was 1.3 (95% CI: 0.8-2.1). The corresponding relative risks for elective abortion were 1.2 (95% CI: 0.7-2.0) and 1.3 (95% CI: 0.9-1.8). There was no apparent relationship to dosing and no difference between groups in gestational age at the time of spontaneous or elective abortion. In conclusion there is no statistical evidence that the investigational HSV vaccine increased the risk of spontaneous or elective abortion.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Female; Herpes Genitalis; Herpes Simplex Virus Vaccines; Humans; Lipid A; Middle Aged; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic; Vaccines, Subunit; Young Adult

Herpes simplex virus (HSV) Type-1 and -2 are common infections that can cause primary and recurrent herpes labialis and genitalis, as well as gingivostomatitis, keratoconjunctivitis, encephalitis, disseminated infections in immunocompromised persons and neonatal infections. Despite several decades of HSV vaccine development, no effective vaccine has been developed until recently. The following review of the genital HSV-2 glycoprotein D (gD2t, t is for truncated) subunit vaccine formulated with a new adjuvant (AS04) containing alum and 3-O deacylated monophosphoryl lipid A (MPL) provides a background in which to evaluate the vaccine as well as a brief review of other approaches to herpes vaccines. The gD2t-AS04 vaccine has been demonstrated to be safe in several large clinical trials. In two trials, the vaccine reduced genital herpes disease by 73 and 74%, but only in females with no previous HSV infection. A large ongoing trial in HSV seronegative females will provide additional data on protection from HSV disease and infection.

Topics: Adjuvants, Immunologic; Adolescent; Alum Compounds; Animals; Chemistry, Pharmaceutical; Child; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Herpes Genitalis; Herpes Simplex Virus Vaccines; Humans; Lipid A; Male; Vaccination; Viral Envelope Proteins

Herpes simplex virus (HSV) type 2 (HSV-2) is the main cause of genital and neonatal herpes and is highly prevalent worldwide. Previous phase I and II studies showed the immunogenicity and safety of the candidate prophylactic HSV-2 glycoprotein D-based subunit vaccine (gD2-AS04), containing aluminum hydroxide and 3-O-deacylated monophosphoryl lipid A (MPL) as adjuvant (AS04), in healthy adults. The primary objective of the study presented here was to compare the immunogenicity and safety of five different vaccine formulations: 3 different antigen doses [20, 40 or 80 μg of truncated glycoprotein D from HSV-2 strain (gD-2t)], different aluminum salts [AlPO₄ or Al(OH)₃], different preservatives or different volumes of vaccine (0.5 or 1 ml). One hundred and fifty healthy men and women aged 18-45 years, with negative serological markers for HSV-1 and HSV-2 infection, were vaccinated with one of 5 formulations of the gD2-AS04 candidate vaccine according to a 0-, 1-, 6-month schedule. No statistically significant difference was observed in humoral or cellular immune responses between different antigen doses or the different aluminum salts, preservatives or volumes of vaccine. The gD2-AS04 vaccine was well tolerated by study participants for the duration of the study period. Local symptoms were more frequently reported than general symptoms, with muscle stiffness and/or injection site redness being the most frequently reported. Overall, the incidence of adverse events was comparable in all groups. Based on these results the gD2-AS04 formulation, containing 20 μg of gD-2t, was selected for evaluation of prophylactic efficacy in further clinical trials.

Topics: Adolescent; Adult; Aluminum Hydroxide; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Healthy Volunteers; Herpes Genitalis; Herpesvirus Vaccines; Humans; Immunity, Cellular; Immunity, Humoral; Incidence; Lipid A; Male; Vaccination; Vaccines, Subunit; Viral Envelope Proteins; Young Adult

There is currently no licensed prophylactic or therapeutic vaccine for HSV-2 infection.. We developed a novel preclinical vaccine candidate, G103, consisting of three recombinantly expressed HSV-2 proteins (gD and the UL19 and UL25 gene products) adjuvanted with the potent synthetic TLR4 agonist glucopyranosyl lipid A (GLA) formulated in stable emulsion. The vaccine was tested for immunogenicity and efficacy in pre-clinical models for preventative and therapeutic vaccination.. Vaccination of mice with G103 elicited antigen-specific binding and neutralizing antibody responses, as well as robust CD4 and CD8 effector and memory T cells. The T cell responses were further boosted by subsequent challenge with live virus. Prophylactic immunization completely protected against lethal intravaginal HSV-2 infection in mice, with only transient replication of virus in the genital mucosa and sterilizing immunity in dorsal root ganglia. Supporting the use of G103 therapeutically, the vaccine expanded both CD4 and CD8 T cells induced in mice by previous infection with HSV-2. In the guinea pig model of recurrent HSV-2 infection, therapeutic immunization with G103 was approximately 50% effective in reducing the number of lesions per animal as well as the overall lesions score.. Taken together, the data show that G103 is a viable candidate for development of a novel prophylactic and therapeutic HSV-2 vaccine.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Neutralizing; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Female; Glucosides; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Herpesvirus Vaccines; Immunologic Memory; Lipid A; Mice, Inbred C57BL; Treatment Outcome; Vaccines, Subunit; Vaccines, Synthetic

Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data generated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated cotton rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in cotton rats, and yet the model allowed for comparative evaluation of gD/AS04 immunogenicity and efficacy. Cotton rats were intramuscularly vaccinated using a prime boost strategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in cotton rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized cotton rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine strategies and the identification of new correlates of protection.. In spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized cotton rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.

Topics: Aluminum Hydroxide; Aniline Compounds; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Female; Herpes Genitalis; Herpesvirus 1, Human; Herpesvirus 2, Human; Injections, Intramuscular; Lipid A; Sigmodontinae; Vaccines, Subunit; Viral Envelope Proteins; Viral Vaccines

A prophylactic vaccine for genital herpes disease remains an elusive goal. We report the results of two studies performed collaboratively in different laboratories that assessed immunogenicity and vaccine efficacy in herpes simplex virus 1 (HSV-1)-seropositive guinea pigs immunized and subsequently challenged intravaginally with HSV-2. In study 1, HSV-2 glycoproteins C (gC2) and D (gD2) were produced in baculovirus and administered intramuscularly as monovalent or bivalent vaccines with CpG and alum. In study 2, gD2 was produced in CHO cells and given intramuscularly with monophosphoryl lipid A (MPL) and alum, or gC2 and gD2 were produced in glycoengineered Pichia pastoris and administered intramuscularly as a bivalent vaccine with Iscomatrix and alum to HSV-1-naive or -seropositive guinea pigs. In both studies, immunization boosted neutralizing antibody responses to HSV-1 and HSV-2. In study 1, immunization with gC2, gD2, or both immunogens significantly reduced the frequency of genital lesions, with the bivalent vaccine showing the greatest protection. In study 2, both vaccines were highly protective against genital disease in naive and HSV-1-seropositive animals. Comparisons between gD2 and gC2/gD2 in study 2 must be interpreted cautiously, because different adjuvants, gD2 doses, and antigen production methods were used; however, significant differences invariably favored the bivalent vaccine. Immunization of naive animals with gC2/gD2 significantly reduced the number of days of vaginal shedding of HSV-2 DNA compared with that for mock-immunized animals. Surprisingly, in both studies, immunization of HSV-1-seropositive animals had little effect on recurrent vaginal shedding of HSV-2 DNA, despite significantly reducing genital disease.

Topics: Analysis of Variance; Animals; Antibodies, Neutralizing; Baculoviridae; CHO Cells; Cricetinae; Cricetulus; Enzyme-Linked Immunosorbent Assay; Female; Guinea Pigs; Herpes Genitalis; Herpesvirus 1, Human; Injections, Intramuscular; Lipid A; Pichia; Real-Time Polymerase Chain Reaction; Viral Envelope Proteins; Viral Vaccines

Herpes Simplex Virus Type 2 (HSV-2) infection can result in life-long recurrent genital disease, asymptomatic virus shedding, and transmission. No vaccine to date has shown significant protection clinically. Here, we used a mouse model of genital HSV-2 infection to test the efficacy of a vaccine consisting of whole, formalin-inactivated HSV-2 (FI-HSV2) formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Vaccine components were administered alone or as a prime-boost immunization together with DNA vaccines encoding a truncated glycoprotein D2 (gD2t) and two conserved HSV-2 genes necessary for virus replication, UL5 (DNA helicase) and UL30 (DNA polymerase). Our results show: (1) compared with mock immunized controls, mice immunized with FI-HSV2 plus MPL/alum consistently showed protection against disease burden and total viral shedding while the mice immunized with gD2t protein with MPL/alum did not; (2) protection against genital disease and viral replication correlated with the type of boost in a prime-boost immunization with little advantage afforded by a DNA prime; (3) intramuscular (i.m.) immunization with FI-HSV2 in MPL/Alhydrogel adjuvant provided nearly complete protection against vaginal HSV-2 shedding after a lethal intravaginal (i.vag.) short-term challenge and long-term rechallenge; (4) single formulation immunization with DNA vaccines, FI-HSV2, and MPL in an aluminum phosphate (Adju-Phos) adjuvant did not increase protection relative to FI-HSV2/MPL/Adju-Phos alone; and (5) addition of MPL/alum to the FI-HSV2 was required for optimal protection against disease, viral replication, and latent virus load in the dorsal root ganglia (DRG). Most notably, an optimized vaccine formulation of FI-HSV2 MPL/Alhydrogel given i.m. completely protected against detectable vaginal HSV-2 shedding in the majority of animals and HSV-2 latent DNA in the DRG of all animals.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antigens, Viral; Disease Models, Animal; Female; Ganglia, Spinal; Herpes Genitalis; Herpesvirus 2, Human; Herpesvirus Vaccines; Lipid A; Mice; Mice, Inbred BALB C; Survival Analysis; Vaccination; Vaccines, DNA; Vagina; Virus Shedding

To date, no vaccine that is safe and effective against herpes simplex virus 2 (HSV-2) disease has been licensed. In this study, we evaluated a DNA prime-formalin-inactivated-HSV-2 (FI-HSV2) boost vaccine approach in the guinea pig model of acute and recurrent HSV-2 genital disease. Five groups of guinea pigs were immunized and intravaginally challenged with HSV-2. Two groups were primed with plasmid DNAs encoding the secreted form of glycoprotein D2 (gD2t) together with two genes required for viral replication, either the helicase (UL5) and DNA polymerase (UL30) genes or the single-stranded DNA binding protein (UL29) and primase (UL52) genes. Both DNA-primed groups were boosted with FI-HSV2 formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Two additional groups were primed with the empty backbone plasmid DNA (pVAX). These two groups were boosted with MPL and alum (MPL-alum) together with either formalin-inactivated mock HSV-2 (FI-Mock) or with FI-HSV2. The final group was immunized with gD2t protein in MPL-alum. After challenge, 0/9 animals in the group primed with UL5, UL30, and gD2t DNAs and all 10 animals in the mock-immunized control group (pVAX-FI-Mock) developed primary lesions. All mock controls developed recurrent lesions through day 100 postchallenge. Only 1 guinea pig in the group primed with pVAX DNA and boosted with FI-HSV2 (pVAX-FI-HSV2 group) and 2 guinea pigs in the group primed with UL5, UL30, and gD2t DNAs and boosted with FI-HSV2 (UL5, UL30, gD2t DNA-FI-HSV2 group) developed recurrent lesions. Strikingly, the UL5, UL30, gD2t DNA-FI-HSV2 group showed a 97% reduction in recurrent lesion days compared with the mock controls, had the highest reduction in days with recurrent disease, and contained the lowest mean HSV-2 DNA load in the dorsal root ganglia.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; DNA, Viral; Female; Ganglia, Spinal; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Herpesvirus Vaccines; Immunization, Secondary; Lipid A; Secondary Prevention; Vaccination; Vaccines, DNA; Vaccines, Inactivated

Despite several attempts to develop an effective prophylactic vaccine for HSV-2, all have failed to show efficacy in the clinic. The most recent of these failures was the GlaxoSmithKline (GSK) subunit vaccine based on the glycoprotein gD with the adjuvant monophosphoryl lipid A (MPL). In a phase 3 clinical trial, this vaccine failed to protect from HSV-2 disease, even though good neutralizing antibody responses were elicited. We aimed to develop a superior, novel HSV-2 vaccine containing either gD or gB alone or in combination, together with the potent adjuvant CpG oligodeoxynucleotides (CPG). The immunogenic properties of these vaccines were compared in mice. We show that gB/CPG/alum elicited a neutralizing antibody response similar to that elicited by gD/CPG/alum vaccine but a significantly greater gamma interferon (IFN-γ) T cell response. Furthermore, the combined gB-gD/CPG/alum vaccine elicited significantly greater neutralizing antibody and T cell responses than gD/MPL/alum. The efficacies of these candidate vaccines were compared in the mouse and guinea pig disease models, including a novel male guinea pig genital disease model. These studies demonstrated that increased immune response did not correlate to improved protection. First, despite a lower IFN-γ T cell response, the gD/CPG/alum vaccine was more effective than gB/CPG/alum in mice. Furthermore, the gB-gD/CPG/alum vaccine was no more effective than gD/MPL/alum in mice or male guinea pigs. We conclude that difficulties in correlating immune responses to efficacy in animal models will act as a deterrent to researchers attempting to develop effective HSV vaccines.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antibodies, Neutralizing; Antibodies, Viral; Disease Models, Animal; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Herpesvirus Vaccines; Interferon-gamma; Lipid A; Mice; Oligodeoxyribonucleotides; Severity of Illness Index; T-Lymphocytes; Viral Envelope Proteins