Efficacy Results of a Trial of a Herpes Simplex Vaccine

Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University, St. Louis, MO 63104, USA.
New England Journal of Medicine (Impact Factor: 55.87). 01/2012; 366(1):34-43. DOI: 10.1056/NEJMoa1103151
Source: PubMed


Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women.
We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20.
The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26).
In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; number, NCT00057330.).

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Available from: Peter Leone, Apr 22, 2014
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    • " , while antibody may provide some protection to neonates ( Brown et al . , 1991 ) , and recently antibody concentration was associated with preventing HSV - 1 genital disease and infection in gD2 vaccine immunized HSV - seronegative women , there is minimal evidence that antibody alone is effective against acquisition of HSV - 2 genital disease ( Belshe et al . , 2012 , 2013 ) , or virus reactivation and recurrent disease ( Spruance et al . , 1995 ) . This observation was nicely characterized in a study of patients with a history of frequent recurrences who had higher median serum antibody titers to HSV that were coincident with lower HSV - 2 - specific IFN - γ and IL - 2 production from PBMC ( Sprua"
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    ABSTRACT: Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2 pos) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS™, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2 pos) and virus-exposed seronegative (HSV-2 neg) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2 neg or asymptomatic HSV-2 pos individuals, compared to symptomatic recurrent HSV-2 pos subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.
    Virology 08/2014; 464-465(1). DOI:10.1016/j.virol.2014.07.018
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    • "Unfortunately, however, the numerous attempts to develop anti-HSV vaccines have thus far proved unsuccessful [9]–[20]. Chiron and GlaxoSmithKline vaccine candidates based on recombinant HSV envelope glycoproteins have failed to show efficacy [21], [22]. This has prompted researchers to increase their efforts to define immune correlates of protection and new vaccination strategies able to induce protective immunity [8], [19], [20], [23]. "
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    ABSTRACT: Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.
    PLoS ONE 07/2014; 9(7):e100844. DOI:10.1371/journal.pone.0100844
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    • "The vaccine used in this study was developed and manufactured by GlaxoSmithKline [15] [16] [19]. It contained 20 lg of truncated glycoprotein D from HSV-2 strain G and the AS04 adjuvant system comprising 50 lg of MPL, and 0.5 mg of aluminum hydroxide. "
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    ABSTRACT: Objective To evaluate the consistency of three commercial scale lots of candidate herpes simplex virus (HSV) type 2 (HSV-2) vaccine in adolescent girls. Methods A total of 554 healthy girls aged 10-17 years, from Belgium, Canada, and United States, were enrolled and randomized to receive one of the three manufacturing lots of the candidate glycoprotein D2 vaccine (gD2-AS04, GlaxoSmithKline Vaccines) according to a 0, 1 and 6-month schedule. Consistency was based on anti-gD geometric mean titers (GMTs) 1 month post-dose 3 among HSV seronegative subjects complying to study procedures (N = 312): two-sided 90% confidence interval (CI) for the GMT ratio between each pair of vaccine lots had to be within the [0.67; 1.5] consistency interval. Results Pre-specified consistency criteria were reached. At month 2 (1 month after the second vaccine dose) anti-gD antibodies were detected in all study participants, while the proportion of subjects with HSV-2 neutralizing antibodies ranged from 93% to 96.2%, remaining >90% throughout the study (between 93.7% and 96.1% for the three vaccine lot groups at month 12). The three vaccine lots had similar reactogenicity profiles. The incidence of grade 3 solicited or unsolicited adverse events (AEs) ranged from 17.9% to 22.2% of subjects. Conclusions This study demonstrated the lot-to-lot consistency of three commercial scale production lots of herpes simplex candidate vaccine. The vaccine was immunogenic and had a clinically acceptable safety profile when administered in HSV type 1 and HSV-2 seronegative girls aged 10-17 years. The study was registered at (identifier NCT00224471).
    Trials in Vaccinology 12/2013; 2(1):10-18. DOI:10.1016/j.trivac.2013.03.001
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