Rapid and frequent induction of protective immunity exceeding UK recommendations for healthcare settings by MF59-adjuvated hepatitis B vaccine.

The ability of three doses of a novel MF59-adjuvanted hepatitis B virus (HBV) vaccine containing surface and pre-S2 antigens given at 0, 1, and 6 months to induce levels of HBV surface antibody (sAb) > or = 100 mIU/ml was compared with a UK licensed alum-adjuvanted yeast-derived HBV vaccine in HBV-naive healthcare workers (HCWs). One month after second immunization with HBV/MF59, 100% of HCWs had sAb > or = 100 mIU/mL, compared with only 11% and 85% after two or three immunisations with Engerix-B. The sAb GMT of the Engerix B immunised group remained below 100 mIU/mL until month seven, (compared with month one for HBV/MF59), and was 123-fold lower at this time (208,561 vs. 1,686 mIU/mL). In our subjects HBV/MF59 vaccine rapidly induced sAb to levels far in excess of those recommended by the Department of Health for high-risk situations (e.g. HCWs and patients on dialysis). It has the potential for shorter schedules and reduced need for serology and boosters.

Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women.

CONTEXT: Herpes simplex virus type 2 (HSV-2) is one of the most common sexually transmitted infections in the United States. No prospective study has shown the ability of condoms to reduce transmission of HSV-2. OBJECTIVE: To evaluate risk factors for HSV-2 acquisition and efficacy of condoms in prevention of HSV-2 transmission. DESIGN: Analysis of data from a randomized, double-blind, placebo-controlled trial conducted December 13, 1993, to June 28, 1996, of an ineffective candidate HSV-2 vaccine with 18 months of follow-up. SETTING: Eighteen clinical trial centers in the United States. PARTICIPANTS: A total of 528 monogamous couples discordant for HSV-2 infection, including an HSV-2-susceptible population of 261 men and 267 women. MAIN OUTCOME MEASURE: Acquisition of HSV-2 infection by susceptible partners, compared with those remaining free of HSV-2 with regard to demographic characteristics, sexual activity, and condom use. RESULTS: Twenty-six women (9.7%) vs 5 men (1.9%) acquired HSV-2, for a rate per 10 000 sex acts (episodes of sexual intercourse) of 8.9 vs 1.5, respectively (P<.001). In multivariable analysis, younger age (adjusted hazard ratio [HR] per 5 years, 1.57; 95% confidence interval [CI], 1.22-2.04), seropositivity for HSV-1 and HSV-2 vs HSV-2 alone in the source partner (adjusted HR, 2.34; 95% CI, 1.14-4.82), and more frequent sexual activity (adjusted HR per additional sex act per week, 1.10; 95% CI, 1.01-1.19) were associated with higher risk of HSV-2 acquisition. Condom use during more than 25% of sex acts was associated with protection against HSV-2 acquisition for women (adjusted HR, 0.085; 95% CI, 0.01-0.67) but not for men (adjusted HR, 2.02; 95% CI, 0.32-12.50). Risk of HSV-2 transmission declined from 8.5 per 100 person-years in the initial 150-day interval to 0.9 per 100 person-years in the final 150-day interval (P =.002 for trend), concurrent with a decrease in sexual activity and proportion of sex acts occurring when the source partner had genital lesions. CONCLUSIONS: Condom use offers significant protection against HSV-2 infection in susceptible women. Changes in sexual behavior, correlated with counseling about avoiding sex when a partner has lesions, were associated with reduction in HSV-2 acquisition over time. These data suggest that identification of discordant couples can reduce transmission of HSV-2, especially for heterosexual couples in which the male partner has HSV-2 infection.

Limited antibody-dependent cellular cytotoxicity antibody response induced by a herpes simplex virus type 2 subunit vaccine.

The humoral response to a herpes simplex virus (HSV) type 2 subunit vaccine containing recombinant glycoproteins B (gB2) and D (gD2) was tested in 3 groups of patients. These included HSV-seronegative, HSV-1-seropositive, and HSV-2-seropositive individuals. There were excellent antibody responses, as measured by gB2- and gD2-specific ELISAs and HSV-2 neutralization assays. However, in 2 HSV-2 antibody-dependent cellular cytotoxicity (ADCC) assays, there were relatively low antibody responses, especially among HSV-seronegative individuals. The low ADCC responses may be associated with the poor efficacy of this vaccine observed in clinical trials.

A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group.

BACKGROUND AND METHODS: Herpes simplex virus (HSV) infections are endemic, but the clinical characteristics of newly acquired HSV type 1 (HSV-1) and HSV type 2 (HSV-2) infections in adults have not been rigorously defined. We monitored 2393 sexually active HSV-2-seronegative persons for clinical and serologic evidence of new HSV infection. Of the participants, 1508 were seropositive for HSV-1 and 885 were seronegative. Charts were reviewed in a blinded manner for classification of those with genitourinary or oropharyngeal symptoms. Charts were also reviewed for all 174 persons with HSV seroconversion. RESULTS: The rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years, respectively. Of the 155 new HSV-2 infections, 57 (37 percent) were symptomatic, 47 of which (82 percent) were correctly diagnosed at presentation. Among the 74 patients given a clinical diagnosis of genital HSV-2 during the study, 60 were given a correct diagnosis and 14 were given an incorrect diagnosis of genital herpes, for a ratio of true positive results to false positive results of 4:1. Among the 98 persons with asymptomatic HSV-2 seroconversion, 15 percent had genital lesions at some time during follow-up. Women were more likely than men to acquire HSV-2 (P<0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion, as compared with symptomatic seroconversion, by a factor of 2.6 (P<0.001). Of the 19 new HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years). CONCLUSIONS: Nearly 40 percent of newly acquired HSV-2 infections and nearly two thirds of new HSV-1 infections are symptomatic. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.

An acellular pertussis vaccine in healthy adults: safety and immunogenicity. Pennridge Pediatric Associates.

Recent data indicate that Bordetella pertussis can be an important cause of illness in adolescents and adults. In a randomized observer- and subject-blinded study, adults (> or = 18 years of age) received an acellular pertussis (aP) vaccine containing genetically inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN), or a saline placebo, and were monitored for safety and immunogenicity. IgG antibodies to PT, FHA, and PRN were measured by enzyme-linked immunosorbent assay (ELISA) and PT neutralization by a Chinese hamster ovary (CHO) cell assay. Local reactions, more common in the aP group, were mild and transient. One month after immunization, geometric mean ELISA antibody concentrations for the aP and placebo groups, respectively, were: anti-PT, 463 and 7.6; anti-FHA, 417 and 18; and anti-PRN, 855 and 14. The anti-PT neutralization titers for the aP and placebo groups were 1:3439 and 1:58 respectively. This aP vaccine is a safe and immunogenic candidate booster vaccine against pertussis for adults.

Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group.

CONTEXT: In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. OBJECTIVE: To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. DESIGN: Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. SETTING AND PARTICIPANTS: We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. MAIN OUTCOME MEASURE: Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. RESULTS: Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. CONCLUSIONS: Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.

Cervical antibody responses to a herpes simplex virus type 2 glycoprotein subunit vaccine.

Effective vaccines against genital herpes simplex virus type 2 (HSV-2) may need to induce genital tract immune responses. To determine local antibody responses to HSV-2 glycoproteins gB2 and gD2 in an intramuscular subunit vaccine, cervical secretions from HSV-seronegative women and HSV-1-seropositive women were tested for IgG and IgA to gB2 and gD2 by enhanced chemiluminescence Western blot. Most (94%) of the seronegative subjects developed cervical IgG to gB2, IgG to gD2, and IgA to gB2; 72% developed IgA to gD2. All HSV-1-seropositive subjects had cervical IgG responses to vaccine gB2 and gD2, 85% had IgA responses to gB2, and 50% had IgA responses to gD2. Responses were more rapid and titers more consistently sustained in the HSV-1-seropositive women. Further, vaccination resulted in cervical IgG and IgA titers comparable to those to HSV-2 gB2 and gD2 in response to recurrent HSV-2 genital infection.

Immunotherapy of recurrent genital herpes with recombinant herpes simplex virus type 2 glycoproteins D and B: results of a placebo-controlled vaccine trial.

To determine the safety, immunogenicity, and efficacy of a recombinant herpes simplex virus type 2 glycoprotein D and B vaccine in the treatment of recurrent genital herpes, a randomized, placebo-controlled trial was held at two referral centers. Healthy patients with 4-14 recurrences per year received injections of both glycoproteins in MF59 adjuvant or of MF59 alone at 0, 2, 12, and 14 months. For 18 study months, the rate and number of recurrences, the duration and severity of the first confirmed recurrence, vaccine immunogenicity, and rates of local and systemic reactions were determined. The monthly rate of recurrences was not significantly improved, but the duration and severity of the first study outbreak was reduced significantly by vaccination. Glycoprotein-specific and neutralizing antibodies were boosted by vaccination for the duration of the study. This vaccine is safe and immunogenic and ameliorated an observed first postvaccination genital recurrence, but it does not reduce recurrence frequency.

A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity [corrected].

OBJECTIVE: To evaluate the safety and immunogenicity of a recombinant glycoprotein vaccine for herpes simplex virus type 2 (HSV-2), which contains glycoproteins gD2 and gB2 combined with the novel MF59 adjuvant emulsion, in HSV-2-seronegative persons. DESIGN: Integrated summary of two phase I and two phase II studies. SETTING: University and private outpatient clinics. PATIENTS: 137 persons seronegative for HSV-2 antibodies as determined by HSV Western blot assay. INTERVENTION: Open-label vaccine administration with a dose-escalating design (phase I) was followed by randomized vaccine administration (phase II). Vaccine was administered intramuscularly into the deltoid at 0, 1, and 6 months. MEASUREMENTS: Neutralizing, HSV-2-binding antibodies and HSV-2-stimulated proliferative responses were measured before and after immunization. RESULTS: Among HSV-seronegative patients, the gD2 and gB2 enzyme-linked immunosorbent assay (ELISA) and HSV-2-neutralizing antibody titers increased to levels equal to or higher than those seen in naturally acquired HSV-2 infection after the full three-dose immunization schedule. Among HSV-1-seropositive patients, one immunization produced increases in gD2 and gB2 ELISA antibody titers and HSV-2-neutralizing antibody titers that were 3 to 5 times greater than those in persons with naturally acquired HSV-2 infection. Among HSV-seronegative patients, frequency analysis assays showed a marked increase in the precursor frequency of gD2- and gB2-specific T cells after vaccination: T-cell responses after two immunizations were equal to the responses of HSV-2-seropositive patients and were sustained at day 180. The vaccine was well tolerated. CONCLUSIONS: This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.