Allen Izu

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.

The relationship between condom use and herpes simplex virus acquisition

Context We need other means to reduce the risk for transmitting genital herpes (herpes simplex virus type 2 [HSV-2]). Are condoms effective? Content In a trial of an ineffective HSV-2 vaccine, 1843 participants were divided into 3 groups according to the frequency of condom use (for 0% to 25%, 25% to 75%, and >75% to 100% of sexual acts). Frequent condom users had fewer HSV-2 infections. Compared with participants in the next lowest category, participants in a category had a 26% lower risk for HSV-2 infection. Limitation In this observational cohort study, many unmeasured factors could also contribute to altered rates of HSV-2 acquisition. Conclusion Condom use is associated with a lower rate of acquisition of HSV-2. The Editors Genital herpes is a common sexually transmitted infection that can be transmitted during episodes of recurrent lesions and during subclinical shedding (1). In the absence of an effective vaccine, condoms have been routinely recommended for prevention of transmission, and a recent study showed that daily antiviral therapy also decreases the risk for transmission of herpes simplex virus type 2 (HSV-2) in discordant couples (2, 3). In a previous study of monogamous HSV-2discordant couples who were enrolled in an ineffective candidate HSV-2 vaccine trial, we showed that condoms protect women from HSV-2 infection (4). However, very few cases of genital HSV-2 occurred among men who were sexual partners of women infected with HSV-2, precluding definitive conclusions about the effectiveness of condoms for prevention of transmission to men. We present data from a concurrent trial of the candidate vaccine among HSV-2seronegative persons attending sexually transmitted disease clinics (5). A total of 1862 participants were enrolled in this study; 85 cases of genital herpes were documented in men, and 33 cases were documented in women. We analyzed the effect of condom use on HSV acquisition in this prospectively followed cohort of men and women. Methods Study Sample Participants included in this analysis took part in a randomized, double-blind, placebo-controlled efficacy trial of a candidate subunit HSV-2 vaccine that was subsequently shown to be ineffective (5). The trial involved 22 centers located at sexually transmitted disease clinics and enrolled 1862 participants. Initial serologic testing was done at screening; participants who were seronegative for HIV and HSV-2 and reported 4 or more sexual partners in the past year or 1 or more sexually transmitted diseases in the past year were eligible to enroll. The effectiveness of condom use among the 528 discordant couples enrolled in a parallel vaccine study was reported previously (4, 5). Participants were enrolled and followed for 18 months, during which they were evaluated at 11 study visits. At enrollment, we collected demographic information and information about sexual history. At each study visit, we took blood samples and recorded the following information about sexual history, which described behavior since the last visit: frequency of sexual activities, defined as vaginal or anal intercourse; frequency of condom use; number of partners; number of new partners; and number of partners with a known history of genital herpes. The information regarding number of partners was gender-specific. In addition, participants were counseled routinely about safer sexual behavior and were offered condoms at each study visit. Genitourinary signs and symptoms were evaluated as needed at additional interim visits. Laboratory Methods The Western blot assay done at the University of Washington, Seattle, Washington, established HSV serologic status at study entry and was used to document seroconversion (6). Type-specific cultures using standard techniques were done at local study sites. Statistical Analysis Acquisition of HSV-2 was defined by seroconversion on the Western blot assay or by a positive culture for HSV-2. Time to HSV-2 acquisition was defined as the number of days from screening to the first positive culture for HSV-2 or as the midpoint between the last negative result of the HSV-2 antibody test and the first positive result of the HSV-2 antibody test. In this analysis of condom use and HSV acquisition, we included the time from screening to enrollment in the study, whereas in the vaccine trial participants were followed beginning at enrollment. Thus, our report includes 109 participants who were not included in the efficacy analysis of the original vaccine trial. Twenty of these participants seroconverted to HSV-2 during the screening period before enrollment, and 89 were lost to follow-up after enrollment. Participants who did not acquire HSV-2 were censored at the last blood draw taken during the study or at enrollment if they did not report any sexual activity thereafter. Participants who reported no sexual activity for the entire time from screening to study termination were excluded from the analysis because they were not at risk for HSV-2 infection. Participants with follow-up longer than 65 days beyond the 18 months specified in the protocol (3%) were censored at day 605. Participants who were seronegative for HSV type 1 (HSV-1) and HSV-2 at screening were included in the analysis of HSV-1. Time to HSV-1 acquisition was defined as the number of days from screening to the first positive culture for HSV-1 or the midpoint between the last negative result of the HSV-1 antibody test and the first positive result of the HSV-1 antibody test. Participants who did not acquire HSV-1 were censored at the last blood draw or at enrollment if they did not report any sexual activity thereafter. Participants who reported no sexual activity for the duration of the study were excluded from the analysis of HSV-1. KaplanMeier curves, log-rank tests, and univariate and multivariate Cox regression models were used to determine baseline risk factors associated with HSV-2 acquisition. To relate sexual behavior to HSV-2 acquisition during the study, we constructed time-dependent covariate Cox regression models. The analysis time was divided into four 150-day intervals, and information about sexual history collected at interim visits was used to calculate covariate summaries for each period. Because continuous variables did not satisfy the assumption of a linear effect in the log hazard, they were categorized. Our choice for the cut-points was motivated by maintaining equal numbers of participants in each category (for example, age was split at the median value, 27 years), by consistency with observed risk patterns, or by interpretation considerations. Frequency of sexual activity was expressed as the average number of sexual acts per week in the time period, calculated by averaging the reported estimates over the visits for each interval. This average was then categorized as greater than 2 versus 2 or fewer to correspond to observed risk patterns. Use of condoms during the study period was described categorically in each interval (used for 0% to 25%, for 25% to 75%, or for >75% of sexual acts). This grouped linear parameterization was chosen to remain consistent with published analyses (4) while allowing a doseresponse relationship, assuming constant change in the risk with increasing category of condom use. The use of condoms was not evaluated during intervals for which the participants did not report any sexual activity. The number of partners reported was summarized for each period and was modeled in a binary fashion. Partner cut-points were chosen for interpretation reasons to describe ways in which this patient group may differ from monogamous couples who were studied in a previously published report addressing condom use and infection with HSV (4). Total number of partners was modeled as more than 1 versus 1 or fewer, and both new partners and partners with a history of genital herpes were modeled as any versus none. These analyses did not adjust for receipt of placebo versus receipt of vaccine, because this factor was not statistically significant in acquisition of HSV and did not influence the covariates of interest for this study. An interaction term between condom use and gender was used to check the hypothesis of a difference in the effect of condoms by gender and to provide gender-specific estimates of condom use. Two-sided P values for model covariates were calculated by using the likelihood ratio test. The same methods were used to explore baseline risk factors and time-varying risk factors for time to infection with HSV-1. Poisson regression was used to provide P values for comparisons involving incidence rates. Tests for changes in sexual behavior with time used generalized estimating equations. Statistical analyses were done by using Stata statistical software (version 8.1, Stata Corp., College Station, Texas). Role of the Funding Source The funding for the analyses for this study was provided by federal grants; design, data analysis, and interpretation were done at the University of Washington. The initial clinical trial was funded by Chiron Corporation. This study was supported in part by National Institutes of Health Herpes Program Project Grant AI-30731 and Centers for Disease Control and Prevention Research Initiative UR6/CCU017828-02. Results Of the 1862 participants who enrolled for the vaccine trial, 19 did not report any sexual activity during the entire study and thus were excluded from this analysis. The remaining 1843 participants included 1365 men and 478 women. The median age of the participants was 27 years. Sixty-two percent were white, 32% were African American, and 6% were people of other races; 1184 participants (64%) were seropositive for HSV-1 at study entry. Most men and women qualified for the study by reporting 4 or more partners in the past year (66% of men, 70% of women); some reported 1 or more sexually transmitted diseases in the past year (12% of men, 19% of women); and the remainder met both criteria (22% of men, 1

Clinical Efficacy of Cell Culture—Derived and Egg-Derived Inactivated Subunit Influenza Vaccines in Healthy Adults

BACKGROUND More efficient methods are needed to manufacture influenza vaccines. This trial compared the efficacy of cell culture-derived influenza vaccine (CCIV) and egg-derived trivalent inactivated vaccine (TIV) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States, Finland, and Poland during the 2007-2008 influenza season. METHODS A total of 11,404 study participants aged 18-49 years were randomized equally to receive CCIV (Optaflu; n = 3828), TIV (Agrippal; n = 3676), or placebo (n = 3900). Each participant was observed during a 6-month study surveillance period. Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness. Vaccine immunogenicity was evaluated in a subset of 1045 participants. RESULTS Efficacy of CCIV and TIV against vaccine-like (83.8% [1-sided 97.5% confidence interval [CI] lower limit, 61.0%] and 78.4% [1-sided 97.5% CI lower limit, 52.1%], respectively) and all circulating influenza virus strains (69.5% [1-sided 97.5% CI lower limit, 55.0%] and 63.0% [1-sided 97.5% lower limit, 46.7%], respectively) exceeded the Center for Biologics Evaluation and Research efficacy criteria. Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria. Both vaccines were well tolerated, with similar safety profiles. Most solicited reactions were mild to moderate in severity and transient. No vaccination-related serious adverse events were reported; no withdrawals resulted from vaccine-related adverse events. CONCLUSIONS Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains, were well tolerated, and had good safety profiles. Both vaccines can be considered for annual influenza vaccination campaigns. CLINICAL TRIALS REGISTRATION NCT00630331.

Subunit Influenza Vaccines Produced from Cell Culture or in Embryonated Chicken Eggs: Comparison of Safety, Reactogenicity, and Immunogenicity

BACKGROUND This study assessed the safety, reactogenicity, and immunogenicity of an injectable cell culture-derived influenza vaccine (CCIV), compared with those of an injectable egg-based trivalent inactivated influenza vaccine (TIV). METHODS Adult subjects (n = 613; 18 to <50 years of age) were randomized (1:1) to receive either CCIV or TIV. The safety and reactogenicity of the 2 vaccines were assessed on the basis of solicited indicators and other adverse events (AEs) within 7 days of vaccination. All serious AEs and those AEs resulting in withdrawal were recorded throughout the study. Antibody titers were determined by the hemagglutination inhibition assay, using egg- and cell-derived antigens. Immunogenicity was assessed on the basis of the ratio of postvaccination (day 22) geometric mean titers (GMTs) between the 2 vaccines, seroprotection rates, and seroconversion rates. RESULTS There was no clinically relevant difference between the safety and reactogenicity profiles of the 2 vaccines. The immunogenicity of CCIV was demonstrated to be noninferior to that of TIV on the basis of the ratio of postvaccination GMTs between the 2 vaccines. GMTs, seroprotection rates, and seroconversion rates were comparable between the 2 vaccines. CONCLUSIONS The safety, reactogenicity, and immunogenicity of the CCIV and the egg-based TIV are comparable.

Immunogenicity, safety and reactogenicity of a mammalian cell-culture-derived influenza vaccine in healthy children and adolescents three to seventeen years of age.

Background: The safety and immunogenicity of the cell-culture–derived seasonal trivalent influenza vaccine ([CCIV]; Optaflu) has been reported previously in adults and the elderly. In this study, we compared the safety, reactogenicity and immunogenicity of CCIV with a conventional egg-derived trivalent influenza vaccine (TIV) in a healthy pediatric population. Methods: A total of 3604 subjects were randomized to receive 2 doses of CCIV or TIV (3–8 years, n = 2630) at a 28-day interval or a single vaccination (9–17 years, n = 974). Antibody levels on days 1, 29 and 50 were measured by hemaglutination inhibition assay using egg-derived and cell-derived test antigens. Adverse reactions were solicited via memory aids for 7 days after each injection, and unsolicited adverse events/serious adverse events were collected for 6 months postvaccination. Results: Noninferiority of CCIV versus TIV was demonstrated for most immunogenicity measures, particularly by using cell-derived antigen in the hemaglutination inhibition assay. In 3- to 8-year-olds (the primary objective), both CCIV and TIV met all 3 Committee for Medicinal Products for Human Use immunogenicity criteria for A/H1N1 and A/H3N2 strains. Lower immune responses were observed against the B strain, fulfilling Committee for Medicinal Products for Human Use criteria only for geometric mean ratio (TIV, CCIV) and seroconversion rate (TIV, CCIV [cell-derived antigen]). Both CCIV and TIV were safe and well tolerated, with no differences in local and systemic solicited reactions or in unsolicited adverse events/serious adverse events. Conclusion: CCIV produced in mammalian cell culture is a safe, well-tolerated and immunogenic alternative to conventional egg-derived influenza vaccines for children and adolescents.

Antibody persistence and response to a booster dose of a quadrivalent conjugate vaccine for meningococcal disease in adolescents.

Background: In a previous randomized phase 2 study in adolescents, a CRM197 meningococcal conjugate vaccine against serogroups A, C, W-135 and Y (MenACWY-CRM) was well tolerated and immunogenic, compared with a plain polysaccharide vaccine (MenACWY-PS). Methods: This extension study assessed antibody persistence 5 years after primary vaccination with MenACWY-CRM (n = 50) or MenACWY-PS (n = 51), and the immunogenicity and reactogenicity of a dose of MenACWY-CRM given 5 years after primary vaccination; antibody response was also compared with vaccine-naive controls (n = 54). The primary endpoints were the percentage of subjects with titers ≥8 by serum bactericidal activity assay using human complement (hSBA) 5 years after primary vaccination and hSBA geometric mean titers 1 month after the MenACWY-CRM dose given in the current study. Results: Five years after primary vaccination, over 70% of subjects who had received MenACWY-CRM were seropositive (hSBA titers ≥8) for serogroups C, W-135 and Y; for serogroups C and Y, the percentages of seropositive subjects were significantly higher in subjects previously vaccinated with MenACWY-CRM than in subjects previously vaccinated with MenACWY-PS. The MenACWY-CRM dose given 5 years postprimary vaccination elicited an anamnestic response across serogroups in those previously vaccinated with MenACWY-CRM. Responses in those previously vaccinated with MenACWY-PS were less robust but adequate and similar to that seen in the vaccine-naive group, both in magnitude and kinetics. MenACWY-CRM was well tolerated in all 3 groups. Conclusion: MenACWY-CRM provided a broad and persistent immune response in adolescents. A subsequent dose of MenACWY-CRM elicited an adequate antibody response, regardless of vaccine history.

Safety and immunogenicity of Chiron/Biocine® recombinant acellular pertussis-diphtheria-tetanus vaccine in infants and toddlers

OBJECTIVE To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine). STUDY DESIGN This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine. RESULTS The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine. CONCLUSION The Chiron/Biocine aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product.

Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: Results of an open-label, randomized, phase 3b controlled study in healthy infants

BACKGROUND The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants. METHODS Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1-7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%). RESULTS A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI -0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference -0.1% [95% CI -4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups. CONCLUSION In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone.

Five year follow-up after primary vaccination against tick-borne encephalitis in children.

BACKGROUND A first tick-borne encephalitis (TBE) vaccine booster in children is currently suggested 3 years after completing either a conventional (doses on Days 0, 28 and 300) or accelerated conventional (doses on Days 0, 14 and 300) TBE immunization schedule. This recommendation, however, may not be appropriate in cases where different TBE vaccines have been used interchangeably during the primary immunization series. METHODS To provide robust data to better inform such recommendations, TBE antibody persistence was evaluated after 3-5 years in four groups of children (aged 5-15 years): two groups previously primed with three doses of Encepur(®) Children (conventional/accelerated conventional schedule); and two groups previously primed with two doses of FSME-IMMUN(®) followed by a third dose of Encepur(®) Children (conventional/accelerated conventional schedule). Immunogenicity was evaluated using neutralization (NT) assays based on both vaccine antigens as well as on the Enzyme Linked Immunosorbent Assay (ELISA). RESULTS In the two Encepur(®) Children groups (full series), protective NT titers of ≥10 were detected in 98-100% of children up to 5 years after their last primary vaccination, irrespective of schedule. In contrast, only 65-70% subjects in the FSME-IMMUN(®) Junior groups (mixed series) displayed NT titers ≥10 after 3 years. Thus, due to lower probability of achieving/maintaining long-term protective antibody levels (recently defined by the World Health Organization as an NT titer ≥10) after this time point, both FSME-IMMUN Junior groups were discontinued. CONCLUSION A strong antibody response persists for at least 5 years after full primary vaccination with Encepur(®) Children. The study thus provides support for extending the time interval for a first booster dose after primary vaccination (conventional/accelerated conventional schedule) with Encepur(®) Children from 3 to 5 years.

Sample size for equivalence trials: a case study from a vaccine lot consistency trial.

For some trials, simple but subtle assumptions can have a profound impact on the size of the trial. A case in point is a vaccine lot consistency (or equivalence) trial. Standard sample size formulas used for designing lot consistency trials rely on only one component of variation, namely, the variation in antibody titers within lots. The other component, the variation in the means of titers between lots, is assumed to be equal to zero. In reality, some amount of variation between lots, however small, will be present even under the best manufacturing practices. Using data from a published lot consistency trial, we demonstrate that when the between-lot variation is only 0.5 per cent of the total variation, the increase in the sample size is nearly 300 per cent when compared with the size assuming that the lots are identical. The increase in the sample size is so pronounced that in order to maintain power one is led to consider a less stringent criterion for demonstration of lot consistency. The appropriate sample size formula that is a function of both components of variation is provided. We also discuss the increase in the sample size due to correlated comparisons arising from three pairs of lots as a function of the between-lot variance.