Richard Rupp

Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults.

BACKGROUND The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults. METHODS Sixty subjects 18-49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration. RESULTS Doses of 0.03-1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses (p>0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 μg), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release. CONCLUSIONS VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 μg doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation.

Serological Responses to an Avian Influenza A/H7N9 Vaccine Mixed at the Point-of-Use With MF59 Adjuvant: A Randomized Clinical Trial

IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China. OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014. INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 µg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer ≥40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7. RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 µg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 µg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 µg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant. CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01938742.

Factors Associated With Completion of the Human Papillomavirus Vaccine Series

and administration of the first dose of the vaccine between January 1, 2007, and July 1, 2007. Charts were reviewed until November 26, 2008, for a minimum 17 months of follow-up. Completion was defined as receipt of 3 HPV vaccinations. Charts were reviewed for age, race/ethnicity, type of insurance (private vs Medicaid/Child Health Insurance Program [CHIP]), and distance from home to the clinic. Sexual history variables included sexual activity status prior to initiation of the series and history within 3 years of vaccine initiation of a gynecological exam and/or Papanicolaou (Pap) test, HPV DNA test, or sexually transmitted infection. The reason for each visit was classified as nonsick visit (well child, well woman, contraception), sick visit, or vaccine only. If the patient did not complete the series, the chart was reviewed to determine if the patient had any clinic visits after she was due for her next shot. Statistical analyses were performed using SPSS, version 12.0, with an α level of <.05 determining statistical significance. Missing data did not exceed 2% for any of the predictor variables with the exception of sexual activity status for which 27% were missing. Only Caucasian, African American, or Hispanic patients were included in analyses assessing race/ ethnicity, as these 3 groups comprised >98% of the sample. Bivariate relationships between patient characteristics and vaccine series completion were conducted. Variables that were significant were entered into a logistic regression analysis using backward stepwise elimination.

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

BACKGROUND Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. METHODS CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. RESULTS 402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400 EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: -36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: -9; 72, p=0.08. CONCLUSION The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.

Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study.

INTRODUCTION A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. METHODS In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. RESULTS The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100%; DEN-2: 96-100%; DEN-3: 83-100%; and DEN-4: 33-77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. CONCLUSIONS All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).

Maternal and infant outcomes among women vaccinated against pertussis during pregnancy

ABSTRACT Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination is recommended for all women during each pregnancy to prevent pertussis in young infants. However, data on the safety of this protective measure are limited and conflicting. To assess maternal and infant outcomes associated with administration of this vaccine during pregnancy, we reviewed medical records of 1,759 women who delivered a singleton infant at a southeast Texas public hospital between November 1, 2012 and June 30, 2014. After excluding women who had inadequate prenatal care or who delivered at <27 weeks gestation, we used multivariable logistic regression analyses to compare 13 outcomes between those who did and did not receive the Tdap vaccine. We examined 6 maternal outcomes (chorioamnionitis, postpartum endometritis, preterm delivery, preterm premature rupture of membranes, induced labor, and mode of delivery) and 7 infant outcomes (low birth weight, very low birth weight, small for gestational age, 5-minute Apgar score, birth defects, and neonatal intensive care unit admission). Maternal Tdap vaccination was associated with decreased odds of cesarean delivery. No associations between maternal Tdap vaccination and infant outcomes were observed. This study demonstrates that Tdap vaccination during pregnancy does not increase the risk of adverse outcomes.

The potential impact of a prophylactic herpes simplex vaccine

Background: Herpes simplex virus (HSV) infections have a significant impact on health causing a wide range of diseases. Oral-facial and genital sites are the most common locations of infection and may lead to recurrent painful lesions. HSV infection acquired perinatally may result in severe sequelae or even death despite appropriate therapy. Furthermore, it is becoming increasingly clear that genital HSV infections significantly raise the risk of HIV transmission. Objective: To describe the strategies, impediments, and advancements in the development of vaccines to prevent HSV disease. Methods: A review of the literature was performed, limited to prophylactic HSV vaccines and their potential effect on genital herpes, oral-facial disease, and perinatal herpes. Conclusion: There are several vaccine strategies under development that show promise for the treatment these diseases.

School-based vaccination of young US males: Impact of health beliefs on intent and first dose acceptance

Little is known about adolescent males and their parents with respect to intent and first dose uptake of the human papillomavirus (HPV) vaccine outside of primay care settings. The purpose of this study was to evaluate potential predictors of parental intent to vaccinate (study was conducted in November 2010-December 2012) and of first dose uptake of HPV vaccine among a sample of young adolescent males, 11-15 years of age, who received care at a school-based health center (SBHC). We also examined intent as a potential mediator of the relationships between predictors (health beliefs and perceived spousal agreement) and vaccination. Slightly more than half (n=135 of 249) of parents reported an intention to vaccinate and 28% (n=69) of males received their first dose of the HPV vaccine. Two of three health beliefs were significantly associated with both intention and uptake as was perceived spousal agreement. We found intention to vaccinate was a partial mediatator between the perceived benefits of HPV vaccine and first dose acceptance. We also determined that intent was a strong mediator between both general immunization benefits and perceived spousal agreement and first dose uptake. While vaccine uptake was lower than expected, particularly considering that many barriers to vaccine initiation were eliminated because of the SBHC setting, this rate is higher than in traditional settings. After controlling for intent, only perceived benefits of the HPV vaccine remained a significant predictor of first dose acceptance.

Vaginal microbicides and teenagers

Purpose of review Sexually active teens are at significant risk from sexually transmitted infections and girls and women bear the greatest burden of these infections. New methods, such as vaginal microbicides, would provide female controlled options. Microbicides are currently in development and thus it is timely to discuss the progress made and factors that may influence acceptability for teens. Recent findings Microbicide development presents many challenges, and several different potential mechanisms of action are being explored. There is interest in these products from women and men, and specific preferences are being investigated. Adolescents, due to reproductive system immaturity, developing cognitive abilities and the psychosocial context of their relationships, present a special set of challenges in efforts to foster microbicide use. Summary Vaginal microbicides are on the horizon. Further study into teen issues is required to develop successful strategies for marketing and encouraging adolescent use of microbicides.

A human papillomavirus vaccination program for low-income postpartum women

BACKGROUND Effective interventions are needed to address the low rate of human papillomavirus (HPV) vaccination in the United States, particularly among girls and women 16-26 years old. Counseling and offering the vaccine to postpartum patients could be an effective strategy to increase uptake among young women who did not complete the 3-dose series at an earlier age. OBJECTIVE The purpose of this evaluation was to assess the effectiveness of a multicomponent program designed for postpartum women that used patient navigators (PNs) and reminders for follow-up visits to improve uptake and completion of the HPV vaccine series. STUDY DESIGN As part of standard care, patients ≤26 years of age from Galveston County, Texas, who delivered an infant from November 2012 through June 2014 at a public hospital were counseled and offered the HPV vaccine postpartum. PNs assisted with scheduling follow-up injections during postpartum or well-child visits. A program evaluation was conducted after 20 months. RESULTS Of 1038 patients approached, only 161 (15.5%) had previously completed the vaccine series. Of the 877 patients who had not completed the series, 661 (75.4%) received at least 1 dose postpartum, with 575 patients receiving their first dose and 86 receiving their second or third doses. By April 2015, initiation rates had increased as a result of this program from 25.4% before the program was initiated to 80.8% and completion rates from 15.5-65.1%. Missed appointments for injections were less likely among those who received text message reminders and more likely among those with ≥2 prior pregnancies. Those who were Hispanic or had received an influenza vaccination in the last year were more likely to initiate and complete the series through this program. Patients who missed ≥1 follow-up appointments were less likely to complete the vaccine series. CONCLUSION Offering the HPV vaccine postpartum dramatically increased initiation rates among postpartum patients. PN and text messages ensured that a high percentage completed all 3 doses.