Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum.

BACKGROUND: Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge. METHODS: Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion). RESULTS: The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC. CONCLUSIONS: High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics. CLINICAL TRIALS REGISTRATION: NCT02473224.

Participant Retention in a Randomized Clinical Trial in an Outbreak Setting: Lessons From the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE).

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Clinical Surveillance and Evaluation of Suspected Ebola Cases in a Vaccine Trial During an Ebola Epidemic: The Sierra Leone Trial to Introduce a Vaccine Against Ebola.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

The Sierra Leone Trial to Introduce a Vaccine Against Ebola: An Evaluation of rVSV∆G-ZEBOV-GP Vaccine Tolerability and Safety During the West Africa Ebola Outbreak.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Assessment of congenital anomalies in infants born to pregnant women enrolled in clinical trials.

In 2011 and 2012, the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, held a series of meetings to provide guidance to investigators regarding study design of clinical trials of vaccines and antimicrobial medications that enroll pregnant women. Assessment of congenital anomalies among infants born to women enrolled in these trials was recognized as a challenging issue, and a workgroup with expertise in epidemiology, pediatrics, genetics, dysmorphology, clinical trials, and infectious diseases was formed to address this issue. The workgroup considered 3 approaches for congenital anomalies assessment that have been developed for use in other studies: (1) maternal report combined with medical records review, (2) standardized photographic assessment and physical examination by a health professional who has received specific training in congenital anomalies, and (3) standardized physical examination by a trained dysmorphologist (combined with maternal interview and medical records review). The strengths and limitations of these approaches were discussed with regard to their use in clinical trials. None of the approaches was deemed appropriate for use in all clinical trials. Instead, the workgroup acknowledged that decisions regarding the optimal method of assessment of congenital anomalies will likely vary depending on the clinical trial, its setting, and the agent under study; in some cases, a combination of approaches may be appropriate. The workgroup recognized the need for more research on approaches to the assessment of congenital anomalies to better guide investigators in optimal design of clinical trials that enroll pregnant women.

Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.

IMPORTANCE: Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis. OBJECTIVE: To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine. DESIGN, SETTING, AND PARTICIPANTS: Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks' gestation, with crossover immunization postpartum. INTERVENTIONS: Tdap vaccination at 30 to 32 weeks' gestation or postpartum. MAIN OUTCOMES AND MEASURES: Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months' postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP. RESULTS: No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP. CONCLUSIONS AND RELEVANCE: This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00707148.

Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.

BACKGROUND: Although pregnant women are at increased risk of severe illness following influenza infection, there is relatively little information on the immunogenicity of influenza vaccines administered during pregnancy. METHODS: We conducted a clinical trial that enrolled 120 pregnant women in which participants were randomly assigned to receive an inactivated 2009 H1N1 influenza vaccine containing either 25 µg or 49 µg of hemagglutinin (HA) in a 2-dose series with a 21-day period between administration of the first and second doses. RESULTS: Following the first vaccination, HA inhibition (HAI) titers of ≥1:40 were detected in 93% (95% confidence interval [CI], 82%-98%) of subjects who received the 25-µg dose and 97% (95% CI, 88%-100%) of subjects receiving the 49-µg dose. In cord blood samples, HAI titers of ≥1:40 were found in 87% (95% CI, 73%-96%) of samples from the 25-µg dose group and in 89% (95% CI, 76%-96%) from the 49-µg dose group. Microneutralization titers tended to be higher than HAI titers, but the patterns of response were similar. CONCLUSIONS: In pregnant women, 1 dose of an inactivated 2009 H1N1 influenza vaccine containing 25 µg of HA elicited an antibody response typically associated with protection against influenza infection. Efficient transplacental transfer of antibody was also documented.

Safety and immunogenicity of three seasonal inactivated influenza vaccines among pregnant women and antibody persistence in their infants.

OBJECTIVE: Inactivated influenza virus vaccines (IIVs) are recommended for all pregnant women in the United States. We conducted a prospective, randomized, double blind study of three licensed seasonal trivalent IIVs (IIV3s) to assess their safety and immunogenicity in pregnant women and determine the level and persistence of passively transferred maternal antibody in infants. STUDY DESIGN: 139 pregnant women ages 18-39 years and 14-33 weeks' gestation, and 44 non-pregnant women, were randomized 1:1:1 to receive a single intramuscular dose of one of three licensed IIV3s (Agriflu®, Fluzone®, or Fluarix®) prior to the 2010-2011 influenza season. Reactogenicity, adverse events (AEs) and pregnancy outcomes were documented. Serum samples for hemagglutination inhibition (HAI) and neutralization antibody assays were collected prior to and 28 and 180 days after immunization. Maternal sera and cord blood were collected at the time of delivery and sera were obtained from 44 infants at 6 weeks of age. RESULTS: Pregnant and non-pregnant women experienced similar frequency of injection site (92% and 86%, respectively) and systemic (95% and 87%, respectively) reactions, the majority of which were mild. There were no vaccine-associated maternal or infant serious AEs. Antibody responses to the three vaccine antigens were not different between pregnant and non-pregnant women. The ratios of cord blood (infant) to maternal HAI antibody titers at delivery ranged between 1.1 and 1.7 for each of the vaccine antigens. Influenza antibody concentrations in infants were 70-40% of the birth titer by 6 weeks of age. CONCLUSIONS: The three IIV3s were well tolerated in pregnant women. Antibody responses were comparable in pregnant and non-pregnant women, and after second or third trimester vaccination. Transplacental transfer of maternal antibodies to the infant was efficient. However, antibody titers decline rapidly in the first 6 weeks of life.

Safety and immunogenicity of seasonal trivalent inactivated influenza vaccines in pregnant women.

BACKGROUND: In the United States, seasonal inactivated influenza vaccine (IIV) is recommended for pregnant women; however, in early 2009, immunization rates were low, partly due to limited prospective data and concerns about vaccine safety. OBJECTIVE: We conducted a randomized study of two licensed seasonal trivalent IIVs (IIV3) to assess their safety and immunogenicity in pregnant women. STUDY DESIGN: In this prospective, randomized clinical study, 100 pregnant women, 18-39 years of age and ≥14 weeks gestation received a single intramuscular dose of 2008-2009 Fluzone® or Fluarix®. Injection site and systemic reactions were recorded for 7 days after vaccination and serious adverse events (SAEs) and pregnancy outcomes were documented. Serum samples collected before and 28 days after vaccination were tested for hemagglutination inhibition (HAI) antibody levels. RESULTS: The majority of the injection site and systemic reactions were mild and self-limited after both vaccines. No fever ≥100 °F was reported. There were no vaccine-associated SAEs. Immune responses to influenza vaccine antigens were similar for the two study vaccines, with robust HAI responses against influenza A strains, and relatively lower responses for influenza B strains. CONCLUSION: Seasonal inactivated influenza vaccines were well tolerated and immunogenic in pregnant women. SYNOPSIS: In this prospective clinical trial, we demonstrated that immunization with seasonal trivalent, inactivated influenza vaccine in the second and third trimester of pregnancy is immunogenic and safe.