Safety and Immunogenicity of a Subvirion Monovalent Unadjuvanted Inactivated Influenza A(H3N2) Variant Vaccine in Healthy Persons ≥18 Years Old.

BACKGROUND: Variant influenza A(H3N2) viruses (H3N2v) have transmitted recently from pigs to humans in the United States. Vaccines strategies are needed. METHODS: Healthy adults received 2 doses of subvirion H3N2v vaccine (15 µg of hemagglutinin/dose) 21 days apart in this open-label trial. Serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody (Ab) titers were measured before and 8 and 21 days after each dose. Memory B-cell (MBC) responses were assessed. RESULTS: Vaccine was well tolerated. A total of 40% of subjects had an HAI Ab titer of ≥40 before vaccination. Eight-seven percent (95% confidence interval [CI], 79%-93%) and 73% (95% CI, 63%-81%) of subjects 18-64 years old (98 subjects) and ≥65 years old (90 subjects), respectively, had an HAI titer of ≥40 21 days after dose 1 (P = .01); 51% (95% CI, 41%-61%) and 52% (95% CI, 41%-62%) of younger and older subjects, respectively, developed ≥4-fold rises in titer (P = not significant). Neut Ab response patterns were similar. Geometric mean titers were higher in younger subjects. Dose 2 provided no significant enhancement in responses. Cross-reactive MBCs were detected before vaccination and expanded after vaccination. Preexisting H3N2v-specific MBCs positively correlated with early increases in vaccine-induced Ab. CONCLUSIONS: In most healthy adults, one 15-µg dose of vaccine elicited levels of HAI Abs associated with protection. Studies in children and elderly individuals are indicated to define the immunization needs of these groups. CLINICAL TRIALS REGISTRATION: NCT01746082.

Impact of body mass index on immunogenicity of pandemic H1N1 vaccine in children and adults.

Obesity emerged as a risk factor for morbidity and mortality related to 2009 pandemic influenza A (H1N1) infection. However, few studies examine the immune responses to H1N1 vaccine among children and adults of various body mass indices (BMI). Pooling data from 3 trials of unadjuvanted split-virus H1N1 A/California/07/2009 influenza vaccines, we analyzed serologic responses of participants stratified by BMI grouping. A single vaccine dose produced higher hemagglutination inhibition antibody titers at day 21 in obese compared to nonobese adults, but there were no significant differences in responses to H1N1 vaccine among children or adults of various BMI following 2 doses.

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE smallpox vaccine.

INTRODUCTION: Previous research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox. METHODS: We conducted a participant-level meta-analysis (N=275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1×10(8)TCID50/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log2 ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data. RESULTS: In each study the mean peak log2 ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log2-titer in men compared with women (absolute difference [men-women]: 0.32, 95% CI: 0.02-0.60). Fixed effects models controlling for study showed a similar result (log2 ELISA titer, men-women: 0.34, 95% CI: 0.04-0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3-55%). Peak log2 PRNT titers were also higher (although not significantly) in men (men-women: 0.14, 95% CI: -0.30 to 0.58). CONCLUSION: Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.

Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario.

INTRODUCTION: Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE(®) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses. METHODS: Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination. RESULTS: The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BN's Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BN's Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-γ enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7. CONCLUSION: Overall, a standard dose of IMVAMUNE (0.5 mL of 1 x 10(8) TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-γ ELISPOT responses were similar for Group: 0+28 and Group: 0+7.

Alkaline CPD and the preservation of RBC 2,3-DPG.

BACKGROUND: Concentrations of 2,3-DPG decline rapidly in the first week of RBC storage because of the low pH of conventional storage solutions. Alkaline additive solutions, which can preserve RBCs for up to 11 weeks, still do not preserve 2,3-DPG because the starting pH is below 7.2. STUDY DESIGN AND METHODS: Alkaline CPD (pH=8.7) was made with trisodium citrate, dextrose, and disodium phosphate. Twelve units of whole blood were collected into heparin and pooled in groups of four units. Each pool was then aliquoted into four units; 63 mL of CPD with pH 5.7, 6.5, 7.5, or 8.7 was added to one unit of each pool, and 300 mL of the alkaline experimental additive solution-76 was added. In Study 2, 12 units were collected into alkaline CPD, pooled in groups of four, aliquoted as described, and stored in four variants of experimental additive solution-76 containing 0, 9, 18, and 27 mM of disodium phosphate. RBC ATP and 2,3-DPG concentrations, intracellular and extracellular pH and phosphate concentrations, hemolysis, and other measures of RBC metabolism and function were measured weekly. RESULTS: RBCs stored in more alkaline conditions made 2,3-DPG, but at the expense of ATP. Concentrations of 2,3-DPG decreased after 2 weeks storage, but ATP concentrations never fully recovered. Providing more phosphate both increased the duration of 2,3-DPG persistence and raised ATP concentrations in the later stages of storage. CONCLUSIONS: Maintaining both 2,3-DPG and ATP requires both high pH and high concentrations of phosphate.

Twelve-week RBC storage.

BACKGROUND: Better storage can improve RBC availability and safety. Optimizing RBC ATP production and minimizing hemolysis has allowed progressively longer storage. STUDY DESIGN AND METHODS: In the first study, 24 units of packed CPD RBCs were pooled in groups of four, realiquoted, and added to 300 mL of one of four variants of experimental additive solution 76 (EAS-76) containing 45, 40, 35, or 30 mEq per L NaCl. Units were sampled weekly for 12 weeks for morphologic and biochemical measures. In the second study, 10 volunteers donated 2 units of RBCs for a crossover comparison of Tc/Cr 24-hour in vivo recovery of 6-week storage in AS-1 versus 12-week storage in EAS-76 variant 6 (EAS-76v6) having 30 mEq per L NaCl. RESULTS: RBCs stored in the lower salt variants of EAS-76 had higher concentrations of RBC ATP with less hemolysis and microvesiculation. RBC 2,3 DPG was preserved for two weeks. RBCs stored for 12 weeks in EAS-76v6 exhibited 78 +/- 4 percent 24-hour in vivo recovery. CONCLUSIONS: It is possible to store RBCs for 12 weeks with acceptable recovery and 0.6 percent hemolysis and with normal 2,3 DPG concentrations for 2 weeks.