Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial

BackgroundRecent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramusclular or subcutaneous (SC) delivery.MethodsIn this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20–64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 μg HA or two doses (21 days apart) of 15 μg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 μg HA per strain. Immunogenicity was assessed using hemagglutination inhibition (HAI) titer and microneutralization titer on Days 0, 10, 21, and 42. Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination, respectively.ResultsIn both young adults and older adults groups, the geometric titer (GMT) ratios of HAI in the ID 15 μg HA group were higher than those in the SC 15 μg HA group on both Day 10 and Day 21, while those in the ID 6 and ID 9 μg HA groups were comparable with those in the SC 15 μg HA group. The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response, which is rather hampered in older adults as seen in the SC vaccine groups. The injection-site AEs were generally mild and transient, and did not occur in a dose or dosage-dependent manner.ConclusionsThe results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine, while the safety profile of the ID vaccine is similar to that of the SC vaccine. In this exploratory study with almost 100 subjects per each group, single or two-dose administration of the ID vaccine containing 15 μg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden.Trial registrationJAPIC Clinical Trials Information (JapicCTI-132096).     

Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in adults 65 years of age and older: A phase II,observer-blind,randomized, controlled trial

BackgroundH7 influenza strains can cause severe and often fatal human infections, especially in the elderly. This phase II, observer-blind, randomized trial (www.ClinicalTrials.gov: NCT01949090) assessed the immunogenicity and safety of a novel AS03-adjuvanted H7N1 vaccine that may serve as a model H7-subtype vaccine.Methods360 adults ≥65 years of age in stable health received either 1 of 4 adjuvanted A/mallard/Netherlands/12/2000 split virion vaccine formulations (3.75 μg or 7.5 μg hemagglutinin adjuvanted with either AS03_A or AS03_B) or saline placebo, given as a 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays for the per-protocol cohort, comprising 332 participants at 21 days post-each dose, 332 at month 6, and 309 at month 12 (HI assay only). Safety was assessed up to month 12 for all participants who had received ≥1 dose (360 participants).ResultsFor H7N1 HI antibody assessment at day 42 (21 days post-dose 2), seroprotection rates (SPR) in the vaccinated groups were 69.6%–88.7%, seroconversion rates (SCR) 69.6%–88.5%, mean geometric increase (MGI) 11.0–18.9, and HI geometric mean titers (GMTs) 55.0–104.8. These parameters declined by month 6 and month 12. Microneutralization GMTs were 46.2–74.7 in the vaccinated groups at day 42, while vaccine response rate (VRR; proportion with ≥4-fold increase in MN titer) was 46.4%–81.5%. For the cross-reactive H7N9 strain, at day 42, HI GMT were 64.3–201.3, SPR 78.6%–96.3%, SCR 79.3%–96.3%, and MGI 14.1–37.7; MN GMTs were 44.0–85.6, and VRR 46.4–85.2%.The most frequent solicited symptom was injection site pain (41.7%–65.0% of vaccine recipients). In total, 40 participants reported 67 serious adverse events; none were considered causally related to vaccination.ConclusionsIn adults aged ≥65 years, the adjuvanted H7N1 vaccine was immunogenic after 2 doses, and had an acceptable safety profile.www.ClinicalTrials.gov: NCT01949090.     

Immunogenicity,reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III,randomized, open-label,multicenter study

BackgroundIn phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01_B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months.MethodsIn this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2.Results346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination.ConclusionsImmune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals.Clinical Trials Registration: Clinicaltrials.gov (NCT01751165).     

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine compared with two trivalent inactivated influenza vaccines containing alternate B strains in adults: A phase 3, randomized noninferiority study

BackgroundVaccination is the most effective means of influenza prevention. Efficacy of trivalent vaccines may be enhanced by including both B strain lineages. This phase 3, double-blind study assessed the immunogenicity and safety/tolerability of a quadrivalent inactivated influenza vaccine (IIV4) versus the United States (US)-licensed 2014–2015 trivalent inactivated influenza vaccine (IIV3-Yamagata [IIV3-YAM]; Afluria) and IIV3 containing the alternate Victoria B strain (IIV3-VIC) in adults ≥18 years.MethodsParticipants (n = 3484) were randomized 2:1:1 and stratified by age to receive IIV4 (n = 1741), IIV3-YAM (n = 871), or IIV3-VIC (n = 872). The primary objective was to demonstrate noninferiority of the immunological response to IIV4 versus IIV3-YAM and IIV3-VIC. Noninferiority was assessed by hemagglutination inhibition geometric mean titer (GMT) ratio (IIV3/IIV4; upper bound of two-sided 95% confidence interval [CI] ≤ 1.5) and seroconversion rate (SCR) difference (IIV3 – IIV4; upper bound of two-sided 95% CI ≤ 10%) for vaccine strains. Solicited local and systemic adverse events (AEs) were assessed for 7 days postvaccination, AEs recorded for 28 days postvaccination, and serious AEs for 6 months postvaccination.ResultsIIV4 elicited a noninferior immune response for matched strains, and superior response for unmatched B strains not contained in IIV3 comparators. Adjusted GMT ratios (95% CI) for A/H1N1, A/H3N2, B/YAM, and B/VIC strains were 0.93 (0.88, 0.99), 0.93 (0.88, 0.98), 0.87 (IIV3-YAM; 0.82, 0.93), and 0.95 (IIV3-VIC; 0.88, 1.03), respectively. Corresponding values for SCR differences (95% CI) were −1.1 (−4.5, 2.3), −1.7 (−5.0, 1.7), −3.2 (IIV3-YAM; −7.4, 0.9), and −1.6 (IIV3-VIC; −5.8, 2.5). AEs were generally mild and experienced by 52.9% of participants. Serious AEs were reported with a slightly higher frequency with IIV4 (2.3%) versus IIV3-YAM (1.6%) and IIV3-VIC (1.5%).ConclusionsIIV4 demonstrated immunological noninferiority to the US-licensed IIV3, and superiority for unmatched B strains not contained in IIV3 comparators. Safety/tolerability profiles were similar across vaccine groups.Funding: Seqirus; Clinicaltrials.gov: NCT02214225.     

Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial

BackgroundThe use of vaccines with higher doses of antigen is an attractive strategy to improve the immunogenicity of influenza vaccination in transplant recipients. However, the effect of vaccination with a double-dose (DD) containing 30 µg of antigen in this population remains unknown.MethodsWe performed a randomized controlled trial to compare the immunogenicity and safety of DD (30 µg) vs. standard dose (SD, 15 µg) of a trivalent inactivated influenza vaccine in kidney and liver transplant recipients. Immunogenicity was assessed by hemagglutination-inhibition assay. Vaccine response was defined as seroconversion to at least one viral strain 2 weeks after vaccination and seroprotection as a titer ≥40.ResultsSixty-three kidney and 16 liver transplant recipients were enrolled. Forty patients received the DD and 39 the SD vaccine. Overall, 40% of patients in the DD compared to 26% in the SD group (P = 0.174) responded to vaccine. In the DD arm, more patients were seroprotected to all viral strains after vaccination (88% vs 69%, P = 0.048). Post vaccination geometric mean titers of antibodies were 131.9 vs. 89.7 (P = 0.187) for H1N1, 185.4 vs. 138.7 (P = 0.182) for H3N2, and 96.6 vs. 68.8 (P = 0.081) for influenza B with the DD vs. SD. In both groups, most of the adverse events were mild and no vaccine-related severe adverse events were observed.ConclusionDouble-dose influenza vaccine is safe and may increase antibody response in transplant recipients. In this population, DD vaccination could be an alternative when high-dose vaccine is not available. NCT02746783.     

Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b,randomized controlled trial

BackgroundInvasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY-CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups.MethodsThis phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed.ResultsAt 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68–100% and 87–100% of children had hSBA titers ≥5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, ≥96% (post-primary vaccination) and ≥98% (post-booster vaccination) of children in all groups had hSBA titers ≥4. Post-booster vaccination, GMTs increased ≥5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related.ConclusionImmune responses elicited by co-administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants.ClinicalTrials.gov: NCT02106390.An Audio Summary linked to this article that can be found on Figshare https://figshare.com/articles/Immunogenicity_and_safety_of_the_4CMenB_and_MenACWY-CRM_meningococcal_vaccines_administered_concomitantly_in_infants_-_A_phase_3b_randomized_controlled_trial/9945050.     

Cancer-salient messaging for Human Papillomavirus vaccine uptake: A randomized controlled trial

Background and objectivesVaccination with Human Papillomavirus (HPV) vaccine is recommended for 11–12 years-old, but uptake is suboptimal. Current messaging focuses on HPV infection transmission and prevention. Parents and providers are often uncomfortable discussing sexual practices of adolescents, contributing to the delay/refusal of vaccine. We created a cervical cancer-salient message encouraging HPV vaccination, emphasizing disease salience and disease threat, while promoting self-efficacy. We hypothesized this message would have greater effects on vaccine confidence and intent to vaccinate compared to Centers for Disease Control and Prevention (CDC) and non-vaccine control messages.MethodsA 3-arm randomized trial was conducted. Parents of girls aged 9–17 were eligible for the study. We measured participants’ vaccine confidence and intent to vaccinate at baseline and post intervention message. Recruitment and surveys were administered online through Amazon Mechanical Turk.Results762 participants completed both surveys. We saw modest increases in vaccine confidence when comparing cervical cancer arm and control arm, and CDC arm and control arm; estimates were not statistically significant. The odds of reporting intent to vaccinate among the cervical cancer message arm were 1.13 times the odds of reporting intent to vaccinate in the control arm (95% CI: 0.30. 4.29). Intent to vaccinate was also not statistically significantly different between CDC message arm and control arm (OR = 1.25, 95%CI: 0.66, 2.37).ConclusionNeither message had effect on intent to vaccinate, highlighting need for research to identify successful messaging strategies for HPV. Exploratory analyses suggest among parents with ‘Low’ vaccine confidence at baseline, the cervical cancer framed message may be more effective in changing intention than the CDC message or non-vaccine control. Future work should target groups with ‘Low’ or ‘Medium’ vaccine confidence at baseline - they may be more amenable to change, and more receptive to disease-salient messaging.Clinical Trial Registration: Clinicaltrials.gov, Reference #: NCT03002324.     

Safety of a heat-stable rotavirus vaccine among children in Niger: Data from a phase 3, randomized,double-blind,placebo-controlled trial

BackgroundRotavirus remains a major cause of diarrhea among children under 5 years of age. The efficacy of RotaSIIL, a pentavalent rotavirus vaccine, was shown in an event-driven trial in Niger. We describe the two-year safety follow-up of this trial.MethodsFollow-up of safety outcomes began upon administration of the first dose of RotaSIIL or placebo. Adverse events were followed until 28 days after the third dose, and serious adverse events were followed until 2 years of age. Suspected cases of intussusception were evaluated at first point of contact and then referred to hospital for surgical evaluation. Causes of death were obtained by chart review and verbal autopsy. Passive surveillance was carried out in health centers. Community health workers carried out active surveillance in villages. Between-group differences were evaluated using the chi-squared test and Fisher’s exact test.ResultsA total of 4092 children were randomized, and 4086 received at least one dose of RotaSIIL or placebo, constituting the intention-to-treat population, who accrued a total of 7385 child-years of follow-up time. At two years of follow-up, 58 (2.8%) participants who received RotaSIIL and 49 (2.4%) participants who received placebo had died (p = 0.38). Most deaths were due to infectious causes common to the study area. One participant had confirmed intussusception, 542 days after receiving the third dose of RotaSIIL. A total of 395 (19.3%) participants receiving RotaSIIL and 419 (20.5%) participants receiving placebo experienced any serious adverse event (p = 0.36). Most serious adverse events were hospitalizations due to infection (malaria, lower respiratory tract infection and gastroenteritis) or marasmus. Overall, 1474 (72.1%) participants receiving RotaSIIL and 1456 (71.1%) participants receiving placebo had at least one adverse event (p = 0.49) in the follow-up period.ConclusionsAt two years of follow-up, RotaSIIL was found to be safe.Trial registration: ClinicalTrials.gov: NCT02145000.