Immunogenicity and safety of an egg culture-based quadrivalent inactivated non-adjuvanted subunit influenza vaccine in subjects ≥3 years: A randomized,multicenter, double-blind,active-controlled phase III,non-inferiority trial

Subunit influenza vaccine only formulated with surface antigen proteins has better safety profiles relative to split-virion influenza vaccine. Compared to the traditional quadrivalent split-virion influenza vaccine, a novel quadrivalent subunit influenza vaccine is urgently needed in China. We completed a phase 3, randomized, double-blind, active-controlled, non-inferiority clinical study at two sites in Henan Province, China. Eligible volunteers were split into four age cohorts (3–8 years, 9–17 years, 18–64 years, and ≥ 65 years, based on their dates of birth) and randomly assigned (1:1) to the subunit and the split-virion ecNAIIV4 groups. All volunteers were intramuscularly administered a single vaccine dose at baseline, and children aged 3–8 years received a boosting dose at day 28. And the immune response was evaluated by measuring hemagglutinin-inhibition antibody titers against the four vaccine strains in blood samples. Safety profiles had nonsignificant differences between the study groups in ≥ 3 years cohort. Most adverse reactions post-vaccination, both local and systemic, were mild to moderate and resolved within 3 days. And no serious adverse events occurred. The immunogenicity of the trial vaccine was non-inferior to the comparator. Further, a two-dose vaccine series can provide better seroprotection than that of a one-dose series in children aged 3–8 years, with clinically acceptable safety profiles.Clinical Trials Registration. ChiCTR2100049934.     

Immunogenicity of seasonal inactivated influenza and inactivated polio vaccines among children in Senegal: Results from a cluster-randomized trial

Data on influenza vaccine immunogenicity in children are limited from tropical developing countries. We recently reported significant, moderate effectiveness of a trivalent inactivated influenza vaccine (IIV) in a controlled, cluster-randomized trial in children in rural Senegal during 2009, a year of H3N2 vaccine mismatch (NCT00893906). We report immunogenicity of IIV3 and inactivated polio vaccine (IPV) from that trial. We evaluated hemagglutination inhibition (HAI) and polio antibody titers in response to vaccination of three age groups (6 through 35 months, 3 through 5 years, and 6 through 8 years). As all children were IIV naïve, each received two vaccine doses, although titers were assessed after only the first dose for subjects aged 6 through 8 years. Seroconversion rates (4-fold titer rise or increase from <1:10 to ≥1:40) were 74–87% for A/H1N1, 76–87% for A/H3N2, and 54–79% for B/Yamagata. Seroprotection rates (HAI titer ≥ 1:40) were 79–88% for A/H1N1, 88–96% for A/H3N2, and 52–74% for B/Yamagata. IIV responses were lowest in the youngest age group, and they were comparable between ages 3 through 5 years after two doses and 6 through 8 years after one dose. We found that baseline seropositivity (HAI titer ≥ 1:10) was an effect modifier of IIV response. Using a seroprotective titer (HAI titer ≥ 1:160) recommended for IIV evaluation in children, we found that among subjects who were seropositive at baseline, 69% achieved seroprotection for both A/H1N1 and A/H3N2, while among those who were seronegative at baseline, seroprotection was achieved in 11% for A/H1N1 and 22% for A/H3N2. The IPV group had high baseline polio antibody seropositivity and appropriate responses to vaccination. Our data emphasize the importance of a two-dose IIV3 series in vaccine naïve children. IIV and IPV vaccines were immunogenic in Senegalese children.     

A randomized controlled trial of antibody response to 2019–20 cell-based inactivated and egg-based live attenuated influenza vaccines in children and young adults

BackgroundHemagglutination inhibition (HAI) titers to the live-attenuated influenza vaccine (LAIV4) are typically lower than its counterpart egg-based inactivated influenza vaccines (IIV). Similar comparisons have not been made between LAIV4 and the 4-strain, cell-culture inactivated influenza vaccine (ccIIV4). We compared healthy children’s and young adults’ HAI titers against the 2019–2020 LAIV4 and ccIIV4.MethodsParticipants aged 4–21 years were randomized 1:1 to receive ccIIV4 (n = 100) or LAIV4 (n = 98). Blood was drawn prevaccination and on day 28 (21–35) post vaccination. HAI assays against egg-grown A/H1N1, A/H3N2, both vaccine B strains and cell-grown A/H3N2 antigens were conducted. Primary outcomes were geometric mean titers (GMT) and geometric mean fold rise (GMFR) in titers.ResultsGMTs to A/H1N1, A/H3N2 and B/Victoria increased following both ccIIV and LAIV and to B/Yamagata following ccIIV (p < 0.05). The GMFR range was 2.4–3.0 times higher for ccIIV4 than for LAIV4 (p < 0.001). Within vaccine types, egg-grown A/H3N2 GMTs were higher (p < 0.05) than cell-grown GMTs [ccIIV4 day 28: egg = 205 (95% CI: 178–237); cell = 136 (95% CI:113–165); LAIV4 day 28: egg = 96 (95% CI: 83–112); cell = 63 (95% CI: 58–74)]. The GMFR to A/H3N2 cell-grown and egg-grown antigens were similar. Pre-vaccination titers inversely predicted GMFR.ConclusionThe HAI response to ccIIV4 was greater than LAIV4 in this study of mostly older children, and day 0 HAI titers inversely predicted GMFR for both vaccines. Lower prevaccination titers were associated with greater GMFR in both vaccine groups.     

Trivalent inactivated influenza vaccine (IIV3) during pregnancy and six-month infant development

ObjectiveDespite recommendations by professional organizations that all pregnant women receive inactivated influenza vaccine, safety concerns remain a barrier. Our objective was to assess the effect of trivalent influenza vaccines (IIV3) during pregnancy on parent report 6-month infant development.MethodsWe conducted a multi-site prospective birth cohort study during the 2010–2011 influenza season and followed pregnant women and their newborns through 6 months of age. Information on IIV3 during pregnancy was ascertained from the EHR and self-report. The Ages and Stages Questionnaire-3 (ASQ-3) was completed by the mother to assess 6-month infant neurodevelopment in five domains (communication, gross motor, fine motor, problem-solving, and personal adaptive skills). Scores for each domain above the cut-off point indicating typical development were categorized as “on schedule” while scores in the zones indicating the need for either monitoring or further assessment were categorized as “not on schedule”. Multivariable logistic regression was conducted.ResultsOf the 1225 infant-mother pairs, 65% received IIV3 during pregnancy. In bivariate analysis, infants of women who received IIV3 during pregnancy were moderately-less likely to need monitoring or further assessment in the personal social domain compared with infants of unvaccinated women (10.0% vs. 14.1%, p = 0.033; crude OR (cOR): 0.68(95%CI:0.48,0.97)). However, after controlling for potential confounders, the findings were no longer statistically significant (aOR:0.72,95%CI: 0.49,1.06,p = 0.46). No significant unadjusted or adjusted associations emerged in any other ASQ-3 domain.ConclusionThere was no significant association between IIV3 exposure during pregnancy and 6-month infant development. Studies of IIV3 during pregnancy to assess longer-term developmental outcomes are indicated.     

MAS-1, a novel water-in-oil adjuvant/delivery system,with reduced seasonal influenza vaccine hemagglutinin dose may enhance potency,durability and cross-reactivity of antibody responses in the elderly

BackgroundIncreased influenza vaccine efficacy is needed in the elderly at high-risk for morbidity and mortality due to influenza infection. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets.MethodsA phase 1, randomized, double-blind, safety and immunogenicity, adjuvant dose escalation trial was conducted in persons aged 65 years and older. MAS-1 adjuvant dose volumes at 0.3 mL or 0.5 mL containing 9 µg per HA derived from licensed seasonal trivalent influenza vaccine (IIV, Fluzone HD 60 µg per HA, Sanofi Pasteur) were compared to high dose (HD) IIV (Fluzone HD). Safety was measured by reactogenicity, adverse events, and safety laboratory measures. Immunogenicity was assessed by serum hemagglutination inhibition (HAI) antibody titers.ResultsForty-five subjects, aged 65–83 years, were randomly assigned to receive 9 µg per HA in 0.3 mL MAS-1 (15 subjects) or HD IIV (15 subjects) followed by groups randomly assigned to receive 9 µg per HA in 0.5 mL MAS-1 (10 subjects) or HD IIV (5 subjects). Injection site tenderness, induration, and pain, and headache, myalgia, malaise and fatigue were common, resolving before day 14 post-vaccination. Clinically significant late-onset injection site reactions occurred in four of ten subjects at the 0.5 mL adjuvant dose. Safety laboratory measures were within acceptable limits. MAS-1-adjuvanted IIV enhanced mean antibody titers, mean-fold increases in antibody titer, and seroconversion rates against vaccine strains for at least 168 days post-vaccination and enhanced cross-reactive antibodies against some non-study vaccine influenza viruses.ConclusionMAS-1 adjuvant provided HA dose-sparing without safety concerns at the 0.3 mL dose, but the 0.5 mL dose caused late injection site reactions. MAS-1-adjuvanted IIV induced higher HAI antibody responses with prolonged durability including against historical strains, thereby providing greater potential vaccine efficacy in the elderly throughout an influenza season.Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.     

A phase 1 dose-sparing,randomized clinical trial of seasonal trivalent inactivated influenza vaccine combined with MAS-1, a novel water-in-oil adjuvant/delivery system

BackgroundNew influenza vaccines are needed to increase vaccine efficacy. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational low viscosity, free-flowing, water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets.MethodsA phase 1, double-blind, safety and immunogenicity, HA dose escalation, randomized clinical trial was conducted. MAS-1 adjuvant with 1, 3, 5 or 9 µg per HA derived from licensed seasonal trivalent high dose inactivated influenza vaccine (IIV, Fluzone HD 60 µg per HA) in a 0.3 mL dose were compared to standard dose IIV (Fluzone SD, 15 µg per HA). Safety was measured by reactogenicity, adverse events, and clinical laboratory tests. Serum hemagglutination inhibition (HAI) antibody titers were measured for immunogenicity.ResultsSeventy-two subjects, aged 18–47 years, received one dose of either 0.3 mL adjuvanted vaccine or SD IIV intramuscularly. Common injection site and systemic reactions post-vaccination were mild tenderness, induration, pain, headache, myalgia, malaise and fatigue. All reactions resolved within 14 days post-vaccination. Safety laboratory measures were not different between groups. Geometric mean antibody titers, geometric mean fold increases in antibody titer, seroconversion rates and seroprotection rates against vaccine strains were in general higher and of longer duration (day 85 and 169 visits) with MAS-1-adjuvanted IIV at all doses of HA compared with SD IIV. Adjuvanted vaccine induced higher antibody responses against a limited number of non-study vaccine influenza B and A/H3N2 viruses including ones from subsequent years.ConclusionMAS-1 adjuvant in a 0.3 mL dose volume provided HA dose-sparing effects without safety concerns and induced higher HAI antibody and seroconversion responses through at least 6 months, demonstrating potential to provide greater vaccine efficacy throughout an influenza season in younger adults. In summary, MAS-1 may provide enhanced, more durable and broader protective immunity compared with non-adjuvanted SD IIV.Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.     

Serologic response to sequential vaccination with enhanced influenza vaccines: Open label randomized trial among adults aged 65–74 years

BackgroundThe effects of sequential vaccination with enhanced influenza vaccines are poorly understood. We conducted an exploratory open-label study to assess serologic response to sequential vaccination in older adults.Methods160 adults aged 65 through 74 years were randomized (1:1:1) to receive trivalent inactivated standard dose (SD), high-dose (HD), or MF59-adjuvanted (AD) vaccine in 2016/17. In 2017/18, HD and AD recipients received the same vaccine; SD recipients were re-randomized to HD or AD. Hemagglutination inhibition assays were performed using turkey erythrocytes against A/California/7/2009(H1N1)-like and B/Brisbane/60/2008(B/Victoria)-like in both seasons, and A/Michigan/45/2015(H1N1)-like in season 2. Microneutralization assays were performed against cell-propagated A/Hong Kong/4801/2014(H3N2)-like using MDCK-SIAT1 cells. Postvaccination geometric mean titer (GMT), percent with titer ≥ 40, and mean fold rise (MFR, ratio of postvaccination versus prevaccination titer) in season 2 were compared across groups, and ratio of MFR in season 2 versus season 1 was assessed for each strain.ResultsAnalysis included 152 participants (55 HD → HD, 58 AD → AD, 19 SD → HD, and 20 SD → AD). Season 2 postvaccination GMTs and percent with titer ≥ 40 did not differ between HD → HD and AD → AD recipients for vaccine strains examined. However, a higher percent of HD → HD and AD → AD recipients had postvaccination titer ≥ 40 than SD → AD recipients for A/H1N1 (86%-89% versus 60%) and SD → AD and SD → HD recipients for A/H3N2 (83%-87% versus 40%-53%). GMTs were higher in AD → AD versus SD → AD recipients for A/H1N1 (p = .01) and A/H3N2 (p = .002). MFRs in season 2 were low in all groups for A/H3N2 (1.5–2.2) and B/Victoria (1.7–2.3). MFR was lower in season 2 versus 1 for HD → HD and AD → AD recipients for all vaccine strains (1.6–3.7 versus 2.6–6.2).ConclusionsSequential vaccination with enhanced vaccines did not reduce immunogenicity in adults aged 65 through 74 years. Serologic response to cell-propagated A/H3N2 was suboptimal for all vaccines.ClinicalTrials.gov identifier. NCT02872311     

Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac) co-administered with an inactivated quadrivalent influenza vaccine: A randomized,open-label,controlled study in healthy adults aged 18 to 59 years in China

BackgroundStudies are needed for evidence of inactivated COVID-19 vaccine co-administered with influenza vaccine.MethodsA randomized, open-label, controlled study was conducted in Zhejiang Province, China. Eligible healthy adults aged 18–59 years underwent randomization at a ratio of 1:1:2 to receive inactivated quadrivalent influenza vaccine (IIV4) either concomitantly with the first (C1 subgroup) or the second (C2 subgroup) dose of CoronaVac, or 14 days after the first dose of CoronaVac (S group). The primary purpose of the study was to prove the non-inferiority in seroconversion rate of antibody against SARS-CoV-2.ResultsOverall, 480 participants were enrolled, with 120, 120, and 240 randomly assigned to the C1, C2, and S groups, respectively. As lower bound of the two-sided 95% confidence interval (CI) of the difference for the seroconversion rate of antibodies against SARS-CoV-2 was over ?10%, the immune response for CoronaVac in the C group (93.1% [89.0, 96.0]) was non-inferior to that in the S group (95.2% [91.5, 97.6]) in the per-protocol set. A lower GMT of antibody against SARS-CoV-2 was observed in the C group as compared to the S group (27.5 vs. 38.1, P = 0.0001). Decrease of immune response to CoronaVac was mainly observed in participants received IIV4 concomitantly with their second dose of CoronaVac (C2 subgroup), with a seroconversion rate of 89.7% (95CI: 82.6%-94.5%) and a GMT of 23.3. The occurrences of vaccine related adverse reactions were no more than 20% and comparable among different groups. Most of the adverse reactions were mild and moderate.ConclusionCo-administration of inactivated COVID-19 vaccine and seasonal influenza vaccine, especially the administration regimen that the seasonal influenza vaccine co-administered with the first dose of the inactivated COVID-19 vaccine, would be feasible.     

Body mass index and vaccine responses following influenza vaccination during pregnancy

Background and AimsInfluenza vaccination is recommended by the World Health Organisation for pregnant women, offering the dual benefit of protecting pregnant women and their newborn infants against influenza infection. Various factors can influence vaccine immunogenicity, with obesity being one factor implicated in varied responses. This study aimed to investigate the impact of body mass index (BMI) on vaccine responses following influenza vaccination during pregnancy.MethodsPregnant women attending the Women’s and Children’s Hospital in South Australia during 2014–2016 were invited to participate. Participant’s clinical and demographic factors were recorded prior to administration of licensed seasonal influenza vaccination. Blood samples were collected before and one month post-vaccination to measure antibody responses by haemagglutination inhibition (HI) assay. Seroprotection was defined as a post-vaccination HI titre ≥ 1:40. Regression models assessed associations with failure to achieve seroprotective antibodies to H1, H3, and B influenza strains.ResultsA total of 96 women were enrolled in the study at a median gestation of 22 weeks with a BMI range of 18–49 kg/m². Paired sera samples were available for 90/96 (94%). Most pregnant women (72/90, 80%) demonstrated seroprotective antibody titres to all three influenza vaccine antigens (A(H1N1)pdm09, A(H3N2), B/Yamagata) following vaccination. Compared with women with BMI < 30 kg/m², those with high BMI were less likely to fail to achieve seroprotective antibodies, however this was not statistically significant (RR 0.42, 95% CI 0.11–1.68; p = 0.22). A greater proportion of women vaccinated during their second (47/53, 93%) or third trimester (18/25, 72%) demonstrated seroprotection to all three vaccine antigens following vaccination compared with women vaccinated during their first trimester (7/12, 58%).ConclusionHigh BMI did not impair seroprotection levels following influenza vaccination in pregnant women. Gestation at vaccination may be an important consideration for optimising vaccine protection for pregnant women and their newborns. Further assessment of first trimester influenza vaccine responses is warranted.     

Safety and immunogenicity of Multimeric-001 (M-001) followed by seasonal quadrivalent inactivated influenza vaccine in young adults – A randomized clinical trial

BackgroundThe continuing evolution of influenza viruses poses a challenge to vaccine prevention, highlighting the need for a universal influenza vaccine. We evaluated the safety and immunogenicity of one such candidate, Multimeric-001 (M-001), when used as a priming vaccine prior to administration of quadrivalent inactivated influenza vaccine (IIV4).MethodsHealthy adults 18 to 49 years of age were enrolled in a phase 2 randomized, double-blind placebo-controlled trial. Participants received two doses of either 1.0-mg M-001 or saline placebo (60 per study arm) on Days 1 and 22 followed by a single dose of IIV4 on about Day 172. Safety, reactogenicity, cellular immune responses and influenza hemagglutination inhibition (HAI) and microneutralization (MN) were assessed.ResultsThe M-001 vaccine was safe and had an acceptable reactogenicity profile. Injection site tenderness (39% post-dose 1, 29% post-dose 2) was the most common reaction after M-001 administration. Polyfunctional CD4+ T cell responses (perforin-negative, CD107α-negative, TNF-α+, IFN-γ+, with or without IL-2) to the pool of M-001 peptides increased significantly from baseline to two weeks after the second dose of M-001, and this increase persisted through Day 172. However, there was no enhancement of HAI or MN antibody responses among M-001 recipients following IIV4 administration.ConclusionsM-001 administration induced a subset of polyfunctional CD4+ T cells that persisted through 6 months of follow-up, but it did not improve HAI or MN antibody responses to IIV4. (clinicaltrials.gov NCT03058692).     

Motivational interviewing and vaccine acceptance in children: The MOTIVE study

Background and ObjectiveVaccine coverage have been less than desired in young children in part due to parental vaccine hesitancy. Addressing health beliefs through patient-centered communication approaches such as motivational interviewing (MI) may improve vaccine confidence. Thus, the objective of this study was to determine the difference in paediatric vaccination coverage rates based on the Advisory Committee on Immunization Practices (ACIP) and Centers for Disease Control and Prevention (CDC) recommended schedule in children 0–6 years of age after an educational intervention for providers and integration of an MI-based communication tool, MOTIVE (MOtivational Interviewing Tool to Improve Vaccine AcceptancE).MethodsPaediatric and family practice providers in a federally qualified health center in the United States completed an educational intervention regarding vaccine hesitancy and use of the MOTIVE tool. Providers then implemented the MOTIVE tool to address common health beliefs using strong, presumptive vaccine recommendations and an MI framework during encounters with patients 0–6 years of age. Data were collected from 1-year pre-educational intervention (July 2018-June 2019, N = 2504) and post-intervention (July 2019-March 2020, N = 1954) to examine differences in vaccination coverage rates and documented vaccine refusals.ResultsUse of the MOTIVE tool was associated with a statistically significant increase in IIV vaccination coverage rate in children 6 months to 6 years of age (32.4% versus 43.9%, p < 0.01). A significantly increased Hib vaccination coverage rate was observed in children 0–18 months of age. Patients with commercial insurance also had significantly higher vaccination coverage rates for the DTaP, IPV, and VAR vaccines during the intervention period. Use of the MOTIVE tool was associated with a decrease in documented vaccine refusals per 100 patients in children 0–6 years of age (31.5 versus 17.6, p < 0.01).ConclusionUse of an MI-based communication tool may decrease vaccine refusals and improve childhood vaccination coverage rates, particularly for IIV.Clinical Trial Registration: ClinicalTrials.gov, NCT03934008, https://clinicaltrials.gov/ct2/show/NCT03934008, deidentified individual participant data will not be made available.     

Comparison of immunogenicity between candidate influenza A(H3N2) virus vaccine strains in Japan: A randomized controlled trial using a monovalent vaccine of A/Saitama/103/2014 (CEXP-002) and A/Hong Kong/4801/2014 (X-263)

BackgroundFor the 2017–18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain.MethodsA randomized controlled trial of 100 healthy adults aged 20–64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017).ResultsFor the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients.ConclusionThe Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population.Clinical trial registration: UMIN000029293.     

A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent influenza vaccines among older adults in the United States during the 2018–19 influenza season

PurposeTo evaluate the relative vaccine effectiveness (rVE) against influenza-related hospitalizations/emergency room (ER) visits, influenza-related office visits, and cardio-respiratory disease (CRD)-related hospitalizations/ER visits and compare all-cause and influenza-related costs associated with two vaccines specifically indicated for older adults (≥65 years), adjuvanted (aTIV) and high-dose trivalent influenza vaccine (TIV-HD), for the 2018–19 influenza season.MethodsA retrospective analysis of older adults was conducted using claims and hospital data in the United States. For clinical evaluations, adjusted analyses were conducted following inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted rVE against influenza-related hospitalizations/ER visits, influenza-related office visits, and any CRD-related hospitalizations/ER visits. For the economic evaluation, treatment selection bias was adjusted through 1:1 propensity score matching (PSM). All-cause and influenza-related costs associated with hospitalizations/ER, physician office and pharmacy visits were adjusted using generalized estimating equation (GEE) models.ResultsAfter IPTW and Poisson regression, aTIV (n = 561,315) was slightly more effective in reducing influenza-related office visits compared to TIV-HD (n = 1,672,779) (6.6%; 95% CI: 2.8–10.3%). aTIV was statistically comparable to TIV-HD (2.0%; 95% CI: −3.7%-7.3%) in preventing influenza-related hospitalizations/ER visits but more effective in reducing hospitalizations/ER visits for any CRD (2.6%; 95% CI: 2.0–3.2%). In the PSM-adjusted cohorts (n = 561,243 pairs), following GEE adjustments, predicted mean annualized all-cause and influenza-related total costs per patient were statistically similar between aTIV and TIV-HD (US$9676 vs. US$9625 and US$18.74 vs. US$17.28, respectively; both p > 0.05). Finally, influenza-related pharmacy costs were slightly lower for aTIV as compared to TIV-HD ($1.75 vs $1.85; p < 0.0001).ConclusionsDuring the 2018–19 influenza season, influenza-related hospitalization/ER visits and associated costs among people aged ≥ 65 were comparable between aTIV and TIV-HD. aTIV was slightly more effective in preventing influenza-related office visits and any CRD event as compared to TIV-HD in this population.     

Safety of meningococcal B vaccine (4CMenB) in adolescents in Australia

BackgroundFour-component meningococcal B (4CMenB) vaccine is licensed in many countries but has had limited use in adolescents despite this age group being at increased risk of meningococcal disease.ObjectivesTo assess the safety profile of two doses of 4CMenB in adolescents.MethodsCluster randomised controlled trial of senior school students in South Australia (SA) with participating schools randomised to intervention (4CMenB) or control. Vaccine safety was monitored using the South Australian Vaccine Safety Surveillance System (SAVSS), a spontaneous reporting system for adverse events following immunisation (AEFI) with enhanced follow-up of AEFI.Results58,637 doses of 4CMenB vaccine were administered to 30,522 students (median age 16 years) during 2017–2018. Of 18,348 and 12,174 students vaccinated in 2017 and 2018, 97.3% and 84.3%, respectively, received both scheduled doses (N = 28,115). 193 AEFI in 187 students were reported with a reporting rate of 0.32% (95%CI: 0.28–0.39%). Seventy individuals sought medical review, including nine serious adverse events. 98% (166/169) of those who were contactable for AEFI follow-up (87.6% 169/193) reported resolution of the event. Most common AEFI were injection site reaction (126/193), headache (99/193) and nausea (61/193). AEFI were more frequently reported in females (aOR = 1.409 (95%CI: 1.002, 1.980)), schools with high level of educational advantage (adjusted Odds Ratio (aOR) = 1.515 (95%CI: 1.005, 2.284)), following first dose (aOR = 1.619 (95%CI: 1.168, 2.244)), and in 2017 (aOR = 1.437 (95%CI: 1.001, 2.064)). Reported AEFI declined with increasing age (aOR = 0.771 (95%CI: 0.673, 0.883)).ConclusionIn this largest post-licensure use of 4CMenB in adolescents, the low AEFI reporting rate provides real-world evidence of 4CMenB safety in this age group.(ClinicalTrials.gov number: NCT03089086).     

A systematic review and meta-analysis of the effectiveness of LAIV4 and IIV in children aged 6 months to 17 years during the 2016–2017 season

As the real-world effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) and inactivated influenza vaccine (IIV) has varied in recent seasons, a systematic review and meta-analysis was conducted to more precisely estimate effectiveness in the 2016–2017 season. Relevant studies were identified from a systematic review of published literature and personal communication with study investigators. Five studies conducted in Canada, Finland, Germany, the United Kingdom, and the United States were identified for inclusion. Data were analyzed using a random effects model, with heterogeneity testing and a sensitivity analysis restricted to test-negative case–control studies. Consolidated vaccine effectiveness estimates against all strains were 69% (95% CI: 46 to 82) for LAIV4 and 47% (95% CI: 29 to 61) for IIV. Heterogeneity testing was not statistically significant, indicating consistency of individual study results. In conclusion, LAIV4 and IIV showed moderate and comparable effectiveness against influenza in children during the 2016–2017 influenza season.     

A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial

BackgroundAn investigational vaccine containing non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) surface proteins did not show vaccine efficacy (VE) against combined moderate and severe (moderate/severe) exacerbations in a randomised, observer-blinded, placebo-controlled phase 2b trial of patients with chronic obstructive pulmonary disease (COPD). Nevertheless, observations on rates of severe exacerbations and hospitalisations encouraged further evaluation.MethodsPatients with stable COPD (moderate to very severe airflow limitation, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2–4), 40–80 years and at least one moderate/severe exacerbation in the last year received two doses of NTHi-Mcat vaccine or placebo plus standard care. Secondary analyses were conducted on VE against exacerbations according to severity. Potential predictive factors at baseline for VE against severe exacerbations were explored in post-hoc analyses.ResultsOf 606 patients enrolled, 571 were included in the efficacy analysis (279 in NTHi-Mcat vaccine group, 292 in placebo group). VE against severe acute exacerbations of COPD (AECOPD) in various subgroups was 52.11 % (p = 0.015; frequent exacerbators), 65.43 % (p = 0.015; baseline GOLD grade 4), 38.24 % (p = 0.034; previous pneumococcal and/or influenza vaccination). VE was 52.49 % (p = 0.044) for the 6–12 months period after 1 month post-dose 2. Multivariable analysis identified two factors (frequent exacerbator status plus inhaled corticosteroid use at baseline) associated with significant VE against severe AECOPD; in this subpopulation, VE was 74.99 % (p < 0.001).ConclusionResults suggest potential efficacy with the NTHi-Mcat vaccine against severe exacerbations in certain patients with COPD, in particular those who have frequent exacerbations and use inhaled corticosteroids. This potential signal requires confirmation in an appropriately designed prospective clinical trial.Trial registrationClinicalTrials.gov, NCT03281876.     

The impact of immunomodulating treatment on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases compared to healthy controls. A Swedish nationwide study (COVID19-REUMA)

ObjectivesTo elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying anti-rheumatic drugs (b/ts DMARDs).MethodsAntibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2–12 weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or ≥ 4-fold increase in antibodies in individuals seropositive for both spike proteins.ResultsPatients (n = 414) receiving b/ts DMARDs (283 had arthritis, 75 systemic vasculitis and 56 other autoimmune diseases) and controls (n = 61) from five Swedish regions participated. Treatments groups were: rituximab (n = 145); abatacept (n = 22); Interleukin 6 receptor inhibitors [IL6i (n = 79)]; JAnus Kinase Inhibitors [JAKi (n = 58)], Tumour Necrosis Factor inhibitor [TNFi (n = 68)] and Interleukin12/23/17 inhibitors [IL12/23/17i (n = 42)]. Percentage of patients with positive antibody response after two doses was significantly lower in rituximab (33,8%) and abatacept (40,9%) (p < 0,001) but not in IL12/23/17i, TNFi or JAKi groups compared to controls (80,3%). Higher age, rituximab treatment and shorter time between last rituximab course and vaccination predicted impaired antibody response. Antibody levels collected 21–40 weeks after second dose decreased significantly (IL6i: p = 0,02; other groups: p < 0,001) compared to levels at 2–12 week but most participants remained seropositive. Proportion of patients with positive antibody response increased after third dose but was still significantly lower in rituximab (p < 0,001).ConclusionsOlder individuals and patients on maintenance rituximab have an impaired response after two doses of COVID-19 vaccine which improves if the time between last rituximab course and vaccination extends and also after an additional vaccine dose. Rituximab patients should be prioritized for booster vaccine doses. TNFi, JAKi and IL12/23/17i does not diminished humoral response to primary and an additional vaccination.     

Immunogenicity and reactogenicity after booster dose with AZD1222 via intradermal route among adult who had received CoronaVac

BackgroundCurrently, booster dose is needed after 2 doses of non-live COVID-19 vaccine. With limited resources and shortage of COVID-19 vaccines, intradermal(ID) administration might be a potential dose-sparing strategy.ObjectiveTo determine immunologic response and reactogenicity of ID ChAdOx1 nCoV-19 vaccine (AZD1222,Oxford/AstraZeneca) as a booster dose after completion of 2-dose CoronaVac(SV) in healthy adult.MethodsThis is a prospective cohort study of adult aged 18–59 years who received 2-dose SV at 14–35 days apart for more than 2 months. Participants received ID AZD1222 at fractional low dose(1×10¹⁰ viral particles,0.1 ml). Antibody responses were evaluated by surrogate virus neutralization test(sVNT) against delta variant and wild type, and anti-spike-receptor-binding-domain immunoglobulin G(anti-S-RBD IgG) at prior, day14, 28, 90, and 180 post booster. Solicited reactogenicity was collected for 7 days post-booster. Primary endpoint was the differences of sVNT against delta strain ≥ 80% inhibition at day14 and 90 compared with the parallel cohort study of 0.5-ml intramuscular(IM) route.ResultsFrom August2021, 100 adults with median age of 46 years(IQR 41–52) participated. Prior to booster, geometric mean(GM) of sVNT against delta strain was 22.4% inhibition(95 %CI 18.7–26.9) and of anti-S-RBD IgG was 109.3 BAU/ml(95.4–125.1). Post ID booster, GMs of sVNT against delta strain were 95.5% inhibition (95%CI 94.2–96.8) at day14, 73.1% inhibition (66.7–80.2) at day90, and 22.7% inhibition (14.9–34.6) at day180. The differences of proportion of participants achieving sVNT against delta strain ≥ 80% inhibition in ID recipients versus IM were + 4.2% (95 %CI -2.0to10.5) at day14, and ?37.3%(-54.2to-20.3) at day90. Anti-S-RBD IgG GMs were 2037.1 BAU/ml (95%CI 1770.9–2343.2) at day14 and 744.6 BAU/ml(650.1–852.9) at day90, respectively. Geometric mean ratios(GMRs) of anti-S-RBD IgG were 0.99(0.83–1.20) at day14, and 0.82(0.66–1.02) at day90. Only 18% reported feverish, compared with 37% of IM (p = 0.003). Common reactogenicity was erythema at injection site(53%) while 7% reported blister.ConclusionLow-dose ID AZD1222 booster enhanced lower neutralizing antibodies at 3 months compared with IM route. Less systemic reactogenicity occurred, but higher local reactogenicity.     

Survey of influenza vaccine knowledge,attitudes, and beliefs among pregnant women in the 2016–17 season

ObjectivesInfluenza vaccination coverage among pregnant women in the United States is suboptimal. We surveyed women who were pregnant during the 2016–17 influenza season to assess knowledge and attitudes regarding influenza vaccination.MethodsWe identified and sampled pregnant women to include approximately equal numbers of vaccinated and unvaccinated women from strata defined by vaccination status and trimester from four integrated health systems in the Vaccine Safety Datalink (VSD). Potential participants were contacted via mail and telephone to complete a standardized survey. Characteristics and responses of women vaccinated and unvaccinated during pregnancy were compared.ResultsThe survey was completed by 510 (48%) of 1062 contacted women; 500 were included in the analysis. Vaccine receipt while pregnant was associated with primigravida status (p = 0.02), college degree (p = 0.01), employment in health care (p < 0.01), and history of routine annual influenza vaccination (p < 0.01). Among 330 vaccinated women, the primary reasons for vaccination included protection of self and baby from influenza (n = 233, 71%), and medical professional recommendation (n = 46, 14%). Multiple reasons were given for nonvaccination, but concern about ‘negative effects’ was cited most often (n = 44, 29%). Vaccinated women were significantly more likely to believe that influenza vaccines are safe and effective, and to recognize the potential for harm from influenza infection. Nearly all women reported receiving at least one influenza vaccination recommendation from a healthcare provider.ConclusionsVaccinated pregnant women were more likely to receive routine annual influenza vaccine compared to those not vaccinated. Recommendations by obstetric providers should be supplemented with efforts to encourage women of childbearing age to receive annual vaccination.