MF59-adjuvanted Trivalent Influenza Vaccine Research Articles

Relative Effectiveness of the MF59®-Adjuvanted Influenza Vaccine Versus High-Dose and Non-Adjuvanted Influenza Vaccines in Preventing Cardiorespiratory Hospitalizations During the 2019-2020 US Influenza Season.

Adults ≥ 65 years of age have suboptimal influenza vaccination responses compared to younger adults due to age-related immunosenescence. Two vaccines were specifically developed to enhance protection: MF59-adjuvanted trivalent influenza vaccine (aIIV3) and high-dose egg-based trivalent influenza vaccine (HD-IIV3e). In a retrospective cohort study conducted using US electronic medical records linked to claims data during the 2019-2020 influenza season, we compared the relative vaccine effectiveness (rVE) of aIIV3 with HD-IIV3e and a standard-dose non-adjuvanted egg-based quadrivalent inactivated influenza vaccine (IIV4e) for the prevention of cardiorespiratory hospitalizations, including influenza hospitalizations. We evaluated outcomes in the "any" diagnosis position and the "admitting" position on the claim. A doubly robust methodology using inverse probability of treatment weighting and logistic regression was used to adjust for covariate imbalance. rVE was calculated as 100 * (1 - ORadjusted). The study included 4,299,594 adults ≥ 65 years of age who received aIIV3, HD-IIV3e, or IIV4e. Overall, aIIV3 was associated with lower proportions of cardiorespiratory hospitalizations with diagnoses in any position compared to HD-IIV3e (rVE = 3.9% [95% CI, 2.7-5.0]) or IIV4e (9.0% [95% CI, 7.7-10.4]). Specifically, aIIV3 was more effective compared with HD-IIV3e and IIV4e in preventing influenza hospitalizations (HD-IIV3e: 9.7% [95% CI, 1.9-17.0]; IIV4e: 25.3% [95% CI, 17.7-32.2]). Consistent trends were observed for admitting diagnoses. Relative to both HD-IIV3e and IIV4e, aIIV3 provided improved protection from cardiorespiratory or influenza hospitalizations.

Adjuvant-attenuated symptom severity of influenza infections in vaccinated children

BackgroundYoung children are at high risk for developing complications of influenza, as well as severe clinical presentation of disease. Vaccination provides direct protection and reduces symptom severity in breakthrough infections. We assessed whether adjuvanted trivalent seasonal influenza vaccine is associated with symptom severity in children who developed laboratory-confirmed influenza, as compared to children who received quadrivalent inactivated influenza. MethodsA cluster randomized controlled trial of influenza vaccines in Canadian Hutterite colonies was conducted from the 2016–2017 to the 2018–2019 influenza season. Children were vaccinated with either quadrivalent inactivated influenza vaccine (QIV), or the MF59 adjuvanted trivalent influenza vaccine (aTIV). We assessed children who developed PCR-confirmed influenza infection for symptom severity outcomes using multivariable generalized negative binomial regression. ResultsAmong vaccinated children, 49 infections were observed across 1779 person-days. Vaccine formulation (aTIV vs QIV) was not significantly associated with composite symptom outcomes, including total number of symptoms or total duration of symptom presentation (p > 0.05 for all outcomes). Receipt of aTIV vaccination was significantly associated with attenuation of fever, with an estimated 74% reduction in fever severity. In influenza A type infections, adjuvanted vaccination was significantly associated with reduced systemic symptoms (incidence rate ratios: 0.16, 95% confidence intervals: 0.03, 0.64, p = 0.01). No associations were observed between vaccine formulation and symptom severity in influenza B infections. ConclusionsIn vaccinated children who develop an influenza infection, vaccine formulation was associated with attenuated fever severity, leading to reduced systemic symptoms. In influenza A infections, adjuvanted vaccination was significantly associated with reduced systemic symptoms. ConclusionsClinical Trials Registry: NCT02871206

Relative Effectiveness of MF59 Adjuvanted Trivalent Influenza Vaccine vs Nonadjuvanted Vaccines During the 2019-2020 Influenza Season.

BackgroundAge-related immunosenescence may impair the immune response to vaccination in older adults. Adjuvanted influenza vaccines are designed to overcome immune senescence in older adults. This study estimated the relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) vs egg-derived quadrivalent inactivated influenza vaccine (IIV4e) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) in preventing influenza-related medical encounters in the 2019–2020 US season.MethodsThis retrospective cohort study used electronic medical records linked to pharmacy and medical claims data. The study population included adults age ≥65 years with a record of aIIV3, IIV4e, or HD-IIV3 vaccination. A doubly robust inverse probability of treatment weighting model was used to derive adjusted odds ratios (ORs). rVE was calculated by (1 – ORadjusted)*100 and was determined overall and separately for age subgroups. An exploratory analysis evaluated the outcome separately in inpatient and outpatient settings.ResultsSubjects received aIIV3 (n = 936 508), IIV3e (n = 651 034), and HD-IIV3 (n = 1 813 819), and influenza-related medical encounters were recorded in 0.5%, 0.9%, and 0.7% of each cohort, respectively. Overall, the rVE of aIIV3 was 27.5% (95% CI, 24.4% to 30.5%) vs IIV4e and 13.9% (95% CI, 10.7% to 17.0%) vs HD-IIV3. aIIV3 had a more favorable rVE in inpatient and outpatient settings. Findings remained consistent across age subgroups and during alternative seasonal dates.ConclusionsAdults age ≥65 years vaccinated with aIIV3 had fewer influenza-related medical encounters compared with IIV4e or HD-IIV3 during the 2019–2020 US influenza season.

Relative Effectiveness of Adjuvanted Trivalent Inactivated Influenza Vaccine Versus Egg-derived Quadrivalent Inactivated Influenza Vaccines and High-dose Trivalent Influenza Vaccine in Preventing Influenza-related Medical Encounters in US Adults ≥ 65 Years During the 2017–2018 and 2018–2019 Influenza Seasons

BackgroundThe effectiveness of standard, egg-derived quadrivalent influenza vaccines (IIV4) may be reduced in adults ≥65 years of age, largely because of immunosenescence. An MF59-adjuvanted trivalent influenza vaccine (aIIV3) and a high-dose trivalent influenza vaccine (HD-IIV3) offer older adults enhanced protection versus standard vaccines. This study compared the relative effectiveness of aIIV3 with IIV4 and HD-IIV3 in preventing influenza-related medical encounters over 2 US influenza seasons.MethodsThis retrospective cohort study included US patients ≥65 years vaccinated with aIIV3, IIV4, or HD-IIV3. The outcome of interest was the occurrence of influenza-related medical encounters. Data were derived from a large dataset comprising primary and specialty care electronic medical records linked with pharmacy and medical claims. Adjusted odds ratios (OR) were derived from an inverse probability of treatment-weighted sample adjusted for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was determined using the formula (% VE = 1 – ORadjusted) × 100.ResultsIn 2017–2018, cohorts included: aIIV3, n = 524 223; IIV4, n = 917 609; and HD-IIV3, n = 3 377 860. After adjustment, 2017–2018 rVE of aIIV3 versus IIV4 was 18.2 (95% confidence interval [CI], 15.8–20.5); aIIV3 vs. HD-IIV3 was 7.7 (95% CI, 2.3–12.8). In 2018–2019, cohorts included: aIIV3, n = 1 031 145; IIV4, n = 915 380; HD-IIV3, n = 3 809 601, with adjusted rVEs of aIIV3 versus IIV4 of 27.8 (95% CI, 25.7–29.9) and vs. HD-IIV3 of 6.9 (95% CI, 3.1–10.6).ConclusionIn the 2017–2018 and 2018–2019 influenza seasons in the United States, aIIV3 demonstrated greater reduction in influenza-related medical encounters than IIV4 and HD-IIV3 in adults ≥65 years.

Cost-effectiveness of introducing an MF59-adjuvanted trivalent influenza vaccine for older adults in Argentina

IntroductionInfluenza surveillance in Argentina reported influenza-like illness at a rate of 3500/100,000, a hospitalization rate of 15.5/100,000, and a death rate of 0.32/100,000 annually in adults aged over 65 years. The high burden of disease may be due to a combination of immunosenescence and the suboptimal clinical effectiveness of conventional, non-adjuvanted influenza vaccines in this age group. There is a clinical need for more effective influenza vaccines in this population. This study evaluated the cost-effectiveness of an MF59®-adjuvanted trivalent influenza vaccine (aTIV) in adults aged over 65 years in Argentina compared with the non-adjuvanted trivalent influenza vaccine (TIV) used under the current national vaccination policy. MethodsA decision tree cost-effectiveness model was developed to estimate the cost-effectiveness of switching from TIV to aTIV in Argentinian older adults. The model compared cost and health benefits of vaccination in one influenza season from the payer perspective. The main predictions included survival, quality-adjusted survival, and costs. Model inputs were sourced from Argentina or internationally where local data was considered inaccurate. Vaccine efficacy assumptions were extracted from recently published, peer-reviewed scientific literature. ResultsSwitching from TIV to aTIV would result in 170 deaths averted and 1310 incremental quality-adjusted life years (QALYs) gained. The incremental cost-effectiveness ratio per QALY was US $2660.59 from the payer perspective. In all sensitivity analyses, aTIV remained highly cost-effective. The probabilistic sensitivity analyses showed a 95% CI per QALY of US $113.74–7721.67. ConclusionIntroducing an adjuvanted influenza vaccine in Argentina is potentially beneficial and cost-effective relative to the currently-used TIV through the reduction of disease burden and utilization of healthcare resources.

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

Adjuvanted versus nonadjuvanted influenza vaccines and risk of hospitalizations for pneumonia and cerebro/cardiovascular events in the elderly

ABSTRACTBackground: The higher effectiveness of MF59®-adjuvanted trivalent influenza vaccine (MF59-TIV) vs. nonadjuvanted TIV in preventing influenza-related hospitalizations was found considering few influenza seasons, local and heterogeneous settings. This study evaluated the relative vaccine effectiveness (rVE) of MF59-TIV vs. nonadjuvanted TIV on the risk of hospitalization for pneumonia and cerebro/cardiovascular events across 15 consecutive influenza seasons.Research design and methods: Using Health Search Database, a case–control study was nested in a cohort of elderly vaccinated with MF59-TIV or TIV. Conditional logistic regression was used to estimate the odds ratio with 95% confidence intervals (CI) of hospitalizations potentially related to influenza in patients vaccinated with MF59-TIV or TIV.Results: Of 43,000 patients vaccinated with MF59-TIV (66.2%) and TIV (33.8%) for the first time, 103 cases of hospitalization for pneumonia or cerebro/cardiovascular events (0.11 per 1,000 person-weeks) during 15 influenza seasons were identified. The MF59-TIV was associated with a reduced risk of hospitalizations for pneumonia and cerebro/cardiovascular events vs. TIV [rVE: 39% (95% CI: 4–61%)].Conclusions: In a 15-season cohort of elderly, MF59-TIV seems to reduce the risk of hospitalizations for pneumonia and cerebro/cardiovascular events when compared with nonadjuvanted TIV. Our findings support the recommendation for MF59-TIV in the elderly population.

Cumulative clinical experience with MF59-adjuvanted trivalent seasonal influenza vaccine in young children and adults 65 years of age and older

ObjectiveTo assess the long-term safety of MF59-adjuvanted trivalent influenza vaccine (aIIV3; Fluad™) in adults ≥65 years of age. MethodsData from 36 primary vaccination and 7 re-vaccination Phase I through III trials were analyzed; 7532 subjects received aIIV3 and 5198 subjects a nonadjuvanted trivalent inactivated influenza vaccine (IIV3). These trials were evaluated in 2 data poolings: first-dose randomized controlled trials (FD-RCT) and revaccination trials. Spontaneously reported adverse events (AEs) from post-marketing surveillance were also analyzed. ResultsThe percentages of subjects reporting AEs following vaccination were similar between aIIV3 and IIV3: 24.8% for aIIV3 vs 26.7% for IIV3 (relative risk [RR] 0.94; 95% confidence interval [CI] 0.87–1.01). The percentage of subjects with serious AEs was 6.7% for aIIV3 vs 7.0% for IIV3 (RR 0.95; 95% CI 0.82–1.09). Percentages of subjects with AEs leading to withdrawal, hospitalizations, adverse events of special interest (AESIs), and deaths between vaccination groups were similar. There was no signal of disproportionality for AESIs associated with aIIV3 compared to IIV3 in the post-marketing database. ConclusionsThis integrated safety analysis demonstrates an acceptable safety profile for aIIV3 in adults ≥65 years of age.

Cost-effectiveness of influenza vaccine strategies for the elderly in South Korea.

ObjectivesDespite a high vaccine uptake rate of over 80% in South Korea, the disease burden of influenza is still high among the elderly, which may be due to low effectiveness of vaccines. Therefore, the cost-effectiveness of use among the elderly was analyzed in order to compare the current trivalent influenza vaccine (TIV) with a quadrivalent influenza vaccine (QIV) or MF59-adjuvanted trivalent influenza vaccine (ATIV).MethodsA static lifetime Markov model was used. It was assumed that the model would be repeated until individuals reached the age of 100. Cost-effectiveness was analyzed across three age groups (65–74 years, 75–84 years, and ≥85 years), and the at-risk group was studied.ResultsCompared to the TIV, the QIV was expected to reduce the number of influenza infections by 342,873, complications by 17,011, hospitalizations by 8,568, and deaths by 2,031. The QIV was highly cost-effective when compared to the TIV, with a base case incremental cost-effectiveness ratio (ICER) estimated at USD 17,699/QALY (1USD = 1,151KRW), and the ICER decreased with age and was USD 3,431/QALY in the group aged 85 and above. Sensitivity analysis revealed that the ICER was sensitive to the QIV price, the proportion of influenza B, and vaccine mismatching. On the other hand, the ATIV was expected to reduce the number of influenza cases and complications by 1,812,395 and 89,747, respectively, annually, yielding cost-saving among all ages. ATIV price and vaccine efficacy were the most influential parameters for the ICER of ATIV.ConclusionsThe QIV and ATIV strategies were considered more cost-effective in comparison to the TIV for vaccination strategies implemented for the elderly. However, owing to a lack of data on the effectiveness of ATIV among the elderly, a large-scale effectiveness study is required.

MF59-adjuvanted influenza vaccine (FLUAD®) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone®): A randomized, multicenter, Phase III pediatric trial in Mexico

ABSTRACTThe poor immune response elicited by trivalent influenza vaccines (TIVs) in children can be enhanced by the addition of adjuvants. This observer-blind, randomized Phase III trial assessed the immunogenicity and safety of the MF59-adjuvanted trivalent influenza vaccine FLUAD® (aTIV) and a non-adjuvanted TIV, in healthy children (aged 6 to <72 months) from 3 centers in Mexico, during the 2014–2015 season. The primary objectives were to assess the non-inferiority of aTIV to TIV, measured by geometric mean titers (GMTs), and the safety of aTIV and TIV. Seroconversion was one of several secondary objectives. In total, 287 children were enrolled. The non-inferiority criteria for GMTs and seroconversion were met for aTIV for all 3 vaccine strains. Lower bounds of the 95% confidence intervals for all 3 aTIV:TIV vaccine ratios were >2, showing that the immunogenicity of aTIV was superior to that of TIV for all 3 strains. Solicited adverse events (AEs) were experienced more frequently with aTIV than TIV by younger children (aged 6 to <36 months), but were more frequent with TIV than aTIV in older children (aged 36 to <72 months) who had been vaccinated previously. More unsolicited AEs were associated with aTIV than the TIV. All AEs were of mild or moderate severity. No deaths, serious AEs, or AEs leading to premature withdrawal were reported. Overall, aTIV was highly immunogenic and was well tolerated in healthy children 6 to <72 months of age. These results indicate that aTIV may be a beneficial addition to national pediatric vaccination programs.

Safety of MF59-Adjuvanted Influenza Vaccination in the Elderly: Results of a Comparative Study of MF59-Adjuvanted Vaccine Versus Nonadjuvanted Influenza Vaccine in Northern Italy

MF59-adjuvanted trivalent influenza vaccine (Novartis Vaccines and Diagnostics, Siena, Italy) has been shown to be more effective than nonadjuvanted vaccine in the elderly population. Here we present results from a large-scale, observational, noninterventional, prospective postlicensure study that evaluated the safety of MF59-adjuvanted vaccine in elderly subjects aged 65 years or more. The study was performed in 5 northern Italian health districts during the 2006–2007, 2007–2008, and 2008–2009 influenza seasons. The choice of vaccine—either adjuvanted vaccine or a nonadjuvanted influenza vaccine—was determined by individual providers on the basis of local influenza vaccination policy. Hospitalizations for potential adverse events of special interest (AESIs) were identified from hospital databases and then reviewed against recognized case definitions to identify confirmed cases of AESI. Cumulative incidences were calculated for AESIs in predefined biologically plausible time windows, as well as in a 6-month window following vaccination. During the 3-year study period, 170,988 vaccine doses were administered to a total of 107,661 persons. Despite the large study size, cases of AESI resulting in hospitalization were rare, and risks of AESI were similar in both the MF59-adjuvanted and nonadjuvanted vaccination groups. In conclusion, similar safety profiles were observed for both nonadjuvanted and MF59-adjuvanted seasonal influenza vaccines in elderly recipients.

MF59-adjuvanted and virosomal influenza vaccines for preventing influenza hospitalization in older people: Comparative effectiveness using the Valencia health care information system

BackgroundAdjuvanted influenza vaccines offer greater and broader immunogenicity to older adults than conventional vaccines. Studies assessing the comparative effectiveness of adjuvanted influenza vaccines in this age group are lacking. MethodsWe conducted a retrospective cohort study to estimate the comparative effectiveness of MF59-adjuvanted trivalent influenza vaccine (TIV) and virosomal-TIV for prevention of influenza hospitalization in adults aged ≥65 years. We obtained administrative data on immunization status and influenza hospitalization for the 2010–2011 influenza season. We used Cox regression models to assess comparative effectiveness; crude and adjusted by age, sex, comorbidity, deprivation, type of insurance, and travel time to hospital. We accounted for data clustering at the hospital level by using a multilevel random effects model. ResultsOverall, 373,798 vaccinated subjects were evaluated. There were 40 hospitalizations for influenza among 176,618 subjects, contributing 4,288,109 person–weeks at risk in the virosomal-TIV group, and 37 hospitalizations for influenza among 197,180 subjects, contributing 4,786,360 person–weeks at risk in the MF59-TIV group. The crude hazard ratio (HR) was 0.83 (0.53–1.30), and the adjusted Cox estimated HR of MF59-TIV relative to virosomal-TIV was 0.86 (0.55–1.35). After accounting for data clustering, the HR of influenza hospitalization associated with MF59-TIV relative to virosomal-TIV was 0.94 (0.37–2.38). ConclusionDuring the 2010–2011 influenza season, we found no differences in the risk of influenza hospitalization in subjects aged ≥65 years vaccinated with MF59-TIV compared with those vaccinated with virosomal-TIV.

Immunogenicity and Safety of an MF59®-Adjuvanted and a Non- Adjuvanted Inactivated Subunit Influenza Vaccine in Adults Affected by Chronic Diseases

Background: Influenza is a leading cause of morbidity and mortality in subjects with chronic diseases, who may also exhibit reduced immunogenicity to conventional influenza vaccines. MF59-adjuvanted influenza vaccine may enhance their immune response. Methods: We compared immunogenicity and safety of MF59-Adjuvanted Trivalent Influenza Vaccine (ATIV; Fluad®, Novartis Vaccines) and non-adjuvanted subunit (TIV; Agrippal®, Novartis Vaccines) in adults with at least one moderate to severe chronic condition. In this phase III, randomised, controlled, observer-blind study all subjects (18- 60 years of age) received one dose of ATIV (N=180) or TIV (N=179) vaccine during 2006/07 NH influenza season. Immunogenicity was tested using Hemagglutination Inhibition (HI) assay against vaccine and mismatched strains. Subjects were followed for safety for six months. Results: ATIV elicited significantly higher HI geometric mean titres (GMTs; P 97%) were mild to moderate and all resolved spontaneously. Conclusion: ATIV is well tolerated, safe and confers higher and broader immunogenicity, when compared with a TIV, in adults with underlying chronic diseases.

Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad®): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)†.

Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad®): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)†.