MF59-adjuvanted 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.

Immunogenicity of Enhanced Influenza Vaccines Against Mismatched Influenza Strains in Older Adults: A Review of Randomized Controlled Trials.

Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza-related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality. The immunogenicity of enhanced vaccines against heterologous A(H3N2) strains has been examined in nine studies to date. In six studies, an enhanced, licensed MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) consistently increased heterologous antibody titers relative to standard influenza vaccine, with evidence of a broad heterologous immune response across multiple genetic clades. In one study, licensed high-dose trivalent inactivated influenza vaccine (HD-IIV3) also induced higher heterologous antibody titers than standard influenza vaccine. In a study comparing a higher dose licensed quadrivalent recombinant influenza vaccine (RIV4) with HD-IIV3 and aIIV3, no significant differences in antibody titers against a heterologous strain were observed, although seroconversion rates were higher with RIV4 versus comparators. With the unmet medical need for improved influenza vaccines, the paucity of studies especially with enhanced vaccines covering mismatched strains highlights a need for further investigation of cross-protection in older adults.

Immunogenicity and Safety of MF59-Adjuvanted Quadrivalent Influenza Vaccine Compared with a Nonadjuvanted, Quadrivalent Influenza Vaccine in Adults 50-64 Years of Age.

Adults aged 50-64 years have a high incidence of symptomatic influenza associated with substantial disease and economic burden each year. We conducted a randomized, controlled trial to compare the immunogenicity and safety of an adjuvanted quadrivalent inactivated influenza vaccine (aIIV4; n = 1027) with a nonadjuvanted standard dose IIV4 (n = 1017) in this population. Immunogenicity was evaluated on Days 22, 181, and 271. On Day 22, upper limits (UL) of 95% confidence intervals (CI) for geometric mean titer (GMT) ratios (IIV4/aIIV4) were <1.5 and 95% CI ULs for the difference in seroconversion rate (SCR IIV4 - aIIV4) were <10% for all four vaccine strains, meeting primary endpoint noninferiority criteria. Protocol-defined superiority criteria (95% CI ULs < 1.0) were also met for A(H1N1) and A(H3N2). Immune responses following aIIV4 vaccination were more pronounced in persons with medical comorbidities and those not recently vaccinated against influenza. Safety data were consistent with previous studies of MF59 adjuvanted seasonal and pandemic influenza vaccines. These findings support the immunological benefit of aIIV4 for persons aged 50-64 years, especially those with comorbidities.

The CombE-IDMS Assay as an Alternate Potency Method for Adjuvanted Quadrivalent Influenza Vaccines.

The potency of all currently licensed inactivated influenza viral vaccines is assayed by the single radial immunodiffusion (SRID) method. SRID relies upon antisera and reference antigen reagents which are produced, standardized, and distributed in the mass quantities needed for vaccine manufacturers only after a significant amount of time has elapsed from the seasonal strain recommendations issued by the WHO; this time delay is exacerbated under conditions of an emerging pandemic. Previously, the limited trypsin digestion isotope dilution mass spectrometry (LTD-IDMS) method, which does not require antisera or reference antigens, demonstrated comparable quantitation of immunologically active hemagglutinin, the primary viral antigen, to SRID in stressed vaccine materials. Here, we demonstrate a streamlined improvement to the LTD-IDMS method by eliminating the need for its precipitation and washing steps, saving time and labor in the sample preparation process while paving the way for plate-based high-throughput analysis. This is accomplished using dissimilar proteases in the pretreatment (a combination of chymotrypsin and elastase) and analytical (trypsin) digestion steps so that any pretreatment digests will not cause interference while monitoring analytical tryptic digests by IDMS. The combination of enzymes (CombE)-IDMS method is tested alongside LTD-IDMS and SRID for the first time on MF59 adjuvanted seasonal cell-based quadrivalent influenza vaccines (aQIVc) under stressed conditions of heating, oxidation, lowered and elevated pH, and freeze-thaw. Overall, a correlation in the degradation trend is observed between CombE-IDMS and SRID in the four strains of the quadrivalent formulation, highlighting the method's stability indicating capability as a rapid alternate potency assay in a highly complex formulation of aQIVc.

Additional Burden Averted in the United States From Use of MF59-Adjuvanted Seasonal Influenza Vaccine Compared With Standard Seasonal Influenza Vaccine Among Adults ≥65 Years.

The MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) is designed to overcome immunosenescence and enhance vaccine responses in older adults. We expanded on the Centers for Disease Control and Prevention (CDC) modeling method to estimate the number of additional influenza-related outcomes averted with aIIV3 versus generic quadrivalent inactivated influenza vaccine (IIV4) in adults ≥65 years over 3 influenza seasons (2017-2018 to 2019-2020) in the United States. A static compartmental model was developed based on an existing CDC model with 2 previously recommended calculation methods that increased the accuracy of the model in providing estimates of burden averted. Model inputs included vaccine effectiveness, vaccine coverage, population counts, and disease burden estimates. Additional burden averted (symptomatic cases, outpatient visits, hospitalizations, intensive care unit [ICU] admissions, and deaths) was expressed as total incremental cases averted between the vaccines. Sensitivity analyses tested the resilience of the model results to uncertainties in model inputs. The model estimated that vaccination with aIIV3 versus IIV4 would avert 2.24 times as many symptomatic cases, outpatient visits, hospitalizations, ICU stays, and deaths during 2017-2018; the burden averted in 2018-2019 and 2019-2020 with aIIV3 would be 3.44 and 1.72 times that averted with IIV4, respectively. Disease burden estimates and relative vaccine effectiveness of aIIV3 had the greatest impact on model estimates. Over 3 influenza seasons, the model estimated that aIIV3 was more effective than IIV4 in averting influenza-related outcomes, preventing 1.72 to 3.44 times as many influenza illnesses with proportionate decreases in related healthcare use and complications.

Memory-like innate response to booster vaccination with MF-59 adjuvanted influenza vaccine in children

The pediatric population receives the majority of vaccines globally, yet there is a paucity of studies on the transcriptional response induced by immunization in this special population. In this study, we performed a systems-level analysis of immune responses to the trivalent inactivated influenza vaccine adjuvanted with MF-59 in children (15–24 months old) and in young, healthy adults. We analyzed transcriptional responses elicited by vaccination in peripheral blood, as well as cellular and antibody responses following primary and booster vaccinations. Our analysis revealed that primary vaccination induced a persistent transcriptional signature of innate immunity; booster vaccination induced a transcriptional signature of an enhanced memory-like innate response, which was consistent with enhanced activation of myeloid cells assessed by flow cytometry. Furthermore, we identified a transcriptional signature of type 1 interferon response post-booster vaccination and at baseline that was correlated with the local reactogenicity to vaccination and defined an early signature that correlated with the hemagglutinin antibody titers. These results highlight an adaptive behavior of the innate immune system in evoking a memory-like response to secondary vaccination and define molecular correlates of reactogenicity and immunogenicity in infants.

Cost-Effectiveness of the Use of Adjuvanted Quadrivalent Seasonal Influenza Vaccine in Older Adults in Ireland.

Enhanced vaccines (e.g., containing adjuvants) have shown increased immunogenicity and effectiveness in older adults, who often respond sub-optimally to conventional influenza vaccines. In this study, we evaluated the cost-effectiveness of an inactivated, seasonal, MF59-adjuvanted quadrivalent influenza vaccine (aQIV) for use in adults ≥ 65 years in Ireland. A published dynamic influenza model incorporating social contact, population immunity, and epidemiological data was used to assess the cost-effectiveness of aQIV in adults ≥ 65 years of age compared with a non-adjuvanted QIV. Sensitivity analysis was performed for influenza incidence, relative vaccine effectiveness, excess mortality, and the impact on bed occupancy from co-circulating influenza and COVID-19. The use of aQIV resulted in discounted incremental cost-effectiveness ratios (ICERs) of EUR 2420/quality-adjusted life years (QALYs) and EUR 12,970/QALY from societal and payer perspectives, respectively, both of which are below the cost-effectiveness threshold of EUR 45,000/QALY. Sensitivity analysis showed that aQIV was effective in most scenarios, except when relative vaccine effectiveness compared to QIV was below 3%, and resulted in a modest reduction in excess bed occupancy. The use of aQIV for adults ≥ 65 years old in Ireland was shown to be highly cost-effective from both payer and societal perspectives.

An Economic Comparison in the Elderly of Adjuvanted Quadrivalent Influenza Vaccine with Recombinant Quadrivalent Influenza Vaccine in Spain.

Influenza infections impose a high burden of morbidity and mortality among older adults, at great cost to individuals and society. Enhanced influenza vaccines, which contain either an immune adjuvant or higher than normal doses of influenza virus antigens, are recommended for older adults. We used a health economics model to evaluate the cost effectiveness in Spain of a recently licensed recombinant quadrivalent influenza vaccine (QIVr), which contains three times the standard dose of influenza virus hemagglutinin but no neuraminidase, compared with an MF59-adjuvanted quadrivalent influenza vaccine (aQIV). Based on current tender prices in Spain and a conservative assumption that QIVr is 10.7% relatively more effective than aQIV, the incremental cost-effectiveness ratio (ICER) for QIVr was EUR 101,612.41 per quality-adjusted life year (QALY) gained. To meet the Spanish willingness-to-pay threshold of EUR 25,000 per QALY gained, QIVr would need to be 34.1% relatively more effective than aQIV. In a probabilistic sensitivity analysis conducted to confirm the robustness of the analysis, 99.7% of simulations for QIVr were higher than the willingness-to-pay curve. These findings suggest that QIVr is not currently a cost-effective influenza vaccine option relative to aQIV for older persons living in Spain.

Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults.

The reduced effectiveness of standard-dose influenza vaccines in persons ≥65 years of age led to the preferential recommendation to use high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) vaccines for this age group. Sleep is an important modulator of immune responses to vaccines and poor sleep health is common in older adults. However, potential effects of poor sleep health on immune responses to influenza vaccination in older adults remain largely unknown. We conducted a cohort study of 210 healthy participants age ≥65 years, who received either seasonal high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) influenza vaccine. We assessed sleep characteristics in this cohort by standardized questionnaires and measured the antibody titer against influenza A/H3N2 virus in serum of study participants by hemagglutination inhibition assay on the day of immunization and 28 days thereafter. We then assessed the association between sleep characteristics and antibody titers. Our results demonstrated that male, but not female, study participants with excessive daytime sleepiness had an impaired influenza A/H3N2-specific antibody response at Day 28 post-vaccination. No other associations were found between antibody titer and other sleep characteristics, including sleep quality and obstructive sleep apnea. Our results provide an additional and easily measured variable explaining poor vaccine effectiveness in older adults. Our results support that gaining sufficient sleep is a simple non-vaccine interventional approach to improve influenza immune responses in older adults. Our findings extend the literature on the negative influence of excessive daytime sleepiness on immune responses to influenza vaccination in older male adults.

REAL-WORLD EFFECTIVENESS ENHANCED INFLUENZA VACCINES IN OLDER ADULTS DURING THREE CONSECUTIVE INFLUENZA SEASONS: 2017–2020

Abstract Unenhanced influenza vaccines often fail to elicit adequate immune responses in adults ≥65 years due to immunosenescence. Enhanced influenza vaccines, MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) and high-dose vaccine (HD-TIV), were specifically developed to overcome this problem. The relative vaccine effectiveness (rVE) of aTIV vs HD-TIV and standard, egg-derived quadrivalent influenza vaccines (QIVe) was estimated in 3 retrospective cohort studies during the 2017-2020 US influenza seasons. Influenza-related medical encounters (IRMEs) were identified using diagnostic codes specific to influenza disease (ICD J09*-J11*) from a dataset that integrated electronic primary care medical records with pharmacy and medical claims. rVE was estimated using propensity score methods adjusting for variables including age, sex, race, ethnicity, geographic location, week of vaccination, frailty and health status. Subgroup analyses included specific age groups and those with high-risk medical conditions. aTIV demonstrated a consistent benefit over QIVe and HD-TIV across all three seasons in the overall study populations, and greater rVE versus QIVe was consistently observed over all three seasons in all age subgroups as well (65-74, 75-84, 85+). aIIV3 was comparable to HD-TIV and more effective than QIVe in a subgroup with high-risk medical conditions. These findings lend further support to the use of aTIV to prevent influenza-related medical encounters in older individuals.

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.

The New Quadrivalent Adjuvanted Influenza Vaccine for the Italian Elderly: A Health Technology Assessment.

Background. The elderly, commonly defined as subjects aged ≥65 years, are among the at-risk subjects recommended for annual influenza vaccination in European countries. Currently, two new vaccines are available for this population: the MF59-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose quadrivalent influenza vaccine (hdQIV). Their multidimensional assessment might maximize the results in terms of achievable health benefits. Therefore, we carried out a Health Technology Assessment (HTA) of the aQIV by adopting a multidisciplinary policy-oriented approach to evaluate clinical, economic, organizational, and ethical implications for the Italian elderly. Methods. A HTA was conducted in 2020 to analyze influenza burden; characteristics, efficacy, and safety of aQIV and other available vaccines for the elderly; cost-effectiveness of aQIV; and related organizational and ethical implications. Comprehensive literature reviews/analyses were performed, and a transmission model was developed in order to address the above issues. Results. In Italy, the influenza burden on the elderly is high and from 77.7% to 96.1% of influenza-related deaths occur in the elderly. All available vaccines are effective and safe; however, aQIV, such as the adjuvanted trivalent influenza vaccine (aTIV), has proved more immunogenic and effective in the elderly. From the third payer’s perspective, but also from the societal one, the use of aQIV in comparison with egg-based standard QIV (eQIV) in the elderly population is cost-effective. The appropriateness of the use of available vaccines as well as citizens’ knowledge and attitudes remain a challenge for a successful vaccination campaign. Conclusions. The results of this project provide decision-makers with important evidence on the aQIV and support with scientific evidence on the appropriate use of vaccines in the elderly.

Quadrivalent adjuvanted haemagglutinin nanoparticle influenza vaccine: a step towards better protection of older adults from the constantly mutating H3N2 influenza viruses

The H3N2 influenza subtype has been highly researched due to its rapid mutational variability, which allows it to escape a preexisting immune response, meaning that the effectiveness of the H3N2 vaccine component has been extremely low over the past few seasons, since the 2014–15 season. 1 Martin ET Cheng C Petrie JG et al. Low influenza vaccine effectiveness against A(H3N2)-associated hospitalizations in 2016–2017 and 2017–2018 of the hospitalized adult influenza vaccine effectiveness network (HAIVEN). J Infect Dis. 2020; 223: 2062-2071 Crossref Scopus (5) Google Scholar It is therefore not surprising that in seasons when the H3N2 virus predominates, many countries have markedly higher mortality rates than in other seasons, especially in older people, owing to their reduced immune functions. 2 Vestergaard LS Nielsen J Krause TG et al. Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017. Euro Surveill. 2017; 2230506 Crossref PubMed Scopus (79) Google Scholar In attempts to overcome the issue of immunosenescence in older adults, new enhanced influenza vaccines are being developed, such as high-dose vaccines or vaccines formulated with potent adjuvants. To some extent, these approaches have helped increase the breadth of antibody immune responses and to stimulate virus-specific T-cell responses, thus improving vaccine effectiveness in the older population. 3 Beran J Reynales H Poder A et al. Prevention of influenza during mismatched seasons in older adults with an MF59-adjuvanted quadrivalent influenza vaccine: a randomised, controlled, multicentre, phase 3 efficacy study. Lancet Infect Dis. 2021; 21: 1027-1037 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar , 4 DiazGranados CA Dunning AJ Kimmel M et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014; 371: 635-645 Crossref PubMed Scopus (495) Google Scholar Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trialqNIV was well tolerated and produced qualitatively and quantitatively enhanced humoral and cellular immune response in older adults compared with IIV4. qNIV might enhance the effectiveness of seasonal influenza vaccination, and future studies to show clinical efficacy are planned. Full-Text PDF

The cost-effectiveness of an adjuvanted quadrivalent influenza vaccine in the United Kingdom

ABSTRACT In the United Kingdom (UK), both the MF59-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose QIV (QIV-HD) are preferred for persons aged 65 years and older but only aQIV is reimbursed by the National Health Service (NHS). The objective was to determine the potential cost-effectiveness of vaccinating adults aged 65 years and above with aQIV compared with QIV-HD in the UK. A dynamic transmission model, calibrated to match infection data from the UK, was used to estimate the impact of vaccination in 10 influenza seasons. Vaccine effectiveness was based on a meta-analysis that concluded the vaccines were not significantly different. Vaccine coverage, physician visits, hospitalizations, deaths, utility losses and NHS costs were estimated using published UK sources. The list price of aQIV was £11.88 while a range of prices were tested for QIV-HD. The price of the trivalent high-dose vaccine (TIV-HD) is £20.00 but a list price for QIV-HD is not yet available. The projected differences between the vaccines in terms of clinical cases and influenza treatment costs are minimal. Our analysis demonstrates that in order to be cost-effective, the price of QIV-HD must be similar to that of aQIV and may range from £7.57 to £12.94 depending on the relative effectiveness of the vaccines. The results of the analysis were most sensitive to variation in vaccine effectiveness and the rate of hospitalization due to influenza. Given the evidence, aQIV is cost-saving unless QIV-HD is priced lower than the existing list price of TIV-HD.

Improved immunologic responses to heterologous influenza strains in children with low preexisting antibody response vaccinated with MF59-adjuvanted influenza vaccine

Vaccination is the most effective approach to reduce the substantial morbidity and mortality caused by influenza infection. Vaccine efficacy is highly sensitive to antigenic changes causing differences between circulating and vaccine viruses. Adjuvants such as MF59 increase antibody-mediated cross-reactive immunity and therefore may provide broader seasonal protection. A recent clinical trial showed that an MF59-adjuvanted vaccine was more efficacious than a nonadjuvanted comparator in subjects < 2 years of age, although not in those ≥ 2 years, during influenza seasons in which the predominant circulating virus was an A/H3N2 strain that was antigenically different from the vaccine virus. This finding suggested that the increased efficacy of the adjuvanted vaccine in younger subjects may be mediated by strain cross-reactive antibodies. A subset of the trial population, representing subjects with distinct age and/or immunological history, was tested for antibody responses to the vaccine A/H3N2 strain as well as A/H3N2 drifted strains antigenically matching the viruses circulating during the trial seasons. The neutralizing tests showed that, compared with nonadjuvanted vaccine, the adjuvanted vaccine improved not only the neutralizing antibody response to the vaccine strain but also the cross-reactive antibody response to the drifted strains in subjects with lower preexisting antibody titers, regardless of their age or vaccine history. The results demonstrated an immunological benefit and suggested a potential efficacy benefit by adjuvanted vaccine in subjects with lower preexisting antibody responses.

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.

Cross-protective potential of a MF59-adjuvanted quadrivalent influenza vaccine in older adults

A decline in humoral and cell-mediated immunity inevitably accompanies the ageing process. The weakened immunity in older people not only makes them more susceptible to natural influenza infections, but also prevents them from developing protective immunity to standard influenza vaccines. 1 McElhaney JE Influenza vaccine responses in older adults. Ageing Res Rev. 2011; 10: 379-388 Crossref PubMed Scopus (121) Google Scholar Besides immunosenescence, this reduced vaccine effectiveness can be associated with immunological responses to repeated vaccination. 2 Sullivan SG Price OH Regan AK Burden, effectiveness and safety of influenza vaccines in elderly, paediatric and pregnant populations. Ther Adv Vaccines Immunother. 2019; 72515135519826481 Crossref Google Scholar Furthermore, the greatest effect of H3N2 influenza on the risk of hospitalisation relative to H1N1 and influenza B strains in the population aged 65 years or older 3 Thompson WW Shay DK Weintraub E et al. Influenza-associated hospitalizations in the United States. JAMA. 2004; 292: 1333-1340 Crossref PubMed Scopus (1733) Google Scholar suggests that a strong anamnestic response to the original infecting strain can be responsible for the disproportionate burden of H3N2 viruses, as this population was born during the era of circulation of H1N1 viruses. 4 Monto AS Malosh RE Petrie JG Martin ET The doctrine of original antigenic sin: separating good from evil. J Infect Dis. 2017; 215: 1782-1788 Crossref PubMed Scopus (68) Google Scholar This vulnerability of adults aged 65 or older underscores the need for effective preventive measures and ongoing efforts to improve the available influenza vaccines for this age group. To date, the most promising approach is to use so-called enhanced influenza vaccines, which either contain a higher dose of the antigen or are formulated with specific adjuvants. A successful example is the MF59 adjuvant that significantly enhanced the immunogenicity of inactivated influenza vaccines in older adults, 5 Gasparini R Pozzi T Montomoli E et al. Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol. 2001; 17: 135-140 Crossref PubMed Scopus (97) Google Scholar for whom a switch to a quadrivalent formulation did not affect the overall immunogenicity and safety of the vaccine. 6 Essink B Fierro C Rosen J et al. Immunogenicity and safety of MF59-adjuvanted quadrivalent influenza vaccine versus standard and alternate B strain MF59-adjuvanted trivalent influenza vaccines in older adults. Vaccine. 2020; 38: 242-250 Crossref PubMed Scopus (10) Google Scholar However, the question remained regarding to what extent this MF59-adjuvanted quadrivalent influenza vaccine (aQIV) can provide protection for older adults against the disease. Prevention of influenza during mismatched seasons in older adults with an MF59-adjuvanted quadrivalent influenza vaccine: a randomised, controlled, multicentre, phase 3 efficacy studyThe prespecified criterion for showing the efficacy of aQIV in older adults was not met during the influenza seasons with high amounts of vaccine strain mismatch. Vaccine efficacy was higher against influenza cases associated with higher fever, which represent more clinically significant disease. Full-Text PDF

Prevention of influenza during mismatched seasons in older adults with an MF59-adjuvanted quadrivalent influenza vaccine: a randomised, controlled, multicentre, phase 3 efficacy study

The absolute degree of protection from influenza vaccines in older adults has not been studied since 2001. This study aimed to show the clinical efficacy of an MF59-adjuvanted quadrivalent influenza vaccine (aQIV) in adults 65 years or older compared with adults not vaccinated to prevent influenza. We did a randomised, stratified, observer-blind, controlled, multicentre, phase 3 study at 89 sites in 12 countries in 2016-17 northern hemisphere and 2017 southern hemisphere influenza seasons. We enrolled community-dwelling male and female adults aged 65 years and older who were healthy or had comorbidities that increased their risk of influenza complications. We stratified eligible participants by age (cohorts 65-74 years and ≥75 years) and risk of influenza complications (high and low) and randomly assigned them (1:1) via an interactive response technology to receive either aQIV or a non-influenza comparator vaccine. We masked participants and outcome assessors to the administered vaccine. Personnel administering the vaccines did not participate in endpoint assessment. The primary outcome was absolute vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population (full analysis set) from day 21 to 180 or the end of the influenza season. Vaccine efficacy was calculated on the basis of a Cox proportional hazard regression model for time to first occurrence of RT-PCR-confirmed influenza due to any strain of influenza. Safety outcomes were assessed in the overall study population. This trial was registered with ClinicalTrials.gov, NCT02587221. Northern hemisphere enrolment occurred between Sept 30, 2016, and Feb 28, 2017, and southern hemisphere enrolment between May 26, 2017, and 30 June 30, 2017. aQIV was administered to 3381 participants, who subsequently had 122 (3·6%) RT-PCR-confirmed influenza cases, and the comparator was administered to 3380 participants, who subsequently had 151 (4·5%) influenza cases. The majority, 214 (78·4%) of 273, were caused by influenza A H3N2. Most antigenically characterised isolates were mismatched to the vaccine strain (118 [85%] of 139). Vaccine efficacy was 19·8% (multiplicity-adjusted 95% CI -5·3 to 38·9) against all influenza and 49·9% (-24·0 to 79·8) against antigenically matched strains, when the protocol definition of influenza-like illness was used. The most common local solicited adverse event was injection site pain, reported by 102 (16·3%) of 624 participants in the aQIV group and 71 (11·2%) of 632 of participants in the comparator group. Deaths were evenly distributed; none were considered related to study vaccines. The safety profile for aQIV was similar to previously reported trials. The prespecified criterion for showing the efficacy of aQIV in older adults was not met during the influenza seasons with high amounts of vaccine strain mismatch. Vaccine efficacy was higher against influenza cases associated with higher fever, which represent more clinically significant disease. Seqirus UK.

Repeated exposure to an MF-59 adjuvanted quadrivalent subunit influenza vaccine (aQIV) in children: Results of two revaccination studies

BackgroundPediatric adjuvanted seasonal influenza vaccines induce higher immune responses and have the potential to confer better protection against influenza among young vaccine-naïve children. Limited data describe benefits and risks of repeated administration of adjuvanted influenza vaccines in children. Two revaccination studies assess the safety and immunogenicity of repeated exposure to an MF59-adjuvanted quadrivalent influenza vaccine (aQIV; Fluad®) compared to routine non-adjuvanted quadrivalent influenza vaccine (QIV). MethodsChildren previously enrolled in the parent study, who received vaccination with aQIV or nonadjuvanted influenza vaccine (TIV or QIV), were recruited in Season 1 (n = 607) or Season 2 (n = 1601) of the extension trials. Season 1 participants remained in their original randomization groups (aQIV-aQIV or TIV-QIV); Season 2 subjects were re-randomized to either vaccine, resulting in four groups (aQIV-aQIV, aQIV-QIV, QIV-aQIV, or QIV-QIV). All subjects received a single-dose vaccination. Blood samples were taken for immunogenicity assessment prior to vaccination and 21 and 180 days after vaccination. Reactogenicity (Days 1–7) and safety were assessed in all subjects. ResultsHemagglutination inhibition (HI) geometric mean titer (GMT) ratios demonstrated superiority of aQIV revaccination over QIV revaccination for all strains in Season 1 and for A/H1N1, B/Yamagata, and B/Victoria in Season 2. Higher HI titers against heterologous influenza strains were observed after aQIV vaccination during both seasons. Mild to moderate severity and short duration reactogenicity was more common in the aQIV than QIV groups, but the overall safety profiles were similar to the parent study. ConclusionThe safety and immunogenicity results from this study demonstrate benefit of aQIV for both priming and revaccination of children aged 12 months to 7 years.