Adjuvanted Influenza Vaccine Research Articles

Discovery of Self‐Assembling Small Molecules as Vaccine Adjuvants

AbstractImmune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long‐lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self‐assembling small‐molecule library for the development of a novel vaccine adjuvant. Cell‐based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well‐defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus‐like assembly enters the cells and stimulates the innate immune response through Toll‐like receptor 7 (TLR7), an endosomal TLR that detects single‐stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self‐assembling small‐molecule adjuvants against pathogens, including emerging viruses.

Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly enters the cells and stimulates the innate immune response through Toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses.

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.

Synthetic Biology-derived triterpenes as efficacious immunomodulating adjuvants

The triterpene oil squalene is an essential component of nanoemulsion vaccine adjuvants. It is most notably in the MF59 adjuvant, a component in some seasonal influenza vaccines, in stockpiled, emulsion-based adjuvanted pandemic influenza vaccines, and with demonstrated efficacy for vaccines to other pandemic viruses, such as SARS-CoV-2. Squalene has historically been harvested from shark liver oil, which is undesirable for a variety of reasons. In this study, we have demonstrated the use of a Synthetic Biology (yeast) production platform to generate squalene and novel triterpene oils, all of which are equally as efficacious as vaccine adjuvants based on physiochemical properties and immunomodulating activities in a mouse model. These Synthetic Biology adjuvants also elicited similar IgG1, IgG2a, and total IgG levels compared to marine and commercial controls when formulated with common quadrivalent influenza antigens. Injection site morphology and serum cytokine levels did not suggest any reactogenic effects of the yeast-derived squalene or novel triterpenes, suggesting their safety in adjuvant formulations. These results support the advantages of yeast produced triterpene oils to include completely controlled growth conditions, just-in-time and scalable production, and the capacity to produce novel triterpenes beyond squalene.

Cluster-randomized Trial of Adjuvanted Versus Nonadjuvanted Trivalent Influenza Vaccine in 823 US Nursing Homes.

Influenza leads in preventable infection-related hospitalization in nursing home (NH) residents. The adjuvanted trivalent influenza vaccine (aTIV) is more immunogenic than similarly dosed nonadjuvanted trivalent influenza vaccine (TIV), and observational studies suggest aTIV better prevents hospitalizations in older adults. We prospectively tested this in an NH setting. NHs with ≥50 long-stay residents aged ≥65 years were randomized to offer aTIV or TIV for residents for the 2016-2017 influenza season. Using intent-to-treat resident-level analysis with Cox proportional hazards regression models adjusted for clustering by facility and a priori baseline covariates (eg, age, heart failure, and facility-level characteristics), we assessed relative aTIV:TIV effectiveness for hospitalization (ie, all-cause, respiratory, and pneumonia and influenza [P&I]). We randomized 823 NHs, housing 50 012 eligible residents, to aTIV or TIV. Residents were similar between groups by age (mean, ~79 years), heart failure, lung disease, and influenza and pneumococcal vaccine uptake, except aTIV homes housed fewer Black residents (14.5 vs 18.9%). Staff vaccine uptake was similar (~55%). P&I and all-cause resident hospitalization rates were lower (adjusted HR [aHR], .80 [95% CI, .66-.98; P = .03] and .94 [.89-.99; P = .02], respectively) for aTIV versus TIV, while the respiratory hospitalization rate was similar, in a season where vaccine effectiveness was considered poor. aTIV was more effective than TIV in preventing all-cause and P&I hospitalization from NHs during an A/H3N2-predominant season when TIV was relatively ineffective. NCT02882100.

Adjuvanted inactivated influenza Vaccine Quadrivalent for Older People.

Advanced age is associated with an increase in morbidity and mortality from influenza. Immunization is the best option to protect individuals against influenza and its complications. Older people are less likely than their younger counterparts to mount an appropriate immune response to influenza vaccines. The adjuvanted inactivated influenza vaccine quadrivalent (aIIV4) is designed to elicit a more robust immune response in older people compared with traditional inactivated influenza vaccines. The aIIV4 is indicated for active immunization against influenza caused by influenza virus subtypes A and types B contained in the vaccine and is licensed by the Food and Drug Administration for use in persons 65 years of age and older. The aIIV4 should be administered by intramuscular injection. Like other influenza vaccines, aIIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. The most common adverse reactions associated with aIIV4 are injection site pain, fatigue, headache, arthralgia, and myalgia.

Adjuvanted inactivated influenza Vaccine Quadrivalent for Older People

Advanced age is associated with an increase in morbidity and mortality from influenza. Immunization is the best option to protect individuals against influenza and its complications. Older people are less likely than their younger counterparts to mount an appropriate immune response to influenza vaccines. The adjuvanted inactivated influenza vaccine quadrivalent (aIIV4) is designed to elicit a more robust immune response in older people compared with traditional inactivated influenza vaccines. The aIIV4 is indicated for active immunization against influenza caused by influenza virus subtypes A and types B contained in the vaccine and is licensed by the Food and Drug Administration for use in persons 65 years of age and older. The aIIV4 should be administered by intramuscular injection. Like other influenza vaccines, aIIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. The most common adverse reactions associated with aIIV4 are injection site pain, fatigue, headache, arthralgia, and myalgia.

Comparability of Titers of Antibodies against Seasonal Influenza Virus Strains as Determined by Hemagglutination Inhibition and Microneutralization Assays.

We compared titers of antibodies against A/H1N1, A/H3N2, and B influenza virus strains collected pre- and postvaccination using hemagglutination inhibition (HI) and microneutralization (MN) assays and data from two vaccine trials: study 1, performed with a cell-grown trivalent influenza vaccine (TIVc) using cell-grown target virus in both assays, and study 2, performed with an egg-grown adjuvanted quadrivalent influenza vaccine (aQIVe) using egg-grown target virus. The relationships between HI- and MN-derived log-transformed titers were examined using different statistical techniques. Deming regression analyses showed point estimates for slopes generally close to 1 across studies and strains. The slope of regression was closest to 1 for A/H3N2 strain when either cell- or egg-grown viral target virus was used. Bland-Altman plots indicated a very small percentage of results outside 2 and 3 standard deviations. The magnitudes and directions of differences between titers in the two assays varied by study and strain. Mean differences favored the MN assay for A/H1N1 and B strains in study 1, whereas the titers determined by HI were higher than those determined by MN against the A/H3N2 strain. In study 2, mean differences favored the MN assay for A/H3N2 and B strains. Overall, the directions and magnitudes of the mean differences were similar between the two vaccines. The concordance correlation coefficient values ranged from 0.74 (A/H1N1 strain, study 1) to 0.97 (A/H3N2 strain, study 1). The comparative analysis demonstrates an overall strong positive correlation between the HI and MN assays. These data support the use of the MN assay to quantify the immune response of influenza vaccines in clinical studies, particularly for the A/H3N2 strain.

Evaluating the Relative Vaccine Effectiveness of Adjuvanted Trivalent Influenza Vaccine Compared to High-Dose Trivalent and Other Egg-Based Influenza Vaccines among Older Adults in the US during the 2017-2018 Influenza Season.

The influenza-related disease burden is highest among the elderly. We evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent influenza vaccine (aTIV) compared to other egg-based influenza vaccines (high-dose trivalent (TIV-HD), quadrivalent (QIVe-SD), and standard-dose trivalent (TIVe-SD)) against influenza-related and cardio-respiratory events among subjects aged ≥65 years for the 2017–2018 influenza season. This retrospective cohort analysis used prescription claims, professional fee claims, and hospital charge master data. Influenza-related hospitalizations/ER visits and office visits and cardio-respiratory events were assessed post-vaccination. Inverse probability of treatment weighting (IPTW) and Poisson regression were used to evaluate the adjusted rVE of aTIV compared to other vaccines. In an economic analysis, annualized follow-up costs were compared between aTIV and TIV-HD. The study was composed of 234,313 aTIV, 1,269,855 TIV-HD, 212,287 QIVe-SD, and 106,491 TIVe-SD recipients. aTIV was more effective in reducing influenza-related office visits and other respiratory-related hospitalizations/ER visits compared to the other vaccines. For influenza-related hospitalizations/ER visits, aTIV was associated with a significantly higher rVE compared to QIVe-SD and TIVe-SD and was comparable to TIV-HD. aTIV was also associated with a significantly higher rVE compared to TIVe-SD against hospitalizations/ER visits related to pneumonia and asthma/COPD/bronchial events. aTIV and TIV-HD were associated with comparable annualized all-cause and influenza-related costs. Adjusted analyses demonstrated a significant benefit of aTIV against influenza- and respiratory-related events compared to the other egg-based vaccines.

Development of an adjuvanted nanoparticle vaccine against influenza virus, an in vitro study.

Influenza is an infectious respiratory illness caused by influenza viruses. Despite yearly updates, the efficacy of influenza vaccines is significantly curtailed by the virus antigenic drift and antigenic shift. These constant changes to the influenza virus make-up also challenge the development of a universal flu vaccine, which requires conserved antigenic regions shared by influenza viruses of different subtypes. We propose that it is possible to bypass these challenges by the development of an influenza vaccine based on conserved proteins delivered in an adjuvanted nanoparticle system. In this study, we generated influenza nanoparticle constructs using trimethyl chitosan nanoparticles (TMC nPs) as the carrier of recombinant influenza hemagglutinin subunit 2 (HA2) and nucleoprotein (NP). The purified HA2 and NP recombinant proteins were encapsulated into TMC nPs to form HA2-TMC nPs and NP-TMC nPs, respectively. Primary human intranasal epithelium cells (HNEpCs) were used as an in vitro model to measure immunity responses. HA2-TMC nPs, NP-TMC nPs, and HA2-NP-TMC nPs (influenza nanoparticle constructs) showed no toxicity in HNEpCs. The loading efficiency of HA2 and NP into the TMC nPs was 97.9% and 98.5%, respectively. HA2-TMC nPs and NP-TMC nPs more efficiently delivered HA2 and NP proteins to HNEpCs than soluble HA2 and NP proteins alone. The induction of various cytokines and chemokines was more evident in influenza nanoparticle construct-treated HNEpCs than in soluble protein-treated HNEpCs. In addition, soluble factors secreted by influenza nanoparticle construct-treated HNEpCs significantly induced MoDCs maturation markers (CD80, CD83, CD86 and HLA-DR), as compared to soluble factors secreted by protein-treated HNEpCs. HNEpCs treated with the influenza nanoparticle constructs significantly reduced influenza virus replication in an in vitro challenge assay. The results indicate that TMC nPs can be used as influenza vaccine adjuvants and carriers capable of delivering HA2 and NP proteins to HNEpCs.

Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans

There is a need for improved influenza vaccines. In this study we compared the antibody responses in humans after vaccination with an AS03-adjuvanted versus nonadjuvanted H5N1 avian influenza virus inactivated vaccine. Healthy young adults received two doses of either formulation 3 wk apart. We found that AS03 significantly enhanced H5 hemagglutinin (HA)-specific plasmablast and antibody responses compared to the nonadjuvanted vaccine. Plasmablast response after the first immunization was exclusively directed to the conserved HA stem region and came from memory B cells. Monoclonal antibodies (mAbs) derived from these plasmablasts had high levels of somatic hypermutation (SHM) and recognized the HA stem region of multiple influenza virus subtypes. Second immunization induced a plasmablast response to the highly variable HA head region. mAbs derived from these plasmablasts exhibited minimal SHM (naive B cell origin) and largely recognized the HA head region of the immunizing H5N1 strain. Interestingly, the antibody response to H5 HA stem region was much lower after the second immunization, and this suppression was most likely due to blocking of these epitopes by stem-specific antibodies induced by the first immunization. Taken together, these findings show that an adjuvanted influenza vaccine can substantially increase antibody responses in humans by effectively recruiting preexisting memory B cells as well as naive B cells into the response. In addition, we show that high levels of preexisting antibody can have a negative effect on boosting. These findings have implications toward the development of a universal influenza vaccine.

Responsiveness to Influenza Vaccination Correlates with NKG2C-Expression on NK Cells.

Influenza vaccination often results in a large percentage of low responders, especially in high-risk groups. As a first line of defense, natural killer (NK) cells play a crucial role in the fight against infections. However, their implication with regard to vaccine responsiveness is insufficiently assessed. Therefore, this study aimed at the validation of essential NK cell features potentially associated with differential vaccine responsiveness with a special focus on NKG2C- and/or CD57-expressing NK cells considered to harbor memory-like functions. To this end, 16 healthy volunteers were vaccinated with an adjuvanted pandemic influenza vaccine. Vaccine responders and low responders were classified according to their hemagglutination inhibition antibody titers. A majority of responders displayed enhanced frequencies of NKG2C-expressing NK cells 7- or 14-days post-vaccination as compared to low responders, whereas the expression of CD57 was not differentially modulated. The NK cell cytotoxic potential was found to be confined to CD56dimCD16+ NKG2C-expressing NK cells in the responders but not in the low responders, which was further confirmed by stochastic neighbor embedding analysis. The presented study is the first of its kind that ascribes CD56dimCD16+ NKG2C-expressing NK cells a crucial role in biasing adaptive immune responses upon influenza vaccination and suggests NKG2C as a potential biomarker in predicting pandemic influenza vaccine responsiveness.

Comparative Postmarket Safety Profile of Adjuvanted and High-Dose Influenza Vaccines in Individuals 65 Years or Older

Every year, influenza vaccines are administered to millions of people worldwide to reduce morbidity and mortality from influenza. As new vaccine formulations are increasingly used, monitoring and comparing safety, in addition to vaccine effectiveness, in target populations are essential. To assess the postmarketing safety profile of 2018 Southern Hemisphere influenza vaccines, particularly 2 new enhanced trivalent inactivated influenza vaccines: an adjuvanted trivalent inactivated influenza vaccine (aIIV3) and high-dose trivalent inactivated influenza vaccine (HD-IIV3), among Australian individuals 65 years or older. This cohort study used solicited short message service-based self-reported survey data on adverse events occurring within 3 to 5 days after receipt of an influenza vaccination. Participants included individuals 65 years or older who received routinely recommended influenza vaccines at 1 of 265 sentinel immunization sites, including primary care, hospital, and community-based clinics, participating in Australia's AusVaxSafety active vaccine safety surveillance system from April 1 to August 31, 2018. Data were analyzed from September 1, 2018, to June 30, 2019. Any licensed 2018 influenza vaccine administered in clinical practice. Rates (overall, by brand, and by concomitant vaccine receipt) of adverse events, including medical attendance as a proxy for serious adverse events. Of 72 013 individuals 65 years or older who received an influenza vaccine in 2018, 50 134 individuals (69.6%) responded to the initial survey regarding adverse events experienced after vaccination (median [interquartile range] age, 71 [68-76] years; 27 056 [54.0%] women). Most individuals received an enhanced trivalent inactivated influenza vaccine, including 28 003 individuals (55.9%) who received aIIV3 and 19 306 individuals (38.5%) who received HD-IIV3; 2208 individuals (4.4%) received a quadrivalent inactivated influenza vaccine. Individuals who received HD-IIV3 reported significantly higher rates of any adverse event compared with individuals who received aIIV3 (1716 individuals [8.9%] vs 1796 individuals [6.4%]; P < .001) as well as specific adverse events, including fever (195 individuals [1.1%] vs 164 individuals [0.6%]; P < .001), injection site pain (383 individuals [2.1%] vs 350 individuals [1.3%]; P < .001), and injection site swelling or redness (256 individuals [1.4%] vs 248 individuals [0.9%]; P < .001). Adverse event rates reported by those receiving any quadrivalent inactivated influenza vaccine were similar to rates reported by those receiving aIIV3. Rates of medical care seeking for adverse events associated with aIIV3 and HD-IIV3 were low and comparable (80 individuals [0.3%] vs 56 individuals [0.3%]; P = .91). The findings of this large-scale participant-based postmarketing assessment of the safety of 2 new enhanced influenza vaccines used in individuals 65 years or older provide reassuring near-real-time and cumulative data to inform and support confidence in ongoing vaccine use.

BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant

ABSTRACT Better adjuvants are needed for vaccines against seasonal influenza. TLR7 agonists are potent activators of innate immune responses and thereby may be promising adjuvants. Among the imidazoquinoline compounds, 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (BBIQ) was reported to be a highly active TLR7 agonist but has remained relatively unexplored because of its commercial unavailability. Indeed, in silico molecular modeling studies predicted that BBIQ had a higher TLR7 docking score and binding free energy than imiquimod, the gold standard TLR7 agonist. To circumvent the availability issue, we developed an improved and higher yield method to synthesize BBIQ. Testing BBIQ on human and mouse TLR7 reporter cell lines confirmed it to be TLR7 specific with significantly higher potency than imiquimod. To test its adjuvant potential, BBIQ or imiquimod were admixed with recombinant influenza hemagglutinin protein and administered to mice as two intramuscular immunizations 2 weeks apart. Serum anti-influenza IgG responses assessed by ELISA 2 weeks after the second immunization confirmed that the mice that received vaccine admixed with BBIQ had significantly higher anti-influenza IgG1 and IgG2c responses than mice immunized with antigen alone or admixed with imiquimod. This confirmed BBIQ to be a TLR7-specific adjuvant able to enhance humoral immune responses.

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.

Novel Lipidated Imidazoquinoline TLR7/8 Adjuvants Elicit Influenza-Specific Th1 Immune Responses and Protect Against Heterologous H3N2 Influenza Challenge in Mice.

Most licensed seasonal influenza vaccines are non-adjuvanted and rely primarily on vaccine-induced antibody titers for protection. As such, seasonal antigenic drift and suboptimal vaccine strain selection often results in reduced vaccine efficacy. Further, seasonal H3N2 influenza vaccines demonstrate poor efficacy compared to H1N1 and influenza type B vaccines. New vaccines, adjuvants, or delivery technologies that can induce broader or cross-seasonal protection against drifted influenza virus strains, likely through induction of protective T cell responses, are urgently needed. Here, we report novel lipidated TLR7/8 ligands that act as strong adjuvants to promote influenza-virus specific Th1-and Th17-polarized T cell responses and humoral responses in mice with no observable toxicity. Further, the adjuvanted influenza vaccine provided protection against a heterologous H3N2 influenza challenge in mice. These responses were further enhanced when combined with a synthetic TLR4 ligand adjuvant. Despite differences between human and mouse TLR7/8, these novel lipidated imidazoquinolines induced the production of cytokines required to polarize a Th1 and Th17 immune response in human PBMCs providing additional support for further development of these compounds as novel adjuvants for the induction of broad supra-seasonal protection from influenza virus.

Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017–2018

BackgroundLicensed inactivated influenza vaccines (IIV) are recommended for persons aged ≥65 years, including trivalent high-dose IIV (HD-IIV3) and adjuvanted IIV (aIIV3); both are manufactured in eggs. Quadrivalent recombinant vaccine (RIV4) is produced without eggs. We conducted an exploratory study to compare immunogenicity of HD-IIV3, aIIV3 and RIV4 against cell-grown vaccine and circulating A(H3N2) viruses in 2017–18. MethodsEighty-nine adults aged 65–74 years participating in a 2-year, open-label immunogenicity trial (ClinicalTrails.gov: NCT02872311) were randomized 1:1:1 to receive HD-IIV3, aIIV3, or RIV4 after receipt of standard dose IIV3 in 2016–17. Serum was obtained at baseline and day 28 post vaccination. Microneutralization titers were determined using four cell-propagated A(H3N2) viruses: 2017–18 vaccine strain (clade 3C.2a), circulating viruses from clades 3C.2a1 and 3C.2a2, and ‘antigenically advanced’ clade 3C.3a (2019–20 vaccine strain). Active surveillance was conducted to identify influenza illnesses. ResultsPost vaccination geometric mean titer (GMT) against the vaccine strain was <1:60 in each group and <15% seroconverted. RIV4 generated a greater fold-rise (2.0, 95% CI 1.7–2.5) compared to HD-IIV3 (1.6, 95% CI 1.3–1.8). RIV4 generated higher post vaccination titers against 3C.2a1 and 3C.2a2 viruses, and the mean fold-rise after RIV4 was twice as high (3.3 and 3.5, respectively) relative to HD-IIV3 (1.4 and 1.6) and aIIV3 (1.7 and 1.6). Against the antigenically advanced 3C.3a virus, RIV4 generated a greater mean fold-rise (2.9, 95% CI 2.0–4.3) vs HD-IIV3 (1.3, 95% CI 1.1–1.6) and aIIV3 (1.7, 95% CI 1.3–2.1). Postvaccination titers against 3C.2a2 were ≥1:40 in 5 of 7 participants with PCR-confirmed A(H3N2) infection during the ensuing influenza season. ConclusionHigh-dose, adjuvanted, and recombinant vaccines generated suboptimal neutralizing antibody responses to the cell-grown vaccine strain, but RIV4 generated a greater cross-protective response against circulating and antigenically advanced viruses. Recombinant technology may contribute to more broadly protective influenza vaccines, and comparative effectiveness studies are needed.

Effectiveness, immunogenicity, and safety of influenza vaccines with MF59 adjuvant in healthy people of different age groups: A systematic review and meta-analysis.

Influenza is a severe disease burden among all age groups. This study aimed to review the efficacy of inactivated influenza vaccines with MF59 adjuvant and non-adjuvanted inactivated influenza vaccines among all age groups against specific influenza vaccine strains. Literature search of PubMed, Embase, Medline, OVID, and Cochrane Library Trials (CENTRAL) was implemented up to March 1, 2019. Homogeneity qualified studies were included forData were extracted such as study country location, demographic characteristics, and measure outcomes, and were analyzed by a random effect model and sensitivity analyses to identify heterogeneity. Risk of bias was evaluated using the Cochrane Risk of Bias Tool. We retrieved 1,021 publications and selected 31 studies for full review, including 17 trials for meta-analysis and 6 trials for qualitative synthesis. MF59-adjuvanted influenza vaccines demonstrated better immunogenicity against specific vaccine virus strains compared to non-adjuvanted influenza vaccine both in healthy adult group (RR = 2.10; 95% CI: 1.28-3.44) and the healthy aged (RR = 1.26; 95% CI: 1.10-1.44). The quality of evidence is moderate to high for seroconversion and seroprotection rates of influenza vaccine. MF59-adjuvanted influenza vaccines are superior to non-adjuvanted influenza vaccines to enhance immune responses of vaccination in healthy adults and older adults, and could be considered for routine use especially the monovalent prepandemic influenza vaccines.

Fc functional antibody responses to adjuvanted versus unadjuvanted seasonal influenza vaccination in community-dwelling older adults

BackgroundSeasonal influenza vaccination with a standard trivalent influenza vaccine (TIV) induces a modest, and cross-reactive, Fc functional antibody response in older adults. Recent improvements to influenza vaccines include a quadrivalent influenza vaccine (QIV) and a TIV adjuvanted with the squalene-based oil-in-water emulsion MF59. MethodsPre- and post-vaccination serum samples from older adults vaccinated with QIV (n = 27) and adjuvanted TIV (n = 44) were studied using hemagglutination inhibition (HAI) assays and dimeric Fc-gamma receptor IIIa binding ELISAs, as a surrogate of antibody-dependent cellular cytotoxicity (ADCC). ResultsWe found that the unadjuvanted QIV elicited a stronger HAI response against the H1N1 vaccine virus than the adjuvanted TIV. Post-vaccination levels of HA-specific ADCC antibodies were similar for older adults vaccinated with QIV and adjuvanted TIV. The ADCC response to influenza vaccination was largely determined by pre-vaccination or baseline levels of these antibodies, with older adults with low baseline levels of ADCC activity demonstrating greater post-vaccination rises. ConclusionsIn this cohort of community-dwelling older adults, the QIV was at least as good as the adjuvanted TIV in the induction of ADCC and HAI responses. Further studies on how these antibody responses translate to efficacy in preventing influenza infections are warranted.

Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis

Standard inactivated influenza vaccines are poorly immunogenic in immunologically naive healthy young children, who are particularly vulnerable to complications from influenza. For them, there is an unmet need for better influenza vaccines. Oil-in-water emulsion-adjuvanted influenza vaccines are promising candidates, but clinical trials yielded inconsistent results. Here, we meta-analyze randomized controlled trials with efficacy data (3 trials, n = 15,310) and immunogenicity data (17 trials, n = 9062). Compared with non-adjuvanted counterparts, adjuvanted influenza vaccines provide a significantly better protection (weighted estimate for risk ratio of RT-PCR-confirmed influenza: 0.26) and are significantly more immunogenic (weighted estimates for seroprotection rate ratio: 4.6 to 7.9) in healthy immunologically naive young children. Nevertheless, in immunologically non-naive children, adjuvanted and non-adjuvanted vaccines provide similar protection and are similarly immunogenic. These results indicate that oil-in-water emulsion adjuvant improves the efficacy of inactivated influenza vaccines in healthy young children at the first-time seasonal influenza vaccination.