Article

Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates

June 2010
Vaccine 28(25):4123-9

June 2010
28(25):4123-9

DOI:10.1016/j.vaccine.2010.04.030

Source
PubMed

Authors:

Filippo Ansaldi

Università degli Studi di Genova

Marta Zancolli

University of London

Paolo Durando

Università degli Studi di Genova

Emanuele Montomoli

Università degli Studi di Siena

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MF59 is already known to enhance the breadth of antibody response to mismatched influenza seasonal and avian strains. However, little is known on the effect of MF59 on immunogenicity of influenza vaccines when "apparent" good matching between circulating and vaccine strains exists. To this end, we compared the immune response elicited by MF59-adjuvanted or non-adjuvanted subunit vaccine, containing A/California/7/04(H3N2) strain, against circulating viruses isolated between 2004/2005 and 2006/2007 seasons, belonging to different clades. The advantage offered by MF59 in terms of higher immunogenicity, expressed as higher post-vaccination HI titres, is observable also against viruses showing antigenic and molecular pattern undistinguishable from vaccine strain, but it became even more evident as the antigenic and molecular distance between vaccine and circulating strains grew. These data show that seasonal influenza vaccine adjuvanted with MF59 can offer a stronger benefit as compared to non-adjuvanted vaccine in protecting against a broader range of virus strains circulating during the influenza season.

Immunogenicity of intramuscular MF59- Adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: A literature review

Article

Full-text available

Feb 2015

Because of the age-related immune system decline, two potentiated influenza vaccines were specifically licensed for the elderly: Fluad→, an MF59-adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15mcg→, a non adjuvanted vaccine administered intradermally (ID). The objective of this paper was to conduct a systematic review of studies that evaluated antibody responses in the elderly following immunization with IM-MF59 or ID vaccines. The two potentiated vaccines induced immune responses satisfying, in most instances, the European Medicine Agency immunogenicity criteria, both against vaccine antigens and heterovariant drifted strains. Considering pooled data reported in the articles analyzed and papers directly comparing the two vaccines, the antibody responses elicited by IM-MF59 and ID were found to be generally comparable. The use of IM-MF59 and ID vaccines can be proposed as an appropriate strategy for elderly seasonal influenza vaccination although further studies are required for a more complete characterization of the two vaccines.

Relative effectiveness of the adjuvanted versus non-adjuvanted seasonal influenza vaccines against severe laboratory-confirmed influenza among hospitalized Italian older adults

Article

Full-text available

Nov 2022
INT J INFECT DIS

Objectives In this study, we aimed to investigate the relative vaccine effectiveness (rVE) of the MF59-adjuvanted trivalent (aTIV) and non-adjuvanted quadrivalent (QIVe) egg-based standard-dose vaccines against severe laboratory-confirmed influenza. Methods This test-negative case-control study was conducted in hospital setting during four recent Italian influenza seasons (from 2018/19 to 2021/22). The clinical outcome was severe acute respiratory infection (SARI) with laboratory confirmation diagnosed among subjects aged ≥ 65 years. rVE of aTIV versus QIVe was estimated through propensity score matching followed by logistic regression. Results Influenza virus circulated to a significant extent only during the 2018/19 and 2019/20 seasons. The final population included 512 vaccinated older adults, of which 83 were cases and 429 were test-negative controls. aTIV and QIVe users differed substantially from the point of view of several baseline characteristics. The propensity-score adjusted rVE of aTIV vs QIVe was 59.2% (95% CI: 14.6%, 80.5%), 54.7% (95% CI: -28.7%, 84.0%) and 56.9% (95% CI: -7.8%, 82.8%) against any influenza, A(H1N1)pdm09 and A(H3N2), respectively. Conclusions aTIV was more effective than QIVe in preventing laboratory-confirmed SARI. Benefits of aTIV may be obscured by confounding by indication.

Effectiveness of the Adjuvanted Influenza Vaccine in Older Adults at High Risk of Influenza Complications

Article

Full-text available

Aug 2021

MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) elicit an enhanced immune response in older adults compared to standard, quadrivalent inactivated influenza vaccines (IIV4). We sought to determine the relative vaccine effectiveness (rVE) of aIIV3 versus IIV4 and HD-IIV3 in preventing influenza-related medical encounters in this retrospective cohort study involving adults ≥65 years with ≥1 health condition during the 2017–2018 and 2018–2019 influenza seasons. Data were obtained from 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. rVE was determined using the formula (% rVE = 1 − ORadjusted) × 100. Analysis sets included 1,755,420 individuals for the 2017–2018 season and 2,055,012 for the 2018–2019 season. Compared to IIV4, aIIV3 was 7.1% (95% confidence interval 3.3–10.8) and 20.4% (16.2–24.4) more effective at preventing influenza-related medical encounters in the 2017–2018 and 2018–2019 seasons, respectively. Comparable effectiveness was observed with HD-IIV3 across both seasons. Our results support improved effectiveness of aIIV3 vs IIV4 in a vulnerable population of older adults at high risk of influenza and its complications.

Seasonal influenza immunisation: Strategies for older adults

Article

Oct 2018

Adults over the age of 60‐65 years suffer disproportionally from seasonal influenza, experiencing high rates of complications, exacerbation of underlying medical comorbidities, and excess mortality. Thus, older adults are an important priority for influenza immunisation campaigns. Unfortunately, older adults generally display lower immune responses to standard influenza vaccines because of immunosenescence, with resulting suboptimal vaccine effectiveness. Thus, the development of improved vaccines that heighten immune responses and improve effectiveness is an important medical need. To this end, enhanced influenza vaccines specifically targeting this age group have been developed, which seek to overcome the inherent limitations in the immune responses of older adults. Both the licensed high‐dose trivalent influenza vaccine (hdTIV) containing fourfold higher antigen contents than standard vaccine, and the MF59®‐adjuvanted trivalent influenza vaccine (aTIV) have been proven to be safe and well‐tolerated while enhancing the immune response. Healthcare providers for populations of older adults should be advised to routinely use these enhanced influenza vaccines in seasonal immunisation campaigns to provide improved immunity against influenza and its consequences in this particularly susceptible age group.

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

Article

Full-text available

Apr 2024
INFLUENZA OTHER RESP

Background 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). Methods 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). Results 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. Conclusion Relative to both HD‐IIV3e and IIV4e, aIIV3 provided improved protection from cardiorespiratory or influenza hospitalizations.

A clinical and economic assessment of adjuvanted trivalent versus standard egg-derived quadrivalent influenza vaccines among older adults in the United States during the 2018-19 and 2019-20 influenza seasons

Article

Full-text available

Dec 2023

Background Clinical evidence supports use of enhanced influenza vaccines in older adults. Few economic outcome studies have compared adjuvanted trivalent inactivated (aIIV3) and standard egg-derived quadrivalent inactivated influenza vaccines (IIV4e). Research Design and Methods A retrospective cohort study was conducted leveraging deidentified US hospital data linked to claims data during the 2018–19 and 2019–20 influenza seasons. Relative vaccine effectiveness (rVE) was compared in adults aged ≥ 65 years receiving aIIV3 or IIV4e using inverse probability of treatment weighting (IPTW) and Poisson regression. An economic assessment quantified potential real-world cost savings. Results The study included 715,807 aIIV3 and 320,991 IIV4e recipients in the 2018–19 and 844,169 aIIV3 and 306,270 IIV4e recipients in the 2019–20 influenza seasons. aIIV3 was significantly more effective than IIV4e in preventing cardiorespiratory disease (2018–19 rVE = 6.2%; and 2019–20 rVE = 6.0%) and respiratory disease (2018–19 rVE = 8.9%; and 2019–20 rVE = 10.1%). During the 2018–19 influenza season cardiorespiratory hospitalization cost savings for the aIIV3 population were $392 M, and $221 M for the 2019–20 season. Respiratory hospitalization cost savings for the aIIV3 population were $145 M and $97 M, respectively. Conclusions Our findings suggest that aIIV3 provides clinical and economic advantages versus IIV4e in the elderly.

Antibody responses against heterologous H5N1 strains for an MF59-adjuvanted cell culture–derived H5N1 (aH5n1c) influenza vaccine in adults and older adults

Article

Full-text available

Jan 2023

MF59-adjuvanted H5N1, cell culture-derived inactivated influenza vaccine (aH5N1c, AUDENZ®, Seqirus) is available for persons 6 months of age and older. During a pandemic, lack of preexisting immunity to novel influenza strains increases morbidity and mortality. This study examined the potential for an adjuvanted vaccine to provide cross-protection to novel viruses. Two similarly designed studies involving separate cohorts aged 18–64 and ≥65 y assessed immune responses to five heterologous H5N1 influenza strains elicited by two 7.5 μg doses of aH5N1c given 3 weeks apart. Geometric mean titers (GMT) on Days 1 and 43 and Day 43/Day 1 geometric mean ratios (GMRs) were determined with hemagglutination inhibition (HI) and microneutralization (MN). Rates of seroconversion (SC) and percentages of subjects with HI and MN ≥ 1:40 were determined. Significant increases in GMTs were observed on Day 43 after vaccination for all 5 heterologous strains in all ages tested. SC rates were 28–55% and 17–46% among those aged 18–64 and ≥65 y, respectively. MN ≥ 1:40 was observed in 38–100% of younger and 37–97% of older subjects, and HI ≥ 1:40 was achieved by 28–64% of subjects aged 18–64 y and by 17–57% of subjects aged ≥65 y. A SC rate ≥40% (97.5% CI) was met for two heterologous strains tested in adults aged 18–64 y. In adults aged 18–64 and ≥65 y, two 7.5 μg doses of aH5N1c demonstrated increased immunogenicity from baseline against five heterologous H5N1 strains, illustrating the potential for aH5N1c to provide cross-protection against other H5N1 strains.

Surveillance of Severe Acute Respiratory Infection and Influenza Vaccine Effectiveness among Hospitalized Italian Adults, 2021/22 Season

Article

Full-text available

Dec 2022

Following an extremely low incidence of influenza during the first waves of the ongoing COVID-19 pandemic, the 2021/22 Northern Hemisphere winter season saw a resurgence of influenza virus circulation. The aim of this study was to describe epidemiology of severe acute respiratory infections (SARIs) among Italian adults and estimate the 2021/22 season influenza vaccine effectiveness. For this purpose, a test-negative case-control study was conducted in a geographically representative sample of Italian hospitals. Of 753 SARI patients analyzed, 2.5% (N = 19) tested positive for influenza, most of which belonged to the A(H3N2) subtype. Phylogenetic analysis showed that these belonged to the subclade 3C.2a1b.2a.2, which was antigenically different from the 2021/22 A(H3N2) vaccine component. Most (89.5%) cases were registered among non-vaccinated individuals, suggesting a protective effect of influenza vaccination. Due to a limited number of cases, vaccine effectiveness estimated through the Firth’s penalized logistic regression was highly imprecise, being 83.4% (95% CI: 25.8–97.4%) and 83.1% (95% CI: 22.2–97.3%) against any influenza type A and A(H3N2), respectively. Exclusion of SARS-CoV-2-positive controls from the model did not significantly change the base-case estimates. Within the study limitations, influenza vaccination appeared to be effective against laboratory-confirmed SARI.

Relative Effectiveness of MF59® Adjuvanted Trivalent Influenza Vaccine Versus Non-Adjuvanted Vaccines During the 2019-2020 Influenza Season

Article

Full-text available

Apr 2022

Background Age-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) versus 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. Methods This 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 (OR). 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. Results Subjects 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%, 0.7% of each cohort, respectively. Overall, rVE of aIIV3 was 27.5% (95% CI, 24.4 to 30.5) versus IIV4e and 13.9% (95% CI 10.7 to 17.0) vs versus HD-IIV3. aIIV3 had a more favorable rVE in inpatient and outpatient settings. Findings remained consistent across age subgroups and during alternative seasonal dates. Conclusions Adults ≥65 years vaccinated with aIIV3 had fewer influenza-related medical encounters compared with IIV4e or HD-IIV3 during the 2019-2020 US influenza season.

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

Article

Aug 2021
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.

Factors driving choices between types and brands of influenza vaccines in general practice in Austria, Italy, Spain and the UK

Article

Full-text available

Jun 2021
PLOS ONE

Influenza vaccine effectiveness (IVE) assessment is increasingly stratified by vaccine type or brand, such as done by the European network of DRIVE. In 2019/2020, eleven influenza vaccines were licensed in Europe. If more than one vaccine type is recommended or if more than one vaccine brand is available for a specific risk group, it is not clear which factors affect the choice of a specific vaccine (type or brand) by a health practitioner for individual patients. This is important for IVE assessment. A survey tailored to the 2019/20 local vaccine recommendations was conducted among GPs in four European countries (Austria, Italy, Spain, UK) to understand how influenza vaccine is offered to recommended risk groups and, if GPs have a choice between 2 or more vaccines, what factors influence their vaccine choice for patients. Overall, 360 GPs participated. In Austria, Italy and Spain GPs indicated that influenza vaccines are commonly offered when patients present for consultation, whereas in the UK all GPs indicated that all relevant patients are contacted by letter. In Austria and Italy, roughly 80% of GPs had only one vaccine type available for patients <65y. The use of any specific vaccine type in this age group is mostly determined by the availability of specific vaccine type(s) at the clinic. GPs frequently reported availability of more than one vaccine type for patients ≥65y in Austria (45%), Italy (70%) and Spain (79%). In this group, patient characteristics played a role in choice of vaccine, notably older age and presence of (multiple) comorbidities. Knowing that a non-patient related factor usually determines the vaccine type a patient receives in settings where more than one vaccine type is recommended for risk groups <65y, simplifies IVE assessment in this age group. However, patient characteristics need careful consideration when assessing IVE in those ≥65y.

Overcoming immune dysfunction in the elderly: Trained immunity as a novel approach

Article

Full-text available

Aug 2020
INT IMMUNOL

People with advanced age have a higher susceptibility to infections and exhibit increased mortality and morbidity as the ability of the immune system to combat infections decreases with age. While innate immune cells display functional defects such as decreased phagocytosis, chemotaxis and cytokine production, adaptive immune cells exhibit reduced receptor diversity, defective antibody production and a sharp decline in naive cell populations. Successful responses to vaccination in the elderly are critical to prevent common infections such as influenza and pneumonia, but vaccine efficacy decreases in older individuals compared with young adults. Trained immunity is a newly emerging concept that showed that innate immune cells possess non-specific immunological memory established through epigenetic and metabolic reprogramming upon encountering certain pathogenic stimuli. Clinical studies suggest that trained immunity can be utilized to enhance immune responses against infections and improve the efficiency of vaccinations in adults; however, how trained immunity responses are shaped with advanced age is still an open question. In this review, we provide an overview of the age-related changes in the immune system with a focus on innate immunity, discuss current vaccination strategies for the elderly, present the concept of trained immunity and propose it as a novel approach to enhance responses against infections and vaccinations in the elderly population.

Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials

Article

Full-text available

Jun 2020

Influenza carries an enormous burden each year. Annual influenza vaccination is the best means of reducing this burden. To be clinically effective, influenza vaccines must be immunogenic, and several immunological assays to test their immunogenicity have been developed. This study aimed to describe the patterns of use of the various immunological assays available to measure the influenza vaccine-induced adaptive immune response and to determine its correlates of protection. A total of 76.5% of the studies included in our analysis measured only the humoral immune response. Among these, the hemagglutination-inhibition assay was by far the most widely used. Other, less common, humoral immune response assays were: virus neutralization (21.7%), enzyme-linked immunosorbent (10.1%), single radial hemolysis (4.6%), and assays able to quantify anti-neuraminidase antibodies (1.7%). By contrast, cell-mediated immunity was quantified in only 23.5% of studies. Several variables were significantly associated with the use of single assays. Specifically, some influenza vaccine types (e.g., adjuvanted, live attenuated and cell culture-derived or recombinant), study phase and study sponsorship pattern were usually found to be statistically significant predictors. We discuss the principal findings and make some suggestions from the point of view of the various stakeholders.

Preparedness against pandemic influenza: Production of an oil-in-water emulsion adjuvant in Brazil

Article

Full-text available

Jun 2020
PLOS ONE

Increasing pandemic influenza vaccine manufacturing capacity is considered strategic by WHO. Adjuvant use is key in this strategy in order to spare the vaccine doses and by increasing immune protection. We describe here the production and stability studies of a squalene based oil-in-water emulsion, adjuvant IB160, and the immune response of the H7N9 vaccine combined with IB160. To qualify the production of IB160 we produced 10 consistency lots of IB160 and the average results were: pH 6.4±0.05; squalene 48.8±.0.03 mg/ml; osmolality 47.6±6.9 mmol/kg; Z-average 157±2 nm, with polydispersity index (PDI) of 0.085±0.024 and endotoxin levels <0.5 EU/mL. The emulsion particle size was stable for at least six months at 25°C and 24 months at 4–8°C. Two doses of H7N9 vaccine formulated at 7.5 μg/dose or 15 μg/dose with adjuvant IB160 showed a significant increase of hemagglutination inhibition (HAI) titers in sera of immunized BALB/c mice when compared to control sera from animals immunized with the H7N9 antigens without adjuvant. Thus the antigen-sparing capacity of IB160 can potentially increase the production of the H7N9 pandemic vaccine and represents an important achievement for preparedness against pandemic influenza and a successful North (IDRI) to South (Butantan Institute) technology transfer for the production of the adjuvant emulsion IB160.

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

Article

Full-text available

Feb 2020

Background: 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. Methods: 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. Results: 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). Conclusion: 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.

Immunogenicity of aIIV3, MF59-Adjuvanted Seasonal Trivalent Influenza Vaccine, in Older Adults ≥65 Years of Age: Meta-Analysis of Cumulative Clinical Experience

Article

Full-text available

Mar 2019
INT J INFECT DIS

Objective: Compare the immunogenicity of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3; Fluad™) versus conventional trivalent inactivated influenza vaccine (IIV3) in an integrated dataset using a meta-analysis. Methods: In a meta-analysis, the immunogenicity of aIIV3 in subjects ≥65 years of age was compared with IIV3 immunogenicity using hemagglutination inhibition assay results from 23 phase I through III randomized controlled trials, including 16 first-dose vaccination studies and 7 revaccination studies assessing immunogenicity after second or third annual vaccination. Results: The full analysis set consisted of 11,105 subjects (5869 aIIV3 and 5236 IIV3). In the revaccination studies, 822 individuals received 2 consecutive annual influenza vaccinations (492 aIIV3 and 330 IIV3), and 237 received 3 (150 aIIV3 and 87 IIV3). Overall, across all strains, the meta-analyzed point estimates for seroconversion (SC) and geometric mean titer (GMT) ratio were significantly higher for aIIV3 versus IIV3. The meta-analyzed percent differences in SC with corresponding 95% confidence intervals (CI) for A/H1N1, A/H3N2, and B strain were 9.5% (5.2-13.9), 10.5% (6.6-14.5), and 12.7% (8.6-16.8), respectively. The meta-analyzed GMT ratios with corresponding 95% CI for A/H1N1, A/H3N2, and B strain were 1.15 (1.01-1.31), 1.30 (1.18-1.44), 1.23 (1.15-1.31). Antibody responses against heterologous influenza strains were also significantly higher with aIIV3. Revaccination studies showed continued robust immune response to aIIV3 with repeated vaccination. Conclusions: aIIV3 elicited a statistically significantly greater immune response compared to conventional IIV3 in older adults, increasing the breadth and duration of the immune response.

Comparative Immunogenicity of Enhanced Seasonal Influenza Vaccines in Older Adults: A Systematic Review and Meta-analysis

Article

Dec 2018

INTRODUCTION: A number of enhanced influenza vaccines have been developed for use in older adults, including the high-dose, MF59-adjuvanted, and intradermal vaccines. METHODS: We conducted a systematic review examining the improvements in antibody responses measured by the hemagglutination inhibition (HAI) assay associated with these enhanced vaccines, compared to each other, and compared to standard-dose vaccine using random effects models. RESULTS: Thirty-nine trials were included. Compared to adults aged 60 years receiving standard-dose vaccines, those receiving enhanced vaccines had significantly higher post-vaccination titers (for all vaccine strains) and higher proportions with elevated titers ≥40 (for most vaccine strains). High-dose vaccine elicited 82% higher post-vaccination titer to A(H3N2) compared to standard-dose vaccine; this was significantly higher than 52% estimated for MF59-adjuvanted versus standard-dose vaccines (p=0.04), which was higher than 32% estimated for intradermal versus standard-dose vaccines (p<0.01). CONCLUSIONS: Overall, by summarizing current evidence, we found enhanced vaccines had greater antibody responses than standard-dose vaccine. Indications of differences among enhanced vaccines highlight that further research is needed in order to compare new vaccine options; this is especially needed during seasons with mismatched circulating strains and for immune outcomes other than HAI titers as well as vaccine efficacy.

Correlates of adjuvanticity: A review on adjuvants in licensed vaccines

Article

Full-text available

May 2018

After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics. For example, they induce early activation (although at different levels) of innate immunity which then translates into higher antibody and cellular responses to the vaccine antigens. In addition, most of these adjuvants (e.g. MF59, AS03, AS04) clearly induce a wider breadth of adaptive responses able to confer protection against, for example, heterovariants of the influenza viruses (MF59, AS03) or against human papillomavirus strains not contained in the vaccine (AS04). Finally, the use of some of these adjuvants has contributed to significantly enhance the immune response and the efficacy and effectiveness of vaccines in the elderly who experience a waning of the immune responsiveness to infection and vaccination, as shown for MF59- or AS03-adjuvanted influenza vaccines and AS01-adjuvanted herpes zoster vaccine. These results, together with the track record of acceptable safety profiles of the adjuvanted vaccines, pave the way for the development of novel vaccines at the extremes of age and against infections with a high toll of morbidity and mortality. Here, we review the mechanisms associated with the performance of those adjuvanted vaccines in animal models and in humans through recent advances in systems vaccinology and biomarker discovery. We also provide some perspectives on remaining knowledge gaps but also on opportunities that could accelerate the development of new vaccines.

A randomized clinical trial to identify the optimal antigen and MF59® adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects

Article

Mar 2012

AS03- and MF59-Adjuvanted Influenza Vaccines in Children

Article

Full-text available

Dec 2017

Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.

Vaccination choices for older people, looking beyond specific age

Article

Nov 2017
EXPERT REV VACCINES

Introduction: To improve the ability of vaccines to protect older individuals we can no longer consider those over 65 years of age to be an homogenous population termed the “elderly” displaying a condition termed immunosenescence. Area Covered: The most recent figures from the US Census Bureau indicate that the global population exceeds 7,400 million. Of these more than 657 million are currently over 65, an age often designated by policy makers as permitting them access to concessions, pensions and social care benefits. But the spill-over consequences of these policies are the impact they have on access to different vaccine formulations. Aging is associated with a blunted immune system, often termed immunosenescence, and because those of 65 are considered old, by association they are thought to have reduced immunity. Consequently, different vaccines are offered to those over this age. Expert Commentary: We believe it to be an inappropriate policy to ascribe a biological condition and consequent vaccine choices, to a population on the basis of single chronological feature. To ensure better protection within this population we need to consider approaches to stratify this group to ensure the best vaccine choices.

Aging of the immune system: Focus on inflammation and vaccination

Article

Sep 2016
EUR J IMMUNOL

Major advances in preventing, delaying or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching 8–9 decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly. This article is protected by copyright. All rights reserved

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

Article

Full-text available

Aug 2016
PLOS ONE

Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.

Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans

Article

Full-text available

Jun 2016
PLOS ONE

CD4⁺ T follicular helper cells (TFH) have been identified as the T-cell subset specialized in providing help to B cells for optimal activation and production of high affinity antibody. We recently demonstrated that the expansion of peripheral blood influenza-specific CD4⁺IL-21⁺ICOS1⁺ T helper (TH) cells, three weeks after vaccination, associated with and predicted the rise of protective neutralizing antibodies to avian H5N1. In this study, healthy adults were vaccinated with plain seasonal trivalent inactivated influenza vaccine (TIIV), MF59®-adjuvanted TIIV (ATIIV), or saline placebo. Frequencies of circulating CD4⁺ TFH1 ICOS⁺ TFH cells and H1N1-specific CD4⁺IL-21⁺ICOS⁺ CXCR5⁺ TFH and CXCR5⁻ TH cell subsets were determined at various time points after vaccination and were then correlated with hemagglutination inhibition (HI) titers. All three CD4+ T cell subsets expanded in response to TIIV and ATIIV, and peaked 7 days after vaccination. To demonstrate that these TFH cell subsets correlated with functional antibody titers, we defined an alternative endpoint metric, decorrelated HI (DHI), which removed any correlation between day 28/day 168 and day 0 HI titers, to control for the effect of preexisting immunity to influenza vaccine strains. The numbers of total circulating CD4⁺ TFH1 ICOS⁺ cells and of H1N1-specific CD4⁺IL-21⁺ICOS⁺ CXCR5⁺, measured at day 7, were significantly associated with day 28, and day 28 and 168 DHI titers, respectively. Altogether, our results show that CD4⁺ TFH subsets may represent valuable biomarkers of vaccine-induced long-term functional immunity. Trial Registration ClinicalTrials.gov NCT01771367

Antibody responses to natural influenza A/H1N1/09 disease or following immunization with adjuvanted vaccines, in immunocompetent and immunocompromised children

Conference Paper

Full-text available

Jun 2011

To compare antibody responses elicited by influenza A/H1N1/09 disease and immunization with adjuvanted vaccines, in immunocompetent or immunocompromised children. Prospective parallel cohort field study enrolling children with confirmed influenza A/H1N1/09 disease or immunized with 1 (immunocompetent) or 2 (immunocompromised) doses of influenza A/H1N1/09 squalene-based AS03- or MF59-adjuvanted vaccines. Antibody geometric mean titers (GMT) were measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays 4-6 weeks after vaccination/disease. Vaccine adverse events were self-recorded in a 7-day diary. Antibody titers were as high in 48 immunocompetent children after a single immunization (HAI and MN seroprotection rates: 98%; HAI-GMT: 395, MN-GMT: 370) as in 51 convalescent children (seroprotection rates: 98% (HAI) and 92% (MN); GMT: 350 (HAI) and 212 (MN). Twenty-seven immunocompromised children reached slightly lower seroprotection rates (HAI: 89%, MN: 85%) but similar antibody titers (HAI-GMT: 306, MN-GMT: 225) after 2 immunizations. Adverse events increased with age (P=0.01) and were more frequent with Pandemrix® than Focetria® (P=0.03). Similarly high seroresponses may be expected in immunocompetent children after a single dose of adjuvanted vaccines as responses of convalescent children. Two vaccine doses were sufficient for most immunocompromised children. NCT0102293 and NCT01022905.

Influenza Evolution and H3N2 Vaccine Effectiveness, with Application to the 2014/2015 Season

Article

Full-text available

Oct 2015

H3N2 Influenza A is a serious disease which can lead to hospitalization and which causes significant morbidity and mortality. Vaccines against the seasonal influenza disease are of variable effectiveness. In this paper, we discuss use of the $p_{\rm epitope}$ method to predict the dominant influenza strain and the expected vaccine effectiveness in the coming flu season. We illustrate how the effectiveness of the 2014/2015 A/Texas/50/2012 vaccine against the A/California/02/2014 strain that emerged in the population can be estimated via $p_{\rm epitope}$. In addition, we show by a multidimensional scaling analysis of data collected through 2014, the emergence of a new A/New Mexico/11/2014-like cluster that is immunogenetically distinct from the A/California/02/2014-like strains.

A Novel Dynamic Model for Health Economic Analysis of Influenza Vaccination in the Elderly

Article

Full-text available

Sep 2015

Introduction New vaccines are being developed to improve the efficacy of seasonal influenza immunization in elderly persons aged ≥65 years. These products require clinical and economic evaluation to aid policy decisions. Methods To address this need, a two-part model has been developed, which we have applied to examine the potential clinical and economic impact of vaccinating elderly persons with adjuvanted trivalent inactivated influenza vaccine (aTIV) relative to conventional trivalent (TIV) and quadrivalent (QIV) vaccines. We compared outcomes in the US population for (1) aTIV in persons aged ≥65 years and QIV in all other age cohorts; (2) QIV in all cohorts; (3) TIV in all cohorts. Low, average, and high intensity seasons with low, average, and high vaccine match scenarios were compared. Probabilistic sensitivity analysis was conducted within each discrete scenario to explore the impact of variation in model inputs on potential outcomes. Results Assuming current vaccination coverage rates in the US population with (a) 25% better efficacy of adjuvanted versus non-adjuvanted vaccine against any strain and (b) 35% better efficacy of non-adjuvanted vaccine against matched B versus mismatched B strains, use of aTIV in persons aged ≥65 years and QIV in persons <65 years could reduce influenza cases by 11,166–1,329,200, hospitalizations by 1365–43,674, and deaths by 421–11,320 versus use of QIV in all cohorts. These outcomes are reflected in a corresponding increase in quality-adjusted life-years (QALYs) of 3003–94,084. If the prevalence of mismatched influenza B was >54.5% of all circulating strains, use of QIV in all cohorts would offset the clinical benefits of aTIV. Elderly aTIV or QIV vaccination was associated with improved outcomes over non-adjuvanted TIV in many of the scenarios, particularly in low match seasons of any intensity. Total cost savings (including direct and indirect healthcare costs plus productivity impacts) with aTIV in the elderly versus QIV in the whole population ranged from $27 million (low intensity, low match) to $934 million (high intensity, high match). Univariate sensitivity analysis of relative vaccine prices in the average intensity, average match scenario indicated that aTIV could be marginally cost saving relative to QIV at the currently published Medicare price for influenza vaccines offering enhanced efficacy in the elderly. Elderly vaccination with aTIV was associated with a higher overall cost compared with TIV in only two scenarios (low intensity with average or high match); the incremental cost/QALY relative to TIV was $9980 in the average match scenario and $28,800 in the high match scenario. Conclusions Vaccination of persons aged ≥65 years with aTIV has the potential to provide clinical and economic benefit relative to QIV and TIV. The new model allows the assessment of various alternative strategies for available influenza vaccines. Funding Novartis Vaccines.

Influenza vaccination in children primed with MF59®-adjuvanted or non-adjuvanted seasonal influenza vaccine

Article

Full-text available

Jun 2015

Routine annual influenza immunisation is increasingly recommended in young children. We compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine (TIV) versus MF59-adjuvanted TIV (aTIV) in children who received two half or full doses of aTIV or TIV, or non-influenza control vaccine, in an efficacy trial conducted two years earlier. 197 healthy children aged 30-96 months were randomized to receive vaccination with aTIV or TIV in 2010. To evaluate responses to the first follow-up seasonal vaccination after priming we excluded children who received influenza vaccine(s) in the 2009 pandemic year leaving 40 children vaccinated with aTIV, 26 children with TIV and 10 children with aTIV after a control vaccine in the parent study. Hemagglutination inhibiting antibodies were assayed on Days 1, 22 and 181. aTIV vaccination produced 6.9 to 8.0-fold higher antibody responses than the reference TIV-TIV regimen against A/H3N2 and B strains, which remained higher six months following vaccination. The response to the B/Victoria lineage antigen in the second year's vaccine (the first vaccine contained a B/Yamagata lineage antigen) demonstrated that aTIV primed for an adequate response after a single dose on Day 22 (GMTs 160, 95 to antigens in the two lineages, respectively), whereas TIV did not (GMTs 38, 20). Vaccination with aTIV produced slightly higher but acceptable local and systemic reactogenicity compared to TIV-TIV and TIV-aTIV mixed regimens. Within the limitations of a small study, the strong immune responses support the use of aTIV for vaccination in young children.

Impact of Repeated Vaccination on Vaccine Effectiveness Against Influenza A(H3N2) and B During 8 Seasons

Article

Full-text available

Sep 2014

Background: Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. Methods: Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history. Results: There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of historical vaccination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%-80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%-41%; P = .01). VE against B was 75% (95% CI, 50%-87%) and 48% (95% CI, 29%-62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18-49 years. Conclusions: Current- and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination.

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

Article

Apr 2024
INFLUENZA OTHER RESP

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.

Gut Microbiome and the Immune System

Chapter

Sep 2022

A vaccine works by allowing the immune system to “practice” on a weakened or killed version of the pathogen or components thereof, including surface proteins, polysaccharides, or toxins. While age is one very important driver of vaccine efficacy, other factors should be considered, including demographics, comorbidities, previous vaccinations, and medication use, but also the intestinal microbiome. This chapter describes how the gut microbiome has both local and systemic impacts on the immune response, and how these can be used to improve vaccine efficacy. Animal models are usually used so that direct causality can be inferred between the composition of the microbiota to a given treatment and/or infection. The latest research in the human microbiome field has made evident that the gut microbiome can impact vaccine responses, from vaccine efficacy to its effect on extending immune memory against a specific pathogen.

Adjuvanted versus non-adjuvanted standard-dose influenza vaccines in preventing all-cause hospitalizations in the elderly: a cohort study with nested case-control analyses over 18 influenza seasons

Article

Aug 2022

Background The higher effectiveness of adjuvanted trivalent influenza vaccine (aTIV) versus non-adjuvanted (na) formulations in preventing all-cause hospitalization has been demonstrated for a single influenza season and in institutionalized elderly only. This study evaluated the relative vaccine effectiveness for aTIV vs. non-adjuvanted trivalent (naTIV) and/or quadrivalent (naQIV) influenza vaccines in preventing all-cause hospitalizations across 18 influenza seasons in primary care. Research design and methods Using Health Search Database, a nested case-control analysis was conducted in a cohort of older adults being vaccinated with aTIV or naTIV/naQIV. Conditional logistic regression was adopted to estimate the odds ratio (OR) of all-cause hospitalizations occurred during the epidemic period. Results Of 58,252 patients vaccinated with aTIV and naTIV/naQIV for the first time, 2,504 cases of all-cause hospitalization (3.46 per 1,000 person-weeks) during the 18 influenza seasons were identified. Compared with naTIV/naQIV, aTIV was associated with a 12% reduced the odds of all-cause hospitalizations (OR 0.88; 95% CI: 0.80–0.98). Conclusions In an 18-season cohort of older adults, aTIV reduced the risk of all-cause hospitalizations when compared with naTIV/naQIV. Our findings confirm additional benefits for adjuvanted influenza vaccines in older adults.

Resolving adjuvant mode of action to enhance vaccine efficacy

Article

Jun 2022

Adjuvants are a miscellaneous range of molecules and materials that can enhance the magnitude, functionality, breadth and durability of immune responses. Despite the multiplicity of compounds with adjuvant properties, less than a dozen are in clinical use in vaccines against infectious diseases. While many factors have contributed to their slow development, among the major challenges are the high safety and efficacy standards set by current adjuvants in human vaccines and our limited understanding of how adjuvants mediate their effects. This review outlines why it is so difficult to elucidate their mechanism of action, highlights areas that require in-depth research and discusses recent advancements that are revitalising adjuvant development. It is hoped that a fuller understanding of adjuvant sensing, signalling and function will facilitate the design of vaccines that promote sustained protective immunity against challenging bacterial and viral pathogens.

Antibody responses against heterologous A/H5N1 strains for an MF59-adjuvanted cell culture–derived A/H5N1 (aH5N1c) influenza vaccine in healthy pediatric subjects

Article

Oct 2021
VACCINE

Background Vaccines are the main prophylactic measure against pandemic influenza. Adjuvanted, cell culture–derived vaccines, which are not subject to limitations of egg-based vaccine production, have the potential to elicit an antibody response against heterologous strains and may be beneficial in the event of an A/H5N1 pandemic. Methods A prespecified exploratory analysis of data from a phase 2, randomized, controlled, observer-blind multicenter trial (NCT01776554) to evaluate the immunogenicity of a MF59-adjuvanted, cell culture–based A/H5N1 influenza vaccine (aH5N1c), containing 7.5 µg hemagglutinin antigen per dose, in subjects 6 months through 17 years of age was conducted. Geometric mean titers (GMT) were determined using hemagglutination inhibition (HI) and microneutralization (MN) assays, and proportions of patients achieving seroconversion, HI and MN titers ≥ 1:40, and a 4-fold increase in MN titers against 5 heterologous strains (influenza A/H5N1 Anhui/2005, Egypt/2010, Hubei/2010, Indonesia/2005, and Vietnam/1203/2004) three weeks after administration of the second dose were assessed. Results After the second dose, HI GMTs against heterologous strains increased between 8- and 40-fold, and MN GMTs increased 13- to 160-fold on Day 43 vs Day 1. On Day 43, 32–72% of subjects had HI titers ≥ 1:40 and achieved seroconversion against the heterologous strains. Using the MN assay, 84–100% of subjects had MN titers ≥ 1:40 and 83–100% achieved an at least 4-fold increase in MN titers against the heterologous strains. The highest responses were consistently against A/H5N1 Egypt/2010. Conclusions When given to children aged 6 months through 17 years, aH5N1c resulted in increased immunogenicity from baseline against all 5 heterologous A/H5N1 strains tested, demonstrating the potential of an MF59-adjuvanted, cell-derived A/H5N1 vaccine to provide cross-protection against other A/H5N1 strains (NCT01776554).

Approaches in broadening the neutralizing antibody response of the influenza vaccine

Article

Sep 2021

Introduction influenza vaccine is the mainstay for influenza prevention and elicits immune response and antigen-specific neutralizing antibodies against influenza virus. However, antigenic drift and shift can confer influenza virus to escape from the immune response induced by vaccine, and then reduce the vaccine effectiveness. Areas covered To improve effect and neutralizing antibody response of vaccine for heterologous influenza virus, a literature review of preclinical and clinical studies published before August 2021 and searched in PubMed, which evaluated vaccine effectiveness improved by adjuvants and administration route. Expert opinion The review showed that adjuvant, including imiquimod, GLA, MF59, and AS03, can improve the effectiveness of influenza vaccines by regulating immune system. Subjects receiving influenza vaccine combined with these adjuvants showed enhanced antibody response against homologous and heterologous virus strains compared to those vaccinated without adjuvant. This review also discussed the role of intradermal vaccination. In contrast to intramuscular vaccination, intradermal vaccination elicited a robust and prolonged antibody response against vaccine strains and drifted virus than intramuscular vaccination.

Effectiveness of the MF59‐adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta‐analysis

Article

Full-text available

Jun 2021
INFLUENZA OTHER RESP

Background Standard-dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. Objective To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high-dose egg-based influenza vaccines among people ≥65 years old. Methods Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer-reviewed journals and gray literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data; risk of bias was assessed using the ROBINS-I tool. Results Twenty-one studies conducted during the 2006/07–2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I² = 0%) for non-emergency outpatient visits and 58.5% (40.7, 70.9; I² = 52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I² = 0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza-related medical encounters were 13.9% (4.2, 23.5; I² = 95.9%) compared with TIV, 13.7% (3.1, 24.2; I² = 98.8%) compared with QIV, and 2.8% (−2.9, 8.5; I² = 94.5%) compared with HD-TIV. Conclusions Among adults ≥65 years, aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

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

Article

Full-text available

Feb 2021

Background The effectiveness of standard, egg-derived quadrivalent influenza vaccines (IIV4) may be reduced in adults ≥65 years of age, largely due to 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 to IIV4 and HD-IIV3 in preventing influenza-related medical encounters over two US influenza seasons. Methods This 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 comprised of 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. Results In 2017-2018, cohorts included: aIIV3, n=524,223; IIV4, n=917,609; HD-IIV3, n=3,377,860. After adjustment, 2017-2018 rVE of aIIV3 vs. IIV4 was 18.2 (95% confidence interval [CI] 15.8 to 20.5); aIIV3 vs. HD-IIV3 was 7.7 (2.3 to 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 vs. IIV4 of 27.8 (25.7 to 29.9) and vs. HD-IIV3 of 6.9 (3.1 to 10.6). Conclusion In the 2017-2018 and 2018-2019 influenza seasons in the US, aIIV3 demonstrated greater reduction in influenza-related medical encounters than IIV4 and HD-IIV3 in adults ≥65 years.

Triggering of Toll-like Receptors in Old Individuals. Relevance for Vaccination

Article

Nov 2019

Aging is characterized by a general decline in a range of physiological functions, with consequent increasing risk of developing all chronic diseases and geriatric syndromes. Additionally, increasing age is accompanied by a progressive decline in both innate and acquired immune system, referred to as immunosenescence. This impaired ability to mount an efficient immune response after exposure to microorganisms or vaccines represents a major challenge in acquiring protection against pathogens in aging. Therefore, there is still a great need for vaccines that are tailored to optimally stimulate the aged immune system, thus promoting more successful aging. Various strategies can be used to improve vaccine efficacy in old people. Despite this, meta-analyses have clearly shown that the magnitude of protection obtained remains lower in the older adults. Recent studies show that stimulation of Toll-like receptors, using stimulatory ligands, can enhance vaccine efficacy by a number of mechanisms, including the activation of innate immune cells and the consequent production of inflammatory cytokines. Therefore, a possible strategy for more effective vaccination in the older population is the triggering of multiple TLRs, using a combined adjuvant for the synergistic activation of cellular immunity. Preliminary in vitro data suggest that in humans the presence of multiple TLR agonists can result in the greater stimulation of antigen specific immune responses in immune cells both in the young healthy and in the immune senescent older donors. These data suggest that appropriately selected combinations of TLR agonists could enhance the efficacy of vaccination mediated immunity in older people.

Enhanced Passive Safety Surveillance (EPSS) confirms an optimal safety profile of the use of MF59®‐adjuvanted influenza vaccine in older adults: Results from three consecutive seasons

Article

Full-text available

Oct 2019
INFLUENZA OTHER RESP

Background: In Europe, the enhanced safety surveillance (ESS) of seasonal influenza vaccines is mandatory, in order to detect any potential increase in reactogenicity when the vaccine composition is updated. The MF59® -adjuvanted influenza vaccine (Fluad™) is the first and the only licensed adjuvanted seasonal influenza vaccine in Europe. Objective: Our objective was to summarize the safety data of Fluad™ over three consecutive seasons. Methods: A passive approach to ESS (EPSS) was adopted, in which reporting of spontaneous adverse events (AEs) by vaccinees and vaccine exposure was estimated, in order to generate a near real-time reporting rate. EPSS was conducted in Italy during the 2015, 2016, and 2017 influenza seasons in the primary care setting. All AEs reported within 7 days following immunization were analyzed by season, type and seriousness. Fisher's exact test was used to compare frequencies between seasons. Results: Total exposure accounted for approximately 1,000 doses of Fluad™ for each season. A total of 0.5% (2015), 0.7% (2016), and 0.5% (2017) individual case safety reports (ICSRs) were received, corresponding to a total of 9 (2015), 18 (2016), and 12 (2017) spontaneous AEs. The frequencies of AEs of interest were below those expected on the basis of the known safety profile of the vaccine. Most AEs were mild-to-moderate in severity. No between-season difference was found. Conclusions: Our analyses confirmed that the safety data observed were consistent with the known safety profile of Fluad™, which has been amply established over the last 20 years. No significant changes in the safety profile were observed.

Special Considerations for Vaccines and the Elderly

Chapter

Jan 2019

Short-term and mid-term solutions for influenza vaccines

Article

Aug 2018
LANCET INFECT DIS

Effective Immunization of Older Adults Against Seasonal Influenza

Article

Mar 2018
AM J MED

The 2017-18 influenza season reminds us that it is important for healthcare professionals to be prepared for the annual onslaught of this contagious respiratory disease associated with potentially serious complications. Vaccination is by far the best method to prevent and control influenza, reducing illness, hospitalizations, and mortality. The highest rates of influenza-associated morbidity and mortality are observed in older adults. The immune function of older adults decreases with increasing age, a phenomenon termed immunosenescence. Immunosenescence not only confers increased susceptibility to influenza disease, but also renders vaccination less effective. To address the need for improved vaccines that provide enhanced protection to this high-risk group, two formulations - a high-dose vaccine and an adjuvanted vaccine - have been approved in recent years specifically for people aged 65 years and over. Here we discuss: the challenges of influenza immunization in those 65 years and older; the recent advancements in vaccines targeted at this age group; and the latest influenza vaccine recommendations for the 2017-18 influenza season in the United States.

Inactivated Influenza Vaccines: Pre-Vaccination Haemagglutinin-Antibody Titres Influence the Vaccine Response but Not Necessarily the Vaccine Effectiveness Reply

Article

Jan 2011

Novel Strategies for Improved Vaccines for the Elderly: The Example of Influenza

Chapter

Dec 2012

Aging is characterized by a panoply of defects in various compartments of the immune system which render elderly individuals more susceptible to infectious diseases, and can profoundly affect the immunogenicity and the efficacy of various vaccines. Consequently, improved, stronger vaccines are required that are better suited for elderly people. Toward this end, several approaches have been undertaken in the past decade, especially in the field of influenza, an infection which causes a high burden of morbidity and mortality in elderly people. Among the various paths followed toward the improvement of influenza vaccines for the elderly, those which have received most attention are based on the use of high doses of influenza antigens, the use of alternative routes of administration such as the intradermal and the transcutaneous routes, the use of cytokines, intranasal administration, and finally the use of adjuvants. Oil-in-water adjuvants, such as MF59, have probably produced the best results so far in inducing more efficacious responses in elderly individuals, both against the seasonal and against the pandemic influenza viruses. More work is required to decipher the mechanisms by which these strategies, and in particular adjuvants, exert their enhancing effect at older ages. This is particularly important to better tune the development of stronger vaccines in this frail age group.

Optimizing Response to Vaccination in the Elderly

Chapter

Nov 2014

The elderly population is generally immunologically frail and more susceptible to infectious diseases, making the need of preventive treatments (vaccination) a public health issue. However, normal vaccines that are effective in young and adult individuals are less immunogenic and less protective in the elderly, due to their impaired immune responsiveness. It is therefore necessary to design new vaccines especially suited to raise protective immunity in the elderly population. Among the several approaches recently undertaken in this direction, the case of influenza vaccination is exemplary and can be taken as paradigm of how a vaccine for the elderly is designed and developed. The approach includes higher antigen dosage, repeated challenges, different immunization routes, and use of strong adjuvants. Basically, a better knowledge of the anomalous immune responsiveness in the elderly remains the unrenounceable basis on which effective immunization strategies in immunologically frail populations should be based. © 2014 Springer-Verlag Berlin Heidelberg. All rights are reserved.

Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: A single-centre, double-blind, randomised, controlled phase 2b/3 trial

Article

Nov 2015

Background: Pretreatment with topical imiquimod, a synthetic agonist of toll-like receptor 7, significantly improved the immunogenicity of influenza vaccination in elderly people. We aimed to clarify its effect in a younger age group. Methods: In this double-blind, randomised controlled trial, we enrolled healthy volunteers aged 18-30 years in early 2014 to receive the 2013-14 northern-hemisphere winter trivalent influenza vaccine at the Queen Mary Hospital, (Hong Kong, China). Eligible participants were randomly assigned (1:1:1:1) to one of the four vaccination groups: the study group, topical imiquimod-cream followed by intradermal trivalent influenza vaccine (INF-Q-ID), or one of three control groups, topical aqueous-cream control followed by intradermal trivalent influenza vaccine (INF-C-ID), topical aqueous-cream control followed by intramuscular trivalent influenza vaccine (INF-C-IM), and topical imiquimod-cream followed by intradermal normal-saline injection (SAL-Q-ID). Randomisation was by computer-generated lists in blocks of four. The type of topical treatment was masked from volunteers and investigators, although not from the study nurse. Serum haemagglutination-inhibition and microneutralisation-antibody titres were assayed. The primary outcome was seroconversion at day 7 after treatment for three vaccine strains of influenza (A/California/07/2009 H1N1-like virus [A/California/H1N1], A/Victoria/361/2011 H3N2-like virus [A/Victoria/H3N2], and B/Massachusetts/2/2012-like virus [B/Yamagata lineage]) and four non-vaccine strains (A/HK/485197/14 [H3N2 Switzerland-like lineage], prototype A/WSN/1933 [H1N1], A/HK/408027/09 [prepandemic seasonal H1N1], and B/HK/418078/11 [Victoria lineage]). Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02103023. Findings: We enrolled 160 healthy volunteers between March 1 and May 31, 2014, and 40 participants were randomly assigned to each study group. For the A/California/H1N1 strain, seroconversion at day 7 occurred in 39 participants (98%) in the INF-Q-ID group, 25 (63%) in the INF-C-ID group, 18 (45%) in the INF-C-IM group, and none in the SAL-Q-ID group; for the A/Victoria/H3N2, this was 30 (75%) in the INF-Q-ID group, four (10%) in the INF-C-ID group, four (10%) in the INF-C-IM group, and none in the SAL-Q-ID group; and for the B/Massachusetts (Yamagata lineage) strain, this was 36 (90%) in the INF-Q-ID group, 27 (68%) in the INF-C-ID group, 17 (43%) in the INF-C-IM group, and one (3%) in the SAL-Q-ID group (p<0·0001 for all three vaccine strains). Adverse reactions were infrequent and self-limited and did not differ between the four groups. Furthermore, the seroconversion rate against the four non-vaccine strains was better in the INF-Q-ID group than in the control groups on days 7 and 21 (p<0·0001). The most common adverse events were grade 1 redness (five participants in the INF-Q-ID group, three in INF-C-ID, one in INF-C-IM, and one in SAL-Q-ID) and grade 1 swelling (seven participants in INF-Q-ID group, five in INF-C-ID, three in INF-C-IM, and two in SAL-Q-ID. Interpretation: Topical application of imiquimod before intradermal trivalent influenza vaccine significantly improved immunogenicity against the vaccine influenza strains in young healthy individuals and increased immunogenicity against the non-vaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-14 recommended vaccine. Further studies should be done to establish the efficacy and safety of this approach for other injectable vaccines to augment the onset and range of protection. Funding: The Shaw Foundation Hong Kong, Health and Medical Research Fund (Hong Kong, China), The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease for the HKSAR (Department of Health, Hong Kong, China), The Providence Foundation, Respiratory Viral Research Foundation.

Inactivated influenza vaccines

Article

Oct 2012

Prospects for antibody-based universal influenza vaccines in the context of widespread pre-existing immunity

Article

Jul 2015
EXPERT REV VACCINES

Influenza inflicts significant global mortality and morbidity that can be combated by effective immunization. However, the protective efficacy of current vaccines is limited by both the significant antigenic diversity of the viral hemagglutinin protein and the capacity for rapid antigenic change. This necessitates global influenza surveillance efforts, frequent vaccine reformulation and annual readministration. There is, therefore, tremendous interest in the development of novel strategies to elicit broad and durable protection against both seasonal and pandemic infection. This review presents an overview of candidate universal influenza vaccines designed to elicit cross-protective antibody responses to hemagglutinin. In particular, we focus on the potential impact that widespread pre-existing influenza immunity may play upon the design, testing and deployment of universal influenza vaccines.

Trivalent influenza vaccine-induced antibody response to circulating influenza a (H3N2) viruses in 2010/11 and 2011/12 seasons

Article

Feb 2015

To evaluate antibody response induced by trivalent inactivated influenza vaccine (TIV) against circulating influenza A (H3N2) strains in healthy adults during the 2010/11 and 2011/12 seasons, a hemagglutination-inhibition (HI) assay was utilized to calculate geometric mean antibody titer (GMT), seroprotection rate (post vaccination HI titers of ≥1:40), and seroresponse rate (4-fold increase in antibody level). In the 2010/11 season, GMT increased 1.8- to 2.0-fold following the first dose of TIV against three circulating strains and 2.2-fold following the second compared to before vaccination. The seroresponse rate ranged from 22% to 26% following the first dose of TIV and from 31% to 33% following the second (n=54). The seroprotection rate increased from a range of 6% to 13% to a range of 26% to 33% following the first dose of TIV and to a range of 37% to 42% following the second (n=54). In the 2011/12 season, GMT increased 1.4-fold against A/Osaka/110/2011 and 1.8-fold against A/Osaka/5/2012. For A/Osaka/110/2011, the seroresponse rate was 29%, and the seroprotection rate increased from 26% to 55% following vaccination (n=31). For A/Osaka/5/2012, the seroresponse rate was 26%, and the seroprotection rate increased from 68% to 84% following vaccination (n=31). HI assays with reference antisera demonstrated that the strains in the 2011/12 season were antigenically distinct from vaccine strain (A/Victoria/210/2009). In conclusion, the vaccination increased the seroprotection rate against circulating H3N2 strains in the 2010/11 and 2011/12 seasons. Vaccination of TIV might have potential to induce reactive antibodies against antigenically distinct circulating H3N2 viruses.

Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus

Article

Full-text available

Feb 2015

Middle East respiratory syndrome (MERS), an emerging infectious disease caused by MERS coronavirus (MERS-CoV), has garnered worldwide attention as a consequence of its continuous spread and pandemic potential, making the development of effective vaccines a high priority. We previously demonstrated that residues 377-588 of MERS-CoV spike (S) protein receptor-binding domain (RBD) is a very promising MERS subunit vaccine candidate, capable of inducing potent neutralization antibody responses. In this study, we sought to identify an adjuvant that optimally enhanced the immunogenicity of S377-588 protein fused with Fc of human IgG (S377-588-Fc). Specifically, we compared several commercially available adjuvants, including Freund's adjuvant, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59 with regard to their capacity to enhance the immunogenicity of this subunit vaccine. In the absence of adjuvant, S377-588-Fc alone induced readily detectable neutralizing antibody and T-cell responses in immunized mice. However, incorporating an adjuvant improved its immunogenicity. Particularly, among the aforementioned adjuvants evaluated, MF59 is the most potent as judged by its superior ability to induce the highest titers of IgG, IgG1 and IgG2a subtypes, and neutralizing antibodies. The addition of MF59 significantly augmented the immunogenicity of S377-588-Fc to induce strong IgG and neutralizing antibody responses as well as protection against MERS-CoV infection in mice, suggesting that MF59 is an optimal adjuvant for MERS-CoV RBD-based subunit vaccines.Cellular & Molecular Immunology advance online publication, 2 February 2015; doi:10.1038/cmi.2015.03.

Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels

Article

Full-text available

Mar 2009
P NATL ACAD SCI USA

Immune responses to vaccination are tested in clinical trials. This process usually requires years especially when immune memory and persistence are analyzed. Markers able to quickly predict the immune response would be very useful, particularly when dealing with emerging diseases that require a rapid response, such as avian influenza. To address this question we vaccinated healthy adults at days 1, 22, and 202 with plain or MF59-adjuvanted H5N1 subunit vaccines and tested both cell-mediated and antibody responses up to day 382. Only the MF59-H5N1 vaccine induced high titers of neutralizing antibodies, a large pool of memory H5N1-specific B lymphocytes, and H5-CD4(+) T cells broadly reactive with drifted H5. The CD4(+) response was dominated by IL-2(+) IFN-gamma(-) IL-13(-) T cells. Remarkably, a 3-fold increase in the frequency of virus-specific total CD4(+) T cells, measurable after 1 dose, accurately predicted the rise of neutralizing antibodies after booster immunization and their maintenance 6 months later. We suggest that CD4(+) T cell priming might be used as an early predictor of the immunogenicity of prepandemic vaccines.

Molecular Epidemiology of A/H3N2 and A/H1N1 Influenza Virus during a Single Epidemic Season in the United States

Article

Full-text available

Feb 2008
PLOS PATHOG

To determine the spatial and temporal dynamics of influenza A virus during a single epidemic, we examined whole-genome sequences of 284 A/H1N1 and 69 A/H3N2 viruses collected across the continental United States during the 2006-2007 influenza season, representing the largest study of its kind undertaken to date. A phylogenetic analysis revealed that multiple clades of both A/H1N1 and A/H3N2 entered and co-circulated in the United States during this season, even in localities that are distant from major metropolitan areas, and with no clear pattern of spatial spread. In addition, co-circulating clades of the same subtype exchanged genome segments through reassortment, producing both a minor clade of A/H3N2 viruses that appears to have re-acquired sensitivity to the adamantane class of antiviral drugs, as well as a likely antigenically distinct A/H1N1 clade that became globally dominant following this season. Overall, the co-circulation of multiple viral clades during the 2006-2007 epidemic season revealed patterns of spatial spread that are far more complex than observed previously, and suggests a major role for both migration and reassortment in shaping the epidemiological dynamics of human influenza A virus.

Detection of Antibody to Avian Influenza A (H5N1) Virus in Human Serum by Using a Combination of Serologic Assays

Article

Full-text available

May 1999

From May to December 1997, 18 cases of mild to severe respiratory illness caused by avian influenza A (H5N1) viruses were identified in Hong Kong. The emergence of an avian virus in the human population prompted an epidemiological investigation to determine the extent of human-to-human transmission of the virus and risk factors associated with infection. The hemagglutination inhibition (HI) assay, the standard method for serologic detection of influenza virus infection in humans, has been shown to be less sensitive for the detection of antibodies induced by avian influenza viruses. Therefore, we developed a more sensitive microneutralization assay to detect antibodies to avian influenza in humans. Direct comparison of an HI assay and the microneutralization assay demonstrated that the latter was substantially more sensitive in detecting human antibodies to H5N1 virus in infected individuals. An H5-specific indirect enzyme-linked immunosorbent assay (ELISA) was also established to test children's sera. The sensitivity and specificity of the microneutralization assay were compared with those of an H5-specific indirect ELISA. When combined with a confirmatory H5-specific Western blot test, the specificities of both assays were improved. Maximum sensitivity (80%) and specificity (96%) for the detection of anti-H5 antibody in adults aged 18 to 59 years were achieved by using the microneutralization assay combined with Western blotting. Maximum sensitivity (100%) and specificity (100%) in detecting anti-H5 antibody in sera obtained from children less than 15 years of age were achieved by using ELISA combined with Western blotting. This new test algorithm is being used for the seroepidemiologic investigations of the avian H5N1 influenza outbreak.

Quantifying Influenza Vaccine Efficacy and Antigenic Distance

Article

Full-text available

Jun 2006
VACCINE

We introduce a new measure of antigenic distance between influenza A vaccine and circulating strains. The measure correlates well with efficacies of the H3N2 influenza A component of the annual vaccine between 1971 and 2004, as do results of a theory of the immune response to influenza following vaccination. This new measure of antigenic distance is correlated with vaccine efficacy to a greater degree than are current state of the art phylogenetic sequence analyses or ferret antisera inhibition assays. We suggest that this new measure of antigenic distance be used in the design of the annual influenza vaccine and in the interpretation of vaccine efficacy monitoring.

Introduction: The Growth of Wilderness Seeds

Article

Jan 2008

Laboratory Diagnosis of Influenza

Article

Jan 1998

M. Zambon

Vaccines with MF59 Adjuvant Expand the Antibody Repertoire to Target Protective Sites of Pandemic Avian H5N1 Influenza Virus

Article

Jan 2010
Sci Transl Med

Vaccines against influenza viruses with pandemic potential, including H5N1, are under development. Because of a lack of preexisting immunity to these viruses, adjuvants (immune potentiators or enhancers) are needed to improve immune responses, to conserve scarce vaccine, and for cross-protection against strains that have drifted evolutionarily from the original. Aluminum-based adjuvants do not improve vaccine immunogenicity for influenza subunit vaccines, whereas oil-in-water adjuvants are effective, especially with H5N1-inactivated vaccines. We used whole-genome-fragment phage display libraries followed by surface plasmon resonance (SPR) technologies to elucidate the effect of different adjuvants on the antibody repertoire against H5N1 vaccine in humans. The oil-in-water adjuvant MF59 induced epitope spreading from HA2 to HA1 in hemagglutinin (HA) and neuraminidase relative to unadjuvanted or aluminum-adjuvanted vaccines. Moreover, we observed an increase by a factor of 20 in the frequency of HA1-to-HA2-specific phage clones in sera after MF59-adjuvanted vaccine administration and a factor of 2 to 3 increase in the avidity of antibodies binding to properly folded HA1(28-319), as measured by SPR. The adjuvant-dependent increase in binding to conformational HA1 epitopes correlated with broadening of cross-clade neutralization and predicted improved in vivo protection. Thus, MF59 adjuvant improves the immune response to a H5N1 vaccine by inducing qualitative and quantitative expansion of the antibody repertoires with protective potential.

Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant

Article

Aug 2009
PEDIATR INFECT DIS J

Children have high morbidity and hospitalization rates from seasonal influenza. Meta-analyses suggest that conventional inactivated influenza vaccines are of low efficacy in young children, making vaccines that induce greater and broader immune protection in this vulnerable population a medical priority. Adjuvanted influenza vaccines may offer a solution. Unprimed healthy children (6 to <36 months) were enrolled in an observer-blinded study and randomly assigned to receive 2 doses of MF59-adjuvanted vaccine (Sub/MF59, n = 130) or nonadjuvanted split vaccine (split, n = 139); subgroups of these (n = 43 and 46, respectively) received a booster dose 1 year later. Safety and clinical tolerability were assessed after each dose. Hemagglutination inhibition antibody titers were measured against influenza A and B strains included in the formulation of the vaccines and against mismatched strains. Clinical tolerability and safety were generally comparable between vaccine groups, though some transient, mild solicited reactions were more frequent in the Sub/MF59 group. Postvaccination hemagglutination inhibition antibody titers to all 3 vaccine strains were significantly higher with Sub/MF59 than with split vaccine (all comparisons P < 0.001) after each of the 3 vaccine doses. In addition, Sub/MF59 induced significantly higher cross-reactivity against A/H3N2 and A/H1N1 mismatched strains. MF59-adjuvanted influenza vaccine was well tolerated in healthy young children after each of 3 doses and induced greater, longer-lasting, and broader immune responses than a nonadjuvanted split vaccine. The enhanced immunogenicity of the adjuvanted vaccine was most evident in very young children and for the B vaccine strain.

Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages

Article

Jun 2009

This study evaluated whether MF59-adjuvanted subunit trivalent influenza vaccine for the 2003/04 winter season (A/Moscow/10/99, H3N2; A/New Caledonia/20/99, H1N1; B/Hong Kong/330/01) would confer protection against mismatched and frequently co-circulating variants of influenza B/Victoria- and B/Yamagata-like virus strains. Haemagglutination inhibiting (HI) antibodies were measured in middle-aged and elderly volunteers against the homologous B/Victoria-like vaccine strain (B/Hong Kong/330/01) and against mismatched B/Victoria-like (B/Malaysia/2506/04) and B/Yamagata-like (B/Singapore/379/99 and B/Shanghai/361/02) strains. Immunization induced significant increases in the amounts of HI antibodies against all influenza B strains under investigation. However, the responses against the heterologous B/Shanghai/361/02 virus did not reach the desirable values of seroprotection. An age-dependent decline of the responses was found for B/Victoria-like antigens, but not for B/Yamagata-like strains. Although further studies are needed, our data support the recommendation of including influenza B viruses of the B/Victoria and B/Yamagata lineages in the future influenza vaccine preparations.

Antigenically Distinct MF59-Adjuvanted Vaccine to Boost Immunity to H5N1

Article

Nov 2008
NEW ENGL J MED

The authors report on an open-label study of an MF59-adjuvanted vaccine against avian influenza. The findings indicate that priming subjects with H5 antigen induces a rapidly mobilized, long-lasting immune memory after the administration of low-dose, antigenically distinct vaccine.

The adjuvanted influenza vaccines with novel adjuvants: Experience with the MF59-adjuvanted vaccine

Article

Apr 2001
VACCINE

Audino Podda

Elderly people and subjects with underlying chronic diseases are at increased risk for influenza and related complications. Conventional influenza vaccines provide only limited protection in the elderly population. In order to enhance the immune response to influenza vaccines, several adjuvants have been evaluated. Among these, an oil in water adjuvant emulsion containing squalene, MF59, has been combined with subunit influenza antigens and tested in clinical trials in comparison with non-adjuvanted conventional vaccines. Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons. Immunogenicity analyses demonstrate a consistently higher immune response with statistically significant increases of postimmunisation geometric mean titres, and of seroconversion and seroprotection rates compared to non-adjuvanted subunit and split influenza vaccines, particularly for the A/H3N2 and the B strains. The higher immunogenicity profile of the MF59-adjuvanted vaccine is maintained also after subsequent immunisations. An even higher adjuvant effect was shown in subjects with low pre-immunisation titre and in those affected by chronic underlying diseases. In conclusion, the addition of MF59 to subunit influenza vaccines enhances significantly the immune response in elderly subjects without causing clinically important changes in the safety profile of the influenza vaccine.

[The laboratory diagnosis of influenza]

Article

Jan 1963

A M DUDNIAKOVA

Seroprotection rate, mean fold increase, seroconversion rate: Which parameter adequately expresses seroresponse to influenza vaccination?

Article

Aug 2004
VIRUS RES

Serological parameters intend to describe antibody response to influenza vaccine in a population. However, there is uncertainty about the mathematical appropriateness and the biological or clinical meaning of conventionally used parameters. Theoretical considerations and exploration of a data-set of 16 studies with an inactivated (subunit) influenza vaccine involving 1176 adult subjects suggest the following conclusions. In a population seronegative before vaccination, the post-vaccination geometric mean titre (post-GMT) is a meaningful immunological parameter adequately expressing antibody response after vaccination. The related protection rate (PR) is a good surrogate parameter for protection provided by a given vaccine, thus relevant to public health. However, in a population partially seropositive before vaccination (due to previous exposition to influenza antigens), the same parameters may, under certain conditions, seriously overestimate the antibody response, as they do not account for the pre-vaccination state. Conventional attempts to address pre-vaccination antibody are associated with either loss of information (exclusion of seropositive subjects) or incomplete control of pre-vaccination state (mean fold increase (MFI), response rate (RR)). Although not devoid of theoretical limitations (heteroscedasticity), correction of post-GMT and PR by linear regression appears to provide better estimates of antibody response and vaccine immunogenicity.

Antigenic characterisation of influenza B virus with A new microneutralisation assay: Comparison to haemagglutination and sequence analysis

Article

Sep 2004

Although the haemagglutination inhibition assay is considered the "gold standard" for antigenic characterisation of influenza viruses, some limitations of this technique are well known. A new microneutralisation assay, as a tool for antigenic characterisation of influenza B viruses, has been standardised and its performance evaluated in comparison with the haemagglutination inhibition test in the light of molecular characterisation of the haemagglutinin. Twelve B viruses belonging to the two lineages and the four sub-lineages discriminated by phylogenetic analysis of HA were tested. The microneutralisation assay clearly distinguishes viruses belonging to different lineages and, in addition, discriminates strains belonging to different sub-lineages that are poorly or not discriminated using the haemagglutination inhibition test. This new microneutralisation assay could provide a useful tool for antigenic characterisation of circulating influenza viruses and contribute, together with the haemagglutination inhibition test and sequence analysis of the haemagglutinin and neuraminidase, in the choice of the strain for use in vaccine composition.

An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine

Article

Apr 2006
VACCINE

To test whether inactivated influenza vaccines distributed during the 2003-2004 influenza season in the northern hemisphere were able to confer protection against the mismatched variant A/Fujian/411/2002 virus strain, we measured haemagglutination inhibiting (HI) antibodies in elderly subjects vaccinated with three inactivated vaccines against the homologous A/H3N2 vaccine strain (A/Panama) and against the mismatched A/Fujian strain. The results showed that, while 76 to 80% of elder people vaccinated with conventional vaccines had protected levels of antibodies against the A/Fujian heterovariant strain, those vaccinated with the MF59-adjuvanted vaccine have protective levels of antibodies in >98% of the cases. We conclude that MF59-adjuvanted vaccines confer protection also against influenza virus strains which are not fully matched with those included in the vaccine.

Response of Influenza Vaccines Against Heterovariant Influenza Virus Strains in Adults with Chronic Diseases

Article

Oct 2007

The ability of influenza vaccination to provide cross-protection against heterovariant influenza strains was evaluated in a double-blind, randomized, trial in north-east Italy during the winter of 2005-2006. Of 238 adult subjects with underlying chronic diseases, 120 received MF59-adjuvanted subunit vaccine (Sub/MF59) and 118 received a conventional subunit vaccine (Subunit). Immunogenicity was measured for A/H3N2 and B influenza strains against both the homologous vaccine strains (A/New York/55/2004 and B/Jiangsu/10/2003), and the heterovariant strains recommended for the 2006-2007 season (A/Wisconsin/67/2005 and B/Malaysia/2506/2004). Although both vaccines conferred serological protection against the homologous vaccine strains and the 2006-2007 heterovariant A/H3N2 strain for a majority of subjects, the antibody response was highest in the Sub/MF59 vaccine group. For example, MF59-adjuvanted vaccination conferred significantly greater (P = 0.002) protection against the heterovariant A/H3N2 strain than the conventional subunit vaccine (79.2% vs. 61.0% of subjects, respectively). In conclusion, these results demonstrate that protection provided by influenza vaccination in adults affected by chronic diseases is lower against heterovariant strains than for homologous strains. However, addition of MF59 adjuvant to a subunit vaccine enhances immunogenicity against the A/H3N2 heterovariant strain, conferring broader protection than a conventional subunit vaccine in this population, who are at higher risk of influenza-related complications.

Dynamics of antigenic and genetic changes in the hemagglutinins of influenza A/H3N2 viruses of three consecutive seasons (2002/2003 to 2004/2005) in Austria

Article

Sep 2007
VACCINE

Human influenza viruses are subject to continuous antigenic drift and this phenomenon poses great problems for the annual production of vaccines which should ideally be manufactured from strains closely matching the predominant strains of the coming influenza season. We have investigated the dynamics of antigenic and genetic changes in the hemagglutinins of circulating influenza A/H3N2 strains in three consecutive seasons (2002/2003 to 2004/2005) in Austria by sequence analysis of the HA1 domain and by antigenic characterization using a hemagglutination inhibition assay. Each of the three seasons was dominated by a single and different H3N2 variant, but in all cases sequencing revealed the co-circulation of a drift variant which would have been missed by conventional antigenic analysis. These emerging strains always showed already a close genetic relationship to the dominating strain of the following season. Our results underscore the value of monitoring seasonal influenza strain dynamics by sequence analysis as an instrument that can provide important and timely information on the appearance of strains with epidemiologic significance.

Cross-protection by MF59 (TM)-adjuvanted influenza vaccine: Neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses

Article

Apr 2008
VACCINE

Adjuvants enhance antibody response against vaccination. We compared the ability of MF59-adjuvanted and non-adjuvanted subunit influenza vaccines, containing A/Wyoming/3/03(H3N2), to confer cross-protection against four consecutive drifted strains in the elderly. Neutralizing and haemagglutination-inhibiting antibody were measured. MF59-adjuvanted vaccine induced a stronger booster response against A/Panama/2007/99(H3N2) than non-adjuvanted vaccine. A/Panama/2007/99(H3N2) circulated widely during the previous 5 years and was included in vaccines over four consecutive seasons. Broader serological protection against drifted strains that circulated 1 and 2 years after vaccination with A/Wyoming/3/03(H3N2) was observed with MF59-adjuvanted vaccine. Thus, MF59-adjuvanted vaccine confers greater immunogenicity than non-adjuvanted vaccines in vulnerable populations.

Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant Cross-reactive antibodies in middleaged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages

Jan 2009
563-714099

T Vesikari
M Pellegrini
A Karvonen
N Groth
O A Borkowski
Hagan
Dt

Vesikari T, Pellegrini M, Karvonen A, Groth N, Borkowski A, O'Hagan DT, et al. Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. Pediatr Infect Dis J 2009;28:563–71. [18] Camilloni B, Neri M, Lepri E, Iorio AM. Cross-reactive antibodies in middleaged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages. Vaccine 2009;27:4099–103.

Characteristics of human influenza A/H1N1, A/H3N2 and B viruses isolated Annual report. London: WHO Influenza Centre

Sep 2003

Hay
Lin Yp Aj
Gregory X V Zheng
Bennett

Hay AJ, Lin YP, Zheng X, Gregory V, Bennett M. Characteristics of human influenza A/H1N1, A/H3N2 and B viruses isolated. August 2003 to July 2004. Annual report. London: WHO Influenza Centre. Available on http://www.nimr.mrc.ac.uk/wic/report/.

World Health Organization Global Influenza Programme. WHO manual on animal influenza diagnosis and surveillance

Jan 2002

World Health Organization Global Influenza Programme. WHO manual on animal influenza diagnosis and surveillance; 2002. WHO/CDS/NCS/2002/5.

Characteristics of human influenza A/H1N1, A/H3N2 and B viruses isolated

A J Hay
R Daniels
Y P Lin
X Zheng
V Gregory
M Bennett

References [1] Hay AJ, Lin YP, Zheng X, Gregory V, Bennett M. Characteristics of human influenza A/H1N1, A/H3N2 and B viruses isolated. August 2003 to July 2004. Annual report. London: WHO Influenza Centre. Available on http://www.nimr.mrc.ac.uk/wic/report/.

Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates

Abstract

No full-text available

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