Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Effectiveness of Adjuvanted Influenza Vaccination in Elderly Subjects in Northern Italy Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments Cost-benefit evaluation of influenza vaccination in the elderly in the Italian region of Liguria. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Effectiveness of the 2010–2011 seasonal influenza vaccine in preventing confirmed influenza hospitalizations in adults: A case–case comparison, case-control study MF59-adjuvanted and virosomal influenza vaccines for preventing influenza hospitalization in older people: comparative effectiveness using the Valencia health care information system. Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers.
Background Improved influenza vaccines are needed to reduce influenza-associated complications in older adults . The aim of this study was to identify the optimal formulation of adjuvanted seasonal influenza vaccine for use in elderly people . Methods This observer-blind , r and omized study assessed the optimal formulation of adjuvanted seasonal influenza vaccine based on immunogenicity and safety in participants aged ≥65 years . Participants were r and omized ( ~200 per group ) to receive one dose of  non-adjuvanted vaccine or one of eight formulations of vaccine formulated with a squalene and tocopherol oil-in-water emulsion-based Adjuvant System ( AS03C , AS03B or AS03A , with 2.97 , 5.93 and 11.86 mg tocopherol , respectively ) together with the immunostimulant monophosphoryl lipid A ( MPL , doses of 0 , 25 or 50 mg ) . Hemagglutination-inhibition ( HI ) antibody responses and T-cell responses were assessed on Day 0 and 21 days post-vaccination . The ratio of HI-based geometric mean titers in adjuvanted versus non-adjuvanted vaccine groups were calculated and the lower limit of the 90 % confidence interval was transformed into a desirability index ( a value between 0 and 1 ) in an experimental domain for each vaccine strain , and plotted in relation to the AS03 and MPL dose combination in the formulation . This model was used to assess the optimal formulation based on HI antibody titers . Reactogenicity and safety were also assessed . The immunogenicity and safety analyses were used to evaluate the optimal formulation of adjuvanted vaccine . Results In the HI antibody-based model , an AS03 dose – response was evident ; responses against the A/H1N1 and A/H3N2 strains were higher for all adjuvanted formulations versus non-adjuvanted vaccine , and for the AS03A-MPL25 , AS03B-MPL25 and AS03B-MPL50 formulations against the B strain . Modelling using more stringent criteria ( post hoc ) showed a clear dose-range effect for the AS03 component against all strains , whereas MPL showed a limited effect . Higher T-cell responses for adjuvanted versus non-adjuvanted vaccine were observed for all except two formulations ( AS03C and AS03B-MPL25 ) . Reactogenicity increased with increasing AS03 dosage , and with MPL . No safety concerns were raised . Conclusions Five formulations containing AS03A or AS03B were identified as potential c and i date s to improve immune responses to influenza vaccination ; AS03B without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity . Trial registration This trial is registered at Clinical Trials.gov , Case-control study design ed to determine the effectiveness of an MF59-adjuvanted influenza vaccine in the population aged 65 years and older living in the community . Detailed health histories were obtained on both cases and controls that included a functional measure of co-morbidity ( Barthel Index ) . Subjects were all eligible persons admitted to various hospitals with a diagnosis of pneumonia during the winter months and were matched by sex , hospital and admission week to controls admitted for non-medical reasons . The influenza vaccination programme using the MF59-adjuvanted influenza vaccine significantly reduced the probability of being hospitalised for pneumonia in the elderly over 64 years of age , even in a season with a low influenza activity , during which the predominant circulating strains were types B and A ( H1N1 ) Although vaccination against influenza is recommended for elderly and high-risk patients in many countries , efficacy in the elderly has been suboptimal . The MF59 adjuvanted trivalent inactivated vaccine ( ATIV ) was developed to increase the immune response of elderly subjects to influenza vaccination , but its effectiveness has not yet been well documented . This prospect i ve , observational study evaluated the relative effectiveness of ATIV versus nonadjuvanted trivalent inactivated vaccine ( TIV ) in individuals at least 65 years of age in Lombardy , northern Italy . Hospitalizations for influenza or pneumonia ( International Classification of Diseases , Ninth Revision , Clinical Modification , codes 480–487 ) during the 2006–2007 , 2007–2008 , and 2008–2009 influenza seasons were identified from administrative data bases . Stratified and regression analyses , including the propensity score to adjust for confounding , as well as generalized estimating equations to account for repeated vaccination , were used . Overall , 107,661 records were evaluated , contributing 170,988 person-seasons of observation . Since ATIV is preferentially recommended for more frail individuals , subjects vaccinated with ATIV were older and had more functional impairment and comorbidities . In the primary analysis , risk of hospitalization for influenza or pneumonia was 25 % lower for ATIV relative to TIV ( relative risk = 0.75 , 95 % confidence interval : 0.57 , 0.98 ) . To the extent that there is residual bias , ATIV is likely to be even more protective than this result suggests Background Lack of appropriate reporting of method ological details has previously been shown to distort risk of bias assessment s in r and omized controlled trials . The same might be true for observational studies . The goal of this study was to compare the Newcastle-Ottawa Scale ( NOS ) assessment for risk of bias between review ers and authors of cohort studies included in a published systematic review on risk factors for severe outcomes in patients infected with influenza . Methods Cohort studies included in the systematic review and published between 2008–2011 were included . The corresponding or first authors completed a survey covering all NOS items . Results were compared with the NOS assessment applied by review ers of the systematic review . Inter-rater reliability was calculated using kappa ( K ) statistics . Results Authors of 65/182 ( 36 % ) studies completed the survey . The overall NOS score was significantly higher ( p < 0.001 ) in the review ers ’ assessment ( median = 6 ; interquartile range [ IQR ] 6–6 ) compared with those by authors ( median = 5 , IQR 4–6 ) . Inter-rater reliability by item ranged from slight ( K = 0.15 , 95 % confidence interval [ CI ] = −0.19 , 0.48 ) to poor ( K = −0.06 , 95 % CI = −0.22 , 0.10 ) . Reliability for the overall score was poor ( K = −0.004 , 95 % CI = −0.11 , 0.11 ) . Conclusions Differences in assessment and low agreement between review ers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic review Influenza causes considerable morbidity and mortality and the damage to public health can be considerable . The most effective measures available for the prevention of influenza is vaccination . In most industrialised countries the objective of vaccination is to limit the disease among individuals at risk , especially the elderly . During the winter of 2000/2001 , General Practitioners ( GPs ) monitored 14,818 elderly individuals . The objective was to evaluate the weekly incidence of the disease . Furthermore , we carried out a prospect i ve study on 512 elderly individuals , arranged according to vaccination ( 304 vaccinated and 208 non-vaccinated )  , with the main objective of assessing the costs of the disease and the efficacy of vaccination . Finally , in order to assess the percentage of vaccinated elderly individuals  , we carried out a telephone survey on 500 subjects . Our clinical surveillance study enabled us to establish that morbidity was particularly low in elderly individuals . The results of the prospect i ve study allowed us to estimate the cost-benefit ratio at 8.22 , with a net saving of 110.20 Euros for each vaccinated subject . We were also able to establish that the vaccine coverage among elderly individuals was 63 % . Our study , though carried out during a low epidemic year , confirms the economic advantage of vaccination in the elderly A clinical trial to evaluate the safety and tolerability of a new influenza adjuvanted vaccine ( FLUAD , Chiron Vaccines ) , compared with a conventional non adjuvanted influenza vaccine , was conducted in elderly ambulatory patients . Subjects were vaccinated with one dose of either vaccine each year for three consecutive years ; 92 subjects received the first immunization , 74 subjects received the second and 67 subjects received the third . The primary objective of this study was to evaluate the safety of repetitive injections of the adjuvanted vaccine in elderly subjects . There were no reports of any vaccine-related serious adverse event or of safety concerns related to study vaccines after the first , second or third immunization . The adjuvanted vaccine induced more local reactions than the conventional vaccine ; however , the reactions were normally mild and limited to the first 2 - 3 days after immunization . No statistically significant difference between groups in systemic postimmunization reactions was reported except for a mild , transient malaise after the first immunization . Compared with the first immunization , no increase in postimmunization reactions was seen after the second and third immunizations . Despite the small sample size of the trial , which was not powered to test immunogenicity differences , the antibody response was tested and result ed higher in the adjuvanted vaccine recipients , not only against the current season 's vaccine strains , but also against heterologous vaccine strains AIM Adjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly . We evaluated the immunogenicity , safety and clinical effectiveness of an MF59( ® )-adjuvanted trivalent influenza vaccine ( aTIV ) compared with a non-adjuvanted vaccine ( TIV ) in subjects ≥65 years old , with or without co-morbidities . METHODS In 2010 - 2011 , subjects ( N=7082 ) were r and omized to receive one dose of aTIV or TIV . Co- primary objectives were to assess lot-to-lot consistency of aTIV , non-inferiority , superiority and immunogenicity 22 days after vaccination . Clinical effectiveness , reactogenicity and serious adverse events were monitored up to Day 366 . RESULTS The immunological equivalence of three lots of aTIV was demonstrated . aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains , even in subjects with co-morbidities . Superiority was not established . Reactogenicity was higher in the aTIV group , but reactions were mild to moderate and transient . CONCLUSIONS aTIV elicited a significantly higher antibody response than TIV , especially against A/H3N2 strains , although superiority by pre-defined criteria was not formally met . The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly . This trial was registered with www . clinical trials.gov ( NCT01162122 ) Abstract Introduction We estimated influenza vaccine effectiveness ( IVE ) to prevent laboratory-confirmed influenza-related hospitalizations in patients 18 years old or older during the 2010–2011 influenza season . Methods We conducted a prospect i ve case-control study in five hospitals , in Valencia , Spain . Study subjects were consecutive emergency hospitalizations for predefined conditions associated with an influenza-like illness episode < 8 days before admission . Patients were considered immunized if vaccinated ≥14 days before influenza-like illness onset . Cases were those with a real time reverse transcriptase polymerase chain reaction ( RT-PCR ) positive for influenza and controls were RT-PCR positive for other respiratory viruses . Adjusted IVE was estimated as 100 × (1−adjusted odds ratio ) . To account for indication bias we computed adjusted IVE for respiratory syncytial virus related hospitalizations . Results Of 826 eligible hospitalized patients , 102 ( 12 % ) were influenza positive and considered cases , and 116 ( 14 % ) were positive for other respiratory viruses and considered controls . Adjusted IVE was 54 % ( 95 % confidence interval , 11–76 % ) . By subgroup , adjusted IVE was 53 % ( 4–77 % ) for those with high-risk conditions , 59 % ( 16–79 % ) for those ≥60 years of age , and , 54 % ( 4–79 % ) for those ≥60 years of age with high-risk conditions . No influenza vaccine effect was observed against respiratory syncytial virus related hospitalization . Conclusion Influenza vaccination was associated with a significant reduction on the risk of confirmed influenza hospitalization , irrespective of age and high-risk conditions BACKGROUND Adjuvanted influenza vaccines offer greater and broader immunogenicity to older adults than conventional vaccines . Studies assessing the comparative effectiveness of adjuvanted influenza vaccines in this age group are lacking . METHODS We conducted a retrospective cohort study to estimate the comparative effectiveness of MF59-adjuvanted trivalent influenza vaccine ( TIV ) and virosomal-TIV for prevention of influenza hospitalization in adults aged ≥65 years . We obtained administrative data on immunization status and influenza hospitalization for the 2010 - 2011 influenza season . We used Cox regression models to assess comparative effectiveness ; crude and adjusted by age , sex , comorbidity , deprivation , type of insurance , and travel time to hospital . We accounted for data clustering at the hospital level by using a multilevel r and om effects model . RESULTS Overall , 373,798 vaccinated subjects were evaluated . There were 40 hospitalizations for influenza among 176,618 subjects , contributing 4,288,109 person-weeks at risk in the virosomal-TIV group , and 37 hospitalizations for influenza among 197,180 subjects , contributing 4,786,360 person-weeks at risk in the MF59-TIV group . The crude hazard ratio ( HR ) was 0.83 ( 0.53 - 1.30 ) , and the adjusted Cox estimated HR of MF59-TIV relative to virosomal-TIV was 0.86 ( 0.55 - 1.35 ) . After accounting for data clustering , the HR of influenza hospitalization associated with MF59-TIV relative to virosomal-TIV was 0.94 ( 0.37 - 2.38 ) . CONCLUSION During the 2010 - 2011 influenza season , we found no differences in the risk of influenza hospitalization in subjects aged ≥65 years vaccinated with MF59-TIV compared with those vaccinated with virosomal-TIV OBJECTIVES To assess inter-rater reliability and validity of the Newcastle Ottawa Scale ( NOS ) used for method ological quality assessment of cohort studies included in systematic review s. STUDY DESIGN AND SETTING Two review ers independently applied the NOS to 131 cohort studies included in eight meta-analyses .  Inter-rater reliability was calculated using kappa ( κ ) statistics . To assess validity , within each meta- analysis , we generated a ratio of pooled estimates for each quality domain . Using a r and om-effects model , the ratios of odds ratios for each meta- analysis were combined to give an overall estimate of differences in effect estimates . RESULTS Inter-rater reliability varied from substantial for length of follow-up ( κ = 0.68 , 95 % confidence interval [ CI ] = 0.47 , 0.89 ) to poor for selection of the nonexposed cohort and demonstration that the outcome was not present at the outset of the study ( κ = -0.03 , 95 % CI = -0.06 , 0.00 ; κ = -0.06 , 95 % CI = -0.20 , 0.07 ) . Reliability for overall score was fair ( κ = 0.29 , 95 % CI = 0.10 , 0.47 ) . In general , review ers found the tool difficult to use and the decision rules vague even with additional information provided as part of this study . We found no association between individual items or overall score and effect estimates . CONCLUSION Variable agreement and lack of evidence that the NOS can identify studies with biased results underscore the need for revisions and more detailed guidance for systematic review ers using the NOS
BACKGROUND In the elderly , traditional influenza inactivated vaccines are often only modestly immunogenic , owing to immunosenescence .
Given that adjuvantation is a means of enhancing the immune response , the trivalent inactivated vaccine adjuvanted with MF59 ( MF59-TIV ) was specifically design ed to overcome this problem .
Considering that , for ethical reasons , the absolute effectiveness of an influenza vaccine in the elderly can not be demonstrated in placebo-controlled studies , the present study aim ed to assess the effectiveness of MF59-TIV in preventing influenza-related outcomes in the elderly .