Intradermal influenza vaccine for older adults: a randomized controlled multicenter phase III study. Immune responses to intradermal and intramuscular inactivated influenza vaccine among older age group. Immunogenicity and safety of Fluzone(®) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. Comparison of the Immunogenicity and Safety of the Conventional Subunit, MF59-Adjuvanted, and Intradermal Influenza Vaccines in the Elderly T Cell Responses Are Better Correlates of Vaccine Protection in the Elderly1 Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study Head-to-head comparison of an intradermal and a virosome influenza vaccine in patients over the age of 60 Immunogenicity and safety of concomitant MF59-adjuvanted influenza vaccine and 23-valent pneumococcal polysaccharide vaccine administration in older adults. Effectiveness of Adjuvanted Influenza Vaccination in Elderly Subjects in Northern Italy Safety and immunogenicity of an MF59™-adjuvanted subunit influenza vaccine in elderly Chinese subjects Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. Comparison of three different influenza vaccines in institutionalised elderly. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial. 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. A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly Influenza vaccination in patients on long-term anticoagulant therapy. Immunogenicity and safety of Intanza®/IDflu® intradermal influenza vaccine in South Korean adults: A multicenter, randomized trial Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Immunogenicity and safety of intradermal trivalent influenza vaccination in nursing home older adults: a randomized controlled trial. Safety, immunogenicity, and tolerability of three influenza vaccines in older adults Open, Randomized Study to Compare the Immunogenicity and Reactogenicity of an Influenza Split Vaccine with an MF59-Adjuvanted Subunit Vaccine and a Virosome-Based Subunit Vaccine in Elderly Efficacy of high-dose versus standard-dose influenza vaccine in older adults. Superior immunogenicity profile of the new intradermal influenza vaccine compared to the standard subcutaneous vaccine in subjects 65 years and older: A randomized controlled phase III study. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine and an MF59-adjuvanted influenza vaccine after concomitant vaccination in ⩾60-year-old adults.
In a 3-year , r and omized , controlled , open-label phase III trial enrolling 3707 adults aged > or = 60 years we evaluated whether the immunogenicity of an intradermal trivalent inactivated seasonal influenza vaccine , containing 15 microg of haemagglutinin per strain per 0.1 ml dose , is superior to that of a conventional intramuscular vaccine . Intradermal vaccine was given using an intradermal microinjection system . After the first vaccination , both vaccines satisfied the immunogenicity criteria for influenza vaccines for older adults set out in European regulatory guidelines , and geometric mean haemagglutination inhibition antibody titers and seroprotection rates were higher ( statistically superior ) with intradermal vaccination . Higher immune responses with intradermal vaccine were also observed after the 2nd and 3rd annual vaccinations . Both vaccines were well tolerated with similar systemic reactogenicity profiles . This intradermal influenza vaccine for older adults is a beneficial option for influenza protection , consistently enhancing antibody responses without compromising safety BACKGROUD Influenza viruses cause substantial morbidity , especially in older age groups . Thus , they are amongst high priority groups for routine vaccination . However , vaccine-induced immune responses and effectiveness were reported as relatively low . This study aims to systemically compare the immune responses elicited by intramuscular ( IM ) and intradermal ( ID ) injections with inactivated seasonal influenza vaccine among the older age group . METHODS A prospect i ve , open-label , r and omized study with a total of 221 adults ( > 60 years ) were enrolled and r and omized into 2 groups . Group I ( n = 111 ) received an IM inactivated seasonal influenza vaccine while Group II ( n = 110 ) received the same vaccine ID . Demographics and co-morbidity were collected at baseline . Safety data was collected 3 days post-vaccination using diary card . HAI , NAb and NAI titers were assessed prior to vaccination and at 30 , 45 , and 60 days post-vaccination . Data was analyzed using SPSS 11.5 . RESULTS Both groups had similar BMI and co-morbidity . For ID and IM groups , significant differences were observed for seroconversion rate measured using HAI against H1N1 and H3N2 ( 58/111 vs 44/110 and 68/111 vs 54/110 , respectively ) being higher for those aged 60 - 65 years . However , no differences in HI antibody against B/Phuket were seen . For ID route , history of hyperlipidemia and hypertension were factors associated with high seroconversion rate towards influenza A ( p = .001 ) . The seroconversion rate risk ratio were 1.31 and 1.25 ( p < .05 ) against A/California/07/09(H1N1 ) and A/Songkha/308/13 ( H3N2 ) , respectively . Interestingly , the GMT ( 95 % CI ) of baseline NAI antibodies among both groups were high ( 56.57 and 54.01 in the ID and IM groups , respectively ) . A 4-fold increase measured by NAI against A/California/07/09 ( H1N1 ) were detected in 16.67 % and 20 % of participants who received ID or IM vaccination , respectively . CONCLUSIONS The seroconversion rates of HAI , NAb and NAI were modest , especially in those > 65 years of age . However , it was higher in the ID group as compared to the IM group . CLINICAL TRIAL REGISTRATION NCT02101749 We conducted a r and omized , controlled , multicenter , phase II study to evaluate the immunogenicity and safety of an investigational intradermal ( ID ) trivalent influenza vaccine ( TIV ) and a high-dose ( HD ) intramuscular ( IM ) TIV in older adults ( ≥65 years of age ) . Older adult subjects were immunized with ID vaccine containing either 15μg hemagglutinin (HA)/strain ( n=636 ) or 21μg HA/strain ( n=634 ) , with HD IM vaccine containing 60μg HA/strain ( n=320 ) , or with st and ard-dose ( SD ) IM vaccine ( Fluzone ( ® ) ; 15μg HA/strain ; n=319 ) . For comparison , younger adults ( 18 - 49 years of age ) were immunized with SD IM vaccine . In older adults  , post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain . Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain . Results did not differ significantly for the two ID vaccine dosages . Post-vaccination geometric mean titers , seroconversion rates , and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and , for most measures , were comparable to those of younger adult SD IM vaccine recipients . Injection-site reactions , but not systemic reactions or unsolicited adverse events , were more common with the ID vaccines than with the IM vaccines . No treatment-related serious adverse events were reported . This study demonstrated that : ( 1 ) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults ; ( 2 ) the HD vaccine was more immunogenic than the ID vaccines in older adults ; and ( 3 ) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses ( Clinical Trials.gov identifier no. : NCT00551031 ) Safety and immunogenicity of the influenza vaccine adjuvanted with MF59 ( FLUAD ) were compared to those of a non adjuvanted subunit vaccine in elderly subjects during three consecutive influenza seasons .  Geometric mean titres and proportions of subjects with either a > or = four-fold increase in antibody titres or with an HI titre > or = 128 after immunisation were higher in FLUAD recipients . The adjuvant effect on the magnitude of the responses was most pronounced in subjects with pre-vaccination titres < or = 40 . Although associated with more frequent mild local reactions , the adjuvanted vaccine was well tolerated . Thus , the addition of MF59 increased the immunogenicity of the subunit influenza vaccine in elderly persons with low pre-vaccination titres , who are at greatest risk of developing severe influenza disease and vaccine failure , without a clinical ly important increase in reactogenicity BACKGROUND Influenza-associated morbidity and mortality has not decreased in the last decade , despite increased receipt of vaccine . To improve the immunogenicity of influenza vaccine , a high-dose ( HD ) trivalent , inactivated influenza vaccine was developed . METHODS A multicenter , r and omized , double-blind controlled study was conducted to compare HD vaccine ( which contains 60 microg of hemagglutinin per strain ) with the licensed st and ard-dose ( SD ) vaccine ( which contains 15 microg of hemagglutinin per strain ) in adults > or = 65 years of age . RESULTS  HD vaccine was administered to 2575 subjects , and SD vaccine was administered to 1262 subjects . There was a statistically significant increase in the rates of seroconversion and mean hemagglutination inhibition titers at day 28 after vaccination among those who received HD vaccine , compared with those who received SD vaccine .  Mean postvaccination titers for individuals who received HD vaccine were 116 for H1N1 , 609 for H3N2 , and 69 for B strain ; for those who received SD vaccine , mean postvaccination titers were as 67 for H1N1 , 333 for H3N2 , and 52 for B strain . The HD vaccine met superiority criteria for both A strains , and the responses for B strain met non-inferiority criteria . Seroprotection rates were also higher for those who received HD vaccine than for those who received SD vaccine vaccine , for all strains . Local reactions were more frequent in individuals who received HD vaccine , but the reactions were mild to moderate . CONCLUSIONS There was a statistically significant increase in the level of antibody response induced by HD influenza vaccine , compared with that induced by SD vaccine , without an attendant increase in the rate or severity of clinical ly relevant adverse reactions . These results suggest that the high-dose vaccine may provide improved protective benefits for older adults . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00391053 ABSTRACT The influenza vaccination is known as the most effective method for preventing influenza infection and its complications in the elderly .  Conventional subunit ( Agrippal S1 ; Novartis ) , MF59-adjuvanted ( Fluad ; Novartis ) , and intradermal ( IDflu15 ; Sanofi Pasteur ) influenza vaccines are widely used throughout South Korea . However , few comparative studies evaluating the safety and immunogenicity of these vaccines are available . Prior to the beginning of the 2011 - 2012 influenza season , 335 healthy elderly volunteers r and omly received one of three seasonal trivalent influenza vaccines , the conventional subunit , MF59-adjuvanted , or intradermal influenza vaccine .  Serum hemagglutination-inhibiting antibody levels were measured at the time of vaccination and at 1 and 6 months after vaccination . Adverse events were recorded prospect ively . A total of 113 conventional subunit , 111 MF59-adjuvanted , and 111 intradermal influenza vaccine volunteers were followed up during a 6-month postvaccination period . One month after vaccination , all three vaccines satisfied Committee for Medical Products for Human Use ( CHMP ) immunogenicity criteria for the A/H1N1 and A/H3N2 strains but not for the B strain . Compared with the subunit vaccine , the intradermal vaccine exhibited noninferiority , while the MF59-adjuvanted vaccine exhibited superiority . Furthermore , the MF59-adjuvanted vaccine was more immunogenic against the A/H3N2 strain than was the subunit vaccine up to 6 months postvaccination . The most common local and systemic reactions to the conventional subunit , MF59-adjuvanted , and intradermal influenza vaccines were pain at the injection site ( 7.1 % , 10.8 % , and 6.3 % , respectively ) and generalized myalgia ( 0.9 % , 8.1 % , and 5.4 % , respectively ) . Local and systemic reactions were similar among the three vaccine groups . MF59-adjuvanted vaccine exhibited superior immunogenicity compared with a conventional subunit vaccine and had a comparable safety profile . For older adults , the MF59-adjuvanted vaccine is preferable for providing superior immunogenicity It is commonly held that increased risk of influenza in the elderly is due to a decline in the Ab response to influenza vaccination . This study prospect ively evaluated the relationship between the development of influenza illness , and serum Ab titers and ex vivo cellular immune responses to influenza vaccination in community dwelling older adults including those with congestive heart failure ( CHF ) . Adults age 60 years and older ( 90 subjects ) , and 10 healthy young adult controls received the 2003 - 04 trivalent inactivated influenza vaccine .  Laboratory diagnosed influenza ( LDI ) was documented in 9 of 90 older adults .  Pre- and postvaccination Ab titers did not distinguish between subjects who would subsequently develop influenza illness ( LDI subjects ) and those who would not ( non-LDI subjects ) . In contrast , P BMC restimulated ex vivo with live influenza virus preparations showed statistically significant differences between LDI and non-LDI subjects . The mean IFN-γ : IL-10 ratio in influenza A/H3N2-stimulated P BMC was 10-fold lower in LDI vs non-LDI subjects . Pre- and postvaccination granzyme B levels were significantly lower in CHF subjects with LDI compared with subjects without LDI . In non-CHF subjects with LDI , granzyme B levels increased to high levels at the time of influenza infection . In conclusion , measures of the ex vivo cellular immune response to influenza are correlated with protection against influenza while serum Ab responses may be limited as a sole measure of vaccine efficacy in older people . Ex vivo measures of the cell-mediated immune response should be incorporated into evaluation of new vaccines for older adults Background Although seasonal influenza vaccine is effective in the elderly , immune responses to vaccination are lower in the elderly than in younger adults . Strategies to optimise responses to vaccination in the elderly include using an adjuvanted vaccine or using an intradermal vaccination route . The immunogenicity of an intradermal seasonal influenza vaccine was compared with that of an adjuvanted vaccine in the elderly . Methods Elderly volunteers ( age ≥ 65 years ) were r and omised to receive a single dose of trivalent seasonal influenza vaccine : either a split-virion vaccine containing 15 μg haemagglutinin [HA]/strain/0.1-ml dose administered intradermally , or a subunit vaccine ( 15 μg HA/strain/0.5-ml dose ) adjuvanted with MF59C.1 and administered intramuscularly . Blood sample s were taken before and 21 ± 3 days post-vaccination . Anti-HA antibody titres were assessed using haemagglutination inhibition ( HI ) and single radial haemolysis ( SRH ) methods . We aim ed to show that the intradermal vaccine was non-inferior to the adjuvanted vaccine . Results A total of 795 participants were enrolled ( intradermal vaccine n = 398 ; adjuvanted vaccine n = 397 ) . Non-inferiority of the intradermal vaccine was demonstrated for the A/H1N1 and B strains , but not for the A/H3N2 strain ( upper bound of the 95 % CI = 1.53 ) using the HI method , and for all three strains by the SRH method . A post-hoc analysis of covariance to adjust for baseline antibody titres demonstrated the non-inferiority of the intradermal vaccine by HI and SRH methods for all three strains . Both vaccines were , in general , well tolerated ; the incidence of injection-site reactions was higher for the intradermal ( 70.1 % ) than the adjuvanted vaccine ( 33.8 % ) but these reactions were mild and of short duration . Conclusions The immunogenicity and safety of the intradermal seasonal influenza vaccine in the elderly was comparable with that of the adjuvanted vaccine . Intradermal vaccination to target the immune properties of the skin appears to be an appropriate strategy to address the challenge of declining immune responses in the elderly . Trial registration Clinical Trials.gov : NCT00554333 In the present study we first compare immunogenicity against vaccine and heterologous circulating A(H1N1)pdm09 strains , tolerability and safety of intradermal Intanza ® 15 μg and of virosomal adjuvanted , intramuscularly delivered influenza vaccine , Inflexal ® V , in healthy elderly volunteers . Five-hundred participants were enrolled in the study and r and omly assigned to the two vaccine groups to receive either one dose of Intanza ® 15 μg or Inflexal ® V vaccine . All subjects reported solicited local and systemic reactions occurred within 7 d after vaccination and unsolicited adverse events up to 21 d post-immunization and any serious adverse event appeared during the study . A subset of 55 participants was r and omly selected for immunogenicity and cross-protection evaluations . Serum sample s were collected before and 1 and 3 mo after immunization . Antibody responses were measured using hemagglutination inhibition ( HI ) against all viruses used in the study and neutralization ( NT ) assays against A(H1N1)pdm09 strains . At least one of the CHMP criteria for influenza vaccine approval in the elderly was met by virosomal vaccine against all the tested viruses ; intradermal vaccine met all criteria against all strains . Several parameters of immune response against strains with a different antigenic pattern from that of vaccine A/California/04/09(H1N1)pdm09 were significantly higher in the intradermal vaccine group compared with the virosomal group . Safety and systemic tolerability of both vaccines were excellent , but injection site reactions occurred significantly more frequently in the intradermal vaccination group . Immunogenicity of Intanza ® 15 μg intradermal vaccine tended to be higher than that of Inflexal ® V against heterologous strains in healthy elderly BACKGROUND Concomitant administration of influenza and pneumococcal vaccines facilitates their uptake by older adults ; however , data on immunogenicity and safety of concomitant administration of adjuvanted trivalent inactivated influenza vaccine ( aIIV3 ) and 23-valent pneumococcal polysaccharide vaccine ( PPSV23 ) have not been reported . METHODS Subjects aged ≥65 years ( N=224 ) were r and omized 1:1:1:1 to receive MF59-aIIV3 alone , MF59-aIIV3+PPSV23 in contralateral arms , MF59-aIIV3+PPSV23 in the same arm or PPSV23 alone ( Clinical Trial Number - NCT02225327 ) . Hemagglutination inhibition assay and multiplex opsonophagocytic killing assay were used to compare immunogenicity after single or concomitant vaccination . RESULTS All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroconversion rates and geometric mean fold-increases , irrespective of concomitant vaccinations and injection site . For each pneumococcal serotype , opsonic index ( OI ) increased markedly after the PPSV23 vaccination , irrespective of the concomitant influenza vaccine . All subjects showed an OI≥8 for serotypes 6B , 18C and 19A post-vaccination , with a suggestion that the ipsilateral concomitant vaccination might be associated with higher OIs for some antigens . Local and systemic adverse events were more common in subjects receiving PPSV23 compared to those receiving aIIV3 alone . CONCLUSIONS No interference was observed with antibody responses to influenza or pneumococcal antigens when aIIV3 and PPSV23 were administered concomitantly 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 The safety and immunogenicity of an MF59 ™ -adjuvanted subunit influenza vaccine ( Sub/MF59 ™ ; FLUAD ® , Novartis Vaccines ) was evaluated among elderly Chinese subjects ( ≥ 60 years of age ) . After a preliminary Phase I , open-label study ( n = 25 ) to assess safety 1–14 days post-vaccination , a comparative observer-blind , r and omised , controlled clinical trial ( n = 600 ) was performed to assess safety and immunogenicity versus a non-adjuvanted subunit influenza vaccine ( Subunit ; Agrippal ® , Novartis Vaccines ) . Subjects were r and omised ( 2:1 ) to receive Sub/MF59 ™ or Subunit . Results Both vaccines were well tolerated , with no vaccine-related serious adverse events reported during the Phase I trial . During the observer-blind study , local and systemic reactions were generally similar for both vaccines 1–22 days post-vaccination ; however , injection-site in duration was more frequent among the Subunit group ( P < 0.05 ) , and mild pain at the injection site and fever were more frequent among Sub/MF59 ™ recipients ( P ≤ 0.005 ) . Both vaccines induced a significant ( P < 0.001 ) increase in geometric mean titres ( GMTs ) for the three strains tested , versus baseline ; GMTs against A/H1N1 , A/H3N2 and B were significantly higher in the Sub/MF59 ™ group ( P = 0.034 , P < 0.001 and P = 0.005 , respectively ) . GMT ratios against A/H1N1 , A/H3N2 and B were also significantly higher in the Sub/MF59 ™ group ( P = 0.038 , P < 0.001 and P = 0.006 , respectively ) . Similarly , the percentage of subjects achieving seroprotection or seroconversion on Day 22 was greater for Sub/MF59 ™ recipients , reaching significance for A/H3N2 ( P < 0.001 ) . Conclusion MF59 ™ -adjuvanted subunit influenza vaccine is well tolerated by elderly Chinese subjects and induces a higher level of immunogenicity than a non-adjuvanted subunit influenza vaccine in this population that is at high risk of influenza-related complications . Clinical trial registryhttp://www . clinical trials.gov , BACKGROUND Enhanced influenza vaccines are needed to provide improved protection for elderly individuals . The intradermal vaccination route was hypothesized to provide immunogenicity superior to that provided by the intramuscular vaccination route . METHODS In a multicenter , r and omized study , 1107 volunteers > 60 years of age received intradermal trivalent inactivated influenza vaccine containing 15 or 21 microg of hemagglutinin per strain or intramuscular control vaccine . Intradermal vaccines used a novel microinjection system design ed to ensure easy , convenient , consistent vaccination . The primary end points of the study were the strain-specific hemagglutination inhibition geometric mean titers ( GMTs ) noted 21 days after vaccination . Groups were compared using noninferiority and superiority analyses . RESULTS For each strain , the GMTs noted in association with each intradermal vaccine were superior to those noted with the intramuscular control ( adjusted P < .0001 ) . Seroprotection rates , seroconversion rates , and mean titer increases were also superior for intradermally administered vaccine in all but one of the analyses undertaken . Systemic reactogenicity was comparable between routes . Local injection site reactions , particularly erythema but not pain , were more commonly associated with intradermal vaccination . CONCLUSIONS For the first time , the intradermal vaccination route has been used to elicit immune responses significantly superior to those noted in association with the conventional intramuscular vaccination route . This was done using an easy-to-use , reliable microinjection system . This superior response is expected to enhance annual protection against influenza in this vulnerable population . TRIAL REGISTRATION Clinical trials.gov registry number : NCT00296829 BACKGROUND Imiquimod , a synthetic Toll-like receptor 7 agonist enhanced immunogenicity of influenza vaccine in a mouse model . We hypothesized that topical imiquimod before intradermal influenza vaccination ( TIV ) would produce similar effect in human . METHODS We performed a prospect i ve 1-year follow-up , double-blind , r and omized , controlled trial with adults with comorbidities . Participants were r and omized to 1 of the following 3 vaccinations :  topical 5 % 250 mg imiquimod ointment followed by intradermal TIV , topical aqueous-cream followed by intradermal TIV , or topical aqueous-cream followed by intramuscular TIV . Patients and investigators were blinded to the type of topical treatment applied . Hemagglutination inhibition ( HI ) and microneutralization antibody titers were measured . The primary outcome was the day 7 seroconversion rate . RESULTS Ninety-one recruited participants completed the study . The median age was 73 years . On day 7 , 27/30 ( 90 % ) patients who received imiquimod and intradermal TIV achieved seroconversion against the H1N1 strain by HI , compared with 4/30 ( 13.3 % ) who received aqueous-cream and intramuscular TIV ( P < .001 ) , and 12/31 ( 38.7 % ) who received aqueous-cream and intradermal TIV ( P < .001 ) . The seroconversion , seroprotection , and geometric mean titer-fold increase were met in all 3 strains in the imiquimod and intradermal TIV group 2 weeks earlier , and the better seroconversion rate was sustained from day 7 to year 1 ( P ≤ .001 ) . The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia ( P < .05 ) . All adverse reactions were self-limited . CONCLUSIONS Pretreatment with topical imiquimod significantly expedited , augmented , and prolonged the immunogenicity of influenza vaccination . This strategy for influenza immunization should be considered for the elderly population ABSTRACT Although a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children , data on immune protection in the elderly are sparse . A recent vaccine efficacy trial comparing st and ard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness . The high-dose vaccine induced significantly higher antibody titers than the st and ard-dose vaccine for all assays . For the hemagglutination inhibition assay , a titer of 40 was found to correspond with 50 % protection when the assay virus was antigenically well matched to the circulating virus — the same titer as is generally recognized for 50 % protection in younger adults . A dramatically higher titer was required for 50 % protection when the assay virus was a poor match to the circulating virus . With the well-matched virus , some protection was seen at the lowest titers ; with the poorly matched virus , high levels of protection were not achieved even at the highest titers . Strong associations were also seen between virus neutralization test titers and protection , but reliable estimates for 50 % protection were not obtained . An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection ; in particular , the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone . ( This study has been registered at Clinical Trials.gov under registration no. NCT01427309 . Three-hundred and eight outpatient elderly subjects ( ≥ 65 years ) were r and omly assigned to receive the MF59-adjuvanted influenza vaccine ( FLUAD ; n = 204 ) or a conventional subunit influenza vaccine ( AGRIPPAL S1 ; n = 104 ) in order to compare the safety and immunogenicity of the two vaccines . Although mild pain at the injection site was reported more frequently by subjects immunised with the adjuvanted vaccine , both vaccines were shown to be safe and well tolerated . The adjuvanted vaccine was more immunogenic as indicated by higher post-immunisation geometric mean titres ( GMTs ) and by higher proportions of subjects with post-immunisation ≥ four fold increases of antibody titres or subjects with ≥ 1/160 post-immunisation HI titres . These differences , statistically significant for all three strains after immunisation , indicated that , by addition of the MF59 adjuvant emulsion , conventional subunit influenza antigens acquire an enhanced immunogenicity without any clinical ly significant increase of their reactogenicity BACKGROUND Immune responses after influenza immunization are reduced in elderly individuals , the group at greatest risk for complications and death after influenza . Improved vaccines are needed to address this problem . METHODS Ambulatory individuals 65 years and older ( N = 202 ) were assigned r and omly to receive a single intramuscular injection of the 2001 - 2002 formulation of trivalent inactivated influenza vaccine containing 15 , 30 , or 60 microg of hemagglutinin per strain ( up to 180 microg total per dose ) or placebo .  Clinical and serologic responses were assessed during the month after immunization . RESULTS Increasing dosages of vaccine elicited significantly higher serum antibody levels , frequencies of antibody responses , and putative protective titers after vaccination . Mean serum hemagglutination inhibition antibody titers 1 month after immunization in groups given 0- , 15- , 30- , and 60-microg dosages were 23 , 37 , 50 , and 61 against influenza A/H1N1 ; 43 , 86 , 91 , and 125 against influenza A/H3N2 ; and 10 , 14 , 18 , and 24 against influenza B , respectively . Mean serum hemagglutination inhibition and neutralizing antibody levels against the 3 vaccine antigens in participants given the 60-microg dosage were 44 % to 71 % and 54 % to 79 % , respectively , higher than those in participants given the st and ard 15-microg dosage , and the 60-microg dosage level nearly doubled the frequency of antibody responses in those whose preimmunization antibody titers were in the lower half of the antibody range . Dose-related increases in the occurrence of injection site reactions were observed ( P<.001 ) , but all dosages were well tolerated . CONCLUSION The improved immunogenicity of high-dose influenza vaccine among elderly persons should lead to enhanced protection against naturally occurring influenza In a r and omized , observer-blind , three-arm , parallel group , multi-centre trial including 386 elderly subjects in four countries , the immunogenicity and safety was studied of three different trivalent inactivated surface antigen ( subunit ) influenza vaccine types : a conventional subunit influenza vaccine ( SIV , br and : Influvac and two newer vaccines : a MF59-adjuvanted subunit influenza vaccine ( adSIV , br and : Fluad and a virosomal subunit influenza vaccine ( vSIV , br and : Invivac . All vaccines were trivalent containing 15 microg hemagglutinin of each virus strain as recommended by the World Health Organization for the 2004 - 2005 season . The study was design ed to demonstrate the serological non-inferiority of vSIV to both adSIV and SIV in elderly persons . The secondary objective was to investigate whether vSIV is superior to adSIV with respect to local reactogenicity . For all three vaccine strains , the post-vaccination geometric mean titres were comparable between SIV and adSIV and between vSIV and SIV . Seroprotection rates ( i.e. percentages of subjects with a post-vaccination titre > or=40 ) varied between 84.1 - 100 % indicating that the three vaccines all induced a strong antibody response . Local and systemic reactions were more frequently associated with adSIV ( 46 and 32 % , respectively ) than with vSIV or SIV ( approximately 20 % ) . Vaccinations caused only little inconvenience as measured by question naire . In general , all vaccines were safe and well tolerated . In this trial , virosomal vaccine had similar immunogenicity to MF59-adjuvanted and conventional subunit vaccine and was considerably less reactogenic than the MF59-adjuvanted vaccine in the elderly A r and omised , open study was carried out among an elderly population in order to compare the reactogenicity and immunogenicity of an inactivated , split virion influenza vaccine ( Vaxigrip , Aventis Pasteur MSD , Lyon , France ) with that of an MF59-adjuvanted , subunit vaccine ( Fluad , Chiron Vaccines , Siena , Italy ) . Both vaccines contained the three strains : A/Sydney/5/97 ( H3N2 ) , A/Beijing/262/95 ( H1N1 ) and B/Beijing/184/93 , recommended by the WHO for the 1998 - 1999 influenza season . A total of 2150 subjects were vaccinated and included in the reactogenicity analysis . A total of 1076 subjects received Vaxigrip ( age 73.3 + /- 5.9 years , 49.6 % men ) and 1074 subjects received Fluad ( age 73.4 + /- 5.9 years , 52.3 % men ) . All subjects were kept under medical observation for 30 min after vaccination , in order to check any immediate local and /or systemic reaction . A self monitoring diary card was given to all subjects to collect any local and /or systemic reaction occurring during the 3 days following the vaccination , any adverse event occurring between vaccination day and 21st day post-vaccination and any medication taken during the study period . A total of 1186 subjects were included in the immunogenicity analysis . A total of 591 subjects received Vaxigrip ( age 73.4 + /- 5.6 years , 52.3 % men ) and 595 subjects received Fluad ( age 73.8 + /- 5.9 years , 55.8 % men ) . Blood sample s were collected pre- and 21 days post-vaccination and were analysed by the haemagglutination inhibition assay . In terms of reactogenicity both vaccines were generally well tolerated . The frequency of local reactions was lower in the group that received Vaxigrip .  Pain at the injection site occurring from 30 min to 3 days after vaccination was also significantly less frequent ( P = 0.005 ) in the Vaxigrip group . Fever > or = 37.5 degrees C was reported in less than 1 % of all vaccinated subjects . No serious adverse event was related to vaccine administration . In terms of immunogenicity both vaccines induced an effective immune response ( anti-HI titre > or = 40 ) against A/Sydney/5/97 ( H3N2 ) and A/Beijing/262/95 ( H1N1 ) strains in the entire population . Vaxigrip and Fluad induced similar seroprotection and seroconversion rates against the A/Sydney/5/97 ( H3N2 ) strain . For both vaccines a lower percentage of subjects achieved a seroprotective titre > or = 40 against the B/Beijing/184/93 . A lower antibody response against the influenza B strain was also observed in other studies conducted during the same season . In subjects 75 years of age or older , Fluad was more immunogenic than Vaxigrip for all three virus strains The reactogenicity and the humoral immune response to three influenza vaccines were evaluated in a r and omised , double-blind trial at nursing homes in north-east Italy in winter 1998 - 1999 . Of the 285 subjects , who completed the follow-up , 93 were administered  virosomal vaccine  , 99 received MF59-adjuvanted vaccine  and 93 had split vaccine . Ten subjects ( 0.3 % ) reported local and /or systemic reactions in the first week after immunisation . After 4 weeks , protection rates ( > or = 40 ) were near 100 % for the H1N1 and B strain and 76.0 % against H3N2 . The MF59-adjuvanted vaccine group had higher geometric mean titres than the other two . However , the true clinical benefit of the new adjuvanted vaccine should be further substantiated by comparative protective studies . Our results suggest that immune response to influenza vaccination  in institutionalised elderly is satisfactory BACKGROUND Improved influenza vaccines are needed to control seasonal epidemics . This trial compared the protective efficacy in older adults of a quadrivalent , recombinant influenza vaccine ( RIV4 ) with a st and ard‐dose , egg‐grown , quadrivalent , inactivated influenza vaccine ( IIV4 ) during the A/H3N2‐predominant 2014–2015 influenza season , when antigenic mismatch between circulating and vaccine influenza strains result ed in the reduced effectiveness of many licensed vaccines . METHODS We conducted a r and omized , double‐blind , multicenter trial of RIV4 ( 45 μg of recombinant hemagglutinin [ HA ] per strain , 180 μg of protein per dose ) versus st and ard‐dose IIV4 ( 15 μg of HA per strain , 60 μg of protein per dose ) to compare the relative vaccine efficacy against reverse‐transcriptase polymerase‐chain‐reaction (RT‐PCR)–confirmed , protocol ‐defined , influenza‐like illness caused by any influenza strain starting 14 days or more after vaccination in adults who were 50 years of age or older . The diagnosis of influenza infection was confirmed by means of RT‐PCR assay and culture of nasopharyngeal swabs obtained from participants with symptoms of an influenza‐like illness . The primary end point was RT‐PCR – confirmed , protocol defined , influenza‐like illness between 14 days or more after vaccination and the end of the influenza season . RESULTS A total of 9003 participants were enrolled and underwent r and omization ; 8855 ( 98.4 % ) received a trial vaccine and underwent an efficacy follow‐up ( the modified intention‐to‐treat population ) , and 8604 ( 95.6 % ) completed the per‐ protocol follow‐up ( the modified per‐ protocol population ) . Among RIV4 recipients , the RT‐PCR – confirmed influenza attack rate was 2.2 % ( 96 cases among 4303 participants ) in the modified per‐ protocol population and 2.2 % ( 96 cases among 4427 participants ) in the modified intention‐to‐treat population . Among IIV4 recipients , the attack rate was 3.2 % ( 138 cases among 4301 participants ) in the modified per‐ protocol population and 3.1 % ( 138 cases among 4428 participants ) in the modified intention‐to‐treat population . A total of 181 cases of influenza A/H3N2 , 47 cases of influenza B , and 6 cases of nonsubtypeable influenza A were detected . The probability of influenza‐like illness was 30 % lower with RIV4 than with IIV4 ( 95 % confidence interval , 10 to 47 ; P=0.006 ) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4 . The safety profiles of the vaccines were similar . CONCLUSIONS RIV4 provided better protection than st and ard‐dose IIV4 against confirmed influenza‐like illness among older adults . ( Funded by Protein Sciences ; Clinical Trials.gov number , NCT02285998 . BACKGROUND High-dose trivalent influenza vaccine was developed to improve antibody responses to influenza vaccine in the elderly and hence potentially impact favorably on influenza-associated morbidity and mortality in this population . METHODS A phase IIIb , multicenter , r and omized , double-blind , controlled trial was conducted to compare High-Dose ( HD ) trivalent inactivated influenza vaccine ( 60μg of hemagglutinin [ HA ] per strain ) to st and ard dose ( SD ) vaccine ( 15μg of HA per strain ) in adults ≥65 years of age . Assessment s of safety ( serious adverse events [ SAE ] ) , immunogenicity ( hemagglutination inhibition [ HAI ] titers ) and relative efficacy were performed during the 2009 - 2010 influenza season , which coincided with the H1N1 p and emic . RESULTS A total of 9172 participants were enrolled in 99 research centers in the US ( 6117 and 3055 r and omized to the HD and SD groups , respectively ) . Within 180 days after vaccination , 6.7 % and 6.5 % of participants in the HD and SD vaccine groups , respectively , experienced at least one SAE , of which 0.4 % and 0.3 % had a fatal outcome . A total of 0.5 % of participants in both groups discontinued the study due to a SAE . Post-vaccination HAI titers and rate of post-vaccination HAI titer ≥1:40 were significantly higher in the HD group . No cases of influenza caused by viral types/subtypes similar to those in the vaccines were observed . All cases genetically or antigenically characterized were classified as similar to influenza A/California/7/2009 ( H1N1 ) , the p and emic strain . The vaccine efficacy of HD vaccine relative to SD vaccine against any influenza viral type/subtype was 12.6 % ( 95 % CI -140.5 ; 65.8 ) in the intent-to-treat analysis . CONCLUSION High-dose trivalent inactivated influenza vaccine is safe and well tolerated and provides superior immune responses compared to st and ard dose vaccine . Demonstration of a superior vaccine efficacy requires a separate large r and omized , controlled trial BACKGROUND Recent clinical evidence indicates that an intradermal ( ID ) delivery of vaccines confers superior immunogenicity as compared to a st and ard intramuscular or subcutaneous ( SC ) delivery . METHODS In this exploratory study , 600 healthy adults were r and omized to 6 study groups with subgroups of young adults ( 20 - 64 years old ) and older adults ( 65 years and older ) . The subjects were either injected by a novel ID injection system with a single dose of 6 , 9 , or 15 μg HA or two doses ( 21 days apart ) of 15 μg HA per strain or injected by an SC injection method with a single or two doses ( 21 days apart ) of 15 μg HA per strain . Immunogenicity was assessed using hemagglutination inhibition ( HAI ) titer and microneutralization titer on Days 0 , 10 , 21 , and 42 . Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination , respectively . RESULTS In both young adults and older adults groups , the geometric titer ( GMT ) ratios of HAI in the ID 15 μg HA group were higher than those in the SC 15 μg HA group on both Day 10 and Day 21 , while those in the ID 6 and ID 9 μg HA groups were comparable with those in the SC 15 μg HA group . The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response , which is rather hampered in older adults as seen in the SC vaccine groups . The injection-site AEs were generally mild and transient , and did not occur in a dose or dosage-dependent manner . CONCLUSIONS The results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine , while the safety profile of the ID vaccine is similar to that of the SC vaccine . In this exploratory study with almost 100 subjects per each group , single or two-dose administration of the ID vaccine containing 15 μg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden . TRIAL REGISTRATION JAPIC Clinical Trials Information ( JapicCTI-132096 ) 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 ) BACKGROUND Influenza remains a significant problem in elderly despite widespread vaccination coverage . This r and omized , phase-I study in elderly compared different strategies of improving vaccine immunogenicity . METHODS A total of 370 healthy participants ( ⩾65years ) were r and omized equally 1:1:1:1:1:1 to six influenza vaccine treatments ( approximately 60 - 63 participants per treatment arm ) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5 , 15 , and 45μg HA antigen/strain administered intradermally ( ID ) by MicronJet600 ™ microneedle device ( NanoPass Technologies ) or intramuscularly ( IM ) , and three comparator registered seasonal vaccines ; Inflexal V ™ ( Janssen ) and MF59 adjuvanted Fluad ™ ( Novartis ) administered IM and Intanza ™ ( Sanofi Pasteur ) administered ID via Soluvia ™ prefilled microinjection system ( BD ) . Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months . RESULTS Intradermal delivery of virosomal vaccine using MicronJet600 ™ result ed in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V ™ administered intramuscularly across most of the parameters and strains , as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation . Of 370 participants , 300 ( 81.1 % ) reported ⩾1 adverse event ( AE ) ; more participants reported solicited local AEs ( 72.2 % ) than solicited systemic AEs ( 12.2 % ) . CONCLUSIONS Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery . Triple dose ( 45μg ) virosomal vaccine did not demonstrate any benefit on vaccine 's immunogenicity over 15μg commercial presentation . All treatments were generally safe and well-tolerated BACKGROUND A high-dose trivalent inactivated influenza vaccine was licensed in 2009 by the US Food and Drug Administration ( FDA ) on the basis of serological criteria . We sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was st and ard-dose inactivated influenza vaccine . METHODS In this retrospective cohort study , we identified Medicare beneficiaries aged 65 years and older who received high-dose or st and ard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012 - 13 influenza season . Outcomes were defined with billing codes on Medicare cl aims . The primary outcome was probable influenza infection , defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir . The secondary outcome was a hospital or emergency department visit , listing a Medicare billing code for influenza . We estimated relative vaccine effectiveness by comparing outcome rates in Medicare beneficiaries during periods of high influenza circulation . Univariate and multivariate Poisson regression models were used for analyses . FINDINGS Between Aug 1 , 2012 and Jan 31 , 2013 , we studied 929,730 recipients of high-dose vaccine and 1,615,545 recipients of st and ard-dose vaccine . Participants enrolled in each cohort were well balanced with respect to age and presence of underlying medical disorders . The high-dose vaccine ( 1·30 outcomes per 10,000 person-weeks ) was 22 % ( 95 % CI 15 - 29 ) more effective than the st and ard-dose vaccine ( 1·01 outcomes per 10,000 person-weeks ) for prevention of probable influenza infections ( rapid influenza test followed by oseltamivir treatment ) and 22 % ( 95 % CI 16 - 27 % ) more effective for prevention of influenza hospital admissions ( 0·86 outcomes per 10,000 person-weeks in the high-dose cohort vs 1·10 outcomes per 10,000 person-weeks in the st and ard-dose cohort ) . INTERPRETATION Our retrospective cohort study in US Medicare beneficiaries shows that , in people 65 years of age and older , high-dose inactivated influenza vaccine was significantly more effective than st and ard-dose vaccine in prevention of influenza-related medical encounters . Additionally , the large population in our study enabled us to show , for the first time , a significant reduction in influenza-related hospital admissions in high-dose compared to st and ard-dose vaccine recipients , an outcome not shown in r and omised studies . These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people . FUNDING FDA and the office of the Assistant Secretary of Planning and Evaluation Influenza is a leading cause of morbidity and mortality in elderly people . This prospect i ve , observed- blind , r and omized , multicenter trial compares the immunogenicity and safety of three influenza vaccines in a sample of 635 elderly residents of four nursing homes in Milano ( Italy ) . All vaccines were well tolerated : no serious adverse events were recorded , and a small number ( 9 subjects ) of local and systemic reactions were observed . Twenty-nine oropharyngeal swabs were taken during the season from ILI ( influenza-like illness ) patients , none of whom was positive for influenza and other respiratory viruses . Immunogenicity was evaluated in a subgroup of 111 subjects with blood sample s obtained just before vaccination and after 4 and 12 weeks . The adjuvanted vaccines , subunit vaccine with MF59 ( a-SUV ) and virosome subunit vaccine ( v-SUV ) , induced a higher antibody response than whole virus vaccine ( WVV ) . There was no significant difference between groups that received a-SUV and v-SUV , but the a-SUV group had higher values of geometric mean titres than the v-SUV group for H1N1 and B influenza strains . These findings suggest that influenza vaccination is effective , and they underscore the importance of vaccination programs for institutionalized elderly . Further studies are needed to compare other adjuvanted vaccines in order to define their different properties The study evaluates the risk/benefit of influenza vaccination in patients on stable long-term oral anticoagulant therapy ( OAT ) . One hundred and four consecutive patients with indication for influenza vaccination  were r and omized to receive one dose of 2004/2005 influenza vaccine followed by placebo after 6 weeks , or vice versa , in a cross-over blinded trial . All patients were tested for anticoagulation levels and for hemagglutination inhibiting antibody titres against the influenza vaccine antigens . The highly protective antibody titres induced by influenza vaccination and the absence of statistically relevant interactions between vaccination and OAT suggest that influenza vaccination can be used safely and successfully in elderly patients on OAT Intanza ® /IDflu ® ( Sanofi Pasteur , Lyon , France ) is an intradermal inactivated trivalent influenza vaccine developed as an alternative to intramuscular influenza vaccine . The objective of this study was to confirm the immunogenicity and safety of Intanza/IDflu in South Korean adults . In a phase IV multicenter trial , South Korean adults 18–59 y old ( n = 120 ) and ≥ 60 y old ( n = 120 ) were r and omized 1:1 to receive a single dose of Intanza/IDflu ( 9 µg for 18–59 y , 15 µg for ≥ 60 y ) or trivalent intramuscular vaccine ( Vaxigrip ® 15 µg , Sanofi Pasteur , Lyon , France ) . Blood was collected on pre-vaccination ( day 0 ) and on day 21 . Hemagglutination inhibition titers , seroprotection rates and seroconversion rates were determined on day 21 . Geometric mean titers , seroprotection and seroconversion rates were similar between the intradermal and intramuscular vaccines in both age groups for all three vaccine strains ( A/H1N1 , A/H3N2 and B ) . Both vaccines met Committee for Medicinal Products for Human Use criteria for all three strains . Solicited systemic reactions of the intradermal groups were generally mild , transient , and similar to those of the intramuscular groups . Solicited injection site reactions were more frequent in the intradermal groups but were mostly mild , transient , and consisted mainly of pain , erythema , and pruritus . No treatment-related serious adverse events or other safety concerns were reported . These results confirm that Intanza/IDflu is an effective and well-tolerated alternative to IM influenza vaccination . ( Clinical trials.gov NCT ID : NCT01215669 To improve immune responses to influenza vaccine , a trivalent inactivated vaccine containing 60 microg of the HA of each component ( A/H3N2 , A/H1N1 , B ) was compared to a licensed vaccine containing 15 microg of the HA of each . More local and systemic reactions were reported by subjects given the high dosage but only local pain and myalgias were significantly increased . The high dosage vaccine induced a higher frequency of serum antibody increases ( > or = 4-fold ) in both hemagglutination-inhibiting ( HAI ) and neutralization tests for all three vaccine viruses in the total group as well as subjects vaccinated and those not vaccinated the previous year . Mean titers of antibody attained , the magnitude of antibody increases and the frequencies of persons with final HAI antibody titers > or = 1:32 , > or = 1:64 , and > or = 1:128 were all greater for the high dosage group in both serologic tests , for all groups , and for all vaccine viruses . These increased immune responses should provide increased protection against influenza in the elderly OBJECTIVE To compare the immunogenicity and safety between full-dose ( 15 μg ) intramuscular ( i.m . ) and full-dose ( 15 μg ) intradermal ( i.d . ) immunization of the trivalent influenza vaccine in nursing home older adults . DESIGN A single-center , r and omized , controlled , open-label , parallel group trial from October 2013 to April 2014 . SETTING Nine nursing homes in Hong Kong . PARTICIPANTS Hundred nursing home older adults ( mean age : 82.9 ± 7.4 years ) . INTERVENTION Fifty received i.d . ( Intanza ) and 50 received i.m . ( Vaxigrip ) vaccination . MEASUREMENTS Baseline measurements included demographics , comorbidity , frailty and nutritional status . Day 21 and day 180 immunogenicity ( seroconversion rate , seroprotection rate , geometric mean titer [ GMT ] fold increase in antibody titer ) using hemagglutination-inhibition and adverse events were measured . Noninferiority and superiority of i.d . compared with i.m . vaccination in immunogenicity were analyzed . The study was registered on Clinical Trials.gov ; identifier : NCT 01967368 . RESULTS At day 21 , noninferiority in immunogenicity of the i.d . vaccination was demonstrated . The seroconversion rate of the H1N1 strain was significantly higher in the i.d . group . At day 180 , immunogenicity of both groups fell but the GMT of all strains in i.d . group was higher and the difference was significant for H3N2 strain . The seroconversion rate and GMT fold increase of H3N2 strain was significantly higher in the i.d . group . Local adverse events was significantly more in i.d . group , but they were mild and resolved in 72 hours . CONCLUSIONS I.d . vaccination is noninferior , and even superior in some parts of immunogenicity assessment , to i.m . vaccination without compromising safety in nursing home older adults . I.d . vaccination is a good alternative to i.m . vaccination in this population To determine if newer influenza vaccines can safely improve seroprotection rates of older adults , we compared three licensed trivalent inactivated vaccines ( TIVs ) in a r and omized , controlled trial with evaluator blinding . Participants were non-frail adults ≥ 65 y old , annually TIV-immunized . Study vaccines included intradermal ( IDV ) , MF59-adjuvanted ( ADV ) and subunit ( TIV ) formulations of equal potency and strain composition . Blood was obtained before vaccination ( V1 ) and 21 ( V2 ) and 180 d ( V3 ) afterward and tested by hemagglutination inhibition ( HAI ) assay . Safety diaries were completed daily by participants and specific tolerability questions were posed regarding injections and symptoms . In total , 911 participants were immunized and 887 ( 97.4 % ) completed V3 . Groups had similar demographics . General symptom rates post-vaccination were similar among groups . Rates of injection site redness after IDV/ADV/TIV were 75%/13%/13 % and rates of pain were 29%/38%/20 % , respectively , but each vaccine was well tolerated , with symptoms causing little bother . Baseline antibody titers did not differ significantly among groups but B/Brisbane titers were too high for meaningful response assessment s. At V2 , seroprotection rates ( HAI titer ≥ 40 ) were highest after ADV , the rate advantage over IDV and TIV being significant at 11.8 % and 11.4 % for H3N2 and 10.2 % and 12.5 % for H1N1 , respectively . At day 180 , seroprotection rates had declined ~25 % and no longer differed significantly among groups . While IDV and TIV were also well tolerated , ADV induced modestly higher antibody titers in seniors to influenza A strains at 3 weeks but not 6 months post-vaccination . Immune responses to IDV and TIV were similar in this population Abstract . Background : An open , r and omized , multicenter study was carried out in elderly to compare the immunogenicity and reactogenicity of a conventional influenza split vaccine ( SpV ) with an MF59-adjuvanted subunit vaccine ( aSuV ) and a virosome-based subunit vaccine ( vSuV ) since earlier studies reported better immunogenicity for adjuvanted and virosome-based vaccines . Patients and Methods : A total of 840 subjects , aged 60 years or more , who had not been vaccinated or diagnosed with influenza in the preceding season were investigated .  Hemagglutination-inhibition antibody titers were measured , and signs and symptoms recorded . Results : The three vaccines exceeded EU efficacy requirements for subjects aged older than 60 years and seroprotective levels ( titers > 1:40 ) were equally maintained with the three vaccines during 8 months post vaccination . SpV was as immunogenic as aSuV for the A/H3N2 strain ( p < 0.0001 ) and significantly more immunogenic than aSuV for A/H1N1 strain ( p = 0.0006 ) . SpV was as immunogenic as vSuV for all three strains and significantly more immunogenic than vSuV for the A/H1N1 strain ( p < 0.0001 ) . In terms of reactogenicity , aSuV showed a higher rate of solicited local signs and symptoms than SpV ( p = 0.021 ) and vSuV ( p = 0.046 ) , respectively . Incidence of solicited general symptoms was comparable on all treatments . No serious adverse event related to vaccination was reported . Conclusion : These findings suggest that all three vaccines are highly immunogenic with an acceptable reactogenicity profile and that they are appropriate for use in elderly BACKGROUND As compared with a st and ard-dose vaccine , a high-dose , trivalent , inactivated influenza vaccine ( IIV3-HD ) improves antibody responses to influenza among adults 65 years of age or older . This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness . METHODS We conducted a phase IIIb-IV , multicenter , r and omized , double-blind , active-controlled trial to compare IIV3-HD ( 60 μg of hemagglutinin per strain ) with st and ard-dose trivalent , inactivated influenza vaccine ( IIV3-SD [ 15 μg of hemagglutinin per strain ] ) in adults 65 years of age or older . Assessment s of relative efficacy , effectiveness , safety ( serious adverse events ) , and immunogenicity ( hemagglutination-inhibition [ HAI ] titers ) were performed during the 2011 - 2012 ( year 1 ) and the 2012 - 2013 ( year 2 ) northern-hemisphere influenza seasons . RESULTS A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada ( 15,991 were r and omly assigned to receive IIV3-HD , and 15,998 to receive IIV3-SD ) . In the intention-to-treat analysis , 228 participants in the IIV3-HD group ( 1.4 % ) and 301 participants in the IIV3-SD group ( 1.9 % ) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol -defined influenza-like illness ( relative efficacy , 24.2 % ; 95 % confidence interval [ CI ] , 9.7 to 36.5 ) . At least one serious adverse event during the safety surveillance period was reported by 1323 ( 8.3 % ) of the participants in the IIV3-HD group , as compared with 1442 ( 9.0 % ) of the participants in the IIV3-SD group ( relative risk , 0.92 ; 95 % CI , 0.85 to 0.99 ) . After vaccination , HAI titers and seroprotection rates ( the percentage of participants with HAI titers ≥ 1:40 ) were significantly higher in the IIV3-HD group . Conclusions : Among persons 65 years of age or older , IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD . ( Funded by Sanofi Pasteur ; Clinical Trials.gov number , NCT01427309 . ) BACKGROUND Although the elderly are at high risk for influenza , the immunogenicity in the elderly is lower than that in younger adults . We developed the new type of seasonal influenza vaccine with the novel intradermal ( ID ) injection system . In the previous exploratory phase I/II study of the ID vaccine with a dose of 15 μg HA per strain showed the superior immunogenicity profile to that of the st and ard subcutaneous ( SC ) injection vaccine in subjects aged 20 years and older . METHODS In this multicenter , r and omized , double-blind , active controlled study , 900 adults aged 65 years and older were r and omized at an equal ratio to either the  ID vaccine group or the licensed st and ard SC vaccine group . Immunogenicity was assessed using serum hemagglutination inhibition ( HAI ) titers . The co- primary endpoints were the geometrical mean titers ( GMT ) and the seroconversion rates ( SCR ) of HAI titers against 3 vaccine strains on Day 21 ( 21 days after vaccination ) . To evaluate the early phase immunogenicity , the GMTs and SCRs on Day 7 were also assessed in the same way as the secondary endpoints . RESULTS The superiority of the ID vaccine in the GMTs and SCRs were demonstrated in all 3 vaccine strains both on Day 7 and Day 21 . The frequency of any injection-site reactions was higher in the ID vaccine group , while the severity of injection-site reactions and the frequency of systemic AEs were comparable between the ID and the SC vaccine groups . CONCLUSIONS A single-dose of the influenza vaccine with the novel ID injection system and a dose of 15 μg HA was suggested as an appropriate regimen for clinical use in influenza prevention and associated disease burden reduction . It was also suggested that the new ID vaccine has the potential to replace the st and ard influenza vaccine from the view point of immunogenicity and safety . TRIAL REGISTRATION JAPIC Clinical Trials Information ( JapicCTI-142493 ) BACKGROUND Concomitant administration of influenza and pneumococcal vaccines could be an efficient strategy to increase vaccine uptake among older adults . Nevertheless , immune interference and safety issues have been a concern when more than one vaccines are administered at the same time . METHODS Subjects aged ⩾60years were r and omized in a 1:1:1 ratio to receive MF59-adjuvanted trivalent inactivated influenza vaccine (MF59-aTIV)+13-valent pneumococcal conjugate vaccine ( PCV13 ) ( Group 1 ) , PCV13 alone ( Group 2 ) , or MF59-aTIV alone ( Group 3 )  . Hemagglutination inhibition ( HI ) and opsonophagocytic activity ( OPA ) assays were used to compare immunogenicity after single or concomitant vaccination . RESULTS A total of 1149 subjects ( Group 1 , N=373 ; Group 2 , N=394 ; Group 3 , N=382 ) were available for the assessment of immunogenicity and safety . All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroprotection rates , seroconversion rates , and geometric mean titer ( GMT ) fold-increases , irrespective of concomitant vaccination . For each pneumococcal serotype , OPA titers increased markedly after the PCV13 vaccination , irrespective of the concomitant influenza vaccination . After concomitant administration , the non-inferiority criteria of GMT ratios were met for all three influenza subtypes and 13 pneumococcal serotypes . No vaccine-related serious adverse events occurred . CONCLUSIONS Concomitant MF59-aTIV and PCV13 administration showed no interference with antibody response and showed good safety profiles . ( Clinical Trial Number - NCT02215863 )
BACKGROUND A number of enhanced influenza vaccines have been developed for use in older adults , including high-dose , MF59-adjuvanted , and intradermal vaccines .