Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: a phase III, randomized trial. Superior antigen-specific CD4+T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older Quantifying Protection Against Influenza Virus Infection Measured by Hemagglutination-inhibition Assays in Vaccine Trials Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial 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 The Long-Term Effects of a Kampo Medicine, Juzentaihoto, on Maintenance of Antibody Titer in Elderly People after Influenza Vaccination Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Relation of chronic disease and immune response to influenza vaccine in the elderly. Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Immunogenicity and safety of a novel IL-2-supplemented liposomal influenza vaccine (INFLUSOME-VAC) in nursing-home residents. Immunogenicity and safety of intradermal trivalent influenza vaccination in nursing home older adults: a randomized controlled trial. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Safety, immunogenicity, and tolerability of three influenza vaccines in older adults Randomized, controlled trial of high-dose influenza vaccine among frail residents of long-term care facilities. Immunogenicity of an inactivated split influenza vaccine in institutionalized elderly patients. Efficacy of high-dose versus standard-dose influenza vaccine in older adults.
BACKGROUND Two influenza B lineages have been co-circulating since the 1980s , and because inactivated trivalent influenza vaccine ( TIV ) contains only one B strain , it provides little/no protection against the alternate B-lineage . We assessed a c and i date inactivated quadrivalent influenza vaccine ( QIV ) containing both B lineages versus TIV in healthy adults . METHODS Subjects received one dose of QIV ( lot 1 , 2 , or 3 ) or one of two TIVs ( B strain from Victoria or Yamagata lineage ) ; r and omization was 2:2:2:1:1 . Hemagglutination-inhibition assays were performed 21-days post-vaccination ; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95 % confidence interval ( CI ) lower limit for the GMT ratio was ≥1.5 , and non-inferiority against the shared strains was demonstrated if the 95 % CI upper limit for the GMT ratio was ≤1.5 . Reactogenicity and safety were assessed during the post-vaccination period . NCT01196975 . RESULTS Immunogenicity of QIV lots was consistent , QIV was superior to TIV for the alternate B-lineage strain , and QIV was non-inferior versus TIVs for shared strains ( A/H1N1 , A/H3N2 , B-strain ) . Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines . CONCLUSION QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains , and without compromising safety Background The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence . The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence , potentially by bolstering T-cell mediated responses . Methods This observer-blind study , conducted in the United States ( US ) and Spain during the 2008–2009 influenza season , evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine ( TIV ) in ≥65 year-old adults . Medically-stable adults aged ≥65 years were r and omly allocated to receive a single dose of AS03-adjuvanted TIV ( TIV/AS03 ) or TIV .  Healthy adults aged 18–40 years received only TIV . Blood sample s were collected on Day 0 , Day 21 , Day 42 and Day 180 . Influenza-specific CD4 + T cells , defined by the induction of the immune markers CD40L , IL-2 , IFN-γ , or TNF-α , were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells . Results A total of 192 adults were vaccinated : sixty nine and seventy three ≥65 year olds received TIV/AS03 and TIV , respectively ; and fifty 18 - 40 year olds received TIV . In the ≥65 year-old group on Day 21 , the frequency of CD4 + T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV ( p < 0.001 ) . On Days 42 and 180 , the adjusted-geometric mean specific CD4 + T-cell frequencies were also higher in the TIV/AS03 recipients than in the TIV recipients ( p < 0.001 ) . Furthermore , the adjusted-geometric mean specific CD4 + T-cell frequencies were higher in the ≥65 year-old recipients of TIV/AS03 than in the18 - 40 year old recipients of TIV on Days 21 ( p = 0.006 ) and 42 ( p = 0.011 ) . Conclusion This positive effect of AS03 Adjuvant System on the CD4 + T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population .Trial registration ( Clinical trials.gov . ) . NCT00765076 Background : Correlations between  hemagglutination-inhibition titers  ( hereafter “ titers ” ) and protection against infection have been identified in historical studies . However , limited information is available about the dynamics of how titer influences protection . Methods : Titers were measured in r and omized , placebo-controlled vaccine trials in Hong Kong among pediatrics during September 2009–December 2010 and the United States among adults during Oct 2007–April 2008 . Intermediate unobserved titers were imputed using three interpolation methods . As participants were recruited at different times leading to varying exposure to infection relative to entry , a modified proportional hazards model was developed to account for staggered entry into the studies and to quantify the correlation of titers with protection against influenza infections , adjusting for waning in titers . The model was fitted using Markov chain Monte Carlo and importance sampling . Results : A titer of 1:40 was associated with a reduced infection risk of 40%–70 % relative to a titer of 1:10 , depending on the circulating strain ; the corresponding protection associated with a titer of 1:80 was 54%–84 % . Results were robust across interpolation methods . The trivalent-inactivated vaccine reduced cumulative incidence of influenza B and influenza A(H3N2 ) infections by six percentage points ( pp ; 95 % credible interval = 2 pp , 10 pp ) and 1 pp ( 95 % credible interval = 0.3 pp , 2 pp ) respectively , but not for influenza A(H1N1)pdm09 . The live-attenuated vaccine showed little efficacy against influenza A(H3N2 ) infections . Conclusions : Titers are correlated with protection against influenza infections . The trivalent inactivated vaccine can reduce the risk of influenza A(H3N2 ) and influenza B infections in the community 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 , 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 We have performed a broad-ranging analysis of the adjuvant effect of a Kampo medicine , juzentaihoto ( JTT ) , on influenza vaccination in a multicenter r and omized controlled trial . In this study , the enhancing effect of JTT on antibody titer after influenza vaccination was studied for 28 weeks in elderly people who were in the high-risk group for influenza infection . In total , 91 subjects over 65 years old were recruited from four long-term-care facilities located in Chiba , Gunma , and Toyama prefectures in Japan . Participants were r and omly assigned to the JTT and the control groups .  Blood sample s were taken at 4 weeks before vaccination , at the time of vaccination , and then at 4 , 8 , 12 , and 24 weeks after vaccination . The hemagglutination inhibition ( HI ) titers against A/California/7/2009 ( H1N1 ) , A/Victoria/210/2009 ( H3N2 ) , and B/Brisbane/60/2008 were then manually measured . A significant increase in HI titer against H3N2 was observed at week 8 after vaccination in the JTT group compared with the control group ( P = 0.0229 ) , and the HI titer of the JTT group significantly increased from 4 to 24 weeks ( P = 0.0468 ) , compared with the control group . In conclusion , our results indicated that JTT increased and prolonged antibody production against A/Victoria/210/2009 ( H3N2 ) , in particular , after influenza vaccination 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 . BACKGROUND A r and omized trial demonstrated that a high-dose inactivated influenza vaccine ( IIV-HD ) was 24.2 % more efficacious than a st and ard-dose vaccine ( IIV-SD ) against laboratory-confirmed influenza illness in adults ≥65 years . To evaluate the consistency of IIV-HD benefits , supplemental analyses explored efficacy and immunogenicity by baseline characteristics of special interest . METHODS Double-blind , r and omized , active-controlled , multicenter trial . Adults ≥65 years were r and omized 1:1 to receive  IIV-HD or IIV-SD and followed for 6 - 8 months postvaccination for the occurrence of influenza . One third of participants were r and omly selected to provide sera for measurement of hemagglutination inhibition antibody ( HAI ) titers . Efficacy  ( IIV-HD vs. IIV-SD ) against laboratory-confirmed , protocol -defined influenza-like illness ( PD-ILI ) and HAI geometric mean titer ( GMT ) ratios  ( IIV-HD/IIV-SD ) were evaluated by age , and number of high-risk comorbid and frailty conditions . RESULTS Efficacy ( 95 % confidence intervals ) of IIV-HD relative to IIV-SD against laboratory-confirmed PD-ILI was 19.7 % ( 0.4 % ; 35.4 % ) for participants 65 - 74 years , 32.4 % ( 8.1 % ; 50.6 % ) for those ≥75 years , 22.1 % ( 3.9 % ; 37.0 % ) for participants with ≥1 high-risk comorbidity , 23.6 % ( -3.2 % ; 43.6 % ) for those with ≥2 high-risk comorbidities , 27.5 % ( 0.4 % ; 47.4 % ) for persons with 1 frailty condition , 23.9 % ( -9.0 % ; 47.2 % ) for those with 2 frailty conditions , and 16.0 % ( -16.3 % ; 39.4 % ) for those with ≥3 frailty conditions . There was no evidence of vaccine efficacy heterogeneity within age , comorbidity , and frailty strata ( P-values 0.351 , 0.875 , and 0.838 , respectively ) . HAI GMT ratios were significantly higher among IIV-HD recipients for all strains and across all subgroups . CONCLUSIONS Estimates of relative efficacy consistently favored IIV-HD over IIV-SD . There was no significant evidence that baseline age , comorbidity , or frailty modified the efficacy of IIV-HD relative to IIV-SD . IIV-HD significantly improved HAI responses for all strains and in all subgroups . IIV-HD is likely to provide benefits beyond IIV-SD for adults ≥65 years , irrespective of age and presence of comorbid or frailty conditions 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 The ability of elderly patients to mount an adequate immune response to influenza vaccine has been debated . We studied the serum haemagglutination inhibition ( HI ) antibody response in elderly persons to determine whether different degrees of chronic illness were a critical factor in immune response . In autumn 1986 , trivalent split virus vaccine was used to immunize 87 healthy ambulatory elderly adults and 53 institutionalized elderly adults . The pre-vaccination health status of the healthy elderly group was significantly better as measured by the incidence of chronic disorders and drug use ( p less than 0.02 ) and by the Chronic Health Evaluation component of the APACHE severity of disease classification ( p less than 0.001 ) . No group differences were observed in serum HI antibody after immunization with the trivalent influenza vaccine . However , in 28 patients from each group who received the monovalent A/Taiwan/86(H1N1 ) vaccine 1 month after the trivalent vaccine , the percentage with a postvaccination HI titre greater than or equal to 40 was 57 % ( 16 of 28 ) for the healthy elderly vs 7 % ( 2 of 28 ) for the institutionalized elderly ( p = less than 0.001 ) . Geometric mean postvaccination HI titres were 31 and 13 , respectively ( p = 0.004 ) . We concluded that the institutionalized elderly in our study mounted an inferior immune response against the new heterotypic influenza A/Taiwan strain when compared to healthy elderly adults . The Chronic Health Evaluation score may be an effective predictor of a poor immune response to new influenza vaccine strains in the elderly . Increasing age per se and lack of a history of prior influenza immunization did not adversely affect the development of protective levels of serum antibody . ( ABSTRACT TRUNCATED AT 250 WORDS 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 ) Influenza and its complications account for substantial morbidity and mortality , especially among the elderly . In young adults , immunization provides 70 - 90 % protection , while among the elderly the vaccine may be only < /=50 % effective ; hence , the need for new , more immunogenic vaccines . We compared the safety and immunogenicity of a novel , interleukin-2 ( IL-2 ) -supplemented trivalent liposomal influenza vaccine ( design ated INFLUSOME-VAC ) with that of a commercial trivalent split virion vaccine in community-residing elderly volunteers ( mean age 81 years ) in winter of 2000/2001 . Eighty-one individuals were r and omly assigned to be vaccinated intramuscularly , either with the st and ard vaccine ( n=33 ) or with INFLUSOME-VAC ( n=48 ) prepared from the former . The two vaccines contained equal amounts of hemagglutinin ( HA ) ( approximately 15 microgram of each viral strain ) ; INFLUSOME-VAC consisted of liposomal antigens admixed with liposomal human IL-2 ( Lip IL-2 ) ( 33 microgram = 6x10(5 ) IU/dose ) . At 1 month post-vaccination , seroconversion rates ( tested by hemagglutination inhibition ) for the A/New Caledonia ( H1N1 ) and A/Moscow ( H3N2 ) strains were significantly higher ( P=0.04 ) in the INFLUSOME-VAC group ( 65 versus 45 % , 44 versus 24 % , respectively ) . Moreover , INFLUSOME-VAC induced a greater anti-neuraminidase ( NA-N2 ) response ( P<0.05 ) . Anti-IL-2 antibodies were undetected , and no increase in anti-phospholipid IgG antibodies was found in the INFLUSOME-VAC group . Adverse reactions were similar in both groups . Thus , INFLUSOME-VAC appears to be both safe and more immunogenic than the currently used vaccine 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 BACKGROUND We aim ed to compare AS03-adjuvanted inactivated trivalent influenza vaccine ( TIV ) with non-adjuvanted TIV for seasonal influenza prevention in elderly people . METHODS We did a r and omised trial in 15 countries worldwide during the 2008 - 09 ( year 1 ) and 2009 - 10 ( year 2 ) influenza seasons . Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were r and omly assigned ( 1:1 ) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV . R and omisation was done in an internet-based system , with a blocking scheme and stratification by age ( 65 - 74 years and 75 years or older ) . Participants were scheduled to receive one vaccine in each year , and remained in the same group in years 1 and 2 . Unmasked personnel prepared and gave the vaccines , but participants and individuals assessing any study endpoint were masked . The co primary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV ( to be reported elsewhere ) . For the first objective , the primary endpoint was relative efficacy of the vaccines for prevention of influenza A ( excluding A H1N1 pdm09 ) or B , or both , that was confirmed by PCR analysis in year 1 ( lower limit of two-sided 95 % CI had to be greater than zero to establish superiority ) . From Nov 15 , to April 30 , in both years , participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness . After onset of suspected cases , we obtained nasal and throat swabs to identify influenza RNA with real-time PCR . Efficacy analyses were done per protocol . This trial is registered with Clinical Trials.gov , number NCT00753272 . FINDINGS We enrolled 43 802 participants , of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1 . In the year 1 efficacy cohort , fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B , or both ( 274 [ 1·27 % , 95 % CI 1·12 - 1·43 ] of 21 573 vs 310 [ 1·44 % , 1·29 - 1·61 ] of 21 482 ; relative efficacy 12·11 % , 95 % CI -3·40 to 25·29 ; superiority not established ) . Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A ( 224 [ 1·04 % , 95 % CI 0·91 - 1·18 ] vs 270 [ 1·26 , 1·11 - 1·41 ] ; relative efficacy 17·53 % , 95 % CI 1·55 - 30·92 ) and influenza A H3N2 ( 170 [ 0·79 , 0·67 - 0·92 ] vs 205 [ 0·95 , 0·83 - 1·09 ] ; post-hoc analysis relative efficacy 22·0 % , 95 % CI 5·68 - 35·49 ) . INTERPRETATION AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV . Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints . FUNDING GlaxoSmithKline Biologicals SA 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 BACKGROUND Despite vaccination , residents of long-term-care facilities ( LTCFs ) remain at high risk of influenza-related morbidity and mortality . More-effective vaccine options for this population are needed . METHODS We conducted a single-blinded , r and omized , controlled trial comparing high-dose ( HD ) to st and ard-dose ( SD ) inactivated influenza vaccine ( IIV ) in 205 frail , elderly residents of LTCFs during the 2011 - 2012 and 2012 - 2013 influenza seasons .  Hemagglutination inhibition ( HI ) antibody titers were measured at baseline and 30 and 180 days following vaccination . RESULTS A total of 187 subjects ( 91 % ) completed the study . The mean age was 86.7 years .  Geometric mean titers ( GMTs ) were significantly higher ( P < .05 ) at day 30 for HD recipients , compared with SD recipients , for all comparisons except influenza A(H1N1 ) during 2012 - 2013 ( the HD formulation was noninferior to the SD formulation for influenza A[H1N1 ] during 2012 - 2013 ) . GMTs for HD and SD recipients during 2011 - 2012 were as follows : influenza A(H1N1 ) , 78 ( 95 % confidence interval [ CI ] , 45 - 136 ) and 27 ( 95 % CI , 17 - 44 ) , respectively ; influenza A(H3N2 ) , 26 ( 95 % CI , 17 - 40 ) and 10 ( 95 % CI , 7 - 15 ) , respectively ; and influenza B , 26 ( 95 % CI , 19 - 35 ) and 14 ( 95 % CI , 11 - 18 ) , respectively . During 2012 - 2013 , GMTs for HD and SD recipients were as follows : influenza A(H1N1 ) , 46 ( 95 % CI , 33 - 63 ) and 50 ( 95 % CI , 37 - 67 ) ; influenza A(H3N2 ) , 23 ( 95 % CI , 18 - 31 ) and 14 ( 95 % CI , 11 - 18 ) , respectively ; and influenza B , 26 ( 95 % CI , 21 - 32 ) and 17 ( 95 % CI , 14 - 22 ) , respectively . GMTs were significantly higher at day 180 for HD recipients , compared with SD recipients , for influenza A(H3N2 ) in both years ( P < .001 ) . CONCLUSIONS Among frail , elderly residents of LTCFs , HD influenza vaccine produced superior responses for all strains except influenza A(H1N1 ) in 2012 - 2013 . CLINICAL TRIALS REGISTRATION NCT01654224 The immunogenicity of influenza vaccination in elderly institutionalized patients , with a variety of clinical disorders , was tested in an open multicenter study involving 495 people ( mean age 80 years ) . Vaccination with an inactivated split influenza vaccine ( Fluarix ) was clinical ly well tolerated . For all age ranges and all strains of virus , the vaccine elicited a humoral response which surpassed the European Community requirements for influenza vaccines in adults over 60 years . The geometric mean titers for all vaccine strains were significantly increased 28 days after vaccination , and remained higher than prevaccination levels after 6 months . These immunological parameters were unaffected by the clinical status of the patients 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 . )
INTRODUCTION The influenza vaccine is less immunogenic in older than younger adults , and the duration of protection is unclear .
Determining if protection persists beyond a typical seasonal epidemic is important for climates where influenza virus activity is year-round .