Evidence related to immunogenicity of Fluad® vaccine in adults 61 years of age and older
Study		Vaccine	Study Design		Participants		Summary of Key Findings Using Text or Data	Level of Evidence		Quality
Banzhoff et al. A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology. 2003;49 (3):177-84 (10).		MF59 adjuvanted (Fluad®) compared with non-adjuvanted vaccines (Agrippal S1, Influvac, FluShield, Vaxigrip, Alpharix, and Fluvirin)	Meta-analysis of 13 clinical trials (12 phase II/III and a subset of one phase IV)		Subjects ≥65 years with or without underlying disease		GMT, GMR from HI assay at 28 days post-vaccination Day-28 GMT for B antigen (Fluad® vs. comparator): With disease: 202 vs. 147, p<0.001 (GMR: 1.37) Without disease: 168 vs. 144, p=0.003 (GMR: 1.17) Day-28 GMT for A/H3N2 antigen (Fluad®vs. comparator): With disease: 260 vs. 182, p<0.001 (GMR: 1.43) Without disease: 198 vs. 167, p=0.002 (GMR: 1.18) Day-28 GMT for A/H1N1 antigen (Fluad® vs. comparator): With disease: 268 vs. 228, p<0.001 (GMR: 1.17) Without disease: 212 vs. 191, p=0.068 (GMR: 1.10) Significant difference in GMR for A/H3N2 between those with and without underlying chronic disease (p=0.004), but not for A/H1N1 and B MF59-adjuvanted vaccine (Fluad®) is more immunogenic than non-adjuvanted vaccines	N/A		Poor (not systematic review)
Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001;19(17-19):2673-80 (11).		MF59 adjuvanted (Fluad®) compared with non-adjuvanted vaccines 1st, 2nd, 3rd immunization	Meta-analysis (data from a clinical database) of observer-blind RCTs		Subjects ≥65 years with or without underlying disease		GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 28 days post-vaccination Day-28 GMT (Fluad® vs. comparator): With disease: 260 vs. 182, p<0.001 (GMR: 1.43) Without disease: 198 vs. 167, p=0.002 (GMR: 1.18) Significant group difference between those with and without underlying chronic disease (p=0.004) Fluad® vaccine provided higher immune response than non-adjuvanted vaccines as shown by post-vaccination GMT, GMR, seroprotection rates and seroconversion rates, particularly for the A/H3N2 and B strains.	N/A		Poor (not sys tematic
Ansaldi et al. Antibody response against heterogeneous circulating influenza virus strains elicited by MF59-and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. Vaccine. 2010;28 (25):4123-9 (12).		Fluad® (MF59-djuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) IM; A/California/7/04(H3N2) strain	RCT; two-arm; parallel group; single-center		50 healthy subjects (>65 years) randomly assigned (1:1) to receive single dose of vaccine		GMT, MFI, seroconversion rate, seroprotection rate from HI and NT assays at 22±2 days post-accination MFI (>2): Both vaccines Seroprotection (>60%): Both vaccines against circulating viruses isolated between 2004/2005 and 2006/2007. Seroconversion (>30%): Both vaccines against circulating viruses isolated between 2004/2005 and 2006/2007. Post-vaccination HI GMT: higher with Fluad® compared with Agrippal®against a drifted strains Addition of MF59 to subunit influenza vaccine when there is a good or partial match to circulating strains results in a high antibody response that will increase as the antigenic and molecular distance between vaccine and circulating strains grows	I		Poor (small and selected population; method of randomization not reported)
Ansaldi et al. Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses. Vaccine. 2008;26 (12):1525-9 (13).		Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) IM; 15µg of each of the A/New Caledonia/20/99(H1N1); A/Wyoming/3/03(H3N2); B/Shanghai/361/02 strains	RCT; two-arm; parallel group; single-center		50 healthy subjects (≥65 years) randomly assigned (1:1) to receive single dose of vaccine		GMT, MFI, seroconversion rate, seroprotection rate from HI and NT assays at 21 days post-vaccination MFI (>2): Both vaccines Seroprotection (>60%): Both vaccines against Woy/03 Seroconversion (>30%): Only met for Fluad® group Post-vaccination HI and NT GMT: Significantly higher with Fluad® group (p=0.01 for HI and p=0.03 for NT) and when corrected for pre-vaccination status for drifted strains (p<0.05) For drifted strains (Pan/99, Cal/04, Wisc/05), Fluad® met all CHMP requirements; induced significantly (p<0.05) higher HI GMT & seroprotection rates (for Cal/04, Wisc/05) and higher seroconversion rates (for Pan/99, Cal/04) Fluad® showed a broader serological protection against drifted strains that circulated 1 and 2 years after vaccination.			Poor (small sample size; patient characteristic and method of randomization not reported)
Baldo et al. Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol. 2010;2010:517198 (14).		Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; Split) 0.5 ml IM; 15µg of each of the A/Sydney/5/97(H3N2); A/Beijing/262/95(H1N1); B/Beijing/184/93 strains	DB RCT; parallel group; multi-center Retesting sera of subjects participated in previous RCT of Baldo et al. 2001		Nursing home residents (≥65 years with underlying disease) randomly assigned to single dose of Sub/MF59 (n=72) and Split (n=88)		GMT, MFI, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination MFI: Fluad® higher for all homologous and heterologous strains Seroprotection (≥40%): Homologous (Sub/MF59 vs. split) A/H1N1: 100; 98.9 A/H3N2: 77.8; 79.5 B: 100; 97.7 Heterologous (Sub/MF59 vs. split) A/H1N1: 87.5; 68.2 A/H3N2: 79.2; 78.4 B: 69.4; 73.9 Seroconversion (≥4 fold): Homologous (Sub/MF59 vs. split) A/H1N1: 94.4; 85.2 A/H3N2: 76.4; 62.5 B: 66.7; 54.5 Heterologous (Sub/MF59 vs. split) A/H1N1: 68.1; 31.8 A/H3N2: 41.7; 27.3 B: 25.0; 26.1 Post-vaccination GMT: Fluad® significantly higher (p<0.05) than split vaccine For drifted strains (A/New Cal/99, A/Wisc/2005, B/Mal/2004), Fluad® had significantly higher GMT for the A/H3N2 (p<0.01) and A/H1N1 p<0.01) strains than split vaccine. Fluad® induced a stronger and broader response in elderly subjects with chronic conditions than split vaccine, particularly for the A/H3N2 and A/H1N1 strains.			Poor (sera from a subset of previous population; baseline characteristics not balance between groups; method of randomization not reported)
Baldo et al. Response to influenza vaccine in people with non-protective HI antibody titers. Eur J Epidemiol. 2006;21 (11):843-5 (15).	Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; Split) IM; A/New Caledonia/20/99(H1N1); A/Moscow/10/99(H3N2); B/Sichuan/379/99 strains			DB RCT; two-arm; parallel group; multicenter	338 subjects >64 years and unprotected against at least one of the three influenza virus strain	GMT, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination Seroprotection (≥40%): Both vaccines met; Fluad® significantly higher than Mutagrip® for A/H3N2 (p<0.005) and B (p<0.005) strains Seroconversion (≥4 fold): Both vaccines met; Fluad® significantly higher than Mutagrip® for A/H3N2 (p<0.005) and B (p<0.005) strains Post-vaccination GMT: Fluad® significantly higher than Mutagrip® for A/H3N2 (p<0.05) and B (p<0.05) strains Adjuvanted vaccine (Fluad®) induced better immunogenicity in elderly previously lacking an protective antibody titer.			I	Fair (method of randomization not reported)
Baldo et al. Comparison of three different influenza vaccines in institutionalized elderly. Vaccine. b2001;19(25-26):3472-5 (16).	Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; Split) 0.5 ml IM; 15µg of each of the A/Sydney/5/97(H3N2); A/Beijing/262/95(H1N1); B/Beijing/184/93 strains			DB RCT; parallel group; multi-center	Nursing home residents (≥65 years healthy and with underlying disease) randomly assigned to single dose of Sub/MF59 (n=99) and Split (n=93)	GMT, MFI, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination MFI (>2): Both vaccines met Seroprotection (≥40%): Both vaccines met Seroconversion (≥4 fold): Significant difference for H3N2 (Sub/MF59 92.9% vs. Split 78.5%, p<0.005) and B strains (Sub/MF59 62.6% vs. Split 50.5%, p<0.005) Post-vaccination GMT: Fluad® had higher GMT than split vaccine for all strains, but did not reach statistical significance				Fair (method of randomization not reported; no ITT analysis)
de Bruijn et al. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine. 2007;26 (1):119-27 (17).	Fluad® (MF59-adjuvanted subunit influenza vaccine; adSIV) vs. Influvac® (non-adjuvanted subunit influenza vaccine; SIV) Vaccine composition: A/Fujian/411/2002(H3N2); A/New Caledonia/20/99(H1N1); B/Shanghai/361/2002			Observer-blind RCT; parallel group; multi-center	386 subjects >60 years with or without underlying disease randomly assigned to adSIV (n=126) and SIV (n=125)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 3 weeks post-vaccination MFI (>2): Both vaccines met Seroprotection (≥60%): Both vaccines met Seroconversion (≥30%): Both vaccines met Post-vaccination GMT: Both vaccines showed increased titers for all three strains. No significant difference between groups. Post-vaccination GMRs: Immunogenicity of adSIV was comparable to SIV; sub-analysis of subjects 70 years of age and older showed >1.0 GMR for adSIV vs. SIV but not statistically significant The two trivalent inactivated subunit influenza vaccines (Fluad® and Influvac®) were equally immunogenic in elderly.			I	Good (per protocol analysis)
De Donato et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999;17(23-24):3094-101 (18).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal™ (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/H1N1, A/H3N3, and B antigens 3 annual immunizations (1993/94-1995/96)			RCT; two-arm; parallel group; single center	211 subjects ≥65 years having no underlying disease randomly assigned to Fluad® (n=94) and Agrippal™ (n=98)	GMT, GMR, seroconversion rate from HI assay at 28 days post-vaccination (year 1 only) Seroprotection(≥1:120) Fluad® vs. Agrippal™ A/H1N1: 88% vs. 80%, p=NS A/H3N2: 93% vs. 68%, p<0.001 B: 71% vs. 43%, p<0.001 Seroconversion (≥4 fold) Fluad® vs. Agrippal™ A/H1N1: 32% vs. 32%, p=NS A/H3N2: 83% vs. 62%, p<0.01 B: 52% vs. 31%, p<0.001 Post-vaccination HI titres (1/GMT), Fluad® vs. Agrippal™ A/H1N1: 252 (214-298) vs. 177 (151-209), p<0.01 A/H3N2: 331 (267-411) vs. 162 (131-200), p<0.001 B: 137 (115-162) vs. 84 (71-99), p<0.001 Post-vaccination GMRs (Fluad® vs. Agrippal™ for all years): 7/9 GMRs by strain and year for subjects with pre-immunization titre ≤40 were between 1.5 and 2.4; 1/9 GMRs were >1.5 for subjects with pre-immunization titre >40 Difference in % of subjects with tire ≥1:120 and 4-fold rise between vaccines was higher in subjects with pre-titre ≤40 than pre-titre >40 for all strains (except for % 4-fold rise of A/H1N1)			I	Poor (baseline characteristics and method of radomization not reported; no ITT analysis)
de Roux et al. Impact of corticosteroids on the immune response to a MF59-djuvanted influenza vaccine in elderly COPD-patients. Vaccine. 2006;24 (10):1537-42 (28).	Fluad® (MF59-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/H1N1, A/H3N2 and B strains			Cohort study; single-center	162 COPD patients (≥60 years) who received systemic steroid therapy (SS, n=33), inhaled steroids (IS, n=87) or no steroid (CG, n=42)	GMT, seroconversion rate, seroprotection rate from HI assay at 4 weeks and 24 weeks post-vaccination Seroprotection (≥40%): At 4 weeks, all groups met for all 3 antigens (range 64% in CG to 93 in all groups for B strain). No significant difference between groups (p>0.05) Vaccine failed to induced protective HI titres in a significant number of patients (20-44% of groups) with pre-vaccination titre <40 for A strains, and some (11-18%) for B strain Seroconversion (≥40%): At 4 weeks, all groups met for all 3 antigens (range 56% in CG to 89% in IS). No significant difference between groups (p>0.05) Post-vaccination GMT: All groups had significant increase of mean HI titers 4 weeks after vaccination for all 3 antigens. No significant difference between groups (p>0.05); At 24 weeks, GMT fell close to baseline for both A strains, but remained high for B strain (p≤0.05) Systemic steroids did not influence the antibody response towards Fluad® vaccine in elderly COPD patients			II-3	Poor (small sample size; baseline characteristics not reported; risk of selection bias)
Del Giudice et al. An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine. 2006;24 (16):3063-5 (29).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal™ (non-adjuvanted subunit influenza vaccine) vs. Begrivac™ (split subunit influenza vaccine) Vaccine composition: A/Caledonia/20/99(H1N1); A/Panama/2007/99(H3N2); B/Shangdong/7/97 strains			Cohort study; three-arm	119 subjects (61-91 years; patient characteristics not reported) received single dose of Fluad® (n=60), Agrippal™ (n=29) and Begrivac™ (n=30)	GMT from HI assay at 21 days post-vaccination Seroprotection rate (≥40%): Fluad® induced higher seroprotection rates against heterovariant A/Fujian-like strain than Agrippal™ (98.3% vs. 75.9%, p=0.0001) and Begrivac™ (98.3% vs. 80%, p=0.0001) All three vaccines had similar seroprotection rates against homologous strain Post-vaccination GMT: Fluad® had higher GMT against heterovariant A/Fujian-like strain than Agrippal™ (181.0 vs. 122.3, p=0.0064) and Begrivac™ (180.0 vs. 82.2, p=0.0064) Higher post-vaccination GMT against homologous strain observed for all vaccines Fluad® provided broader protection against influenza virus strains not matched with those included in the vaccine			II-2	Poor (small sample size; baseline characteristics not reported; risk of selection bias)
Gasparini et al. Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol. 2001;17 (2):135-40 (19).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) IM; 15µg of each of the A/Shangdong/9/93(H3N2); A/Texas/36/91(H1N1); B/Panama/45/90 strains			DB RCT; two-arm; parallel group; multi-center	308 healthy subjects (≥65 years), non-institutionalized and mentally competent, randomly assigned to Fluad® (n=204) or Agrippal® (n=104)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 28 days post-vaccination Fluad® (n=192) or Agrippal® (n=99) provided blood sample at day 0 and day 28 Seroconversion (≥4 fold), Fluad® vs. Agrippal™ A/H3N2: 52% (44.9-49.1) vs. 29% (20.1-37.9), p≤0.001 A/H1N1: 20% (14.3-25.6) vs. 11% (4.8-17.2), p≤0.01 B: 35% (28.3-41.7) vs. 27% (18.3-35.7), p≤0.05 Seroprotection (≥1/160), Fluad® vs. Agrippal™ A/H3N2: 51% (43.9-58.1) vs. 34% (24.7-43.3), p≤0.001 A/H1N1: 88% (83.4-92.6) vs. 85% (78.0-92.0), p=NS B: 54% (46.9-61.0) vs. 35% (25.6-44.4), p≤0.001 Post-vaccination GMT: Fluad® had higher GMT against A/H3N2 (103 vs. 55, p≤0.001), and B (102 vs. 70, p≤0.001) antigens than Agrippal® Post-vaccination GMR: GMRs were greater than 1.0 in favor of Fluad® with a statistically significant difference for all three strains (H3N2 – 3.3, p≤0.05; H1N1 – 1.9, p≤0.001; B – 2.6, p≤0.01) Day 180 No significant difference in GMT between vaccines; Fluad® had higher percentage of subjects with titres ≥1/160 for B (p<0.01) and H3N2 (p<0.05)			I	Poor (selected population; method of randomization not reported; no ITT analysis)
Giammanco et al. Immunogenicity and tolerability of two subunit influenza vaccines in patients with chronic obstructive bronchopneumopathy. Journal of Preventive Medicine and Hygiene 2005;46 (3):85-7 (20).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® S1 (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/New Caledonia/IVR116(H1N1); A/Mosca/Resvir2002(H3N2); B/Shangdong/7/97 strains			RCT; two-arm; parallel group; single-center	54 adult and elderly subjects (53-85 years) with chronic obstructive bronchopneumopathy randomly assigned to receive Fluad® (n=27), Agrippal® (n=27)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 28 days post-vaccination No significant differences in immunogenicity for both Agrippal and Fluad®.			I	Poor (small sample size; method of randomization not reported; safety data not properly reported)
Li et al. Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Immun Ageing. 2008;5:2 (21).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/New Caledonia/20/99(H1N1); A/California/7/2004(H3N2); B/Shanghai/361/2002 strains			Phase II/III observer-blind RCT; two-arm; parallel group; multi-center	600 healthy Chinese subjects (≥65 years) randomly assigned (2:1) to Fluad® (n=400) or Agrippal® (n=200)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 22 days post-vaccination Fluad® n=367; Agrippal® n=187 Seroprotection rates (≥1/40): luad® (A/H1N1: 99.7%; A/H3N2: 88.0%; B: 35.7%) Agrippal® (A/H1N1: 99.5%; A/H3N2: 72.2%; B: 28.3%) Fluad® significantly higher than Agrippal® for A/H3N2 (p<0.001) Seroconversion rates (in subjects without pre-vaccination immunoprotection): Fluad® (A/H1N1: 83.3%; A/H3N2: 85.1%; B: 33.4%) Agrippal® (A/H1N1: 80.0%; A/H3N2: 66.2%; B: 25.8%) Fluad® significantly higher than Agrippal® for A/H3N2 (p<0.001) Post-vaccination GMT: Fluad® had higher GMT against A/H1N1 (1439 vs. 1197, p=0.034), A/H3N2 (275 vs. 111, p<0.001), B (17 vs. 12, p=0.005) Higher post-vaccination GMTs also found in subjects without seroprotective titres at baseline for Fluad®, and significant for A/H3N2 (p<0.001) and B (p=0.008) Post-vaccination GMR: The ratios were in favor of Fluad® for all 3 antigens (A/H1N1, p<0.038; A/H3N2, p<0.001; B, p<0.006) MF53-adjuvanted vaccine (Fluad®) had higher level of immunogenicity in Chinese elderly subjects than non-adjuvanted subunit vaccine.			I	Poor (selected population; baseline characteristics and method of randomization not reported; no ITT analysis; risk of selection bias)
Menegon et al. Influenza vaccines: antibody responses to split virus and MF59-adjuvanted subunit virus in an adult population. Eur J Epidemiol 1999;15 (6):573-6 (30).	Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; SVV) 0.5 ml IM; 15µg of each of the A/Wuhan/359/95(H3N2); A/Bayern/7/95(H1N1); B/Beijing/184/93 strains			DB RCT; two-arm; parallel group; single-center	200 adult and elderly subjects (23-97 years) with or without comorbidities randomly assigned to receive Fluad® (n=100), Mutagrip ® (n=100) 194 completed the follow-up (96 in Fluad® and 98 in Mutagrip®)	GMT, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination Seroprotection (≥1/40): Fluad® > Mutagrip for B strain (p<0.05) Seroconversion (≥4 fold): Both vaccines met for all 3 antigens. Fluad® > Mutagrip for all 3 strains (p<0.005) Factors associated with seroconversion for all strains include prevaccination titre ≥1:40, assignment to Fluad®, and previous vaccinations (except for B strain) Post-vaccination GMT: Fluad® > Mutagrip for A/H3N2 (221.4 vs. 153.4, p<0.05) and A/H1N1 (346.5 vs. 227.9, p<0.005); but not for B (54.5 vs. 49.0, NS) Both vaccines caused significant rises in GMTs (p<0.001); Fluad® induced greater immune response than Mutagrip				Fair (method of randomization not reported; baseline characteristics not appropriate; no ITT analysis)
Minutello et al. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine. 1999;17 (2):99-104 (22).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal S1® (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of First vaccination: A/Taiwan/1/86(H1N1); A/Beijing/353/89(H3N2);B/Yamagata/16/88 strains Second vaccination: A/Texas/36/91(H1N1); A/Beijing/32/92(H3N2); B/Panama/45/90 strains Third vaccination: A/Texas/36/92(H1N1); A/Shangdong/9/93(H3N2); B/Panama/45/90 strains			Phase II, observer-blind RCT; two-arm; parallel group; single-center; 3 consecutive years of immunization	92 healthy ambulatory subjects (≥65 years) randomly assigned to Fluad® (n=46) or Agrippal® (n=46) in 1st vaccination; 74 subjects in 2nd vaccination and 67 in 3rd vaccination	GMT, GMR, seroprotection rate from HI assay at 28 days post-vaccination Seroconversion (≥4 fold) Fluad® showed higher rates of seroconversion than Agrippal® for all strains in all years except A/H3N2 in year 1 (70 vs. 72%). Significant difference only for A/H3N2 in year 3 (37 vs. 13%, p≤0.05) Seroprotection(≥1:128) Fluad® showed higher rates of seroprotection than Agrippal® for all strains in all years. Significant difference for B in year 1 (63 vs. 41%, p≤0.05) and H1N1 in year 3 (77 vs. 47%, p≤0.05) Post-vaccination GMT: 1st immunization: Fluad® had higher GMT against all 3 antigens than Agrippal® (by 55% for B, by 27% for A/H3N2, by 45% for A/H1N1). Significant difference for B (p≤0.05) 2nd immunization: Fluad® had higher GMT against all 3 antigens than Agrippal® (by 28% for B, by 52% for A/H3N2, by 56% for A/H1N1). Significant difference for A/H1N1 (p≤0.05). 3rd immunization: Fluad® had higher GMT against all 3 antigens than Agrippal® (by 30% for B, by 44% for A/H3N2, by 53% for A/H1N1). Significant difference for A/H1N1 (p≤0.05). Post-vaccination GMR: Similar day 28/day 0 GMRs between Fluad® and Agrippa, but higher month12/day 0 GMRs for Fluad® in year 1 for all 3 antigens. HI response to 1993/94 heterovariants: Fluad®/Agrippal GMT ratios against heterologous strains were higher compared with those seen against homologous vaccine strains (by 90% for B, by 75% for A/H3N2, by 103% for A/H1N1) MF53-adjuvanted vaccine (Fluad®) had higher level of immunogenicity not only against current season’s strains, but also against heterologous strains.			I	Poor (small sample size; selected population of a phase II trial; method of randomization not reported)
Pregliasco et al. Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly. Aging (Milano). 2001;13 (1):38-43 (23).	Fluad® (MF59-adjuvanted subunit influenza vaccine; aSUV) vs. Inflexal® Berna (whole virus vaccine; WVV) 0.5 ml IM; 15µg of each of the A/Beijing/262/95(H1N1); A/Sydney/5/97(H3N2); B/Beijing/184/93 strains			Observed-blind RCT; parallel group; multicenter	Subjects ≥64 years (health status not reported) from four nursing homes randomly assigned to vaccines. A subgroup of 74 subjects [aSUV (n=41) and WVV (n=33)] were assessed for immunogenicity	GMT, seroconversion rate, seroprotection rate from HI assay at 4 weeks and 12 weeks post-vaccination Seroprotection (≥40%): Both vaccines met. aSUV was higher than WVV for all strains at 4 and 12 weeks. Statistically significant for A/H1N1 at 4 weeks (98% vs. 73%, p=0.0038) and at 12 weeks (93% vs. 58%, p=0.0009) post-vaccination. Seroconversion (≥4-fold): Both vaccines met. Rates were higher for aSUV than WVV, but not statistically different. Post-vaccination GMT: Both vaccines showed increased titers for all three strains. aSUV higher than WVV for all strains at 4 and 12 weeks, particularly for A/H1N1 and B, but not statistically different.			I	Poor (small sample size; subset was selected for blood sampling; baseline characteristics not reported; risk of selection bias)
Ruf et al. 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. Infection. 2004;32 (4):191-8 (24).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Fluarix™ (split vaccine) 0.5 ml IM; 15µg of each of the A/New Caledonia/20/99(H1N1); A/Panama/2007/99(H3N2); B/Shangdong/7/97 strains			Open RCT; parallel group; multi-center	Subjects ≥60 years (health status not reported) who, in the previous season, did not receive the influenza vaccine and were not diagnosed with influenza, were randomly assigned to Fluad® (n=275) and Fluarix™ (n=273)	GMT, seroconversion rate from HI assay at 28 days post-vaccination Seroconversion rate (≥4-fold): Fluarix™ A/H1N1: 74.8 (74-84) A/H3N2: 67.4 (62-73) B: 78.0 (73-83) Fluad® A/H1N1: 70.2 (65-76) A/H3N2: 69.5 (64-75) B: 80.4 (76-85) Seroprotection rate (≥1:40): Fluarix™ A/H1N1: 24.5 (19-30) A/H3N2: 34.1 (28-40) B: 28.9 (24-34) Fluad® A/H1N1:27.3 (22-33) A/H3N2: 30.2 (25-36) B: 32.0 (26-34) Post-vaccination GMT: Both vaccines showed increased titers (over 10-fold) for all three strains. Fluarix™ had higher GMTs for A/H1N1 and A/H3N2; Fluad® had higher GMTs for B Split vaccine (Fluarix™) was more immunogenic than MF59-adjuvanted vaccine (Fluad®) for A/H1N1 (p=0.0006) and A/H3N2 (p<0.0001) Persistence (up to 8 months) Split vaccine had higher titres for A/H1N1 than Fluad®, about the same for A/H3N2; Fluad® had higher titres for B up to month 8; high protection rates maintained			I	Good (health status not reported)
Sindoni et al. Comparison between a conventional subunit vaccine and the MF59-adjuvanted subunit influenza vaccine in the elderly: an evaluation of the safety, tolerability and immunogenicity. J Prev Med Hyg. 2009;50 (2):121-6 (25).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/New Caledonia/20/99(H1N1); A/Moscow/10/99(H3N2); B/Shandong/7/97 strains			Open RCT; two-arm; parallel group; multi-center	195 subjects ≥65 years (health status not reported) randomly assigned to Fluad® (n=96), and Agrippal® (n=99)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 28 days post-vaccination Seroprotection (≥60%): Both vaccines met; similar rates in both vaccines for all three strains Seroconversion (≥4-fold): Both vaccines met; Fluad® showed higher rates than Agrippal® for all strains Post-vaccination GMT: Both vaccines showed increased titers for all three strains. Fluad® group had significantly higher GMT against A/H1N1 (256 vs. 185) and A/H3N2 (378 vs. 257) compared with Agrippal® Post-vaccination GMR: Fluad® had higher GMR than Agrippal® for all strains.z MF59-adjuvanted vaccine (Fluad®) provided greater protection for elderly			I	Fair (baseline characteristics not reported)
Squarcione et al. Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. Vaccine. 2003;21(11-12):1268-74 (26).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Vaxigrip® (split vaccine) 0.5 ml IM; 15µg of each of the A/Beijing/262/95(H1N1); A/Sydney/5/97(H3N2); B/Beijing/184/93 strains			Open RCT; phase IV; two-arm’ parallel group; multi-center	2150 healthy subjects (≥65 years) randomly assigned to Fluad® (n=595) and Vaxigrip® (n=591)	GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 21 days post-vaccination Seroprotection (≥40%): Both vaccines met for all 3 strains. Vaxigrip® shown to be equivalent to Fluad® for A/H3N2, but Fluad® had higher responses to A/H1N1 and B in individuals <75 years. In individuals ≥75, Fluad® had higher response for all strains. Seroconversion (≥4-fold): Both vaccines met for all 3 strains Vaxigrip® shown to be equivalent to Fluad® for A/H3N2, but Fluad® had higher responses to A/H1N1 and B in individuals <75 years. In individuals ≥75, Fluad® had higher response for all strains. Post-vaccination GMT: Both vaccines showed increased titers for all three strains. Fluad® group had higher GMT than Vaxigrip® against all 3 strains Post-vaccination GMR: Fluad® had higher GMR than Vaxigrip® against A/H1N1 and B stains, but both vaccines had similar GMR against A/H3N2 Both vaccines induced an effective immune response against A/H3N2 and A/H1N1, similar seroprotection and seroconversion against A/H3N2, and low response against B strain.			I	Fair (baseline characteristics and method of randomization note reported)
Van Damme et al. Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis. 2010;10:134 (27).	Fluad® (MF59-adjuvanted subunit influenza vaccine; 0.5 ml IM) vs. Intanza™ (split vaccine; 0.1 ml ID) 15µg of each of the A/Solomon Islands/3/2006(H1N1); A/Wisconsin/67/2005(H3N2); B/Malaysia/2506/2004 strains			Open RCT; phase III; two-arm; parallel group; multi-center	795 healthy subjects (≥65 years) randomly assigned to Fluad® (n=397) and Intanza™ (n=398)	GMT, GMR, seroconversion rate, seroprotection rate from HI or SRH assay at 21 days post-vaccination Seroprotection (≥60%): Both vaccines met for all 3 strains. Fluad® was higher than Intanza™ for A/H1N1 strain Seroconversion (≥30%): Both vaccines met for all 3 strains. Post-vaccination GMT: Both vaccines showed increased titers for all three strains. Intanza™ (intradermal) was comparable with Fluad® for all 3 strains using SRH method and for A/H1N1 and B strains using HI method Post-vaccination GMR: No significant differences between the two vaccines The immunogenicity of the intradermal split vaccine (Intanza™) in elderly was comparable with that of the MF53-adjuvanted vaccine (Fluad®)			I	Good