Evidence related to safety 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 and without underlying diseases	Local and systemic reactions during the first 3 days after vaccination Local reactions: Most were mild and transient. More frequent with Fluad® than comparator vaccines (15-32% vs. 10-14%) Pain (33% vs. 13%, p<0.001) Erythema (18% vs. 13%, p<0.001) Induration (15% vs. 9%, p<0.001) Systemic reactions: Uncommon, most were mild and transient (<1 to 8% for Fluad® vs. <1 to 4% for comparator). Malaise (6% vs. 4%, p=0.003) Myalgia (8% vs. 3%, p<0.001) Headache (6% vs. 4%, p=0.010) Almost no difference in local or systemic reactions between adjuvanted and comparator groups by day 3	N/A	Poor (not systematic review)
Pellegrini et al. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine. 2009;27(49):6959-65 (38).	MF59 adjuvanted (Fluad®) compared with non-adjuvanted vaccines	Meta-analysis (Integrated database analysis) of 64 clinical trials between 1992-1993 and 2007-2008	Overall population (n=27,998), with 19,590 subjects ≥65 years with or without underlying disease	Local and systemic reactions at day 0 to day 3; AEs at any time during the study Potential autoimmune origin, and unsolicited AEs (diseases, hospitalization and death) occurring at any time during the trials Any reactions: More frequent with Fluad® (RR 1.34; 95% CI 1.28-1.40 for overall; RR 1.32; 95% CI 1.23-1.41 for elderly population) Local reactions: (Pain, injection-site warmth, induration, erythema; mild or moderate) More frequent with Fluad® (RR 1.71; 95% CI 1.61-1.82 for overall; RR 1.74; 95% CI 1.57-1.94 for elderly population) Systemic reactions: (Myalgia, headache, fatigue and malaise) More frequent with Fluad® (RR 1.33; 95% CI 1.22-1.46 for overall; RR 1.29; 95% CI 1.10-1.52 for elderly population) AEs: Serious AEs - All trials: Less frequent with Fluad® (RR 0.86; 95% CI 0.77-0.95 for overall; RR 0.89; 95% CI 0.90-0.99 for elderly population) Serious AEs - Control trials No difference (RR 0.96; 95% CI 0.86-1.06 for overall; RR 0.95; 95% CI 0.85-1.06 for elderly population) Potential autoimmune origin: No significant differences between MF59-adjuvanted (Fluad®) and non-adjuvanted vaccines for overall, non-elderly (<65 years) and elderly (≥65 years) Diseases: All trials CVD - RR 0.44; 95% CI 0.35-0.55 (overall); RR 0.58; 95% CI 0.47-0.73 (elderly) New onset chronic disease (NOCD) - RR 0.71; 95% CI 0.57-0.87 (overall); RR 0.73; 95% CI 0.59-0.91 (elderly) Control trials CVD - RR 0.78; 95% CI 0.63-0.97 (overall); RR 0.82; 95% CI 0.66-1.02 (elderly) New onset chronic disease (NOCD) - RR 0.76; 95% CI 0.62-0.95 (overall); RR 0.70; 95% CI 0.61-0.95 (elderly) Hospitalization: A significantly lower risk of hospitalization (RR 0.88; 95% CI 0.79-0.99) in overall population (but not elderly - all trials) receiving MF59-adjuvanted vs. non-adjuvanted vaccines; no difference in overall or elderly in controlled trials Death: A significantly lower risk of death in overall (RR 0.67; 95% CI 0.51-0.87) and elderly (RR 0.70; 95% CI 0.54- 0.91) population receiving MF59-adjuvanted vs. non-adjuvanted vaccines; no difference in controlled trials in overall or elderly populations	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	Meta-analysis (data from a clinical database) of observer-blind RCTs	Subjects ≥65 years with or without underlying disease	Local and systemic reactions, and all AEs for 28 days post-vaccination Local reactions for Fluad®: % year 1/ % year 2/% year 3 Pain: 32/27/28 Erythema: 18/22/22 Induration: 15/11/13 Local reactions for comparator: % year 1/% year 2/% year 3 Pain: 14/21/16 Erythema: 13/19/9 Induration: 10/8/6 Almost no difference in reported local reactions by day 3 Systemic reactions for Fluad®: % year 1/ % year 2/% year 3 Malaise: 6/8/7 Headache: 6/8/7 Myalgia: 8/3/1 Fever (≥38ºC): 1/1/1 Systemic reactions for comparator: % year 1/ % year 2/% year 3 Malaise: 4/7/3 Headache: 4/7/3 Myalgia: 3/2/2 Fever (≥38ºC): <1/1/0 No difference in reported systemic reactions by day 3 AEs requiring physician visit within 7 days of vaccination: No differences between groups (Relative risk 0.92; 95% CI 0.66-1.30)	N/A	Poor (not systematic review)
Baldo et al. Comparison of three different influenza vaccines in institutionalised elderly. Vaccine. 2001;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=100) and Split (n=100)	First week post-immunization reaction concerning local reactions, and systemic reactions 0.3% reported mild and transient local or systemic reactions within 1st week of immunization. No significant differences in frequency of reactions between vaccines	I	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	Subjects >60 years with or without underlying disease randomly assigned to adSIV (n=130) and SIV (n=129)	Local and systemic reactions during the first 3 days after vaccination; AEs by spontaneous reporting Local reactions: adSIV vs. SIV: 46% vs.19% (p<0.001) Most frequent was pain (37% in adSIV and 9% in SIV) Systemic reactions: adSIV vs. SIV: 32% vs. 22% (p = NS) Most frequent was headache (18% in adSIV and 11% in SIV) and malaise (13.8% in adSIV and 8.6% in SIV) Most local and systemic reactions were mild, but lasted longer with adSIV (3 days). Moderate to severe reactions were more frequent in the adSIV group (7 reports of local and systemic reactions each for adSIV and 2 systemic reactions for SIV) Treatment emergent adverse events: adSIV: 13.8% SIV: 6.3% Most frequent was arthralgia (0.8% in adSIV and 1.6% in SIV) and injection site erythema (2.3% in adSIV and 0.0% in SIV) MF59-adjuvanted vaccine (Fluad®) was more reactogenic than non-adjuvanted subunit vaccine (Influvac®).	I	Good
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	RCT; two-arm; parallel group; single center	192 subjects ≥65 years having no underlying disease randomly assigned to Fluad® (n=94) and Agrippal™ (n=98)	Reactions at 30 minutes after injection; local or systemic reactions at 6 h post-immunization; AEs were followed up until resolved. Local reactions: Pain (resolving within 48h, mild or moderate): more frequent in Fluad® than Agrippal™, with more reports of moderate pain in Fluad® (38%) than Agrippal™ (13%); significantly different in year 1 and 2 (data not provided, p<0.01) Erythema at site of injection: no difference between groups Induration: more frequent in Fluad® than Agrippal™ in year 2 (data not provided) and year 3 (16% vs. 4%, p<0.05). Systemic reactions: Low and the respective rates were similar in both groups. Headache: more frequent in Fluad® than Agrippal™ in year 2 only (10% vs. 3%, p<0.05) AEs: No serious AEs reported within 7 days of vaccination	I	Poor (baseline characteristics and method of randomization not reported; no ITT analysis)
de Roux et al. Impact of corticosteroids on the immune response to a MF59-adjuvanted 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)	Local reactions, systemic reactions, and AEs from day 0 to 4 weeks and to 24 weeks Local reactions: Mild and transient in 21% of patients Systemic reactions: None reported AEs: No serious AEs. No documented case death during the study period	II-3	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) randomly assigned to Fluad® (n=204) or Agrippal® (n=104)	Local and selected systemic reactions at day 0 to day 6; AEs for 28 days requiring physician visit or consultation, with only hospitalizations and deaths considered a serious AE for days 28-180 post-immunization Local reactions: More frequent with Fluad® than Agrippal® Pain: 19% vs. 11%, NS Warmth: 13% vs. 9%, NS Injection-site pain was transient, mild and self-limited. Systemic reactions: No difference between groups. The incidence was low in both groups AEs: No serious AEs	I	Poor (selected population; method of randomization not reported)
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)	Local reactions and systemic reactions during 3 days post-vaccination, and monitoring of body temperature, oxygen saturation and ventilator function during 28 days post-vaccination Local reactions: Injection-site pain and erythema (13 patients total); number of patients in each group not reported Systemic reactions: 3 reports of fever, and 3 reports of ILI (rapid onset of fever, myalgia, sore throat) from Fluad® group AEs: No serious AEs Worsening of ventilator function in some patients without reported ILI in follow-up period (3 patients in Fluad® group, 4 patients in Agrippal® group) No significant differences in frequency of side effects in both groups	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)	Local and systemic reactions, and all AEs for 22 days post-vaccination Fluad® n=391; Agrippal® n=198 Local reactions: Mild or moderate and transient. Significantly more frequent with Fluad® than Agrippal® (24.0% vs. 15.2%, p=0.012) Induration (2.5% vs. 0.5%, p<0.05) Pain (10.2% vs. 3.0%, p≤0.005) Systemic reactions: Mild or moderate and transient. Fever (15.9% vs. 7.6%, p≤0.005) No difference in overall systemic reactions between groups. AEs: High fever: one subject (0.3%) in Fluad®	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 underlying disease randomly assigned to receive Fluad® (n=100), Mutagrip® (n=100) 194 completed the follow-up (96 in Fluad® and 98 in Mutagrip®)	Local reactions and systemic reactions collected by phone-interview 1 week post-vaccination Local reactions: More frequent with Fluad® than Mutagrip® (15.6% vs. 3.1%, p<0.05) All reactions were mild and transient Systemic reactions: No significant differences between groups (28.1% in Fluad® vs. 20.4% in Mutagrip®) All reactions were mild and transient AEs: No serious AEs	I	Fair (method of randomization not reported; baseline characteristics nor 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	Local and systemic reactions at day 0 to day 6, and all AEs Overall, reactions were mild and transient, occurring within first 48h. Local reactions: Significantly more frequent with Fluad® than Agrippal® for Soreness (41% vs. 6.5%, p=0.01) in 1st immunization Erythema (38.5% vs. 14%, p=0.05) in 2nd immunization Systemic reactions: Significantly more frequent with Fluad® than Agrippal® for Malaise (15% vs. 0%, p=0.05) in 1st immunization AEs: No serious AEs in all 3 immunizations	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; multi-center	Subjects ≥64 years (health status not reported) from four nursing homes randomly assigned to vaccines.	Local and systemic reactions within 72 hours of vaccination, and all AEs Local reactions: 4 in aSUV, 1 in WVV Systemic reactions: 2 in WVV AEs: No serious AEs in all 3 immunizations; cumulative ILI incidence of 8.3% equally distributed among sites Death: 30 deaths (1 due to respiratory complications); none related to vaccination	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/797/2001 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=273) and Fluarix™ (n=272)	Local and systemic reactions during days 0-3 post-vaccination, and all AEs for 28±7 days post-vaccination Local reactions: Fluad® vs. Fluarix™ Redness: 20.1 vs. 14.3% Pain: 30.8 vs. 16.9% Induration: 20.5 vs. 14.7% Systemic reactions: Comparable between groups Overall reactions significantly more frequent with Fluad® than Fluarix™ (52.4% vs. 42.3%, p=0.021) AEs: No SAEs reported. Safety similar in subjects ≥60 years and ≥65 years	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)	Local and systemic reactions during 7 days post-vaccination, and all AEs for 1 month post-vaccination Local reactions: More frequent with Fluad® than Agrippal® (50% vs. 27.27%, p<0.001, reporting at least one local reaction) Systemic reactions: More frequent with Fluad® than Agrippal® (23.96% vs. 18.2%, p<0.001) Reactions in both vaccines were mild or moderate and transient AEs: No serious AEs	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 phase IV RCT; two-arm’ parallel group; multi-center	2150 healthy subjects (≥65 years) randomly assigned to Fluad® (n=1074) and Vaxigrip® (n=1076)	Local and systemic reactions at day 0 to day 3; AEs at day 0 to day 21 Local reactions: Similar between groups, except for delayed (30 min-3 d) pain (6.6% of Fluad® vs. 3.9% of Vaxigrip®, p=0.005) Systemic reactions: Similar for both groups (6.5% of Fluad® vs. 6.0% of Vaxigrip®), except for any immediate (within 30 min) systemic reaction (0.6% Fluad® vs. 0% Vaxigrip®, p=0.015) Overall, the frequency of local and systemic reactions was low in both vaccines. The reactions were mild or moderate and transient AEs: 9 SAE reported, but none considered related to vaccine	I	Fair (baseline characteristics and method of randomization note reported)
Van Damme P, 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).	Intanza™ (15 µg HA per strain)	Phase III RCT, open-label NCT00554333 Compared to Fluad® (split virion, MF59C.1 adjuvanted, IM) 2007-08	N=795 (n=398 ID, n=397 IM) Adults ≥65 years	• Erythema (63.1% versus 13.4%), swelling (34.2% versus 8.6%), induration (32.9% versus 10.6%) and pruritis (28.1% versus 6.5%) were reported more frequently in the ID group • Incidence of systemic reactions was comparable for the two groups • 2/6 serious adverse events were determined to be vaccine-related; pneumonia and facial herpes zoster in the ID and adjuvanted IM groups respectively	I	Good