Evidence related to safety of Fluad® vaccine in adults (18 – 60 years) with or without comorbidities
Study	Vaccine	Study Design	Participants	Summary of Key Findings Using Text or Data	Level of Evidence	Quality
Baldo et al. Family Medicine Group of Pianiga. MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18-60 years of age) with chronic diseases who are at risk of post-influenza complications. Vaccine. 2007;25 (20):3955-61 (33).	Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Influpozzi Subunità® (non-adjuvanted subunit influenza vaccine; Sub) 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	DB RCT; two-arm; parallel group; multi-center 2005-2006	256 adult subjects (18-60 years) with chronic diseases (cancer, diabetes, heart, lung) randomly assigned to Sub/MF59 (n=128) or Sub (n=128)	Local reactions and systemic reactions during 7 days post-vaccination, and AEs during 4 weeks post-vaccination Local reactions: More frequent with Sub/MF59 than with Sub (46.9% vs. 24.2%. p<0.001) Pain (28.9% vs. 8.6%, p<0.001) Erythema (12.5% vs. 4.7%, p<0.05) Systemic reactions: No significant difference between groups(25.7% vs 18.8%) AEs: No serious AEs	I	Good
Durando et al. Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immuno-deficiency virus type 1-seropositive and -seronegative adults. Clin Vaccine Immunol. 2008;15 (2):253-9 (34).	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	Open-label RCT; two-arm; Parallel group; single-center 2005-2006	256 adult (18-65 years) with HIV-1-seronegative or HIV-1-seropositive randomly assigned to receive Fluad® (n=127) or Agrippal® (n=129) 4 groups: Fluad®, HIV-1(-) (n=81); Fluad®, HIV-1(+) (n=46); Agrippal®, HIV-1(-) (n=80); Agrippal®, HIV-1(+) (n=49)	Local reactions and systemic reactions during 4 days post-vaccination, and AEs during 4 weeks post-vaccination Local reactions: More frequent with Fluad® than with Agrippal® ® in both HIV-1(-) and HIV-1(+) groups Significance noted for pain and induration (p<0.01 in HIV-1 (-), NS in HIV-1 (+)) Systemic reactions: More frequent with Fluad® than with Agrippal® ® in both groups. HIV-1 (negative) group: Shivering, malaise, asthenia (p<0.05), headache, fever (p<0.01) HIV-1 (positive) group: Shivering (p<0.05) Fever (p<0.01) AEs: No serious AEs Fluad was better tolerated in HIV(+) participants than in HIV(-) participants. Most symptoms and signs were classified as mild and disappeared within 48-72 hours No significant changes in CD4 cell counts and HIV-1 RNA levels, analyzed by vaccine group, were observed after immunization	I	Poor (small sample size; method of randomization not reported)
Frey et al. Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults. Vaccine. 2003;21(27-30):4234-7 (35).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Fluzone™ (non-adjuvanted subunit influenza vaccine) 0.5 ml IM; 15µg of each of the A/Texas/39/91(H1N1); A/Johannesburg/33/94(H3N2); B/Harbin/7/94 strains (1st immunization) and A/Texas/39/91(H1N1); A/Nanchang/933/95(H3N2); B/Harbin/7/94 strains (2nd immunization)	Observer-blind RCT; two-arm; parallel group; multi-center 2 seasons (1995-1996 and 1996-1997)	301 healthy adult subjects (18-64 years) randomly assigned to receive Fluad® (n=150) or Fluzone™ (n=151) Study extension in season 2: N=200 returning subjects Fluad® (n=104) or Fluzone™ (n=96)	Local reactions and systemic reactions during 7 days post-vaccination for 1st and 2nd injections. Local reactions: More frequent with Fluad® than with Fluzone™ for pain (90% vs. 64%, p≤0.001) and warmth (28% vs. 18%, p≤0.05) during 1st immunization; and pain (84% vs. 69%, p≤0.05) during 2nd immunization) Systemic reactions: More frequent with Fluad® than with Fluzone™ for chills (5% vs. 1%, p≤0.05) and myalgia (15% vs. 6%, p≤0.05) and analgesic/antipyretic use (39% vs. 26%, p≤0.05) during 1st immunization; and no significant difference during 2nd immunization) In both groups, most local and systemic reactions were classified as mild		Poor (method of randomization not reported; not followed up for AEs)
Gabutti et al. Safety and immunogenicity of conventional subunit and MF59-adjuvanted influenza vaccines in human immunodeficiency virus-1-seropositive patients. J Int Med Res. 2005 ;33 (4):406-16 (36).	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/Hong Kong/330/2001 strains	RCT; two-arm; parallel group; single-center 2002-2003	37 adult subjects (18-65 years) with HIV-1-seropositive randomly assigned to receive Fluad® (n=18) or Agrippal® (n=19)	Local reactions and systemic reactions during 4 days post-vaccination, and AEs during 30 days post-vaccination Local reactions: More frequent with Fluad®than with Agrippal® Pain and redness (5 vs. 2 patients) Systemic reactions: No significant differences between groups (fever (2 vs 1 patient) AEs: No serious AEs All reactions were resolved completely within 48-72 hours No significant changes in CD4 counts in subjects who received Fluad. No significant changes in viraemia at any time point in either group. Both Fluad® and Agrippal are safe and can be used in HIV-1-seropositive patients	I	Poor (small sample size; method of randomization not reported
Magnani et al. Safety and efficacy of two types of influenza vaccination in heart transplant recipients: a prospective randomised controlled study. J Heart Lung Transplant 2005;24 (5):588-92 (37).	Fluad® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine) vs. no vaccinaton 0.5 ml IM; 15µg of each of the A/Beijing/262/95(H1N1); A/Sidney/5/97(H3N2); B/Beijing/184/93 strains	RCT; three-arm; parallel group; single-center 1999	58 adult heart transplant recipients (stable, > 6 months passed since transplant) randomly assigned to receive Fluad® (n=21), Agrippal® (n=21), or control (no vaccine; n=16	Local reactions and systemic reactions during 4 days post-vaccination, and AEs during 30 days post-vaccination Local reactions: Not reported Systemic reactions: No significant differences between vaccine groups AEs: No serious AEs related to vaccination	I	Poor (small sample size; method of randomization not reported; safety data not completed
Tsai et al. Exposure to MF59-adjuvanted influenza vaccines during pregnancy--a retrospective analysis. Vaccine 2010;28 (7):1877-80 (39).	MF59-adjuvanted influenza vaccines (Fluad®, Aflunov®, Focetria®, experimental adjuvanted tetravalent influenza vaccines) vs. non-adjuvanted influenza vaccines (Agrippal®, Optaflu®)	Retrospective study (data from Novartis Vaccines’ pregnancy database from 1991 to 2009)	Female subjects (16-42 years) with unintended pregnancy exposures to MF59-adjuvanted influenza vaccines (n=43) and non-adjuvanted influenza vaccines (n=60)	Pregnancy outcomes (MF59-adjuvanted vs. non-adjuvanted): Normal: 70% vs. 75% Abnormal: 21% vs. 23% Induced abortion: 9% vs. 2% Similar results for analysis focused on exposures occurring within the interval of -30 to +45 days of the last menstrual period. Pregnancy outcomes were similar in both groups	II-2	Poor (small sample size; risk of selection bias)