NACI Statement: MF59-Adjuvanted Trivalent Influenza Vaccine

Seroconversion or significant increase rate

HI method:
Percentage of vaccines with pre-vaccination titre <10 and post-vaccination titre of ≥40
OR
≥10 and at least 4-fold rise in post-vaccination titre

SRH method:
Percentage of vaccines with negative pre-vaccination titre and post-vaccination area ≥25 mm²
OR
≥50% increase in area post-vaccination

>30%

Seroprotection

Percentage of vaccinees achieving post-vaccination HI titre of ≥40

OR

SRH titre > 25 mm²

Mean geometric increase

Post / prevaccination GMT ratio

>2.0

Baldo et al. 2006^{Footnote 15}

(With and without comorbidities)

Mutagrip^®

(2004-2005)

60.3 vs. 43.5, p<0.05

[90 vs. 65, p<0.005]

104.7 vs. 120.2, NS

[98.8 vs. 98.8, NS]

51.5 vs. 40.2, p<0.05

[88 vs. 74, p<0.005]

Baldo et al. 2001^{Footnote 16}

(With and without comorbidities)

Mutagrip^®

(1998-1999)

48.6 vs. 47.0

[79.8 vs. 80.6, NS]

157.8 vs. 123.3

[100 vs. 100, NS]

75.6 vs. 65.6

[98 vs. 100, NS]

Baldo et al. 2010^{Footnote 14}

(With comorbidities)

Mutagrip^®

(1998-1999) retesting sera of elderly with comorbidities, who participated in the trial of Baldo et al. 2001¹⁷

Fluad^® had higher GMT against 2006/2007 heterologous strain (p<0.01)

[77.8 vs. 79.5, NS]

Fluad^® had higher GMT against 2006/2007 heterologous strain (p<0.01)

[100 vs. 98.9, NS]

Both vaccines had similar GMT against 2006/2007 heterologous strain (NS)

[100 vs. 97.7, NS]

Del Giudice et al. 2006^{Footnote 29}

(With and without comorbidities)

Begrivac^®

(2003-2004)

Fluad^® had higher GMT against 2004/2005 heterologous strain (p=0.006)

[98.3 vs. 96.7, NS]

Not determined

Not determined

Menegon et al. 1999^{Footnote 30}

(with and without comorbidities)

Mutagrip^®

(1997-1998)

221.4 vs. 153.4, <0.05

[NS difference; numerical data not reported]

346.5 vs. 227.9, p<0.005

[NS difference; numerical data not reported]

54.5 vs. 49.0, NS

[Fluad^® > Mutagrip, p<0.05)

Ruf et al. 2004^{Footnote 24}

(With and without comorbidities)

Fluarix^®

(2002-2003)

Fluad^® had lower GMT (p<0.0001)

[88.4 vs. 90.1, overlap 95% CI]

Fluad^® had lower GMT (p<0.0001)

[89.8 vs. 93.8, overlap 95% CI]

Fluad^® had higher GMT (NS)

[94.9 vs. 91.2, overlap 95% CI]

Squarcione et al. 2003^{Footnote 26}

(Healthy)

Vaxigrip^®

(1998-1999)

214.3 vs. 183.2

[94.0 vs. 90.4, NS]

154.4 vs. 87.1

[83.4 vs. 71.6, p not reported]

24.0 vs. 18.9

[38.0 vs. 29.5, p not reported]

Van Damme et al. 2010^{Footnote 27}

(Healthy)

Intanza^™

(2007-2008)

332.8 vs. 266.5 GMR: 1.25 (non-inferiority was demonstrated; upper bound of 95% CI was <1.5)

[similar; numerical data not reported]

121.6 vs. 108.8 GMR: 1.12 (non-inferiority was demonstrated; upper bound of 95% CI was <1.5)

[similar; numerical data not reported]

38.9 vs. 37.9 GMR: 1.03 (non-inferiority was demonstrated; upper bound of 95% CI was <1.5)

[similar; numerical data not reported]

De Donato et al. 1999^{Footnote 18}

(Healthy)

Agrippal^®

(1993-1994)

331 vs. 162, p<0.001

[83 vs. 68, p<0.001]

252 vs. 177, p<0.001

[88 vs. 80, NS]

137 vs. 84, p<0.001

[71 vs. 43, p<0.001]

Gasparini et al. 2001^{Footnote 19}

(Healthy)

Agrippal^®

(1994-1995)

103 vs. 55, p≤0.001

[51 vs. 34, p≤0.001]

191 vs. 167, NS

[88 vs. 85, NS]

102 vs. 70, p≤0.001

[54 vs. 35, p≤0.001]

Li et al. 2008^{Footnote 21}

(Healthy)

Agrippal^®

(2005-2006)

274.61 vs. 110.85, p<0.001

[88 vs. 72, p<0.001]

1439.01 vs. 1197.39, p=0.034

[99.7 vs. 99.5, NS]

16.59 vs. 11.95, p=0.0005

[35.7 vs. 28.3, NS]

Minutello et al. 1999^{Footnote 22}

(Healthy)

Agrippal^®

(1992/1993)

189 vs. 149, NS

Fluad^® had higher GMT against 1993/1994 heterologous strains (by 75%)

[83 vs. 61, NS]

45 vs. 31, NS

Fluad^® had higher GMT against 1993/1994 strain* (103%)

[22 vs. 17, NS]

115 vs. 74, p≤0.005

Fluad^® had higher GMT against 1993/1994 strain* (by 90%)

[63 vs. 41, p≤0.05]

Ansaldi et al. 2010^{Footnote 12}

(Healthy)

Agrippal^®

(2005-2006)

Fluad^® had higher GMT against 2004/2005 and 2006/2007 heterologous strains (p<0.05)

[Both vaccines met EMA criteria]

Not determined

Not determined

Ansaldi et al. 2008^{Footnote 13}

(Healthy)

Agrippal^®

(2004-2005)

Fluad^® had higher GMT against 2005/2006 and 2007/2008 heterologous strains (p<0.05)

[Both vaccines met EMA criteria]

Not determined

Not determined

Del Giudice et al. 2006^{Footnote 29}

(With and without comorbidities)

Agrippal^®

(2003/2004)

Fluad^® had higher GMT against 2004/2005 heterologous strains (p=0.006)

[98.3 vs. 75.9, p=0.0001] for heterologous strains

Not determined

Not determined

Giammanco et al. 2005^{Footnote 20}

(Chronic obstructive pulmonary disease)

Agrippal^®

(2003-2004)

NS difference

[NS difference]

NS difference

[NS difference]

NS difference

[NS difference]

Sindoni et al. 2009^{Footnote 25}

(With and without comorbidities)

Agrippal^®

(2002-2003)

378 vs. 257, p<0.05

[98.9 vs. 98.9, NS]

256 vs. 185, p<0.05

[95.8 vs. 96, NS]

160 vs. 170, NS

[96.6 vs. 98, NS]

de Bruijn et al. 2007^{Footnote 17}

(With and without comorbidities)

Influvac^®

(2004-2005)

740 vs. 595, NS

[100 vs. 99.2, NS]

109 vs. 136, NS

[84.1 vs. 88.8, NS]

195 vs. 188, NS

[94.4 vs. 89.6, NS]

Baldo etal. 2007^{Footnote 33}

(with comorbidities)

Influpozzi Subunita^® (non-adjuvanted sub-unit vaccine)

(2005-2006)

Higher,p<0.001

[75.0% vs. 57.6%, p=0.002]

NS difference

[97.5% vs. 96.6%, NS]

Higher,p<0.02

[69.2% vs. 61.0%, NS]

Durandoet al. 2008^{Footnote 34}

(HIV-1-seronegative and HIV-1-seropositive)

Agrippal^® (non-adjuvanted subunit vaccine)

(2005-2006)

NS for HIV-1 negative

Higher, p=0.003 for HIV-1 positive

[NS difference; numerical data not reported]

Higher,p=0.005 for HIV-1 negative

NS for HIV-1 positive

[NS difference; numerical data not reported]

Higher,p=0.023 for HIV-1 negative

NS for HIV-1 positive

[NS difference; numerical data not reported]

Frey etal. 2003^{Footnote 35}

(Healthy)

Fluzone™(split vaccine)

(1995-1996) Year 1

511 vs.418, NS

[94% vs. 91%, NS]

951vs. 850, NS

[99% vs. 95%, NS]

698vs. 601, NS

[99% vs. 97%, NS]

(1996-1997) Year 2

Higher p<0.001

[53% vs. 26%, p<0.0001]

216 vs 263, NS

[79% vs. 86%, NS]

160 vs 176, NS

[73% vs. 69%, NS]

Gabuttiet al. 2005^{Footnote 36}

(HIV-1-seropositive)

Agrippal^® (non-adjuvanted subunit vaccine)

(2002-2003)

NS difference

[72% vs. 74%, NS]

NS difference

[83% vs. 100%, NS]

NS difference

[94% vs. 89%, NS]

Iobet al. Evidence of increased clinical protection of an MF59® -adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect. 2005;133(4):687-93.Footnote 4

Fluad^® ( MF59^® -adjuvanted subunit influenza vaccine) vs. Agrippal S1^® (non-adjuvanted subunit influenza vaccine)

IM; 15µg of each of the A/Sydney/5/97(H3N2); A/Beijing/262/95(H1N1); B/Beijing/184/93 strains

Uncontrolled observational multi-center study

Italy

3173 residents from 25 long-term care facilities (mean age 85 ± 10 years); 3.65%persons <65 years

Categorizedas having no underlying disease, heart disease alone, respiratory disease alone, renal disease alone, or having more than one of these diseases

Incidence of influenza-like illness; stratified based on respiratory, cardiovascular and renal disease.

Vaccination effectiveness:
Overall (vaccine vs. no vaccine): OR 2.16, 95% CI 1.56-2.98)
Fluad^®: 94% (47-100%)
AgrippalS1^®: 24.5% (0-45%)

Influenza-like illness:
AgrippalS1^® vs. Fluad^®

• Facilities reporting ILI and underlying chronic disease: OR 1.52 (95% CI 1.22-1.88)
• Above + facilities reporting no ILI: OR 1.72 (95% CI 1.39-2.12)
• Above + facilities missinginformation on chronic diseases: OR 1.80 (95% CI 1.47-2.21)
• Underlying respiratory disease: OR2.27, 95% CI 1.09-4.82)
• Underlying heart disease: OR 1.8895% CI 1.31-2.72)

MF59-adjuvanted vaccine (Fluad^®) provided better protection for elderly subjects, especially those with comorbidities in having influenza-like illness

II-2

Poor

(risk of bias; reason for choosing product by long term care facility unknown; frequency of risk factors for complications in each vaccine group unknown; impact of outbreaks not discussed)

Manninoet al. Effectiveness of influenza vaccination with Fluad® versus a subunit influenza vaccine. Canadian Geriatrics Society 31st Annual Scientific Meeting; Vancouver; 2011.Footnote 7

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal® (non-adjuvanted subunit influenza vaccine)

Cohort study; multi-season (may have looked at the same patients for more than one season)

164,007 person-seasons, subjects ≥65 years with or without comorbidities

Hospitalization Fluad® group had more underlying co-morbidities and a higher risk of hospitalizations outside of influenza season vs. Agrippal® group (RR 1.19;95% CI 0.98-1.45)

Asignificantly lower risk of hospitalization during influenza season (RR 0.77;95% CI 0.59-0.99) in population receiving Fluad® vs. Agrippal®

A significantly lower risk of hospitalization for all respiratory disease during influenza season (RR 0.79; 95% CI 0.66-0.95) in population receiving Fluad® vs. Agrippal®

During influenza season, vaccination with Fluad^® reduced hospitalizations for influenza and pneumonia by 23% compared with Agrippal®.

II-2

Poor

(Personal communication)

Puig-Barberaet al. Effectiveness of MF59-adjuvanted subunit influenza vaccine inpreventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine. 2007;25(42):7313-21.Footnote 5

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. No vaccination

3 case-control studies; multi-center

November 2004 to March 2005

Subjects>64 years; Cases n=134-198; Controls n=246-321

Cases: Consecutive non-institutionalized elderly living in hospital catchment area for previous 6 months, and admitted for emergency hospitalization between Nov 2004 and Mar 2005 acute coronary syndrome (ACS), cerebrovascular accidents (CVA) or pneumonia

Controls: Hospital and gender matched with same inclusion criteria as cases for acute surgical process or trauma within 0-10 days of case admission date

Risk of hospitalization for ACS, CVA or pneumonia

Hospitalization for Fluad^® vs. no vaccination

ACS - greater reduction in risk observed after peak of influenza circulation

• OR:0.89; 95% CI 0.37-2.08
• Adjusted OR: 0.13; 95% CI 0.03-0.65

CVA – greater reduction in risk during peak of influenza circulation

• OR:0.66; 95% CI 0.31-1.40
• Adjusted OR 0.07; 95% CI 0.01-0.48)

Pneumonia – greater reduction in risk during peak influenza circulation

• OR: 0.73; 95% CI 0.40-1.35
• AdjustedOR 0.31; 95% CI 0.14-0.71

Adjusted OR accounted for likelihood of vaccination and relevant confounding factors (e.g. underlying chronic disease, use of therapeutics, caregiver vaccination, smoking, etc.)

Vaccine effectiveness (Risk reduction) ACS: 87%; 95% CI 35-97 CVA: 93%; 95% CI 52-99 Pneumonia: 69%; 95% CI 29-86

II-2

Fair

Thorough methodology with identification of potential confounding factors and controlling potential bias using propensity score

Puig-Barberaet al. Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine. 2004;23(3):283-9.Footnote 6

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. No vaccination

Case-controlstudy; multi-center

November 2002 to March 2003

Subjects≥65 years; Cases n=290; Controls n=525

Cases: Non-institutionalized elderly living in hospital catchment area for previous 6 months, and admitted for emergency hospitalization between Nov 2002 and Mar 2003 with confirmed pneumonia

Controls: Hospital and gender matched with same inclusion criteria as cases for surgical or traumatological acute condition within 0-7 days of case admission date

Risk of hospitalization (emergency admission) for pneumonia

Fluad^® vs. novaccination

Preventing emergency admission for pneumonia: Adjusted effectiveness of 48%; 95% CI 20-66%

Adjusted for heart disease, COPD, asthma, Barthel index score <60, smoking, administered pneumococcal vaccine, attending out patient clinics

II-2

Fair

Banzhoffet 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. Footnote 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):
Withdisease: 260 vs. 182, p<0.001 (GMR: 1.43)
Withoutdisease: 198 vs. 167, p=0.002 (GMR: 1.18)

Day-28 GMT for A/H1N1 antigen (Fluad^® vs. comparator):
Withdisease: 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)

PoddaA. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001;19(17-19):2673-80.Footnote 11

MF59 adjuvanted (Fluad^®) compared withnon-adjuvanted vaccines

1^st, 2^nd, 3^rd 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 dayspost-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 systematic review)

Ansaldiet al. Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with goodor partial matching between vaccine strain and clinical isolates. Vaccine. 2010;28(25):4123-9.Footnote 12

Fluad^® (MF59-adjuvanted 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±2days post-vaccination

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 etal. 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.Footnote 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):
Bothvaccines

Seroprotection (>60%):
Both vaccines against Woy/03

Seroconversion (>30%):
Onlymet 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.

I

Poor

(small sample size; patient characteristic and method of randomization not reported)

Baldo etal. Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol. 2010;2010:517198.Footnote 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 weekspost-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.

I

Poor

(sera from a subset of previous population; baseline characteristics not balance between groups; method of randomization not reported)

Baldo etal. Response to influenza vaccine in people with non-protective HI antibody titers. Eur J Epidemiol. 2006;21(11):843-5.Footnote 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; multi-center

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 etal. Comparison of three different influenza vaccines in institutionalised elderly. Vaccine.2001;19(25-26):3472-5.Footnote 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

I

Fair

(method of randomization not reported; no ITT analysis)

deBruijn et al. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine. 2007;26(1):119-27. Footnote 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 toadSIV (n=126) and SIV (n=125)

GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 3 weekspost-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)

DeDonato et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999;17(23-24):3094-101. Footnote 18

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal™ (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/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 1only)

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 randomization not reported; no ITT analysis)

deRoux et al. Impact of corticosteroids on the immune response to aMF59-adjuvanted influenza vaccine in elderly COPD-patients. Vaccine. 2006;24(10):1537-42.Footnote 28

Fluad^® (MF59-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/H1N1, A/H3N2 and B strains

Cohortstudy; single-center

162COPD 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 allgroups 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)

DelGiudice et al. An MF59-adjuvanted inactivated influenza vaccine containingA/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.Footnote 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

Cohortstudy; 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)

Gaspariniet 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.Footnote 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)

Giammancoet al. Immunogenicity and tolerability of two subunit influenza vaccines inpatients with chronic obstructive bronchopneumopathy. Journal of Preventive Medicine and Hygiene 2005;46(3):85-7. Footnote 20

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® S1 (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/IVR116(H1N1); A/Mosca/Resvir2002(H3N2); B/Shangdong/7/97strains

RCT;two-arm; parallel group; single-center

54adult 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 dayspost-vaccination

Nosignificant differences in immunogenicity for both Agrippal and Fluad^®.

I

Poor

(smallsample size; method of randomization not reported; safety data not properly reported)

Liet al. Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Immun Ageing. 2008;5:2. Footnote 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/361/2002strains

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): Fluad® (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 etal. Influenza vaccines: antibody responses to split virus and MF59-adjuvanted subunit virus in an adult population. Eur J Epidemiol 1999;15(6):573-6. Footnote 30

Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; SVV)

0.5 ml IM; 15µg of each of theA/Wuhan/359/95(H3N2); A/Bayern/7/95(H1N1); B/Beijing/184/93 strains

DB RCT; two-arm; parallel group; single-center

200adult 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 weekspost-vaccination

Seroprotection (≥1/40):
Fluad^® > Mutagrip for Bstrain (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

I

Fair

(methodof randomization not reported; baseline characteristics not appropriate; no ITT analysis)

Minutelloet al. Safety and immunogenicity of an inactivated subunit influenza virusvaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine. 1999;17(2):99-104. Footnote 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/16/88strains

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

PhaseII, observer-blind RCT; two-arm; parallel group; single-center; 3 consecutiveyears 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:
1^st 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)
2^nd 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).
3^rd 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)

Pregliascoet al. Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly. Aging (Milano). 2001;13(1):38-43. Footnote 23

Fluad® (MF59-adjuvanted subunit influenza vaccine; aSUV) vs. Inflexal® Berna (whole virus vaccine; WVV)

0.5 ml IM; 15µg of each of theA/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. A subgroup of 74 subjects [aSUV (n=41) andWVV (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/H1N1at 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)

Rufet al. Open, randomized study to compare the immunogenicity andreactogenicity of an influenza split vaccine with an MF59-adjuvanted subunitvaccine and a virosome-based subunit vaccine in elderly. Infection.2004;32(4):191-8. Footnote 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, wererandomly 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)

Sindoniet 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.Footnote 25

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/Moscow/10/99(H3N2); B/Shandong/7/97 strains

Open RCT; two-arm; parallel group; multi-center

195subjects ≥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)

Squarcioneet al. Comparison of the reactogenicity and immunogenicity of a split and asubunit-adjuvanted influenza vaccine in elderly subjects. Vaccine. 2003;21(11-12):1268-74. Footnote 26

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Vaxigrip^® (split vaccine)

0.5 ml IM; 15µg of each of theA/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%):
Bothvaccines met for all 3 strains.
Vaxigrip^® shown to be equivalent to Fluad^® for A/H3N2, but Fluad^® had higher responses to A/H1N1 andB in individuals <75 years. In individuals ≥75, Fluad^® had higher response forall 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)

VanDamme et al. Evaluation of non-inferiority of intradermal versus adjuvantedseasonal influenza vaccine using two serological techniques: a randomisedcomparative study. BMC Infect Dis. 2010;10:134. Footnote 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/SolomonIslands/3/2006(H1N1); A/Wisconsin/67/2005(H3N2); B/Malaysia/2506/2004 strains

Open RCT; phase III; two-arm; parallel group; multi-center

795healthy 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 dayspost-vaccination

Seroprotection (≥60%):
Bothvaccines met for all 3 strains. Fluad^® was higher than Intanza™for A/H1N1strain

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

Banzhoffet al. A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicitymeta-analysis. Gerontology. 2003;49(3):177-84.Footnote 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

Localand 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)

Pellegriniet al. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integratedanalysis from a large safety database. Vaccine. 2009;27(49):6959-65. Footnote 38

MF59 adjuvanted (Fluad^®) compared withnon-adjuvanted vaccines

Meta-analysis (Integrated database analysis) of 64 clinical trials between 1992-1993 and2007-2008

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)

PoddaA. The adjuvanted influenza vaccines with novel adjuvants: experience withthe MF59-adjuvanted vaccine. Vaccine. 2001;19(17-19):2673-80. Footnote 11

MF59 adjuvanted (Fluad^®) compared withnon-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 etal. Comparison of three different influenza vaccines in institutionalised elderly. Vaccine.2001;19(25-26):3472-5. Footnote 16

Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; Split)

0.5 ml IM; 15µg of each of theA/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 transientlocal or systemic reactions within 1^st week of immunization.

No significant differences in frequency of reactions between vaccines

I

Fair

(method of randomization not reported; no ITT analysis)

deBruijn et al. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine. 2007;26(1):119-27. Footnote 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)

Localand systemic reactions during the first 3 days after vaccination; AEs by spontaneous reporting

Local reactions:
adSIVvs. 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

DeDonato et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999;17(23-24):3094-101. Footnote 18

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal™ (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/H1N1, A/H3N3, and B antigens

3 annual immunizations

RCT;two-arm; parallel group; single center

192subjects ≥65 years having no underlying disease randomly assigned to Fluad^® (n=94) and Agrippal™(n=98)

Reactionsat 30 minutes after injection; local or systemic reactions at 6 hpost-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 etal. Impact of corticosteroids on the immune response to a MF59-adjuvanted influenzavaccine in elderly COPD-patients. Vaccine. 2006;24(10):1537-42. Footnote 28

Fluad^® (MF59-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/H1N1, A/H3N2 and B strains

Cohortstudy; single-center

162COPD 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:
Mildand 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)

Gaspariniet 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.Footnote 19

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

IM; 15µg of each of theA/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-sitepain 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)

Giammancoet al. Immunogenicity and tolerability of two subunit influenza vaccines inpatients with chronic obstructive bronchopneumopathy. Journal of Preventive Medicine and Hygiene 2005;46(3):85-7. Footnote 20

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® S1 (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/IVR116(H1N1); A/Mosca/Resvir2002(H3N2); B/Shangdong/7/97strains

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-sitepain 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)

Liet al. Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Immun Ageing. 2008;5:2. Footnote 21

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/California/7/2004(H3N2); B/Shanghai/361/2002strains

PhaseII/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 etal. Influenza vaccines: antibody responses to split virus and MF59-adjuvanted subunit virus in an adult population. Eur J Epidemiol 1999;15(6):573-6. Footnote 30

Fluad® (MF59-adjuvanted subunit influenza vaccine; Sub/MF59) vs. Mutagrip® (split influenza vaccine; SVV)

0.5 ml IM; 15µg of each of theA/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)

Minutelloet 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. Footnote 22

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal S1^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of Firstvaccination: A/Taiwan/1/86(H1N1); A/Beijing/353/89(H3N2); B/Yamagata/16/88strains

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

PhaseII, 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 1^st immunization
Erythema (38.5% vs. 14%, p=0.05) in 2^nd immunization

Systemic reactions:
Significantly more frequent with Fluad^® than Agrippal^® for Malaise (15% vs. 0%, p=0.05) in 1^st 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)

Pregliascoet al. Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly. Aging (Milano). 2001;13(1):38-43. Footnote 23

Fluad® (MF59-adjuvanted subunit influenza vaccine; aSUV) vs. Inflexal® Berna (whole virus vaccine; WVV)

0.5 ml IM; 15µg of each of theA/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:
4in 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)

Rufet al. Open, randomized study to compare the immunogenicity andreactogenicity 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. Footnote 24

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Fluarix^™ (split vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/Panama/2007/99(H3N2); B/Shangdong/797/2001strains

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, wererandomly assigned to Fluad^® (n=273) and Fluarix^™ (n=272)

Local and systemic reactions during days 0-3 post-vaccination, and all AEs for 28±7days 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)

Sindoniet 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. Footnote 25

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/Moscow/10/99(H3N2); B/Shandong/7/97 strains

Open RCT; two-arm; parallel group; multi-center

195subjects ≥65 years (health status not reported) randomly assigned to Fluad^® (n=96), and Agrippal^® (n=99)

Localand 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

I

Fair

(baseline characteristics not reported)

Squarcioneet al. Comparison of the reactogenicity and immunogenicity of a split and asubunit-adjuvanted influenza vaccine in elderly subjects. Vaccine. 2003;21(11-12):1268-74. Footnote 26

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Vaxigrip^® (split vaccine)

0.5 ml IM; 15µg of each of theA/Beijing/262/95(H1N1); A/Sydney/5/97(H3N2); B/Beijing/184/93 strains

Openphase IV RCT; two-arm’ parallel group; multi-center

2150healthy 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)

VanDamme 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.Footnote 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

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.Footnote 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

238 adult subjects (18-60 years) with chronic diseases (cancer, diabetes, heart, lung) randomly assigned to Sub/MF59 (n=120) or Sub (n=118)

GMT, MFI, GMR, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination

Seroprotection (>70%): Sub/MF59 met for A/H1N1 and A/H3N2; Sub met for A/H1N1 only

Sub/MF59 vs. Sub:
A/H3N2:75.0% vs. 57.6%, p=0.002
A/H1N1:97.5% vs. 96.6%, NS
B:69.2% vs. 61.0%, NS

Seroconversion (>40%): Sub/MF59met for all 3 antigens; Sub met for A/H1N1 only Sub/MF59 vs. Sub: A/H3N2:52.5% vs. 33.1%, p=0.02 A/H1N1:57.5% vs. 55.9%, NS

B: 46.7% vs. 36.4%, NS

Post-vaccination GMT:
BothVaccines had significant increase in post-vaccination GMT against all 3strains.

Post-vaccination GMR:
Sub/MF59had significant higher GMT than Sub for A/H3N2 (p<0.001) and B (p<0.02)strains

MFI (>2.5):
Bothvaccines met for all 3 antigens

Addition of MF59 enhances the immunogenicity of subunit influenza vaccine in adults with chronic disease

I

Good

Durando et al. Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults. Clin Vaccine Immunol. 2008 ;15(2):253-9. Footnote 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)

GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 4 weeks and 12 weeks post-vaccination

Seroprotection (>70%):
Both vaccines met for all 3 antigens. NS difference between groups

Seroconversion (>40%):
Both vaccines met for all 3 antigens. NS difference between groups

Post-vaccination GMT: AfterBeyer’s correction , Fluad® had significant higher GMT than Agrippal for all influenza vaccine subtypes, although statistical significant was reached for only AH1N1 (p=0.005) and B (p=0.023) strains in HIV-1-seronegative subjects;for seropositive subjects, Fluad had significantly higher GMT than Agrippal for A/H3N2 (p=0.003) strain only in HIV-1-seropositive subjects. A value near significance was observed for A/H1N1 strain in seropositive subjects(p=0.097)

Both vaccines had good immunogenicity for both uninfected and HIV-1-infected adults. No definitive conclusions could be drawn for the superiority of Fluad^® over Agrippal.

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. Footnote 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

1995-1996

Study extension for a subsequent injection in year2: 1996-1997

301 healthy adult subjects (18-64 years) randomly assigned to receive Fluad^® (n=150) or Fluzone^™ (n=151)

Year 2:
Fluad (n=99)
Fluzone (n=94)

GMT, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination and 180 days post-vaccination

Seroprotection (>70%):
Both vaccines met for all 3 antigens. NS difference between groups

Seroconversion (>40%):
Both vaccines met for all 3 antigens. Significant difference reached for B strain(Fluad^®: 83% vs. Fluzone: 71%,p=0.008)

Post-vaccination GMT:
NS difference between groups

Year 2: 28 days post-injection

Seroprotection:
Significantdifference reached for A/H3N2 strain (Fluad 53% vs Fluzone 26%, p<0.0001)

Seroconversion:
Significantdifference reached for A/H3N2 strain (Fluad^® 55% vs. Fluzone 32%,p≤0.0005)

Post-vaccination GMT:
GMT higher for H3N2 strain in Fluad vs Fluzone (112 vs. 71, p≤0.001)

No significant differences were seen at day 180 except in the % of subjects witha titer: 160 for A/H1N1 antigen (Fluad 57% vs Fluzone 73%, p=0.025)

Fluad was slightly more immunogenicin healthy adults for the B strain after the 1^st injection and for the A/H3N2 strain after the 2^nd injection.

I

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 IntMed Res. 2005 ;33(4):406-16. Footnote 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)

GMT, GMR, seroconversion rate, seroprotection rate from HI assay at 4 weeks post-vaccination and 180 days post-vaccination

Seroprotection (>70%):
Both vaccines met for all 3 antigens. NS difference between groups

Seroconversion (>40%):
Both vaccines met for all 3 antigens. NS difference between groups

Post-vaccination GMT:
NS difference between groups

Both Fluad and Agrippal were immunogenic, and there was prolonged persistence of antibodies towards all 3 strains after 180 days.

I

Poor

(small sample size; method of randomization not reported

Baldoet al. Family Medicine Group of Pianiga. MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18-60 years of age) withchronic diseases who are at risk of post-influenza complications. Vaccine. 2007;25(20):3955-61. Footnote 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 theA/New Caledonia/20/99(H1N1); A/California/7/2004(H3N2); B/Shanghai/361/2002strains

DB RCT; two-arm; parallel group; multi-center

2005-2006

256adult 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

Durandoet al. Safety and immunogenicity of two influenza virus subunit vaccines,with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults. Clin Vaccine Immunol. 2008 ;15(2):253-9. Footnote 34

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/California/7/2004(H3N2); B/Shanghai/361/2002strains

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)

Freyet al. Comparison of the safety, tolerability, and immunogenicity of aMF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine innon-elderly adults. Vaccine. 2003;21(27-30):4234-7. Footnote 35

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Fluzone^™ (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/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/7/94strains (2nd immunization)

Observer-blind RCT; two-arm; parallel group; multi-center

2seasons (1995-1996 and 1996-1997)

301healthy adult subjects (18-64 years) randomly assigned to receive Fluad^® (n=150) or Fluzone^™ (n=151)

Study extension in season 2:
N=200returning 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

I

Poor

(methodof randomization not reported; not followed up for AEs)

Gabutti etal. Safetyand 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. Footnote 36

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine)

0.5 ml IM; 15µg of each of theA/New Caledonia/20/99(H1N1); A/Moscow/10/99(H3N2); B/Hong Kong/330/2001strains

RCT;two-arm; parallel group; single-center

2002-2003

37adult 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:
Morefrequent with Fluad^®than with Agrippal^®
Painand 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 etal. Safety and efficacy of two types of influenza vaccination in hearttransplant recipients: a prospective randomised controlled study. J Heart Lung Transplant 2005;24(5):588-92. Footnote 37

Fluad^® (MF59-adjuvanted subunit influenza vaccine) vs. Agrippal^® (non-adjuvanted subunit influenza vaccine) vs. no vaccinaton

0.5ml IM; 15µg of each of the A/Beijing/262/95(H1N1); A/Sidney/5/97(H3N2); B/Beijing/184/93strains

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 etal. Exposure to MF59-adjuvanted influenza vaccines during pregnancy - a retrospective analysis. Vaccine 2010;28(7):1877-80. Footnote 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)

Seroconversion or significant increase rate

HI method:
Percentage of vaccines with pre-vaccination titre <10 and post-vaccination titre of ≥40
OR
≥10and at least 4-fold rise in post-vaccination titre

SRH method:
Percentage of vaccines with negative pre-vaccination titre and post-vaccination area≥25 mm²
OR
≥50% increase in area post-vaccination

>40%

Seroprotection

Percentage of vaccinees achieving post-vaccination HI titre of ≥40

OR

SRH titre > 25 mm²

>70%

Meangeometric increase

Pre /post-vaccination GMT ratio

>2.5