Supplementary tables eTable 1. Description of vaccines against each subtype as well as circulating strains in both trials. HK trial A/Brisbane/59/2007(H1 Trivalent N1)-like virus inactive influenza vaccine 08/091 A/Brisbane/10/2007(H3N 2)-like virus B/Brisbane/60/2008like virus - B/Brisbane/60/2008like virus A/Solomon Trivalent Islands/3/2006 (H1N1)inactive influenza vaccine like virus 07/082 A/Wisconsin/67/2005(H3 N2) -like virus B/Malaysia/2506/2004 -like virus A/Solomon Live attenuated influenza vaccine Islands/3/2006 (H1N1) like virus 07/083 A/Wisconsin/67/2005(H3 N2) -like virus B/Malaysia/2506/2004 -like virus A/Uruguay/716/2007(H3 N2)-like virus - Circulating Strain A/California/7/2009(H1 N1)-like virus US trial Circulating Strain - Each 0.5ml dose of the TIV contained 15μg of hemagglutinin from each of the following strains: A/Brisbane/59/2007(H1N1)-like, A/Brisbane/10/2007(H3N2)-like, and B/Brisbane/60/2008-like (Victoria lineage) strains 1 Each 0.5ml dose of the TIV contained 15μg of hemagglutinin for each of A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005(H3N2), and B/Malaysia/2506/2004 (B/Victoria lineage) 2 3 Each 0.2ml dose of the live attenuated vaccine contained 106.5–7.5 fluorescent focus units of live attenuated influenza virus reassortants of the same strains 1 eTable 2. Descriptive Characteristics of Participants Recruited in the Hong Kong (HK) Trial, 2009–10; and in the United States (US) Trial, 2007–8. Total participants N = 773 in the HK trial and N = 1952 in the US trial. P-values are calculated by Pearson’s chi-square test, comparing proportions with RT-PCR confirmed infection within each study arm. TIV Placebo (N = 465) (N=308) Hong Kong trial n % n % 6–8 164 35 99 32 9–11 147 32 106 34 12–17 154 33 103 33 Male 241 52 168 55 Influenza A(H1N1)pdm09a 10 2 5 2 Influenza Bb 10 2 21 7 Age group, years RT-PCR-confirmed infections Live attenuated United States trial Inactivated vaccine Placebo (N = 813) (N = 325) vaccine (N = 814) n % n % n % 18–35 736 90 728 90 300 94 36–50 78 10 85 10 25 6 Male 320 39 294 36 124 38 53 7 22 3 30 9 Age group, years RT-PCR-confirmed influenza A(H3N2) infectionc a p = 0.80. p= 0.003. c p < 0.001. b 2 eTable 3. Probability Distribution of Hemagglutination-inhibition (HAI) Titers and the Risk of Infection per HAI Titer Interval for Influenza A(H1N1)pdm09 and Influenza B in the HK Trial. Influenza A (H1N1)pdm09 Influenza B Titer Proportion Risk of infection Proportion Risk of infection <1:10 0.54 (0.50, 0.59) 0.04 (0.02, 0.06) 0.77 (0.74, 0.80) 0.05 (0.03, 0.07) 1:10 — 1:20 0.01 (0.00, 0.01) 0.20 (0.01, 0.61) 0.02 (0.01, 0.03) 0.06 (0.00, 0.22) 1:20 — 1:40 0.02 (0.01, 0.03) 0.10 (0.00, 0.38) 0.06 (0.04, 0.08) 0.06 (0.01, 0.14) 1:40 — 1:80 0.08 (0.06, 0.11) 0.03 (0.00, 0.09) 0.05 (0.03, 0.06) 0.03 (0.00, 0.09) 1:80 — 1:160 0.14 (0.11, 0.15) 0.02 (0.00, 0.05) 0.05 (0.04, 0.07) 0.02 (0.00, 0.09) 1:160 — 1:320 0.12 (0.10, 0.15) 0.02 (0.00, 0.07) 0.04 (0.02, 0.05) 0.04 (0.00, 0.12) 1:320 — 1:640 0.06 (0.04, 0.08) 0.04 (0.00, 0.13) 0.01 (0.00, 0.02) 0.10 (0.00, 0.34) 1:640 — 1:1280 0.02 (0.01, 0.04) 0.08 (0.00, 0.27) 0.00 (0.00, 0.00) 0.33 (0.01, 0.84) 1:1280 — 1:2560 - - 0.00 (0.00, 0.01) 0.25 (0.01, 0.69) 3 eTable 4. Probability Distribution of Hemagglutination-inhibition (HAI) Titers and the Risk of Infection per HAI Titer Interval for Influenza A(H3N2) in the US Trial. Influenza A(H3N2) Titer Proportion Risk of infection <1:4 0.23 (0.18, 0.29) 0.34 (0.31, 0.38) 1:4 — 1:8 0.26 (0.18, 0.35) 0.14 (0.12, 0.17) 1:8 — 1:16 0.10 (0.04, 0.16) 0.14 (0.11, 0.17) 1:16 — 1:32 0.11 (0.04, 0.20) 0.08 (0.06, 0.10) 1:32 — 1:64 0.13 (0.06, 0.23) 0.09 (0.07, 0.11) 1:64 — 1:128 0.10 (0.04, 0.19) 0.09 (0.07, 0.11) 1:128 — 1:256 0.08 (0.02, 0.19) 0.05 (0.03, 0.07) 1:256 — 1:512 0.08 (0.01, 0.21) 0.03 (0.02, 0.05) 1:512 — 1:1024 0.14 (0.02, 0.36) 0.02 (0.01, 0.03) 1:1024 — 1:2048 0.25 (0.01, 0.71) 0.00 (0.00, 0.01) 1:2048 — 1:4096 - - 0.17 (0.01, 0.53) 0.01 (0.00, 0.01) >1:4096 4 eTable 5. Posterior Mean Log-likelihoods for Functional Forms of Protection Curve, by Subtype and Interpolation Method. As the parameter dimensionality is the same for all models, absolute differences between the means of 10 or more points indicate overwhelming evidence. Posterior mean log-likelihoods Method 1 Mean 95% CrI Method 2 Method 3 Mean 95% CrI Mean 95% CrI Influenza A(H1N1)pdm09 – HK Log titer -3,266 -3,321, -3,243 -3,664 -3,675, -3,653 -3,617 -3,629, -3,606 Titer -11,152 -11,159, -11,145 -11,488 -11,495, -11,483 -11,258 -11,263, -11,253 Influenza B – HK Log titer -3,824 -3,833, -3,815 -4,394 -4,403, -4,386 -4,277 -4,287, -4,267 Titer -12,469 -12,483, -12,475 -13,023 -13,029, -13,018 -12,609 -12,613, -12,606 Influenza A(H3N2) – US Log titer -5556 -5591, -5524 -7219 -7243, -7194 -7329 -7350, -7306 Titer -28,285 -28,302, -28,270 -30,011 -30,026, -29,996 -28,285 -28,302, -28,270 Abbreviations: CrI, Credible interval. 5 eTable 6. Absolute Decrease in Infection Probability Over Duration of Influenza Season. Posterior mean and 95% credible intervals (CrI) for the percentage point difference are tabulated. Positive differences mean the vaccine is protective relative to the placebo. Method 1 Method 2 Method 3 Mean 95% CrI Mean 95% CrI Mean 95% CrI Influenza A(H1N1)pdm09 – HK -0.05 -0.17, 0.06 -0.08 -0.26, 0.08 -0.09 -0.26, 0.07 Influenza B – HK 0.05 0.02, 0.10 0.07 0.03, 0.12 0.06 0.02, 0.10 Influenza A(H3N2) – US (live attenuated vaccine) 0.00 0.00, 0.01 0.00 0.00, 0.01 0.00 0.00, 0.01 Influenza A(H3N2) – US (inactivated vaccine) 0.01 0.00, 0.02 0.01 0.00, 0.02 0.01 0.00, 0.02 6 eTable 7. Relative Risk of Infection Comparing With Placebo Over Duration of Influenza Season. Posterior mean and 95% credible intervals (CrI) for the risk ratio (vaccine relative to placebo) are tabulated. Method 1 Method 2 Method 3 Mean 95% CrI Mean 95% CrI Mean 95% CrI Influenza A(H1N1)pdm09 – HK 1.44 0.74, 2.64 1.43 0.80, 2.70 1.41 0.79, 2.60 Influenza B – HK 0.47 0.29, 0.70 0.52 0.33, 0.78 0.52 0.33, 0.78 Influenza A(H3N2) – US (live attenuated vaccine) 0.94 0.63, 1.36 0.94 0.63, 1.37 0.92 0.61, 1.36 Influenza A(H3N2) – US (inactivated vaccine) 0.46 0.28, 0.71 0.47 0.29, 0.74 0.47 0.28, 0.74 7 eTable 8. Posterior Distribution of the Ratio of RT-PCR Confirmed Infections to All Infections, 𝜃, and Its Reciprocal. Posterior mean and 95% credible intervals (CrI) are tabulated. Method 1 Method 2 Method 3 Mean 95% CrI Mean 95% CrI Mean 95% CrI Influenza A(H1N1)pdm09 – HK 5.40 3.89, 7.15 9.70 7.46, 12.26 10.78 8.41, 13.49 Influenza B – HK 0.98 0.65, 1.34 1.12 0.78, 1.53 1.37 0.95, 1.86 Influenza A(H3N2) – US 0.17 0.11, 0.23 0.17 0.11, 0.23 0.17 0.11, 0.23 Influenza A(H1N1)pdm09 – HK 0.19 0.14, 0.26 0.10 0.08, 0.13 0.09 0.07, 0.12 Influenza B – HK 1.02 0.75, 1.54 0.89 0.65, 1.28 0.73 0.54, 1.05 Influenza A(H3N2) – US 6.19 4.28, 8.90 6.16 4.32, 8.88 6.19 4.29, 8.81 𝜃 1/𝜃 8