Higher priming doses enhance HIV-specific humoral but not cellular. responses in a randomized, double-blind phase Ib clinical trial of

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1 Higher priming doses enhance HIV-specific humoral but not cellular responses in a randomized, double-blind phase Ib clinical trial of preventive HIV-1 vaccines Pierre-Alexandre Bart a,b, Yunda Huang c, Shelly T. Karuna c, Samuel Chappuis a, Julien Gaillard a, Nidhi Kochar c, Xiaoying Shen d, Mary A. Allen e, Song Ding b, John Hural c, Hua- Xin Liao d, Barton F. Haynes d, Barney S. Graham f, M. Juliana McElrath c,g,h,i, David C. Montefiori d, Georgia D. Tomaras d, Giuseppe Pantaleo a,j, Nicole Frahm c,g# and the NIAID HIV Vaccine Trials Network Service of Immunology and Allergy, University Hospital, Lausanne, Switzerland a ; EuroVacc Foundation, Lausanne, Switzerland b ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA c ; Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA d ; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA e ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland, USA f ; Departments of Global Health g, Laboratory Medicine h and Medicine i, University of Washington, Seattle, Washington, USA; Swiss Vaccine Research Institute, Lausanne, Switzerland j Running Head: Antibodies but not T cells benefit from stronger prime

2 Net Response (MFI - Blank) for clade AE gp /29 7.1% 23.1% 3/ % 1 Placebo NYVAC/Ad5 hi Ad5 lo /NYVAC Ad5 med /NYVAC Ad5 hi /NYVAC Supplemental Figure 1: Clade AE Env-specific binding antibody responses elicited in HVTN 078 two weeks after the final vaccination. IgG responses to clade AE Env gp120 (A244 gdneg/293f/mon) were measured as mean fluorescence intensity (MFI) of protein-labeled minus blank beads (see Methods).

3 0. 3.4% 1/ % 3/ % 7/ /14 60,000 IgG Titer (AUC) to clade B p Placebo NYVAC/Ad5 hi Ad5 lo /NYVAC Ad5 med /NYVAC Ad5 hi /NYVAC Supplemental Figure 2: Gag-specific binding antibody responses elicited in HVTN 078 two weeks after the final vaccination. IgG titer (AUC) to clade B Gag-p24.

4 Supplemental Figure 3. Env-specific binding IgG against linear peptides. Binding IgG in serum samples from 10 vaccinees that were among those with the highest neutralizing antibody responses were mapped using overlapping peptide (15-mers overlapping by 12) microarrays covering the entire gp160 of Consensus A, B, C, D, CRF01_AE, CRF02_AG and group M. All vaccinees within this subset had binding IgG responses to the V3 and C5 region of gp120; albeit at various levels. The C1 region of gp120 was also targeted by these vaccinees to different levels. No binding to linear gp41 peptides was detected (not shown). Shown here are three vaccinees that also had the strongest overall neutralizing antibody responses against multiple tier 1 viruses.

5 A B C Net Response (MFI - blank) for clade A IgA Net Response (MFI - blank) for clade C IgA Net Response (MFI - blank) for ConS IgA % 13/ % 19/ % 22/29 7.1% 14.3% 2/14 7.1% Placebo NYVAC/Ad5 hi Ad5 lo /NYVAC Ad5 med /NYVAC Ad5 hi /NYVAC Supplemental Figure 4: Env-specific IgA responses elicited in HVTN 078 two weeks after the final vaccination. IgA responses to A) consensus clade A gp140, B) consensus clade C gp140 and C) consensus group M gp140 were measured as mean fluorescence intensity (MFI) of protein-labeled minus blank beads (see Methods).

6 A 0/20 11% 3/ /15 62% 8/13 64% 9/14 29% 8 85% 79% 8/28 13/15 11/13 1 0/28 1/15 25% 7/28 73% 11/15 69% 9/13 64% 9/14 % CD8 T cells expressing IFN-γ and/or IL-2 % CD4 T cells expressing IFN-γ and/or IL-2 P Env Gag Nef Pol B 0/20 14% 4/29 7/15 46% 6/13 5 8/14 41% 4 54% 71% 12/29 6/15 7/13 1 0/29 1/15 45% 13/29 6 9/15 54% 7/13 64% 9/14 P Env Gag Nef Pol Supplemental Figure 5: T-cell responses elicited in HVTN 078. CD4+ (A) and CD8+ (B) T-cell responses to vaccine inserts were measured two weeks after the final vaccination by ICS and reported as % of CD4+ or CD8+ T cells producing IFN-γ and/or IL-2 for placebo recipients (P, combined for groups 1-4) and vaccinees in each treatment group (T1-T4). Positive responses are shown in red symbols, negative responses in blue. Box-whiskers represent positive responders only (see Methods). P: placebo, T1: NYVAC/Ad5 hi, T2: Ad5 lo /NYVAC, T3: Ad5 med /NYVAC, T4: Ad5 hi /NYVAC