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OA18.03 E. Andersen-Nissen (1); V. Voillet (2); A. Naidoo (2); J. Kee (1); A. Fiore-Gartland (1); O. Dintwe (2); N. Grunenberg (1); L. Polakowski (3); L. Fleurs (4); I. Jani [...], Background: Vaccine adjuvants are detected by the innate immune system and influence adaptive immune responses. The modestly efficacious RV144 Thai trial used alum to adjuvant the gp120 protein boost, whereas the non-efficacious HVTN 702 South African trial used MF59. Volunteers enrolled in HVTN 107 (NCT03284710) were administered these adjuvants with a subtype C pox-protein vaccine, affording a unique opportunity to contrast systemic innate immune responses and potentially inform the results of HVTN 702. Methods: Eighteen volunteers were enrolled per group. T1, T2 and T4 received 2 doses of ALVAC-HIV followed by 3 doses of ALVAC-HIV plus subtype C gp120 administered with MF59 (T1), alum (T2), or un-adjuvanted (T4). T3 received 4 doses of ALVAC-HIV with MF59-adjuvanted gp120. Innate immune responses were measured pre-vaccination and at days 1, 3 and 7 after the first (T3) or third (T1,T2, T4) vaccinations. Alterations in circulating leukocytes were assessed by CBC. Thirty-one serum immunomodulatory mediators were quantitated. Results: Neutrophil concentrations increased on day 1 in all groups (FDR-p&apos;s < 0.02) and monocyte concentrations increased in T2,T3 and T4 (FDR-p&apos;s < 0.12); lymphocyte concentrations significantly decreased at day 1 only in T1 (FDR-p = 0.03). Serum cytokines were also significantly altered post-vaccination in all groups (FDR-p&apos;s < 0.2). On Day 1, nine cytokines were induced in T1, including pro-inflammatory IFN-g, CXCL10, TNF-a, IL-6, as well as CCL4 and IL-2, with many factors remaining elevated at Day 3 and returning to baseline on Day 7. In contrast, only IL-2 and IL-6 were induced in T2 on Day 1 and twelve factors were repressed on Day 7 relative to pre-vaccination, including IFN-g and monocyte-chemotactic factors CCL8, CCL13, and CCL22. Responses in the MF59 groups differed when co-administered at the first vaccination (T3) relative to the third vaccination (T1) with 12 cytokines repressed on Day 1 in T3. Conclusions: Alum-adjuvanted protein administered in a prime/boost regimen including ALVAC-HIV reduced early systemic serum cytokine and chemokine responses to the vaccine, in stark contrast to MF59, where induction of a diverse immunomodulatory cytokine profile was observed in Southern African volunteers. Work on elucidating the differential effect of these two adjuvants on the types of innate immune cell responses in humans continues.

OA18.01 F. Laher (1); C. DiazGranados (2); C. Innes (3); E. Andersen-Nissen (4); G.E. Gray (5); H. Lu (6); J. Hutter (7); K. Mngadi (3); K. Marshall (6); L. Polakowski [...], Background: RV144 demonstrated modest HIV preventive vaccine efficacy in Thailand. Amongst multiple identified correlates, IgG V1V2 antibodies were associated with 43% HIV risk reduction. The P5 aimed to further this by investigating subtype C vaccine regimens with different vectors (canarypox, DNA plasmid), adjuvants (alum, MF59, AS01.sub.B], or none), gp120 protein doses (40mcg, 200mcg, 600mcg), dosing strategies (prime-boost, co-administration) and administration methods (needle-syringe, Biojector). We compare IgG V1V2 responses across P5 trials with available data. Methods: In the HVTN100, HVTN107, HVTN108, and HVTN111 trials, serum specimens were obtained two weeks after the fourth vaccination. We measured the frequency and, amongst positive responders, the magnitude (MFI*: background-subtracted mean fluorescence intensity minus blank responses) of HIV-1-specific IgG (1:50 dilution) responses against V1V2 antigens for subtype C, gp70-TV1.GSKvacV1V2/293F (matched to subtype C protein vaccine), or subtype CRF01_AE, AE.A244 V1V2 Tags/293F (matched to subtype B/E protein vaccine), depending on protein administered. Responses were measured on Bio-Rad using a standardized custom Luminex HIV-1 binding antibody multiplex assay. Results: Amongst these subtype C regimens, the lowest response rate was induced by a regimen of two subtype C ALVAC primes followed by three boosts of subtype C ALVAC +200 mcg unadjuvanted gp120 (4/17 = 23.5%, CI 9.6%-47.3%); median magnitude 727.1MFI* (IQR 430.1 to 1152.1). The highest response rates were in co-administration groups of adjuvanted protein plus DNA or ALVAC at all timepoints). Rates, median magnitudes were 93.8%, 12124.8MFI* (DNA +40 mcg gp120 + [AS01.sub.B] at 3 timepoints); 91.4%, 21756.9MFI* (DNA + 200 mcg gp120 + [AS01.sub.B] at 3 timepoints); 89.1%, 7147.25MFI* (DNA + 200 mcg gp120 + MF59 by needle-syringe at 3 timepoints); 88.5%, 7745MFI* (DNA by Biojector + 200 mcg gp120 + MF59 by needle-syringe at 3 timepoints); 86.7%, 6205.1MFI* (subtype C ALVAC + 200 mcg gp120 + MF59 at 4 timepoints). For subtype C regimens, pooled response rates were higher for: (i) co-administration regimens versus regimens omitting protein in the first two doses (152/169 = 89.9% versus 233/374 = 62.3%, p < 0.00,001) and (ii) groups with DNA vaccines versus those with ALVAC (202/253 = 79.8% versus 187/299 = 62.5%, p < 0.00,001). Conclusions: Strategies which optimized IgG V1V2 responses in P5 subtype C vaccine trials included adjuvanted protein, and co-administration of adjuvanted protein + DNA or ALVAC vaccination. Responses to DNA administration by needle and syringe or Biojector were equivalent.

OA18.02 P. Goepfert (1); K. Mngadi (2); Z. Moodie (3); N. Grunenberg (3); J.J. Kee (3); K. Seaton (4); G. Tomaras (4); E. Andersen-Nissen (5); O. Dintwe (5); F. Laher [...], Background: The partially efficacious RV144 HIV-1 vaccine trial utilized a gp120 protein boost adjuvanted with alum, whereas the non-efficacious HVTN 702 preventive HIV vaccine utilized a gp120 protein boost adjuvanted with MF59. We compared Env-specific IgG and IgA responses in HVTN 107, a phase 1/2a partially double-blinded clinica trial, utilizing a Clade C ALVAC-HIV prime and 100 mcg gp120 protein boost adjuvanted with alum or MF59 vs. a protein-only boost. Methods: We randomized 132 participants into 4 groups and analyzed Env-specific IgG and IgA binding antibodies at Months 6.5 and 12 (NCT03284710). Results: Robust IgG (96.3% to 100%) and IgA (92% to 93%) responses were seen for all trial arms at the month 6.5 timepoint to gp120 Env proteins contained in the vaccine regimen (ZM96, TV1.C and 1086.C). Compared to all other trial arms, T3 (MF59-adjuvanted co-administration) exhibited significantly greater response rates and magnitudes to vaccine-matched Env proteins at the month 12 time-point. Comparable IgG response rates and magnitudes to vaccine-matched Env proteins were observed between the alum and MF59 prime-boost trial arms. Compared to other groups, T3 exhibited significantly higher IgG response rates to V1V2 panel antigens gp70_B.CaseA_V1V2 (83% vs. 18%-48%, p Conclusions: Env-specific antibody response rates between Alum and MF59-adjuvanted vaccine regimens were similar, including V1V2 IgG response rates that correlated with decreased HIV risk in RV144. On the other hand, co-administration of ALVAC-HIV with gp120 in MF59 induced the highest antibody response rates and magnitudes. Additional studies of vaccine-elicited antibody specificity and function will inform adjuvant-specific induction of potentially protective humoral immune responses.