Alum-adjuvanted protein administered in combination with ALVAC-HIV downregulates early serum cytokine responses to the vaccine whereas MF59 enhances the early cytokine burst

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's < 0.02) and monocyte concentrations increased in T2,T3 and T4 (FDR-p'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'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.