Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

Abstract

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

HIV-1 Vaccine Sequences Impact V1V2 Antibody Responses: A Comparison of Two Poxvirus Prime gp120 Boost Vaccine Regimens

“…Both Unadjusted p values for response rate (p.rate) and magnitude (p.mag) are listed on top of each panel. Data shown here are for a serum dilution of 1:50, which is lower than the 1:200 reported for HVTN 100 previously 32 (thus higher antibody concentration) and the same as reported for HVTN 097 previously 35 . the antibody magnitude and positivity rates to the V2 hotspot were higher in HVTN 097 compared to HVTN 100 ( Fig.…”

“…Both MN and A244 gp120 constructs were made with an 11-amino acid deletion at the gp120 N-terminus and an HSV gD peptide tag inserted in place of the mutation 46 . The actual dose for ALVAC-HIV vCP1521 in HVTN 097 is 5.2 × 10 7 CCID 50 35 ; and dose for gp120 proteins was 300 µg each protein, similar to that in RV144 2 .…”

“…HVTN 100 elicited an overall higher magnitude of binding to gp120 antigens, but lower magnitude and breadth of binding to subtype C V1V2 antigens compared to HVTN 097. We previously reported that HVTN 097 and HVTN 100 elicited a high magnitude of gp120 IgG responses 32,35 . Serum samples collected at 6.5 months (2 weeks after the second bivalent protein boost) were measured for binding response to gp120 antigens that match to the five subtype C and E HIV-1 envelope vaccine strains in HVTN 097 and HVTN 100 at the same 1:50 serum dilution (Fig.…”

“…Differences between the two regimens include: (1) the envelope vaccine strain was 92TH023 for the ALVAC prime and A244 and MN for the gp120 boost in HVTN 097, whereas HVTN 100 contained the ZM96 sequence for the ALVAC prime and 1086 and TV1 for the gp120 boost; (2) the adjuvant was aluminum hydroxide for HVTN 097 compared to MF59 for HVTN 100; (3) the protein dose in HVTN 097 was 3 times higher than that in HVTN 100; (4) the actual dose of ALVAC-HIV in HVTN 097 was 2.7 times more than that in HVTN 100 (ref. 35 and unpublished data); and (5) a 11-amino-acid (aa) sequence at the gp120 N terminus was removed and replaced with a herpes simplex virus (HSV) gD sequence for the gp120 proteins used as boosts in HVTN 097, whereas similar modifications were not made to the HVTN 100 gp120 constructs 33 .…”

The search for an HIV vaccine, the journey continues

“…Rather than perform a direct repeat of RV144 in Thailand, where the epidemic is driven by viruses from clades AE and B, a clade C‐specific regimen was developed for testing in Southern Africa. When evaluated in the HVTN100 trial, the relevant correlate responses were detected and shown to be longer lasting than those of RV144 [5‐7]. With the go‐no‐go criteria for advancement met, the HVTN702 study moved ahead.…”