Safety and immunogenicity of a DNA vaccine with subtype C gp120 protein adjuvanted with MF59® or AS01B: a phase 1/2a HIV-1 vaccine trial

Abstract

Despite progress in HIV prevention and treatment, an estimated 1.3 million people were newly infected with HIV in 2022,1 highlighting the urgent need for an effective vaccine. To date, the RV144 trial remains the only HIV vaccine trial that has demonstrated partial efficacy against acquisition.2 The Pox-Protein Public-Private Partnership (P5) was established with the aims of improving on RV144 by developing a vaccine capable of protecting against a broader diversity of HIV strains and achieving a better understanding of immune responses associated with preventing HIV infection.3 Vaccine concepts in the P5 program have focused on clade C immunogens, targeting predominant strains of East and Southern Africa, where approximately half of the 39 million people living with HIV reside.1 The RV144 regimen, originally designed to protect against subtype B/E strains, was adapted to incorporate clade C antigens and adjuvanted with MF59®.4 This regimen demonstrated adequate immunogenicity in the HVTN100 phase 1/2a trial,5 and was further evaluated in the HVTN702 efficacy trial in South Africa, but ultimately discontinued due to non-efficacy.6 In parallel, the P5 designed the correlates program: a series of phase 1/2a trials to evaluate vaccine candidates based on favorable immune profiles of putative correlates of protection. These trials employed novel prime-boost and co-administration regimens, varied protein doses, and used new adjuvants and vaccine delivery systems, with an emphasis on shared immunological endpoints to allow for cross-study comparisons. Preclinical studies have shown promising immune responses using DNA/protein combination vaccines.7,8 A comparison of responses between HVTN100 (ALVAC) and HVTN111 (DNA) trials indicated that DNA priming with a protein boost led to increased antibody and cellular responses compared to priming with the canarypox vector.9 In the HVTN105 trial, both a DNA prime-protein boost and a co-administration regimen induced potent and durable V1/V2 binding antibody responses (a known correlate of lower HIV-1 infection risk in RV144), with co-administration inducing early antibody responses.10 Furthermore, in the HVTN096 trial, including gp120 Env protein at the priming stage, co-administered with either NYVAC or DNA, elicited earlier and even greater antibody responses.11 The adjuvant system 01 (AS01) has been successfully tested in vaccine trials for other infectious diseases including malaria,12 shingles,13,14 and tuberculosis.15 Some HIV vaccine studies have also used AS01 and have shown that it contributes to the induction of robust and persistent cellular and humoral responses.16,17 MF59® has likewise been used in several licensed vaccines and pre-clinical studies,18 inducing strong and durable T-cell memory and humoral responses. MF59® was also used in HVTN studies with ALVAC 5 and was therefore chosen for comparison with AS01B in this trial. Thus, the aim of the HVTN108 trial was to evaluate the safety and immunogenicity of the DNA vaccine with different HIV clade C protein doses, adjuvanted with MF59® or AS01B, and dosed in prime-boost or co-administration regimens.