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Introduction
The global HIV/AIDS pandemic remains one of the most significant public health challenges for us. Despite significant advancements in antiretroviral therapy (ART) and pre-exposure prophylaxis, ~1.3 million people become infected with the human immunodeficiency virus (HIV) every year.1 This epidemiological paradox underscores the critical need for an effective prophylactic vaccine – the only sustainable solution for epidemic control.2 Unlike many pathogens successfully controlled through vaccination, HIV presents great challenges for vaccine design, including extraordinary genetic diversity, rapid mutation rates, genomic integration, viral reservoirs, and sophisticated immune evasion mechanisms. Over three decades of HIV vaccine research have yielded important insights but limited clinical success. More than 300 HIV vaccine trials have been conducted, including 11 efficacy trials, with most failing to demonstrate protective immunity.3 Of 300+ clinical trials conducted since 1987, only RV144 demonstrated modest 31% efficacy, using a prime-boost regimen of replication-incompetent recombinant canarypox-ALVAC-HIV (vCP1521) and alum-adjuvanted AIDSVAX subtypes B/E HIV envelope gp120.4 Shortly after RV144, the Pox-Protein Public Private Partnership (P5) developed an RV144-analogous efficacy trial in South Africa (HVTN 702) to test and prospectively define correlates of protection, incorporating the regionally predominant subtype C strain and MF59 adjuvant.5,6 However, the HVTN 702 trial did not confirm the results from RV144 and was halted for lack of protection. The estimated HIV hazard ratio was 1.02 for the first 24 months of follow-up.6 These contradictory outcomes emphasized the need to better understand regional immunological landscapes and subtype-specific antigenic variations. To elicit stronger and broader immune responses, recent advances in vaccine design have focused on inducing cross-reactive immune responses. Polyvalent mosaic antigens were designed and delivered by another replication-incompetent recombinant adenovirus serotype 26 (Ad26) vector, which induced robust cellular immune responses in non-human primates, and reduced per-exposure infection risk by 94%.7,8 However, in the phase IIb/III clinical trials, HVTN 705 and 706, the investigational regimen consisting of Ad26.Mos4.HIV and clade C gp140 protein failed to offer protection from HIV infection.9 All these attempts in HIV vaccine research referred to the fact that vaccine-induced immunity and durability needed to be further improved.
Compared to replication-incompetent vectors that provide transient antigen exposure, replication-competent viral vectors are promising alternatives for HIV antigen delivery because they have the ability to replicate...