Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

Abstract

Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ + CD8 + T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4 + T-cells associated HIV-1 DNA. ( NCT01712425 ). Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/10 6 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms. Interpretation Heterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocused pre-cART T-cell responses towards more protective epitopes, in which immune escape is frequently associated with reduced HIV-1 replicative fitness and which are common to most global HIV-1 variants. Funding HIVACAT Catalan research program for an HIV vaccine and Fundació Gloria Soler. Vaccine manufacture was jointly funded by the Medical Research Council (MRC) UK and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (G0701669. Research in Context Evidence Before this Study: T cells play an important role in the control of HIV infection and may be particularly useful for HIV-1 cure by killing cells with reactivated HIV-1. Evidence is emerging that not all T-cell responses are protective and mainly only those targeting conserved regions of HIV-1 proteins are effective, but typically immunologically subdominant, while those recognizing hypervariable, easy-to-escape immunodominant ‘decoys’ do not control viremia and do not protect from a loss of CD4 T cells. We pioneered a vaccine strategy focusing T-cell responses on the most conserved regions of the HIV-1 proteome using an immunogen designat...

In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

“…This rapid viral rebound after treatment interruption is due to the existence of a latent viral reservoir and the inability of the immune system to effectively contain viral replication. To date, numerous strategies have been pursued to achieve a functional cure or virus eradication, including early ART initiation, ART intensification (2)(3)(4)(5)(6), passive administration of antibodies (7), therapeutic vaccination (8)(9)(10)(11)(12)(13) and gene therapy (14,15), among others.…”

“…The proof-of-concept BCN02 trial evaluated a kick&kill strategy that combined the HIVconsv T-cell vaccines with the HDACi RMD in a cohort of early-treated, HIV-1infected individuals. Fifteen participants of BCN01 (12), who previously received simian adenovirus-vectored vaccine ChAdV63.HIVconsv and MVA.HIVconsv, were invited 2-3 years later to receive two more dosing of the MVA.HIVconsv vaccine before (MVA 1 ) and after (MVA 2 ) three weekly-doses of RMD (RMD 1−2−3 ) followed by a monitored antiretroviral pause (MAP) for a period of 32 weeks (NCT02616874). The combined strategy was proven to be safe and vaccination was highly immunogenic.…”

Dose Effects of Recombinant Adenovirus Immunization in Rodents

“…However, recent studies have highlighted the fact that rAd vaccines can be used effectively as therapeutics. Studies have shown that rAd vaccines can accelerate the control of tuberculosis, they can be used to refocus T cell responses towards conserved HIV-1 epitopes and have shown efficacy in preclinical trials to resolve hepatitis C virus in a rat model where viremia was terminated within 14 days of virus challenge [36][37][38]. In addition, there have been many attempts to modify rAd vaccines to improve vaccine efficacy and oncolytic activity.…”

Novel Nested Peptide Epitopes Recognized by CD4+ T Cells Induced by HIV-1 Conserved-Region Vaccines

“…This was not the case following HIVconsv vaccination, which induced prominent Pol epitope responses directly proportional to the relative length of the Pol segment in the HIVconsv sequence (Table 3). These results would support the ability of a potent vector delivery to (re)focus immune responses including CD4 + T cells toward regions that are generally subdominant in natural HIV-1 infection [59,60]. A different study reported over half of tested variant peptides not being recognized by CD4 + T cells [51], emphasizing even for the more promiscuous HLA class II molecules peptide selectivity and the importance of focusing on and matching vaccine responses to less variable regions of the HIV-1 proteome.…”