Humoral responses to HIVconsv induced by heterologous vaccine modalities in rhesus macaques

Abstract

Vaccines delivering T cell immunogen HIVconsv vectored by plasmid DNA, non-replicating simian adenovirus and non-replicating modified vaccinia virus Ankara (MVA) are under clinical evaluation in phase I/IIa trials in UK, Europe, and Africa. While these vaccines aim to induce effector T cell responses specific for HIV-1, we here characterized the humoral responses induced by HIVconsv administration to macaques using six different vaccine modalities: plasmid DNA, human adenovirus serotype 5, simian adenovirus serotype 63, MVA, Semliki Forest virus replicons, and adjuvanted overlapping synthetic long peptides (SLP). We found that only the SLP formulation, but none of the genetic vaccine platforms induced antibodies recognizing linear HIVconsv epitopes, median 32/46 SLP.HIVconsv peptides. These antibodies bound to 15-mer and SLP peptides, recombinant gp120 and trimeric gp140 of HIV-1 Bal, YU2, JRFL, and UG037, but failed to react with HIV-1 Bal and IIIB virions and HIV-1 Bal- and IIIB-infected human cells, and consequently failed to induce neutralizing antibodies. The HIVconsv immunogen contains conserved regions derived from Gag, Pol, Vif, and Env proteins of HIV-1, and antibodies induced by the SLP.HIVconsv vaccination resulted in positive signals in routine HIV-1 tests. Thus, only HIVconsv delivered by SLP resulted in seroconversion, an observation that provides important guidance for recruiting volunteers into future clinical trials. Furthermore, our data confirms that vaccine delivery by SLP induces humoral as well as cellular immune responses and could be considered for inclusion in future vaccine regimens where this is required.

Safety and Immunogenicity of ChAd63 and MVA ME-TRAP in West African Children and Infants

“…7,8,9,10,11,12,13 We report here the first evaluation of this approach to inducing T-cell and antibody responses in young children and infants. This is also to our knowledge, the first evaluation of a simian adenovirus in children or infants.…”

“…Heterologous prime-boost regimens with adenovirus priming and MVA boosting are currently being developed for a wide range of diseases including respiratory syncytial virus, malaria, tuberculosis, human immunodeficiency virus, pandemic influenza, hepatitis C, Ebola virus disease, and cancer. 7 , 8 , 9 , 10 , 11 , 12 , 13 We report here the first evaluation of this approach to inducing T-cell and antibody responses in young children and infants. This is also to our knowledge, the first evaluation of a simian adenovirus in children or infants.…”

Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA

“… 10 HIVconsv was tested extensively in pre-clinical settings. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 To date in regimens involving plasmid DNA, simian (chimpanzee) adenovirus (ChAdV-63), and poxvirus-modified vaccinia virus Ankara (MVA), the HIVconsv vaccines have been tested in eight clinical trials, showed promising immunogenicity and in vitro control of replication of four major clades of HIV-1 and, in combination with latency-reverting agent, produced a signal of viremic control during monitored antiretroviral treatment (ART) pause in early treated patients (Fidler et al., 2018, Intern. AIDS Soc., abstract; Mothe et al., 2017, Intern.…”

Complete protection of the BALB/c and C57BL/6J mice against Ebola and Marburg virus lethal challenges by pan-filovirus T-cell epigraph vaccine

“…In our experience with chimeric T-cell immunogens similar to the FILOcep1&2 proteins delivered by DNA, recombinant simian adenoviruses and MVA, and administered to mice, NHPs and humans, induction of transgene product-specific antibodies was extremely rare [20–22]. Because the intracellularly expressed proteins in the absence of any naturally evolved folding are unstable and there is no surface GP included, no readily detectable filovirus-specific antibodies were induced.…”