I-107 Optimisation of a therapeutic vaccine; the importance of immune modulation

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Vacc-4X is a p24 (gag) peptide based vaccine, shown to reduce viral load (HIVRNA) in HAART interrupted patients, confirmed in a randomised phase II study, which also confirmed vaccination had no effect on the CD4 count. A programme to improve the efficacy of Vacc4X has included peptide modifications to increase uptake by dendritic cells and the breadth of the responses to these peptides.A recent study (Sorensen B et al, ARHRV 2017) showed that in 3 cohorts of patients, antibodies to the novel heterodimeric construct designed to enhance the immunogenicity of this region containing C5 (501-512) and gp41 (732-44), was associated with slower disease progression and lower viral loads, antibodies to the C5 (501-506) domain correlated with preserved CD4 counts. It is proposed to combine this construct with the Vacc4X to enhance efficacy.These patient cohorts are all long term infected patients with compromised immune responses, even on HAART. The IMiDs, including Lenalidomide, have been shown to enhance immune responses to cell based vaccines in-vivo and Prevnar in clinical trials. Priming patients with Lenalidomide before Vacc4X led to an increase in CD4 counts in a small randomised study. It is proposed that if Lenalidomide had been given for longer, the effect would have been more significant.In addition, an immune modulator, M.vaccae, has been shown to reduce the incidence of TB in a randomised study in HIV infected subjects in Africa. M.vaccae and its commercial derivative (IMM-101) have been shown to be ideal adjuvants for anticancer based vaccines. It is proposed that immune modulation by Lenalidomide and IMM-101 could enhance clinical benefit seen with Vacc4X and enhanced responses to C5.

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