Nucleic acid-based formulation of cytomegalovirus-vectored HIV vaccines - This grant is for translational development of a scalable, nucleic acid-based formulation of
cytomegalovirus-vectored vaccines that can be distributed without a cold chain. HIV candidate
vaccines that use cytomegalovirus (CMV) as delivery vector and immunomodulatory adjuvant have shown
extraordinary promise. In our preliminary work, for example, a rhesus cytomegalovirus-vectored SIV vaccine
lacking the viral IL-10 gene (RhCMVdIL10-SIVgag) protected 4/6 infants from SIV infection. Tendel Therapies
Inc. is licensing a portfolio of technology centered on these second-generation, CMV-vectored vaccines.
Manufacturing and distribution of CMV-based vaccines present daunting challenges: (i) replication of CMV in
culture is markedly slower than that of other vaccine vectors; (ii) CMV undergoes rapid genetic change when
amplified in culture; (iii) the virus is enveloped and thus difficult to separate from cell- and virus-derived lipid
bilayers of a similar size; (iv) methods for extreme concentration of the heterogenous particles are unknown;
and (v) a cold chain is required for distribution.
To eliminate these problems, Tendel is also licensing technology for vaccine delivery using purified CMV
genomes propagated in E. coli. The technology permits efficient “rescue” of the genomes after introduction to
mammalian cells. Similarly efficient rescue in vivo should lead to immune responses that are equivalent to
those provoked by conventional vaccination with virions.
We hypothesize that viral IL-10-deficient, CMV-vectored vaccine genomes (DNA) provoke immune responses
that are indistinguishable from the protective responses stimulated by encapsidated live vaccine.
Aim 1. Assess antigen expression and vaccine vector replication after delivery of vaccine genomes to
macaques. CMV-vectored vaccines given as virions first replicate locally, leading to inflammatory cell influx,
and then systemically, leading to viral gene expression in distant tissues. Our hypothesis predicts that
successful rescue of vaccine genomes should lead to the same events.
Aim 2. Test if innate and adaptive immune responses to vaccination with nucleic acid are comparable
to protective anti-SIV responses observed previously. Previous studies have shown that protection
against SIV is associated with specific immune responses, particularly Mamu-E-restricted CD8+ T cell
responses.
These innovative Phase I experiments will be sufficient to establish both the technical merit and—in light of the
proven commercial interest in CMV-vectored vaccines—the commercial potential of Tendel's approach. Phase
II experiments will build on this work to (i) demonstrate that macaques vaccinated with nucleic acid are
protected against SIV challenge (ii) continue development of replication-defective HCMV-HIV Gag and Env
vaccines.
