Abstract
BackgroundLive attenuated viruses are among our most potent and effective vaccines. For human immunodeficiency virus, however, a live attenuated strain could present substantial safety concerns. We have used the live attenuated rubella vaccine strain RA27/3 as a vector to express SIV and HIV vaccine antigens because its safety and immunogenicity have been demonstrated in millions of children. One dose protects for life against rubella infection. In previous studies, rubella vectors replicated to high titers in cell culture while stably expressing SIV and HIV antigens. Their viability in vivo, however, as well as immunogenicity and antibody persistence, were unknown.ResultsThis paper reports the first successful trial of rubella vectors in rhesus macaques, in combination with DNA vaccines in a prime and boost strategy. The vectors grew robustly in vivo, and the protein inserts were highly immunogenic. Antibody titers elicited by the SIV Gag vector were greater than or equal to those elicited by natural SIV infection. The antibodies were long lasting, and they were boosted by a second dose of replication-competent rubella vectors given six months later, indicating the induction of memory B cells.ConclusionsRubella vectors can serve as a vaccine platform for safe delivery and expression of SIV and HIV antigens. By presenting these antigens in the context of an acute infection, at a high level and for a prolonged duration, these vectors can stimulate a strong and persistent immune response, including maturation of memory B cells. Rhesus macaques will provide an ideal animal model for demonstrating immunogenicity of novel vectors and protection against SIV or SHIV challenge.
Highlights
Live attenuated viruses are among our most potent and effective vaccines
Three types of vectors were produced, with membrane proximal external region (MPER) or Gag sequences inserted into the RA27/3 rubella vaccine background
Each antigenic insert is preceded by the transmembrane domain of E2 (E2TM) and the signal peptidase site of E1 (E1SP), and it is followed by another transmembrane domain (TM) and E1SP peptidase site
Summary
Live attenuated viruses are among our most potent and effective vaccines. For human immunodeficiency virus, a live attenuated strain could present substantial safety concerns. Despite the urgent need for a safe and potent vaccine against HIV, efforts to produce a vaccine have been thwarted by antigenic variation, weak immunogenicity of critical epitopes, and short duration of the immune response to HIV vaccine antigens [1,2,3] For other viruses, such as measles, mumps and rubella, similar immunogenicity problems were solved by developing live attenuated vaccine strains [4,5,6]. The insert was expressed as a fusion protein with nonstructural protein P150 This deletion/insertion strategy resulted in the first replicating rubella vectors capable of expressing zGFP, the HIV membrane proximal external region (MPER) determinant, and SIV Gag antigens [17,18]. Since each insert was expressed as a fusion protein with P150, preservation of essential P150 functions could limit the size and composition of the insert
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