Live attenuated viruses are among our most potent and durable vaccines. We have adapted the rubella vaccine strain RA27/3 as a live vector to express vaccine inserts such as HIV env, SIV gag, and other viral proteins. The vector combines the antigenicity of HIV with the safety, potency, and durability of Rubella vaccine, which have been demonstrated in millions of children: one dose protects for life against rubella infection. We have greatly expanded the size and range of vaccine inserts that can be accommodated by the vector. Initially, we inked together 2 to 4 discrete gag T cell epitopes in tandem. Recently, we have expressed the entire SIV Gag P27. Initially, we expressed Env determinants such as the MPER sequence. Currently, we can express the engineered outer domain of gp120 (from Bill Schief) or gp120 core structures (from Leo Stamatatos). These antigens range from 180 to 360 amino acids and are stably expressed for at least 6 passages, after which most inserts are stable. Vector growth and the Immunogenicity of gag inserts was tested in rhesus macaques. Anti-Gag titers increased steadily for 6 weeks after a single dose, and were comparable to SIV infection. The antibodies persisted for >6 months and declined at the same rate as anti-rubella antibodies, which protect for lilfe. Re-exposure to the vector boosted antibody titers strongly. The T cell response (measured with Barbara Felber) depended on priming with DNA vaccine, followed by a vector boost. This reached levels comparable to the best adeno vectors. Immunogenicity testing is pending for gp120 core structures. Binding antibodies will be tested by ELISA, and neutralizing activity will be tested agaisnt the same or different HIV isolates. Rhesus macaques are readily infected by rubella vectors, and they are the animal model of choice for SHIV challenge. If the animals develop neutralizing antibodies to Env, they will be tested by SHIV challenge. Rubella vectors can infect monkeys or man. Any signs of protective immunity could be readily translated into human vaccine design.
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