Following
HIV infection, most people make
antibodies to gp120 and gp41, yet only a few make
broadly neutralizing antibodies that target key antigenic sites on the envelope
glycoproteins. The induction of
broadly neutralizing antibodies by immunization remains a major challenge of
HIV vaccine research. Difficulties include: variable
protein sequence,
epitopes that depend on the native conformation, glycosylation that conceals key
antigenic determinants, and the assembly of Env trimers that mimic viral spikes. In addition, more potent immunogens may be needed to initiate the response of germline antibody precursors and drive B cell maturation toward
antibodies with broad neutralizing activity. We have expressed HIV
Env glycoproteins by incorporation into live attenuated
rubella viral vectors. The
rubella vaccine strain RA27/3 has demonstrated its safety and potency in millions of children. As a vector, it has elicited potent and durable immune responses in macaques to SIV Gag
vaccine inserts. We now find that
rubella/env vectors can stably express Env core derived
glycoproteins ranging in size up to 363
amino acids from HIV clade C strain 426c. The expressed
Env glycoproteins bind
broadly neutralizing antibodies that target the native CD4 binding site. The vectors grew well in rhesus macaques, and they elicited a
vaccine "take" in all animals, as measured by anti-
rubella antibodies. By themselves, the vectors elicited modest antibody titers to the Env insert. But the combination of
rubella/env prime followed by a homologous
protein boost gave a strong response.
Neutralizing antibodies appeared gradually after multiple
vaccine doses. The vectors will be useful for testing new
vaccine inserts and immunization strategies under optimized conditions of vector growth and
protein expression.