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P02.12

Development of a HIV-1 Vaccine Using an Orally-Administered, Replication-Competent Adenovirus Serotype 4 Vector Expressing Env Clade C Glycoprotein


Development of Adenovirus Serotype 4 Replicating Vector Vaccine Expressing HIV-1 Env gp160 1086.C

Background

There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV-1 infection and limits in vivo viral replication and the associated pathogenesis. Unfortunately the barriers are significant and include lack of a predictive animal model and lack of well-defined correlates of protection. Of major concern is the failure of three large efficacy trials, two based on the use of a recombinant HIV-1 Env gp120 (AIDSVAX) and the third (“STEP” study) based on the use of a replication-deficient Ad5 vectored vaccine. Recently, however, the results of a large Phase 3 trial in Thailand, combining Sanofi’s ALVAC-HIV and AIDSVAX, “RV144,” suggest that a vaccine to prevent HIV-1 may be closer than previously thought. In that study, there was statistically significant vaccine efficacy, but the ~30% vaccine efficacy waned with time.  In part, IgG binding antibodies to Env V1/V2 loop may have contributed to protection against infection.

Approach

The project goal is to develop a replicating vector vaccine, based on the adenovirus serotype 4 (Ad4) virus expressing HIV-1 full-length (gp160) envelope (Env), 1086 clade C protein.  Ad4 vectors expressing Env gp140 and gp120 proteins were also generated. During the CHAVI 001 protocol,  the Env 1086.C was derived from an African subject with acute clade C HIV-1 infection. In this infection, CHAVI investigators documented only one quasispecies of transmitted/founder (T/F) virus that began the infection. The Ad4Env160 recombinant vector vaccine could be used as a prime immunization (potentially with Ad4 expressing HIV-1 Gag) followed by a heterologous boost immunization using recombinant Env protein.

Methods

The Ad4Env160 vaccine was generated with a partial deletion of the E3 region of Ad4 to accommodate the HIV-1 Env gene.  The vaccine was analyzed in vitro following infection of A549 cells for Env-specific protein expression and for recognition of cell surface Env by broadly neutralizing antibodies (bNAbs).  The capacity of the Ad4Env160 vaccine to induce humoral immunity in rabbits was evaluated for Env-specific binding antibodies and HIV-1 pseudovirus neutralization.]

Results

Env protein expression was confirmed by western blot analysis and recognition by multiple bNAbs.  Following Ad4Env160 vaccine immunization of rabbits, immune sera were generated that recognized Env 1086 gp140 recombinant protein and V1V2 loop sequences derived from 1086 clade C, AE A244 clade AE, and clade B. Immune sera neutralized Tier 1 clade C pseudovirus MW965.26 but only weak to sporadic neutralization of Tier 2 clade C viruses was observed.

Conclusions

•Ad4-Env vectors were generated that expressed 120, 140, and 160 proteins •A549 cells infected with Ad4-Env160 expressed surface Env as detected by bNAbs (V3 loop, CD4 binding site, and MPER) •Rabbits immunized (vector prime/protein boost) induced binding antibodies to: Env 140, V1V2 loop (clades C, AE, and B) (160>140>120) •Rabbit immune sera neutralized Tier 1 clade C pseudovirus MW965
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