Overview of STEP and Phambili trial results: two phase IIb test-of-concept studies investigating the efficacy of MRK adenovirus type 5 gag/pol/nef subtype B HIV vaccine.
OBJECTIVE
Two phase IIb test-of-concept studies evaluated the replication-defective adenovirus type 5 (Ad5) vaccine MRK gag/pol/nef HIV vaccine to prevent infection or decrease early plasma viral load in disparate populations. The STEP study enrolled men and women in the Americas, Caribbean and Australia; the Phambili trial enrolled men and women in South Africa, where the modes of sexual transmission and HIV-1 risk, subtypes of HIV-1, and background Ad5 seroprevalence differed.


RESULTS
Vaccination in both studies were stopped, after the first interim efficacy analysis of the STEP study crossed predetermined nonefficacy boundaries. Neither trial demonstrated a decrease in HIV acquisition nor decreased early plasma viral load in vaccinees compared with placebo recipients. Post-hoc analyses of men enrolled in the STEP study showed a larger number of HIV infections in the subgroup of vaccinated men who were Ad5-seropositive and uncircumcised compared with a comparable placebo group. This was not demonstrated in the Phambili study, in which most men were heterosexual, whereas most in STEP were homosexual/bisexual. Further analysis of the STEP study has yet to explain the effect of Ad5 seroprevalence on increased HIV-1 susceptibility in men receiving the vaccine. However, promising vaccine effects on early viral control were seen, and the possibility of effects on early viral load set-point in women in Phambili was seen.


CONCLUSIONS
These trials have provided a number of lessons about the importance of clinical trials in the HIV vaccine discovery process, and insight into the type and level of immune response that will be required for control of viral replication.
Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa. gray@pixie.co.za
Glenda
G
Gray
Susan
S
Buchbinder
Ann
A
Duerr
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics*; D000569:Americas; D001315:Australia; D017691:Caribbean Region; D005260:Female; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D008297:Male; D010919:Placebos / Q000008:administration & dosage; D013019:South Africa; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
D016915:AIDS Vaccines; D010919:Placebos; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus