Investigational HIV-1 vaccine failed to protect against HIV-1 in South Africa

Issue: June 2011

The investigational MRKAd5 HIV-1 gag/pol/nef subtype B vaccine did not decrease early viral load or prevent HIV-1 infection in adenovirus serotype 5-seropositive or seronegative adults, according to data from a phase 2b double-blind, randomized, test-of-concept study conducted across five sites in South Africa.

The current HVTN 503/Phambili study followed the Step study — the first phase 2b HIV vaccine test-of-concept study that aimed to assess vaccine efficacy in areas where the predominating HIV subtype is clade B, according to background data in the study. However, after the lack of efficacy of the HIV-1 vaccine in the Step study, enrollment and vaccination in the current study was halted and treatment was unmasked, but follow-up continued.

Glenda E. Gray, MBBCH, of the Perinatal HIV Research Unit at the University of the Witwatersrand in South Africa, and colleagues assessed the safety and efficacy of the MRKAd5 HIV-1 gag/pol/nef subtype B vaccine in 801 adults (55% men; and 29% circumcised) aged 18 to 35 years across five sites in South Africa (Soweto, Cape Town, Klerksdorp-Orkney-Stilfontein-Hartbeesfontein, eThekwini, and Medunsa). These areas have high levels of pre-existing immunity to adenovirus serotype 5 (Ad5) and the major circulating clade is subtype C.

The researchers randomly assigned participants to receive either the vaccine or placebo administered intramuscularly at baseline, 1 month, and 6 months. Coprimary endpoints were vaccine-induced decrease in HIV-1 acquisition and viral-load setpoint. Endpoints were independently assessed in a seperate modified intention-to-treat analysis grouped by gender.

Adenovirus serotype 5 (Ad5) titres greater than 200 were observed in 56% of participants. HIV-1 was diagnosed in 34 participants in the modified intention-to-treat analysis and in 28 of those assigned placebo. At baseline, prevalence of HSV2 was significantly higher in women than in men (49% of women vs. 16% of men; P<.0001).

No differences were observed in vaccine efficacy after adjusting for gender, age, HSV2 status, circumcision or Ad5 titre, according to the researchers. Coprimary endpoints did not reach statistical significance (both adjusted P=.39). Compared with vaccine responders who were Ad5-seropositive, those who were seronegative showed greater response for clade B (P=.004) and clade C (P=007).

“Our findings support those of Step: The MRKAd5 HIV-1 gag/pol/nef vaccine had no effect on preventing HIV-1 acquisition,” the researchers wrote. “We did not identify an association between Ad5 seropositivity or being uncircumcised and an increase in HIV-1 acquisition in those receiving the vaccine. This finding could be attributable to the early cessation of enrollment and vaccination, and possibly differences in risk behavior.”

“Post-hoc analyses of our study suggest trends of a vaccine effect in women who received the vaccine who subsequently became infected, toward lower viral-load setpoint and slower CD4 decline compared with women who received placebo. The importance of gender and route of HIV-1transmission in vaccine clinical trials might warrant stratification.”

In an accompanying editorial, Zaneeta Dhesi and Justin Stebbing, both of the Imperial College in London wrote that, “It is regrettable that interim analyses of Step were not done before the Phambili study started, but stratification by gender is a relevant future direction, along with follow-up of AIDS-defining and other illnesses.”

For more information:

Dhesi, Z. Lancet Infect Dis.2011;doi:10.1016/S1473-3099(11)70103-7.

Gray G. Lancet Infect Dis.2011;doi:10.1016/S1473-3099(11)70098-6.

Disclosure: The researchers report no relevant financial disclosures.

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