Could the Experimental V520 HIV Vaccine Actually Increase the Risk of Infection?

By Liz Highleyman

New data suggest that volunteers who received an investigational HIV vaccine in clinical trials may be at increased risk of HIV infection -- a finding that so far has baffled researchers.

As previously reported, Merck and the National Institutes of Allergy and Infectious Disease’s HIV Vaccine Trials Network (HVTN) announced in late September that they were discontinuing development of an HIV vaccine candidate known as V520 (or MRKAd5) due to interim study data showing that it did not lower the risk of HIV infection or disease progression.

V520, a trivalent vaccine containing 3 recombinant (man-made) HIV genes carried by an adenovirus type 5 vector -- a virus that causes the common cold -- was being studied both for prevention of infection and to slow HIV replication in people who became infected; it was among the vaccine candidates furthest along in clinical trials. The vaccine does not contain the complete HIV virus, and therefore carries no risk of directly infecting recipients.

The international Phase II STEP study enrolled 3000 HIV negative individuals in 9 countries who were considered at high risk for infection, including gay and bisexual men, female sex workers, and injection drug users. A review of preliminary data led the study’s Data Safety and Monitoring Board to recommend that the trial should not proceed due to lack of effectiveness.

At that time, data from about half the study participants showed that after about 1 year of follow-up, volunteers who received 1 dose of V520 were at no less risk of infection than those who received a placebo injection (3.23% vs 2.75%, respectively); response rates did not improve significantly among those who received a second booster dose. Among people who became infected, HIV viral load rose to comparable levels in those who received the active vaccine and the placebo.

A more complete analysis of data from all study volunteers -- released last week at an HTVN meeting in Seattle -- revealed that the problem may be greater than a simple lack of efficacy, since the active vaccine group actually had a higher rate of HIV infection. Among men who have sex with men, 49 of 914 (5.36%) who received the active vaccine contracted HIV, compared with 33 of 922 (3.85%) who received the placebo.

A subgroup analysis showed that the increase in HIV infection risk -- 21 vs 9 cases -- occurred among volunteers who already had substantial pre-existing immunity to adenovirus type 5. There was no difference in risk in the active vaccine and placebo groups among people with minimal adenovirus type 5 immunity (28 vs 24 cases).

During vaccine development, there was concern that people already immune to the adenovirus vector might not respond as well or at all to the V520 vaccine. However, researchers do not know why this might have led to an increased risk of HIV infection. One hypothesis is that the adenovirus may have increased immune activation in a way that heightened susceptibility to HIV infection, perhaps by increasing production of HIV-prone CD4 T-cells.

Other factors may also have played a role, potentially including differences in sexual practices or circumcision rates. Study volunteers were randomly assigned to receive either the active vaccine or the placebo, so there is no apparent reason why these factors would have differed in the 2 groups, although they may have varied in some systematic way between people with and without pre-existing adenovirus 5 immunity. Interestingly, only 1 woman became HIV infected, even though women made up more than one-third of study participants. The findings could also be the result of chance or a statistical anomaly.

The trial investigators have begun counseling study volunteers about the possibility of increased HIV infection risk. Researchers and patient advocates have urged caution going forward with any vaccine trials until the results of the V520 study are more fully understood.

“These data are deeply disappointing and troubling, and raise more questions than answers for the field of AIDS vaccines,” said Mitchell Warren of the AIDS Vaccine Advocacy Coalition.

11/13/07

Sources

NIAID. Immunizations Are Discontinued in Two HIV Vaccine Trials. Press release. September 21, 2007.

Merck & Co. Vaccination and Enrollment Are Discontinued in Phase II Trials of Merck's Investigational HIV Vaccine Candidate. Press release. September 21, 2007.

L Altman and A Pollack. In Tests, AIDS Vaccine Seemed to Increase Risk. New York Times. November 8, 2007.