When HIV-1 was first discovered, scientists were optimistic about a vaccine. Small pox, polio, measles, meh– HIV-1 is a virus. We can handle viruses. Give us 6 months. No prob.
Well, >25 years later and we still dont have a damn vaccine. Strategies that worked against other viruses? HIV-1 doesnt bat an eyelash.
So weve been trying to think of new approaches to vaccine design. One of these ideas was to paste HIV-1 genes into adenovirus vectors. Adenoviruses are double-stranded DNA viruses, normally give you a cold-like illness, or make you a little poopy. Not real pathogenic. The idea is, if you can get an adenovirus to make HIV-1 proteins (like gag and pol), you can get a cytotoxic T-cell response to HIV-1, without infecting anyone with HIV-1! Used to be, the only way you could get a CTL response is through live attenuated virus!
And apparently, the time we have to create a CTL vaccine is limited… this is a pretty sweet idea!
Except it wasnt. Scientists put the HIV-1 genes in adenovirus serotype-5. Because adenoviruses are rather ubiquitous, some people who got the vaccine already had Ad5 antibodies. Well, no big whoop… except it turns out people who already had those Ad5 antibodies were 2.3 times more likely to get infected with HIV-1 than people who didnt get the vaccine.
* In volunteers who could be considered as having no pre-existing immunity to Ad5 at enrollment (baseline Ad5 titer less than 18 units), 20 cases of HIV infection were seen in the 382 volunteers in the vaccine group and 20 cases were seen in the 394 volunteers in the placebo group.
* In volunteers with immunity to Ad5 between 18 to 200 units, eight HIV infections were observed in the 140 volunteers in the vaccine group compared to four infections in the 142 volunteers in the placebo group.
* In volunteers with immunity to Ad5 between 200 to 1000 units, 14 cases were seen in the 229 volunteers in the vaccine group and seven cases were seen in the 229 volunteers in the placebo group.
* In volunteers with very high levels of immunity to Ad5, defined as greater than 1000 units, seven cases of HIV infection were observed in the 163 volunteers in the vaccine group and two cases were observed among the 157 in the placebo group.
This was a really good idea, so what went wrong??? Some scientists hypothesized that the vaccine activated a bunch of Ad5 CD4+ T-cells, thus created more nommynommy targets for HIV-1 once the people were exposed. This could be fixable, maybe. Make a collection of vaccines with different adenoviral vectors. Serotype everyone– they get the vaccine with the vector theyve never been exposed to.
But turns out that this probably wasnt the problem with the vaccine. Retrospective analysis of the Merck STEP data indicates that there were not more Ad5-reactive CD4+ T-cells in either population 8 weeks post-vaccination.
Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans– The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study.
Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells– The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5-HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4+ T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4+ T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4+ T cells in increasing HIV-1 susceptibility in the STEP trial.
Vaccine making more HIV-1 targets doesnt appear to be the right answer to what went wrong in the Merck STEP trial. We still dont know what happened.
At this point, they dont even think the original vaccine worked in the non-Ad5 people. As time goes by, infections in the ‘vaccine’ group are catching up with the ‘placebo’. But researchers working on similar vaccines want… need to know what went wrong in this study so they can avoid it.