Vaccine vectors based on adenoviruses—which are
common in nature and cause severe colds—were once viewed as promising for HIV
and other intractable diseases due to their ability to induce antigen-specific
CD8 T cell responses in the majority of recipients. The subsequent Icarus-like
trajectory of the approach in HIV has been covered in some detail on this blog,
starting with the results of the first efficacy trial of Merck’s now-discontinued
adenovirus serotype 5 (Ad5) candidate (the Step study), which showed that the
vaccine significantly increased the risk of HIV acquisition and did not
significantly lower viral load or preserve CD4 T cell counts in participants
who became infected.
The HIV vaccine section of TAG’s new 2013 Pipeline Report covers the latest round of
grim news, which emerged earlier this year with the announcement that immunizations in the lone
ongoing HIV vaccine efficacy trial, HVTN 505, were being stopped at the
recommendation of the Data Safety Monitoring Board (DSMB). An interim analyses conducted
by the DSMB on April 22, 2013 found that the vaccine regimen—comprised of three
priming immunizations with a DNA vaccine and a booster shot with an Ad5 vector
(both designed by the NIH’s Vaccine Research Center)—did not show efficacy
either in terms of preventing HIV infection or lowering post-infection viral load
set points, and there was no possibility of efficacy being demonstrated if the
trial ran to completion. The total number of infections was greater in the
vaccine arm compared to placebo (41 vs. 30), but many of these infections
occurred prior to the administration of the Ad5 boost and the difference was
not statistically significant. Post-boost, there were 27 infections in the
vaccine arm and 21 in the placebo arm.
On the heels of this announcement came word that extended
follow up from the second efficacy trial of Merck’s Ad5-based HIV vaccine, the
Phambili trial in South Africa, had documented significantly more infections
among vaccine recipients compared to placebo recipients. The data were
described by principal investigator Glenda Gray at the HIV Vaccine Trials Network meeting in Washington DC on May 7th, and reported by Jon Cohen in Science on
May 10th. Although it went largely unnoticed at the time, on May 14th the
National Institute of Allergy and Infectious Diseases (NIAID) issued a bulletin reporting that regulatory authorities had been notified of
the Phambili findings. The bulletin notes that while the initial published analysis of the trial results did not reveal significant
differences between vaccine and placebo arms, “in the current analysis of the
full 3.5 year follow-up period, the researchers found that 100 study
participants became HIV-infected: 63 participants who received the
investigational vaccine and 37 participants who received a placebo injection.
The increased number of HIV infections among the vaccinated recipients was
greatest among men and more pronounced roughly 30 months after initial
vaccination.” There are some potential caveats: the additional infections occurred after the study was unblinded, and there was a substantial drop-out rate that was slightly greater in the placebo arm. Also, in contrast to the Step trial where the enhanced HIV risk has been reported to have waned over time, the increased rate of infection occurred late (>2 years post vaccination).
The accumulation of negative data has left a cloud of
suspicion hanging over all investigational adenovirus-based vaccines, including
those based on alternate human serotypes to Ad5 and chimpanzee-derived
adenovirus serotypes. The mechanism of the apparent enhancement of HIV acquisition
risk in the Step and Phambili trials remains unclear. Importantly, it is not
yet known if the adenovirus vectors were somehow solely responsible or if the
effect was interlinked with the immune responses to HIV that were induced by
the constructs (as one small but as yet unconfirmed macaque study has
suggested). Complicating matters further, evidence from the Step study
indicated that the degree of pre-existing immunity to natural Ad5 (as measured
by antibody titers) was correlated with the magnitude of the vaccine-associated
enhancement of HIV risk. In the absence of clarity regarding these issues, there
remains the worrying possibility that experimental adenovirus-based vaccines
for other diseases (such as TB, malaria, and hepatitis C) could place
recipients at increased risk of becoming HIV infected if they are exposed to
the virus.
Currently the various stakeholders in the development of
adenovirus-based vaccine candidates, including major sponsors such as NIAID and
the International AIDS Vaccine Initiative (IAVI), are conducting meetings to
discuss the new findings and their implications for the future. It is not yet
known if planned or ongoing trials will be affected. In a related development—as
reported by Mike Frick in the TB vaccine section of TAG’s Pipeline Report—plans for a large efficacy trial of
an Ad35-based TB vaccine candidate have been significantly scaled back due to
the observation that the approach is less immunogenic than preliminary results
had suggested.
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