Possible reasons why the Merck HIV vaccine failed

Going along with the theme of the previous few blog posts, I was going to blog about the failed Merck HIV vaccine trials.  Instead, I decided to delve a little bit deeper into the hypotheses attempting to explain WHY this vaccine, even the promising results of increased CD8+ killer T cell numbers, may have ultimately failed.

The MRKAd5 vaccine was based on the premise of inserting copies of 3 artificially generated HIV genes into a genetically engineering viral vector (2).  The vector used in the HIV vaccine, and many other viral vaccines, is adenovirus5, an inactivated form of a "common cold" virus.  The hopes for this vaccine were that the immune system would recognize the viral components enough that if a vaccinated individual were exposed to HIV, there would be enough of a response to prevent, or at least delay, the onset of AIDS (1).  However, after a conference in Seattle to discuss the new evidence that the MRKAd5 vaccine is "not efficacious" and may result in INCREASED risk for HIV infection (3), several ideas have been brought forth in an attempt to explain why the vaccine failed.  One theory is based on the idea that if a vaccinated volunteer was previously exposed to adenovirus5 (the viral backbone of the vaccine), the subsequent response would be biased towards CD4+ cells rather than the Cd8+ cells the vaccine was intended to amplify.  An increase in CD4+ cells only results in the production of more cells that the HIV virus can go on to infect (Dr. Keith Gottesdiener, unpublished data). Some preliminary results suggest that some people who have prior immunity to adenovirus5 may indeed be the ones who are at higher risk for HIV infection.  The second theory depends on the idea that perhaps this system generates too much antigen for a prolonged period of time.  The excess antigen causes "exhaustion" of the immune cells, which then fail to proliferate and die (6).

Regardless of the actual unforeseen mechanisms that caused the MRKAd5 vaccine to fail,  the outcome of this trial raises questions concerning the use of similar adenovirus vectors in vaccine creation.  Several other vaccine trials, including an Ebola vaccine and another HIV vaccine, have been slowed, postponed or altered so that the test population pool are individuals with low risk of exposure to colds (4).  It also reminds us that while data generated in model organisms is invaluable, care must be taken when extrapolating the putative animal model into human applications, as we've seen several times during this course.  In the case of the MRKAd5 vaccine, the data generated in primates suggested that the vaccine upregulated the number of CD8+ cells (7), although later on, it was shown in mouse that these additional cells may not be completely functional (2).

1.  Ho, DD.  (2007).  A Shot in the Arm for AIDS Vaccine Research.  PLoS Med 2(2) :e36.

2.  Lin, SW et al.  (2007).  Recombinant adeno-associated virus vectors induce functionally impaired transgene product-specific CD8 T cells in mice.  J Clin Invest.  2007 Nov. 15 [Epub ahead of print].

3.  Cohen, J.  (2007).  Did Merck's vaccine cause harm?  Science 312(5853):1048-9.

4.  Stark, K.  (2007).  HIV trial's halt reverberates.  www.philly.com/philly/business/20071116_HIV_trials_halt_reverberates.html

5.  Cohen, J.  (2007).  Promising AIDS vaccine's failure leaves field reeling.  Science 318(5847):28.

6.  Kaiser Daily AIDS/HIV report from November 16, 2007.  www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=48904

7.  Shiver, JW and Emini EA.  (2004).  Recent advances in the development of HIV-1 vaccines using replication-incompetent adenovirus vectors.  Annu Rev Med 55:355-72.