SAV001 (Canadian) HIV vaccine trials

Human trials for HIV vaccine approved by FDA (SAV001)

http://www.youtube.com/watch?feature=player_embedded&v=1NohdDy2J54#!
http://www.youtube.com/watch?feature=endscreen&NR=1&v=jFpwHe6KjDA

What could happen for this trial?  Will it work this time?

If yes, what is the difference?  Why will it be different from previous numerous unsuccessful trials?

If it fails, why will it be the case?  

I wish I can be more enthusiastic and positive this time than many previous trials.  However, there is a concern as usual.  This trial is different from others in that it uses inactive form of whole HIV as immunogen, while many previous trials use a piece of HIV gene (or combination of HIV genes) using various delivery system (different virus as a vector).  Nevertheless, there is no differences in terms of leaving HST unprotected from infection and depletion by HIV.
During vaccination, *HST will expand as I outlined previously (http://soonhong-hivandaids.blogspot.kr/2012/04/r5-tropic-hiv-susceptible-cd4-t-cells.html).  Even with multiple failures of generating HIV vaccine, it never seems to ring the bell.  It is even more so to whom his (her) interests are geared towards infectious agents, such as HIV itself.  Early expansion of HST immediate after infection is critical for protective immunity for any pathogens.  However, unfortunately, it has not provided any protection from HIV infection in all cases of HIV vaccine trials up to now.  Instead of protecting it, the expanded HST becomes preferable and ample targets for HIV for their maximum expansion.  This should be the main concern for any HIV vaccine trials, whether it is based on live recombinant, attenuated or chemical and radiation inactivated (killed) recombinant HIV, as in SAV001.  Unfortunately, this issue has never been brought up in any of HIV vaccine trials.  It is probably due to the lack of current immunological understanding on HST even among the top-notch immunologists.  HIV, especially CCR5 (R5)-tropic HIV, is unique among any pathogens known to man by infecting and depleting CCR5 expressing CD4 T cells (HST).  As I outlined elsewhere (http://soonhong-hivandaids.blogspot.kr/2012/04/lacking-hst-leads-to-aids-and-providing.html), presence or absence of HST determines the outcome of the HIV infection, getting AIDS or not.  
There is always a possibility that it may work this time, like a magic as had been the case in polio and smallpox about decades and century ago.  In a very fortuitous situation, there will be abundant high affinity, pre-made broad neutralizing antibodies against the surface antigen of HIV and it will immediately cover up the incoming HIV, before they infect widely available HST.  It is also highly likely that killed HIV vaccination will generate cytotoxic T cells specific for any HIV antigen.  But the boosting anti-HIV immune response has never been the problem during the stage of HIV vaccine trials.

The foremost problem lies in the specificity of target cells for HIV, unlike any other pathogens known.  HIV is unique pathogen known, which attacks and depletes HST.  By immunization, we provide more target cells (HST) for HIV to attack and propagate.  At the same time, it generates more soldiers (both antibodies and T cells) to fight against HIV.  

At the moment, the pendulum of the field of HIV vaccine development swings in favor of the antibody mediated protection against HIV infection from the cell mediated protection mediated by CD8 T cells.  This is mainly due to the fact that T cell based STEP trials had just failed in recent years.  We will see what will happen within a few years. If we failed antibody based HIV vaccine trials, will it swing back to T cell based vaccine development?  It has been back and forth by the same (handful) group of investigators.  At least, UWO is the newcomer for our endeavor of obtaining an HIV vaccine.  In addition, killed whole HIV immunization is something that we have not tried, even though the idea are nothing new.  At he moment, we are not in position to discriminate one method or another to fight against HIV and AIDS.

There is an innate problem on the SAV001 trial as well.  It is expected and hoped that the whole HIV vaccination (minus nef, vpu and signal peptide) approach will cover not only antibody mediated, but also T cell mediated immune responses against HIV.  As shown by Klatt et al (Klatt, et al. SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination Blood 2011 118:5803-5812) in non-human primate model, lacking HST affects both types of immune responses.   This suggests that follicular helper T cells (TFH), which helps B cell maturation and differentiation, could be derived from HST.  If that will be the case, generating an HIV vaccine is almost an impossible task without any major breakthrough in human intelligence.

It seems that we are desperate to generate HIV vaccine ASAP.  At the same time, we have too many unknowns at the moment.  We need a big scale collaboration from all over the field (and world), basic immunologists, virologists and vaccinologists!!

Wish I were more positive on this urgent issue as an immunologist!!

I would welcome any comments, suggestions and corrections in English.

The following is cited from an original report from The University of Western Ontario:

"Before it can be commercialized, the SAV001 vaccine must go through three phases of human clinical trials:

• Phase I, set to begin in January 2012, will double check the safety of the vaccine in humans, involving only 40 HIV-positive volunteers.
• Phase II will measure immune responses in humans, involving approximately 600 HIV-negative volunteers who are in the high-risk category for HIV infection.
• Phase III will measure the efficacy of the vaccine, involving approximately 6,000 HIV-negative volunteers who are also in the high-risk category for HIV infection."

Key words:
HST, AIDS, HIV, AIDS vaccine, SAV001, STEP, T cell, B cell, antibody, immunology, virology, vaccinology, nef, vpu, clinical trial