quinta-feira, 22 de julho de 2010

Um novo encontro mundial sobre HIV, agora em Viena. O tema vacina está presente.
Veja Editorial do NEJM

The Renaissance in HIV Vaccine Development — Future Directions
Wayne C. Koff, Ph.D., and Seth F. Berkley, M.D.

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From July 18 through July 23, 2010, delegates from around the globe will convene for the biennial International AIDS Conference in Vienna. They will discuss our current risk of losing the war against the human immunodeficiency virus (HIV). Despite an unprecedented outpouring of resources and proliferation of programs, today, for every two patients who begin receiving treatment for HIV, five people are newly infected. Furthermore, new guidelines from the World Health Organization recommending that infected persons begin receiving treatment earlier will significantly increase the number of patients targeted for therapy. If we are to control this pandemic, we must recognize the urgent need to develop and deploy better prevention tools and, most important, a safe and effective HIV vaccine.

Among the most exciting developments the delegates will hear about this year are a series of recent advances that collectively represent a renaissance in HIV vaccine development. These include the first demonstration of protection — albeit modest protection — against HIV infection in humans through immunization, with a vaccine regimen consisting of a canary-pox–vector prime plus a protein-subunit boost in the RV144 trial in Thailand,1 new vaccine approaches that have significantly improved control of simian immunodeficiency virus (SIV) infection in rhesus monkeys and are now advancing to clinical trials, and the identification of novel potent and broadly neutralizing monoclonal antibodies against HIV that have revealed vulnerable targets on the virus that are now being exploited for vaccine design2,3 (see diagram). In fact, just last week, a team of scientists from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases published new findings that identified the latest of these broadly neutralizing antibodies and the structural basis for its broad and potent neutralization of HIV.3

Figure 1
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Vulnerable Targets for Potential Vaccines on the Trimeric HIV Envelope Spike Glycoproteins (gp120 and gp41).

Broadly neutralizing monoclonal antibodies have been identified that target the CD4 binding site (b12, VRC01, HJ16) on glycoprotein 120 (gp120), the membrane proximal external region (MPER) (2F5, 4E10, Z13e1) of gp41, the glycan shield (2G12), and epitopes that reside in the variable loops 1, 2, and 3 on gp120 (PG9, PG16).

Building on this progress, HIV vaccine developers in the coming era will pursue three tracks. In the short term, efforts will focus on broadening the limited protection observed in the RV144 efficacy trial, including studies aimed at elucidating the immune correlates of protection. By 2013, trials should be under way to evaluate vaccine candidates related to the RV144 vaccine. Data should also be emerging from an ongoing phase 2B test-of-concept trial assessing a regimen consisting of a DNA prime plus an adenovirus serotype 5 vector boost. By then, heterologous prime–boost regimens of different adenovirus vectors containing mosaic antigens aimed at overcoming HIV's genetic diversity will also have advanced to clinical trials, and they will reach phase 2B trials if warranted by the initial data on safety and immunogenicity.

In the midterm, efforts in clinical trials will focus on prioritizing and advancing novel vaccine candidates based on replicating viral vectors and additional regimens consisting of heterologous vector primes and vector or subunit boosts. Developers of these vaccine candidates will attempt to achieve the robust efficacy demonstrated by live attenuated SIV vaccines in nonhuman primates (in which infection has been either prevented or controlled with viral loads suppressed to undetectable levels), while making their vaccines safe enough for human use.

For the long term, many researchers are focused on designing vaccine candidates that can elicit broadly neutralizing antibodies against HIV to maximize the potential for prevention of infection. Preclinical studies of broadly neutralizing monoclonal antibodies in nonhuman primates have provided proof of the principle that such antibodies are capable of conferring protection.4 Moreover, analysis of HIV isolates susceptible to neutralization by these antibodies suggests that a combination of two of these new and more potent antibodies that target complementary sites on the HIV spike protein would be expected to neutralize more than 95% of globally diverse isolates of HIV. Large-scale efforts are now focused on dissecting these antibodies' binding sites on HIV and then reverse-engineering immunogens capable of eliciting antibodies with similar potency and breadth of neutralization. Recently, a team of researchers at Merck provided proof of the underlying principle by showing that they could identify an immunogen starting from an HIV-specific antibody.5

These recent advances indicate that the increased investments in AIDS vaccine research over the past decade are now paying off. Unfortunately, the global financial crisis has resulted in a decrease of approximately 10% in investments in HIV vaccine research and development, according to the HIV Vaccines and Microbicides Resource Tracking Working Group. But this is not the time to slow the effort. Creating an effective HIV vaccine will require continued scientific innovation on the part of both academia and the biotechnology industry, long-term commitments of stable and flexible funding from donors, contributions from the best and brightest young scientists, continued engagement of communities in the developing world where efficacy trials will be undertaken, and partnership with the vaccine industry for advanced development and deployment of a vaccine. Fully capitalizing on the recent developments in the HIV vaccine field will help to ensure that we have the requisite tools for prevention, making it possible for discussions at future international AIDS conferences to focus on how we are winning the war against HIV.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the International AIDS Vaccine Initiative, New York.

This article (10.1056/NEJMp1007629) was published on July 14, 2010, and updated on July 15, 2010, at NEJM.org.


  1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009;361:2209-2220. [Free Full Text]
  2. Walker LM, Phogat SK, Chan-Hui PY, et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 2009;326:285-289. [Free Full Text]
  3. Zhou, T. Georgiev, I, Wu X et al. Structural basis for the broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010 July 8 (Epub ahead of print).
  4. Hessell AJ, Rakasz EG, Tehrani DM, et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol 2010;84:1302-1313. [Free Full Text]
  5. Bianchi E, Joyce JG, Miller MD, et al. Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates. Proc Natl Acad Sci U S A 2010;107:10655-10660. [Free Full Text]


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