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Are we going "Back to the Future" in vaccine research?
Jul 12, 2010

Hi Dr. Bob,

First off, I hope you had a spectacular 4th of July complete with all of the food fixings....:) (I myself ate almost all the pan brownies that my daughter baked in the firm, unshakable belief that chocolate in the proper thickness and amount can cure just about anything that ails you...)

Ok, onto the question(s).

What is your opinion of the WSJ.com article entitled, "Advance in Quest for HIV Vaccine" by Mark Schoofs concerning Donor 45 and the statement of 91% of HIV strains are neutralized by the one antibody found in him and the research attached to that? The article continues onward in information that sails straight over my capacity of understanding...that's why I decided to wave it in front of you for your humble opinion.

In addition, Dr. Fauci, NIAID director is noted for commenting that the technique used to find this holy grail type of antibody in Donor 45 could be used for any viral disease and possibly even for cancer vaccines.

Hmmm. I don't wish to sound disrespectful (disclaimer: I'm not a trained scientist) but to my concrete operational mind of thinking that sounds like if I have a hammer, I can use it to fix just about anything on my car. Somehow, it just doesn't work out that way for me. But, if it is somehow true wouldn't that be just fantastic?

Is this new research very premature to be thinking of something that people could actually go to a clinic in some type of foreseeable future and utilize?

And, (promise this is the last one) I noted the gene research in a multi-step process making antibodies.....what about just finding the gene in some people that don't contract HIV and replicating that for others to take? Somehow that seems easier....but I realize, if it was THAT easy we would already have a cure, right?

Wishing you and your family the very best!

janelle

P.S. Are you going to Vienna? (Oops! Broke my promise!)

Response from Dr. Frascino

Hi Janelle,

Regarding the brownies, I'm a firm believer that chocolate is one of the four basic food groups (coffee, pasta and dry martinis with double olives would constitute the remaining three).

As to the neutralizing-antibody story that is evolving, the information is preliminary and I expect to hear much more about it in Vienna next month at the World AIDS Conference. See below for what we know so far.

Dr. Fauci's comments were directed at the technique. He was not suggesting a cure for viral-induced cancers is just around the proverbial corner. When and if neutralizing antibodies will be ready for prime time is anyone's guess at the moment. That said, I do find this information fascinating. I've always felt part of the "cure" will involve some sort of immune-based therapy. (I'm sure it's my immunology training that helps formulate my treatment theories.)

Finally, regarding gene therapy, as it turns out nothing about it is as easy as we had hoped. The gene therapy studies are continuing to evolve, but very slowly.

Vienna is still an open question at the moment. I love that city, but I may need to attend the conference primarily via the Internet due to other pressing commitments.

Be well.

Dr. Bob

New Antibody Discovered for HIV Jul 10, 2010

I have just watched a CNN interview with Dr. Fauci that revealed the discovery of a new antibody to fight the transmission of the HIV virus. Will this new antibody also become the basis for a possible cure for the disease. It sounds to good to be true. Please tell me it is so.

Response from Dr. Frascino

Hi,

This information is still hot off the press and very preliminary. Perhaps we'll hear more at the upcoming International AIDS Meetings in Vienna. See below for what we know so far. Stay tuned to The Body and we'll keep you informed as the story evolves.

Be well.

Dr. Bob

Scientists Find Antibodies That Prevent Most HIV Strains From Infecting Human Cells Discovery to Advance HIV Vaccine Design, Antibody Therapy for Other Diseases July 8, 2010

Atomic structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area of viral attachment to the primary immune cells HIV infects. Credit: NIAID VRC.

Scientists have discovered two potent human antibodies that can stop more than 90 percent of known global HIV strains from infecting human cells in the laboratory, and have demonstrated how one of these disease-fighting proteins accomplishes this feat. According to the scientists, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Moreover, the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well.

"The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. "In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases."

Led by a team from the NIAID Vaccine Research Center (VRC), the scientists found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV-infected individual's blood. They found the antibodies using a novel molecular device they developed that homes in on the specific cells that make antibodies against HIV. The device is an HIV protein that the scientists modified so it would react only with antibodies specific to the site where the virus binds to cells it infects.

The scientists found that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than previously known antibodies to the virus.

The researchers also determined the atomic-level structure of VRC01 when it is attaching to HIV. This has enabled the team to define how the antibody works and to precisely locate where it attaches to the virus. With this knowledge, they have begun to design components of a candidate vaccine that could teach the human immune system to make antibodies similar to VRC01 that might prevent infection by the vast majority of HIV strains worldwide.

NIAID scientists Peter D. Kwong, Ph.D., John R. Mascola, M.D., and Gary J. Nabel, M.D., Ph.D., led the two research teams. A pair of articles about these findings appears today in the online edition of Science.

"We have used our knowledge of the structure of a virus -- in this case, the outer surface of HIV -- to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells," explains Dr. Nabel, the VRC director.

Finding individual antibodies that can neutralize HIV strains anywhere in the world has been difficult because the virus continuously changes its surface proteins to evade recognition by the immune system. As a consequence of these changes, an enormous number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV's surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. VRC01 and VRC02 block HIV infection by attaching to the CD4 binding site, preventing the virus from latching onto immune cells.

"The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains," says Dr. Mascola, the deputy director of the VRC.

With these antibodies in hand, a team led by Dr. Kwong, chief of the structural biology section at the VRC, determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. They then examined this structure in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination.

Antibody development begins with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The researchers also confirmed that VRC01 does not bind to human cells -- a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease.

In the final stage of antibody development, antibody-producing B cells recognize specific parts of a pathogen and then mutate, or mature, so the antibody can bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV, but rather mature extensively into more powerfully neutralizing forms. This extensive antibody maturation presents a challenge for vaccine design. In their paper, Dr. Kwong and colleagues explore how this challenge might be addressed by designing vaccine components that could guide the immune system through this stepwise maturation process and facilitate the generation of a VRC01-like antibody from its precursors. The scientists currently are performing research to identify these components.

"The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design," says Dr. Kwong.

The two research teams included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; as well as researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.

References

Wu X et al. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. DOI: 10.1126/science.1187659 (2010). Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. DOI: 10.1126/science.1192819 (2010).



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