Back to basics (but not too far back) with vaccine research: an interview with Anthony S. Fauci, MD.
Article Type: Interview
Subject: Immune response (Health aspects)
Immune response (Research)
AIDS vaccines (Usage)
AIDS vaccines (Health aspects)
HIV infection (Prevention)
HIV infection (Research)
HIV infection (Care and treatment)
Author: Mascolini, Mark
Pub Date: 06/22/2009
Publication: Name: Research Initiative/Treatment Action! Publisher: The Center for AIDS: Hope & Remembrance Project Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 The Center for AIDS: Hope & Remembrance Project ISSN: 1520-8745
Issue: Date: Summer, 2009 Source Volume: 14 Source Issue: 1
Topic: Event Code: 540 Executive changes & profiles; 310 Science & research
Organization: Government Agency: United States. National Institute of Allergy and Infectious Diseases
Persons: Named Person: Fauci, Anthony S.
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220766444
Full Text: Dr. Fauci is Director of the National Institute of Allergy and Infectious Diseases (NIAID) and Chief of the NIAID Laboratory of Immunoregulation at the National Institutes of Health (NIH), Bethesda, Maryland.

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Mascolini: Some people think more attention should shift back to basic vaccine research before another phase 2b or 3 trial is launched. Do you agree?

Fauci: In the meeting that we held in March 2008 to discuss vaccine research after the STEP trial, (1,2) I made the point that we are not going to abandon phase 1 trials to test certain concepts in humans because this is part of fundamental discovery research. But given the disappointments that we have had with phase 2b and even phase 3 trials thus far, we all agree that there are some basic questions that need to be answered before we move ahead with another phase 2b or 3 trial.

Some of those questions are rather fundamental: Why is it that the body does not seem to induce an effective immune response against HIV? What are the proper immunogens to induce that response? What is the nature of a protective immune response? We do not even know that because we do not have the benefit of a successful experiment of nature, as we do with so many other viruses.

If you look at any other infection, particularly viral infections for which we have a safe and effective vaccine, nature always seems to do us a favor by proving that a vaccine is feasible. Even when there is morbidity and some mortality after infection with smallpox, measles, and polio, at the end of the day the vast majority of people recover, eradicate the virus from their bodies, and go on to develop what is usually lifelong immunity against subsequent infection with the same virus. So when you try to make a vaccine against those other viruses, you already have a proof of concept that it can be done. The body is capable of protecting itself against this pathogen.

We do not have such a privilege with HIV because nature has not provided us with the proof of concept. We know that the body does not respond well to HIV under natural circumstances. The body does not mount an immune response that protects us, except in very rare individuals, or a response that can eradicate the virus.

So there are some fundamental questions about HIV that are very different from what we see with other viruses. We need to ask and answer those questions before we empirically try yet another vaccine candidate in a large phase 2b or 3 trial.

Mascolini: Is basic research addressing those fundamental questions?

Fauci: Yes it is. We are defining the structural components of the virus in its different conformations. We are determining the binding sites of the few neutralizing antibodies that we have been able to identify. We are trying to design immunogens that could elicit such a response in humans. We are developing animal models to determine if we can get the animal model to predict what is going on in humans more accurately. There are a lot of things going on at the basic level.

Mascolini: Do you believe basic research is moving along as fast as it should be?

Fauci: With all basic research, it is not like an empiric study in which you ask a question, do a trial, and get an answer. Basic research is discovery, and it is very hard to predict when you are going to make the discovery that breaks the logjam. You just do not know. I believe the effort being put forward now in very robust, and I am satisfied with that. Hopefully, we will get the answers sooner rather than later.

I do not think you need to do a large-scale clinical trial to manifest your commitment to developing a vaccine. The kinds of basic research and the early clinical work we are doing are a clear-cut signal that we are very interested in developing a vaccine.

Mascolini: The Merck vaccine that failed in the STEP trial tried to stimulate cell-mediated immunity. Can a vaccine that stimulates only T-cell-based immunity have a significant impact on the HIV epidemic?

Fauci: It might, but we are not sure. We know from animal models that--under certain circumstances, many of which are somewhat artificial, such as the type of challenge virus you use--there is a potential that a T-cell vaccine could do what we hope it will. The goal is not necessarily to prevent infection, but at least to maintain the viral set point low enough and long enough that you can do two things: first that you can forestall the need for initiating therapy until later than you would otherwise, and second that you can keep the viral load so low in these people that they would not readily infect other people. That is a hypothesis, and it has not yet been proven to be attainable. I still keep open the hope that there would be some benefit from a T-cell-stimulating vaccine, but the real benefit would be if we get a vaccine that actually prevents infection in the first place.

Mascolini: And an antibody-stimulating vaccine would be more likely to do that?

Fauci: Yes. There is no doubt about that. T-cell vaccines and T cells themselves generally are directed at cells that are already infected. What you would like to do is prevent the initial infection because with HIV, once the infection is established, thus far we have not been able to eradicate it. So although you may keep the virus level low for a considerable period of time with a T-cell approach, it does very little to actually eradicate the infection.

Mascolini: Is ongoing research focusing on a vaccine that stimulates antibody-mediated immunity?

Fauci: Yes, there is a lot of antibody work going on. For example, right here at the NIH Peter Kwong (3) is working on an antibody-directed vaccine, as is Dennis Burton at the Scripps Research Institute in California. (4) A number of researchers are very involved in developing an antibody-based vaccine.

Mascolini: What's the rationale for the canary-pox vector-AIDSvax prime-boost strategy, (5) and do you think it will work?

Fauci: That is the vaccine being tested in Thailand right now. We will probably hear the results in the fall or winter. The rationale for that particular candidate is that the prime did not work alone, and the boost did not work alone, so the question was whether they would work together. It was an empiric decision. I hope we will get some information from that trial, but it is very difficult to predict.

Mascolini: Given everything we have learned so far, do you think it is feasible to devise an HIV vaccine that confers sterilizing immunity?

Fauci: I am hoping so, but I do not know if that will be possible. People are reluctant to say that a sterilizing-immunity vaccine may be unattainable because they do not want to give the impression that we are giving up. We are certainly not giving up. I have cautious optimism that we will be able to do it.

Mascolini: Do you have any other points you'd like to make about how research is going or what you think might be done better?

Fauci: I think developing a vaccine remains a major challenge because of what I said at the beginning of the interview--there are still some basic unanswered questions that will not allow us to jump into the empirical trial mode. We still need to ask and answer those fundamental questions.

References

(1.) Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008; 372:1881-1893.

(2.) McElrath MJ, De Rosa SC, Moodie Z, et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet. 2008;372:1894-1905.

(3.) Huang CC, Lam SN, Acharya P, et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science. 2007;317:1930-1934.

(4.) Zwick MB, Burton DR. HIV-1 neutralization: mechanisms and relevance to vaccine design. Curr HIV Res. 2007;5:608-624.

(5.) Thongcharoen P, Suriyanon V, Paris RM, et al. A phase 1/2 comparative vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gpl60 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost. J Acquir Immune Defic Syndr. 2007;46:48-55.
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