6.4 Barton Haynes — Development of HIV Vaccine: Steps and Missteps

Bart Haynes: [00:00:00] Thanks very much. I want to thank the organizers for this wonderful honor to be here. This has been a phenomenal meeting and I'm just very grateful to be here. For the next few minutes I will talk about some of the early contributions to HIV science, specifically collaborations with the NCI (National Cancer Institute)/[Robert C.] Gallo AIDS working group from '83, '84. Then move into early mapping of HIV-1 neutralizing antibodies in '88 and '89. Which [00:00:30] lead right into HIV-1 vaccine development. The topic I was given to talk about was vaccine development steps and missteps.

First of all about what happened in the early part of the epidemic. I got into retroviral research in 1981 after I'd come from Tony Fauci’s laboratory at the NIH in 1980 where I had undergone—taken an ID (infectious disease) fellowship as well as the clinical immunology fellowship. But actually as Tony said yesterday, we actually studied rheumatology [00:01:00] patients with perturbed immune systems. I was studying at that time the HuT-102 cell line which turned out to have HTLV-I back in the mid-'70s and figured out that it was mediated. It was a CD4 cell line and mediated T cell help along with other lines from Adi Gazdar (1937–2018).

At Duke I was studying cutaneous T cell lymphoma referred an individual Japanese female who saw the bomb go off in Nagasaki. She [00:01:30] married an American sailor, moved to the United States. 30 years later after being in the United States for that period of time, developed severe arthritis and cutaneous T cell lymphoma with necrotizing lesions. I had interacted with Bob [Gallo] through his friendship with Dani Bolognesi, and I had seen all the pictures and followed the HTLV-I work, and realized that this was a possibility. Bob was very generous and sent us all the reagents. We isolated HTLV-I from this lady's peripheral blood. For those [00:02:00] rheumatologists out there, we aspirated from her joints, HTLV-I positive cells. This was the first patient with a complication of HTLV-I associated arthritis, which is actually quite common, that had been previously diagnosed as rheumatoid arthritis in Japan at that time. We wrote this up and published it and there's the EM (electron microgram) of this isolated HTLV-I SD.

Also, we're [00:02:30] talking about what the NIH did to get ready for the epidemic. The NCI in the mid-1970s built at Duke a BSL-4 (biosafety level 4) facility that was run by Darell Bigner and Dani Bolognesi called the ALIF, the Animal Laboratory Isolation Facility. It was designed to work on cancer viruses. With Dani, we joined the Gallo AIDS working group, which means you go to the Gallo monthly lab meetings. My job was to find a hemophiliac cohort, which [00:03:00] there was the Southern Center for Hemophilia was at the University of North Carolina and we partnered with Gil White.

We needed a place to study this and we fired up this thing called the Blickman Line here, which was the "state of the art"  BSL-4 at the time with Richard Scearce. We set it up for tissue culture, microscopy, ultracentrifugation, and the ability to do a radioimmunoassay for HTLV-I based upon Max Essex's [00:03:30] work, and the theory is that this was a retrovirus, maybe like HTLV at the time.

What we did was we established a sensitive, but not so specific radioimmunoassay for disrupted HTLV-I that we got from the Gallo lab. We analyzed 136 plasmas from hemophilia individuals that had undergone clotting factor replacement. We identified individuals that were HTLV-I reactive with these essays and also obtained laboratory blood, lymph [00:04:00] nodes, other tissues. HTLV-I as Bob said yesterday, was isolated from one of these individuals, HTLV-I SN. And we found a red hot serum that reacted—the ET serum that was also, turned out to have HTLV-III antibodies and which uses a diagnostic reagent. (2)

Incidentally, in this cohort after [unintelligible 00:04:21], Carl Saxinger and Marjorie Guroff finished all of their assays several months after the test was [00:04:30] established. 53% of them turned out to be HIV positive, 11% were HTLV-I positive. This was just one of the four papers that came out in May of 1984. (2)

Bob showed this yesterday. (3) This was one of the charts of some of the virus isolates. There is SN, and also the electron micrograph from Mika [Popovic], this is at the actual micrograph from Mika, and the use of this particular serum.

[00:05:00] After the discovery of the virus by Françoise [Barré-Sinoussi] and the determination that this was the cause of HIV, we became involved in vaccine efforts. Our efforts were with the Bolognesi group at Duke in mapping of HIV-1 neutralizing antibodies. In 1988 and '89, three papers came out [00:05:30] defining the principal neutralizing domain of the HIV envelope. (4, 5 6) Tom Palker in my lab made synthetic peptides, and the tenth synthetic peptide turned out to be the left-hand side, the crown, and part of the right-hand side of the V3 loop that induced very potent neutralizing antibodies against lab adapted strains. About a half a year later, Jaap Goudsmit (b. 1951), in experimentally infected chimpanzees. identified the V3 loop as the primary neutralizing determinant. Then on a [00:06:00] paralleled study with Scott Putney at Repligen, with Danny Bolognesi and Tom Matthews showed with peptides the exact same phenomenon.

We were very, very excited about this. We thought that to make the vaccine it was going to take about two years. We partnered with Wyeth (1860–2009). I learned what an IND was and wrote one. We did two clinical trials with four valent peptides designed by a fellow [00:06:30] of Gerry Myers at Los Alamos [National Laboratory] named Bette Korber. We studied these four valent T cell B cell epitope peptide mixture in infected individuals and boosted V3 antibodies, and then in uninfected individuals, and induced not only V3 antibodies but also CD8 responses.

We were very excited until the first major blow to the vaccine effort happened with a whole series of papers from [00:07:00] Tom Matthews, Cole Hansen, John Mascola. A whole host of individuals. David Ho found that primary isolates were not sensitive, were from the community and not grown in tissue culture, were not sensitive to soluble CD4 and nor were they sensitive to the easy to induce V3 or other gp120 antibodies.

That really leads us into the next stage of HIV vaccine development and where we are now. [00:07:30] In 1987 was the first of six failed HIV vaccine trials. With the MicroGeneSys gp160 envelope. Then gp120 Vax003 was a B/E two gp120s had failed and high-risk population in Thailand. Vax004 was B/B and several cohorts in the United States, South America, and elsewhere. The STEP [00:08:00] trials, two Merck trials of recombinant Ad5 vaccine which was primarily to induce CD8 T cells failed in Phambili in South Africa and in the United States. Then in 2013, the VRC vaccine which VRC DNA prime recombinant Ad5 boost to trivalent vaccine with envelope as well as other components to induce both antibodies and CD8 cells, also showed [00:08:30] no efficacy.

As you all know, there was a trial called RV 144 [trial] (2003–2009) published in the New England Journal (7). Then a follow up from Merlin Robb in The Lancet that showed—Someone was talking earlier about the evanescent nature of the antibody response due to envelope vaccines. (8) The efficacy was 60% through 12 months and 31.2% at nearly two years. We were able to lead, in the CHAVI, a [00:09:00] international immune correlate study of those that became infected versus those that didn't and found that there were two correlates antibodies to the V1-V2 region as well as and a binning essay by Susan Zolla-Pazner, and antibody that correlated with decreased transmission risk, and antibodies that envelope that the higher the antibody, the greater the risk that one had. [00:09:30] Then in a secondary study, ADCC (antibody-dependent cellular cytotoxicity) activity in the absence of IgA strongly correlated with protection. Subsequent studies have suggested that there was no enhanced susceptibility to infection but that basically what the IgA did was blocked the ability of ADCC antibodies.

There are two follow-ups or three follow-ups going into the clinic. The first is a Pox-Protein Public-Private Partnership or [00:10:00] P5, in which an RV 144-like vaccine has been designed by this partnership and is being tested in the HVTN (HIV Vaccine Trials Network), which is the ALVAC or canarypox with a C-envelope and other genes, and bivalent envelope gp120s that are two clade Cs plus the ALVAC as a boost as it was used in Thailand with an AE boost. The efficacy Phase IIB trial [00:10:30] will start in the HVTN sometime this fall, hopefully, later in October or November. And the fundamental question there that Larry Corey is asking: Is clade C ALVAC gp120 vaccine replicate the protection in South Africa that the AE vaccine showed in Thailand? With a different adjuvant and set of immunogens, can it improve on that protection? There's a second follow-up, the Janssen trial. This is on rAd26 mosaic [00:11:00] prime and an MVA mosaic boost with a gp140 boost and some combination. I'm not sure it's been decided yet. This has been developed by Dan Barouch and Bing Chen, and the mosaic inserts were designed in the CHAVI-ID with Bette Korber working with Dan.

I'll just mention what Bruce just mentioned. This is the only preclinical study that I'll mention, but the results were striking that Louis Picker has a rhesus CMV vaccine, as Bruce said, that stimulates atypical CD8 [00:11:30] killing recognizing peptide in the context of class 2 and atypical class 1 instead of classical MHC (major histocompatibility complex) class 1. But "protect" is really not the right term here, it really clears the infection. In 50% of non-human primates, they all get infected. The question is, can this be replicated in humans? Is this something that can lead to protection? Jeff Lifson is also quite involved as a collaborator in the work with Louis.

Now, a major [00:12:00] roadblock for inducing an HIV vaccine, as Dennis [Burton] said, is our inability to induce broadly neutralizing antibodies (bnAbs). This is the associate trimer structure contributed by all of these individuals here. John Moore and Rogier Sanders designed this, and with beautiful crystallography work initially from the Scripps group and then from the VRC group. These are all the reasons that Dennis talked about, and these are the targets that are more conserved [00:12:30] and therefore give rise to broadly neutralizing antibodies. The point is, as Dennis said, they arise in infected individuals, but not in vaccinated individuals.

What our team in the CHAVI Immunogen Discovery and the original CHAVI grant decided to do, was to go to Africa and to set up observational clinical trials to be able to screen over half a million individuals at sexual transmission disease clinics—this is an effort led [00:13:00] by Mike Cohen to find individuals who had just been infected with HIV and then to be able to follow these individuals until the time of broad neutralizing antibody development.  This was done. As we were talking about earlier about the arms race between the host and the virus. What we study is the arms race between the virus and the antibody [00:13:30] response within each individual. George Shaw, I'm sure will talk about the transmitted founder virus work, and the work that he and Beatrice [Hahn] did in the CHAVI. They lead the team that studies the virus evolution and then we have an antibody team from my group that study the antibody evolution. In about 50% of individuals, some level of broad-neutralizing antibodies will eventually develop over years, and that's what we're trying to recreate. [00:14:00] If we can figure out what are the envelopes that are critical for inducing these antibodies, then we should have a successful vaccine regimen, all of the things considered equal.

We began to study these individuals and our first individual was in an individual that made CD4 binding site broad neutralizing antibodies. (9) We mapped the co-evolution of the transmitted founder virus and, by the way, when you have these early samples, as Emilio [Emini] was saying, there is a virus [00:14:30] envelope that does start these lineages off, and when you're able to isolate the transmitted founder, more often than not, you can find the envelope that does this. That there's not a hole in the repertoire for induction. One has to just be able to either find or to design the envelopes that bind to the imitated common ancestors of the germlines.

Secondly, we demonstrated that the broad neutralizing activity did not occur until extraordinary diversity of the virus occurred. That the diversification of the virus is required for the generation of the broad neutralizing [00:15:00] antibodies. Third, the point I just made, te showed that the broad neutralizing antibody germline bound to the founder virus envelope in various forms. One can titer up or down the affinity depending upon the form of the envelope. Finally, the implications are that the founder virus envelope initiates the broad neutralizing antibody lineage. When others have done these studies, these are the observations that have been made.

This is a visual representation [00:15:30] of the sequence of the envelope undergoing evolution. (9) The single transmitted founder virus responding to the autologous neutralizing antibodies that first come up. Then, this explosive diversification. With the diversification comes the development of the affinity mature broad neutralizing antibodies. From this, we have begun to pick out the transmitted founder, and evolved envelopes along the way that we believe are important for driving these lineages. [00:16:00] What we've found, with this particular lineage, that autologous neutralization required about 4% somatic hypermutation, began to see cross-neutralization around 10%, and broad neutralization at 15% such that, in this particular lineage, about 55% or 60% of the viruses could be neutralized.

The important point here, as Dennis said, this is a relatively new concept of realizing how [00:16:30] important it is in our immunogens. If we're trying to direct disfavored lineages that the body doesn't want to make, that we've got to really take into account—it doesn't really matter what binds out here. What matters is what binds here and at the steps along the way. It's a fundamental shift in strategy from vaccine design, from all the other vaccines that have ever been made.

We've come up with what we call is the concept of how to [00:17:00] encapsulate these principles of B cell lineage design because the goal is to initiate broad neutralizing lineages, and to select shorter lineages with fewer mutations because, as Dennis said, these lineages accumulate huge numbers of mutations, very complex lineage pathways. To select lineages with either no self-reactivity or acceptable self-reactivity, or autoreactivity—I’ll come back to that in a moment. To give lineages that are normally subdominant the ability to compete in the germinal center and become dominant because [00:17:30] clearly, as we've said multiple times, we've been trying to do this now for 20 years. These lineages are disfavored for a number of reasons.

This is just a visual representation of what we're talking about. (10) You do what Dennis talked about. You isolate the monoclonal antibodies from a broadly neutralizing antibody-producing individual. Then, through computational techniques or by actually isolating the intermediates or the UCA, you can reconstruct the trees [00:18:00] and figure out what the highest probability of the germline was for a particular lineage. You select envelopes naturally isolated from an individual, or as Bill Schief and Dennis and their team have done, designed these envelopes in order to selectively provide direct stimulus to a lineage that one is trying to drive.

Who's to say that you can isolate an antibody lineage from an African individual in Malawi, and it's [00:18:30] applicable to someone in Cold Spring Harbor, or anywhere else? The reason is because from that picture of the envelope that I showed, and Dennis showed, the carbohydrates that protect those conserved sites, really limit the antibody solutions that can fit in there. Dennis very nicely showed you the solution that the VRC01 antibodies have in binding just like CD4 to the [00:19:00] gp120.

Well this is a picture from Peter Kwong of, I think, nine VRC class 1 antibodies from five different donors. (11) They are superimposable on one another. They all need to use VH1-2. They all have light chains that have five amino acids, and they are all superimposable on CD4. There are very few solutions to these, and that's why a lineage derived [00:19:30] from one individual and a germline are quite similar to a lineage in other in many cases. Here is one of the solutions to this problem, an elegant solution that Bill Schief has come up with, with this construct eOD-GT8 that is designed to bind to the germline of the VRC01 lineage. Here are some of the papers that show that they can bind and that they can actually initiate [00:20:00] these lineages. (12, 13, 14, 15) This was a proof of concept that germline antigens can stimulate the naive B cell lineages from the VRC01 class.

Here are the three papers that just came out a couple of weeks ago from the [Michel] Nussenzweig group, from Dennis' and Bill Schief's group. (16, 17, 18) This is a cool paper because it's from all three groups together. It shows that while the groups are competing in the field, we're also communicating and where it makes sense, we're also exchanging reagents and [00:20:30] working together to get the job done as quickly as possible.

This latter one is through a different mouse that requires rearranging of the VDJ segments. It's much more native-like. The point of this slide is that all of these models are somewhat contrived and create in the mouse the solutions that are difficult for a wild type animal to get around. To some degree, the germlines [00:21:00] are slightly mutated in these models. Here the germline for the heavy chain is not mutated, but there's a critical insertion that has to occur in CDRL1 and deletion that we didn't ask the mouse to make.

This is a study that we've done in knock-in mice with a different broad neutralizing antibody unmutated common ancestor against the membrane-proximal [00:21:30] region, and we immunized with immunogens that bound to this broad neutralizing epitope. (19) It's the 2F5 MPER epitope. In these animals, as I'll talk in a minute, 98% of these germline antibody B cells are deleted in the bone marrow. They're controlled by central tolerance. The 2% that get out we can activate with an immunogen that looks like this. That's designed to look like a virus with the epitope on it. Here we've started with as unmutated heavy and light [00:22:00] CDR3 as we can try to design.

From the status of HIV vaccine development, the field together has made a beachhead. That is we can induce broad neutralizing lineages in contrived knock-in mouse models, but nonetheless, not to de-emphasize this in the least. This is a major accomplishment.

From the work that I just showed you, [00:22:30] as Dennis also said, we're going to have to induce multiple types of antibodies, but this is a sequence of immunogens that have been designed based upon the first mapping of coevolution of virus and antibody. (9) These are the antibodies on the bottom here, with the accumulation of the colored balls, an indication of acquiring somatic mutation events. This is a fragment of the envelope that the crystal structure by Peter Kwong was done with above. [00:23:00] We've picked envelopes that will be transmitted founder, week 53, 78 and 100, based upon their ability to bind to the stages of the lineage we're trying to induce. These have been made GMP and there's a human trial. The first human trial to start with sequential immunization will start in the spring of 2017 as HVTN115 and led by Larry Corey's team.

At the R4P meeting next week, [00:23:30] we'll talk about in non-human primates. We can induce and select non-human primates intermediate stage, broad neutralizing antibodies and outbred macaques with a sequential immunogen. We can't do this in every macaque, but it has occurred. We're working hard to figure out exactly what happened in that animal so that we can understand exactly why this occurs.

The fundamental question is, why are broad neutralizing antibodies made in HIV infection over a long period of time, but rarely [00:24:00] in vaccination? There are many reasons. We're homing in on the host control of these and why they're disfavored. The first clue for us came in 2005. (20) I'm a rheumatologist. I've been working on autoreactive antibodies. Dennis noted that a lot of these antibodies have long CDR3 regions and have high levels of somatic mutations. Back in 2005, we noticed this as well. We noticed that [00:24:30] they had long CDR3s and high mutations were autoreactive. They both reacted with lipids and host proteins. We came up with a hypothesis that broad neutralizing antibodies can be prevented from being made due to immune tolerance.

Now that many antibodies have been made, probably over 100 or so have been reported and many, many more have been isolated, they all have one or more of these traits. Long antibody combining sites, and the importance here is that [00:25:00] Eric Meffre, Michel Nussenzweig, and several others have demonstrated in various models and in humans that long antibody combining site antibodies are culled in the bone marrow and controlled by deletional tolerance mechanisms. Extremely somatically mutated antibodies that are either result of a rare event or jackpot effect and are rare and require rare mutations, or they escape from tolerance controls. They are autoreactive or self-reactive polyreactive antibodies is another term for these antibodies. [00:25:30] While they're an important component, they're not pathogenic always, but these antibodies are frequently culled in the periphery or in the central compartments by tolerance mechanisms.

We decided to make knock-in mice with the broad neutralizing antibody heavy and light chains. This was the first one back in 2009, 2010 by Laurent Verkoczy. (21) We made a mouse with only the broad reactive gp41 membrane-proximal heavy chain. [00:26:00] This was the only heavy chain the mouse could make. We said, "What will the mouse do with it?" As I said earlier with the umutated common ancestor version of this antibody, this was the mature antibody. The mouse deleted 95% of the B cells here with the germline, and more deletion. 5% that survived were anergic or unresponsive. But since this antibody had already gone to the end of the pathway, we could wake these anergic cells up with a strong edge event and make a milligram per mil of antibody in the mouse's peripheral blood. [00:26:30] These antibodies were the mature antibodies and it made the full journey. I showed you on the previous slide that when you start from the unmutated common ancestor, the antibodies tend to get hung up.

Looking at this issue of unusual traits of the antibodies predispose them to be subjected to host tolerance mechanism, there been a host of papers now from our lab, from David Nemazee's lab, Leo Stamatatos working with Michel Nussenzweig with my—Michel's made that also showed deletion [00:27:00] at various stages or energy of broadly neutralizing antibodies getting hung up at some point during their lineage.

Another clue came from us finding a rare individual with HIV infection that also had lupus erythematosus. (22) They're very few of these folks around. We don't understand why. This individual was infected with HIV. She spontaneously controlled the virus and was never on any retroviral treatment. She was diagnosed as [00:27:30] lupus and one of the diagnostic criterias was double-stranded DNA antibody positive. Her plasma was broadly reactive antibody positive, and we so isolated that antibody. It was a CD4 binding site antibody. That neutralizing antibody neutralized 65% of tier two viruses and primary isolates. Then we tested that neutralizing antibody for autoreactivity and it also bound double-stranded DNA. The conclusion from this is that the broadly neutralizing antibodies that SLE autoantibodies can derive from the same pool of B cells.

Then we did a [00:28:00] study of a 51 of our CHAVI cohort that made broadly neutralizing antibodies and 51 at the lowest end of the spectrum that did not make them, and asked what was different about those that made broad neutralizing antibodies and those that didn't? (23) The broad neutralizers made plasma autoantibodies had high levels of T follicular helper cells as Shane Crotty has already shown, has low levels of T regulatory cells and the ones that they had were PD1 positive and exhausted. And this is a phenotype that's [00:28:30] found in SLE. Our conclusion is that HIV infection is why people who are HIV infected make broad neutralizing antibodies, and the virus induces changes in immune control of antibody production in the same pool of cells that autoantibodies are in that allows these unusual broad neutralizing antibodies to be made that have to be this particular characteristic in order to fit into those unusual sites.

What are the ways to make the immunogens better? [00:29:00] Dennis talked about them. I think the field is focused on making stabilized trimers. Then I'll briefly show one slide on what we're thinking with vaccine transient immune modulation. We're making our sequential immunogens, in this case, against the CD4 binding site. One to induce a very potent VRC1-like antibody, one to induce the antibody I've talked about. Here four valent, here five valent and making these as stable trimers, [00:29:30] which is what the negative stained EM showed.

Then the concept of vaccine transient immune modulation. That would be when we'd vaccinate with either inhibitors of immune tolerance to allow the neutralizing antibody precursor to survive and awaken anergic B cells and peripheral immune sites. Which was the question that was talked about before with Bruce with CD8 cells. We don't believe that wholesale breaking of immune tolerance is really feasible [00:30:00] for a vaccine, and so work is ongoing to define the specific pathways of the broad neutralizing antibody lineage development, and to define these in order to develop very specific stimulators of protective antibodies, and specific inhibitors of their controls. What we're talking about are antigen-specific tolerance controls.

In conclusion, the biology of HIV-1, the escape mechanisms of the virus from broad neutralizing antibody induction, and the unusual traits of broad neutralizing antibodies when they are induced [00:30:30] are necessitating new strategies of vaccine design. The new strategies for driving and selecting broad neutralizing lineages to be dominant are B cell lineage design, mapping the virus and antibody during the virus antibody arms race and then recreating this scenario with a vaccine and a strong adjuvant. And then if necessary to transiently and selectively release tolerance and controls of bnAb lineages.

John Mascola—we just recently had our CHAVI eminence and discovery retreat, [00:31:00] where Dennis came and was the kickoff plenary speaker and then John Mascola also gave a plenary talk. At John's talk, he challenged us and made some predictions. And so, to the two beachheads that I've talked about, which I think we and the field are very excited about, John predicted that the next advance is going to be on non-human primates. We'll go from inducing broad neutralizing antibodies that neutralize tier 2 viruses [00:31:30] in the occasional macaque to routinely inducing these. And then the critical advance will be in humans. We'll induce serum neutralizing antibodies against tier 2 primary isolates in humans. The key to this is going to be to move these immunogens into human clinical trials. This virus has evolved on the background of the human immune system. We found that monkeys are not exactly like humans, they don't have the germlines that we need, in most cases in order to test these [00:32:00] concepts. We're having to do this in humans. That means working to get the products made, and then working with Larry Corey to get the clinical trials going. Lots and lots of collaborators, many of whom I've tried to mention. Of course, we're very grateful to our funders who have funded this work over the years. Thanks very much.

[applause]

Harriet Robinson (Moderator): Quick question for Barton. 

Haynes: Robin. [00:32:30]

Robin Weiss: Very nice, Bart. I want to put you on the spot a moment because you've been involved in the analysis of RV 144 and you've got this wonderful CHAVI-ID going. It seems to be the conclusions of the correlates of protection in RV 144 don't include [00:33:00] neutralizing antibodies, but your main CHAVI-ID focus is to induce neutralizing antibodies. What's going to win out in the end?

Bart: It's very interesting. An answer just to the programmatic aspect of it, I would fundamentally our CHAVI-ID is to basically test the hypothesis that sequential immunogens and B cell lineage design will work. In the previous grant, when the 2009 [00:33:30] and the RV 144 came out, MHRP (Military HIV Research Program) and the NIH came and said, "We need you to help do this." We had all the assays, and so we helped organize that effort. We have done some work with immunogen design in that regard. The RV 144 vaccine, I think the field believes now doesn't have anything to do with tier 2 neutralizing antibodies, and rather has to do with Fc-receptor-mediated mechanisms. [00:34:00]

There are a number of people who have animal studies, that in addition to RV 144, that shows some degree of protection. Presumably, all of these studies are related to ADCC, phagocytosis non-tier two neutralizing antibodies. Dennis has shown, we've shown, others have shown that when you compare broad neutralizing antibodies side by side with the ADCC mediating antibodies and all the challenge essays that we have [00:34:30] bnAbs always win out. They're much more potent. An answer to your question, if we can have broad neutralizing antibodies, I think we'd take it and run with it.

The fundamental question is that in the field when challenges occur in humans, are these Fc-receptor-mediated antibodies, if they're broad enough and potent enough, as induced as easy to induce antibodies [00:35:00] those, Joe's weNabs, then—Can we get that above 50%, 60%, 70% protection? That's the fundamental question, I think that Larry Corey is asking what this B5 thing. In the meantime, we're spending the lion's share of our time trying to solve this immunologic problem—I think the structural biology of the envelope has been stunning and we have a really good view of that. Still that BG505 [00:35:30] induce these antibodies against these glycan-bare holes, and not against what appear to be bnAb lineages. We're really thinking that this is-- Now we're deep into the immunology of why these precursors with the long CDR3s are being called down and the precursor pools are small, et cetera. Is that helpful?

Robin: Thank you.

[00:35:53] [END OF AUDIO]

Citations

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Index

• 1.4 Robin Weiss — Retrovirus History and Early Searches for Human Retroviruses
• 1.7 Max Essex — From Feline Leukemia Virus to AIDS in Africa
• 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future
• 2.5 Françoise Barré-Sinoussi — Discovery of HIV
• 4.0.1 Jeffrey Lifson — Session 4, Introduction 1
• 4.3 Beatrice Hahn — Apes to Humans: The Origin of HIV
• 6.2 Dennis Burton — How Does HIV Evade the Antibody Response?
• 6.3 Bruce Walker — Role of T Cells in Controlling HIV Infection
• 6.5 Emilio Emini — Issues in HIV Vaccine Development: Will the Future be any Easier than the Past?
• 8.2 David Ho — Unraveling of HIV Dynamics In Vivo
• adjuvant
• antibody test, antigen test, serological test, serology
• antibody, immunoglobulin (Ig)
• arms race
• B cell
• Bigner, Darell D.
• blood — banks, donors, plasma, screening, transfusions, clotting factors (factor VIII), PBMCs
• bnAb (broadly neutralizing HIV-1 antibody)
• Bolognesi, Dani P.
• bone marrow
• canarypox virus (CNPV)
• cell culture, tissue culture, immortalized cell line
• centrifuge
• Chen, Bing
• chimpanzee (Pan troglodytes)
• clinical trials (phases of clinical research)
• Cohen, Myron S. "Mike" (b. 1950)
• cohort study
• Cold Spring Harbor Laboratory (CSHL)
• Corey, Lawrence "Larry" (b. 1947)
• Crotty, Shane
• cytomegalovirus (CMV)
• diagram
• Duke University, Duke University School of Medicine
• early theories of AIDS etiology
• Gazdar, Adi F. (1937–2018)
• Goudsmit, Jaap (b. 1951)
• gp120
• hemophilia
• HIV vaccine
• HIV Vaccine Trials Network (HVTN)
• HTLV (human T-lymphotropic virus)
• HuT-102 cell line
• immunology
• infectious disease (medical specialty)
• Investigational New Drug (IND)
• Japan
• Korber, Bette
• Kwong, Peter D.
• lab safety, biosafety levels, safety protocol
• Lancet (journal)
• Los Alamos National Laboratory
• lupus
• lymphatic system (lymph, lymph nodes, etc.)
• macaque, rhesus macaque
• major histocompatibility complex (MHC)
• Malawi
• Mascola, John R.
• Matthews, Thomas J.
• medical school, residency, and fellowship
• Meffre, Eric
• mice
• microscope — electron and optical
• Military HIV Research Program (MHRP)
• models (model systems, model organisms, modeling)
• Moore, John P.
• Myers, Gerry
• National Cancer Institute (NCI)
• National Institutes of Health (NIH)
• New England Journal of Medicine (NEJM)
• NIH Vaccine Research Center (VRC)
• non-human primates
• Nussenzweig, Michel C.
• Palker, Thomas J.
• Picker, Louis
• Popovic, Mikulas
• Putney, Scott D.
• radionuclide, radiolabeling, radioactive tracer
• Repligen
• Robb, Merlin L.
• Robert-Guroff, Marjorie
• RV 144 (2003–2009)
• Sanders, Rogier W.
• Saxinger, W. Carl
• Scearce, Richard
• Schief, William R.
• scientific competition and collaboration
• Scripps Research Institute (TSRI)
• sensitivity and specificity; false positive, false negative; biological specificity
  specimen exchange
• Session 6: Immunology and Prevention
• Session 7: Prospects for an HIV Vaccine
• South Africa
• structural biology
• Thailand
• Verkoczy, Laurent
• White, Gilbert, II
• Wyeth (1860–2009)