Session 7: Prospects for an HIV Vaccine

Panel participants:

1. Glenda Gray (b. 1962, moderator) is a South African AIDS expert and pediatrician, and a member of Treatment Action Campaign
2. Genoveffa "Veffa" Francini is a hematologist and virologist at the National Cancer Institute
3. Susan Zolla-Pazner is an infectious disease expert, microbiologist, and immunochemist at Mount Sinai Hospital, New York, and was one of the first investigators of the AIDS outbreak in New York City in 1981
4. Lawrence "Larry" Corey (b. 1947) is former director of the AIDS Clinical Trials Group, is a founding director and PI with the HIV Vaccine Trials Network and was president of the Fred Hutchinson Cancer Research Center from 2010 to 2015
5. Dan Barouch is an immunologist and virologist at Harvard Medical School and the Ragon Institute of Massachusetts General Hospital

Glenda Grey: [00:00:00] Good afternoon. Bob. Can everyone be seated? Bob is trying to convince the panel that he has enough women participating. We do have women on the panel, which is a good thing. [00:00:30] Bob, can you take a seat? We do have women on the panel. Thank you for inviting so many women to participate on this panel. This is the last part of the afternoon session. It is the duty of the panel to be [00:01:00] provocative and push boundaries and answer and reflect and give some historical and personal perspective as well as scientific perspective.

I wanted to just contextualize why medical interventions are important. I think Emilio [Emini] started to show why it's important to scale up interventions. This slide just shows you [00:01:30] the life expectancy of South Africans from 2000 to 2014. You can see that HIV made a huge dramatic drop in life expectancy in South Africans and this was mostly evident from 2000 to 2006 where we saw a huge decline in mortality in South Africa. You can see, we started to roll out ARVs (antiretrovirals), [00:02:00] the South African government did the investment case and put aside money from our own coffers to roll out the program. We have the largest ARV program worldwide, and largely funded by our own fiscals. You can see that with the rollout of ARVs in South Africa, we've increased life expectancy by nine years, which is quite dramatic. You usually need a lot of development [00:02:30] to try and achieve that kind of thing. By 2014, our life expectancy has increased, for men to 60 and women to 65 years. You can see this is quite phenomenal. This is all because of the rollout of ARVs and response by the South African government to the program post [Thabo] Mbeki's denialism.

Emilio also mentioned the issue around PMTCT (prevention of mother-to-child transmission) and how [00:03:00] this also has a dramatic impact. You can see in South Africa, this is very evident that rolling out PMTCT and putting children onto therapy really dramatically from about 2005, you started to see a decline in the under five and infant mortality rate. (1) This is all largely because of PMTCT, and as a direct reason why we need to make sure that we scale up interventions, because they really, at a population level, [00:03:30] change the lives of ordinary citizens. This is very important.

Also important is to check and see how our mortality is changing in South Africa. We have a quadruple burden of disease, communicable diseases, TB and HIV, non-communicable diseases, maternal and child health issues and injuries. This just shows you how ARVs have changed the profile of mortality in South Africa. This is just [00:04:00] a little introduction. You can put the lights back on to show why it is important to rollout interventions, why it's important to get interventions into humans so that we can see how this affects people on the ground.

We've asked each person on the panel to address certain issues, Veffa is going to go first. I did put it to her to tell us why non-human primate [00:04:30] models are important, what's good and bad about them and why should we as clinicians who do clinical research, care about what we see in animals and whether this really is an important aspect and whether there is utility? It seems that animal models only have utility when you look back from human data and whether it ever has utility in a prospective fashion. We are being provocative and I have [00:05:00] put her on the spot and she can now respond.

Genoveffa Franchini: Okay, I think I have this. Thank you. Historically, I started to work on the HIV vaccine together with Bob [Gallo], early on in the mid-'80s. We started really to look at different possibility of different possible approaches—No, no, it'll be very fast so— [crosstalk]

Glenda: I'm timing her.

Bob Gallo: [unintelligible 00:05:26]—spent a long time looking at—

Genoveffa: No, the point is that [00:05:30] we started—we tried different approaches. Then I continue to do that. One thing that I learned trying to work on vaccine development for HIV is that you've got to be resilient, don't give up and don't give up. Then also, what I learned is that we tend as a group of scientists sometimes to make assumption, and sometimes they're wrong. An example of this was, if [00:06:00] you remember is for the RV 144 [study] (2003–2009), from which we did most of the preclinical studies in macaques using different models and, of course, you can get some answers from some models and some other answer from other models.

I remember the letter that was written, signed by 23 people including you [points at Bob Gallo] saying that RV 144 one should really be terminated when it was already started. (2) It should be interrupted, [00:06:30] because probably it was unlikely—Hold on, because it was unlikely to really give any results. Obviously, I organized together with Marta Marthas a letter saying that we should actually continue. (3) The reason why we did that was because, at the same time, we had done some studies in the non-primates in neonates, using a low dose of virus as a challenge, which I think was the first time that really showed that you can protect now against infection. [00:07:00] This I think prompted people like us to continue to really try to investigate that.

Indeed, being able to recapitulate again recently these results, already twice in two different animal models, that really convinced me that that's probably a real result and therefore, I think we should be a little bit more humble. Yes, I'm sure the neutralizing antibody are very important obviously, there are plenty of [00:07:30] evidence, people have shown early on like Ruth [Ruprecht] and other people that in the non-human primates, again, that natural antibodies are very important, but they are difficult to be elicited. Yet we have another possible mechanism, which is V2, antibody to V2 that we don't understand and she (Susan Zolla-Pazner) will talk more about that. I think we have the duty really to try to understand that non-human primates will be instrumental for that. This is one very important area I think of research that we need to pursue.

The second one [00:08:00] goes back to the Hippocratic oath that we take when we finish up medical school is that don't harm. Now we are starting to realize—and your institute was among the first to really highlight the importance of the CD4 [unintelligible 00:08:19] vaccination is a possible target. Our data suggests that that's really the case. There are different approaches that can actually induce more of those.

Glenda: [00:08:30] You have one minute left.

Genoveffa: For example, a recent study that we published on the use of MA59, which is going to be used in South Africa indicated that perhaps to MA59 might induce this kind of cells as well as the alum, but much more perhaps the MA59. It could be that what we see as a vaccine effect is a balance between protective responses and responses that it might actually enhance.

Although I understand what Emilio [Emini] was [00:09:00] saying before, of course, it's a given that we have to do good experiment by controlling humans but I think also we should really be careful of what we do and think carefully and try to avoid to do any harm.

Glenda: Veffa's point, is it adjuvant or is it adjuvant, and is that the key to understanding the efficacy in RV 144 as compared to P5, but we'll come back to that later. Because we didn't allow for ongoing [00:09:30] discussion. Now Susie is a woman that spends her whole life interested in V3, V1, V2 when everybody else thought she was completely mashugana. Now she's going to give us a little bit of her history and how come she became to be the poster girl of V2.

Susan Zolla-Pazner: Thank you. I'm going to cover 50 years in five minutes. [00:10:00] I have been interested in antibodies since my first immunology course at Stanford. I was an immunochemist when I was studying for my PhD, and was interested in the immunosuppression of plasmacytomas and myeloma when I was a postdoc at NYU. I’ve been interested in antibodies for all of my life and was working on myeloma in 1981 when I got this telephone call from Alvin Friedman-Kien [00:10:30] asking me to look at these first patients with Kaposi’s sarcoma.

At the same time that we were working up these very first patients and seeing that there were essentially no T4 cells there, I was fascinated by the hypergammaglobulinemia in these patients. After the immunologic abnormalities were pretty established in these patients, I began to think that what was important was [00:11:00] to look at the antibodies that the patients were making. We started making human monoclonal antibodies. This is in the mid-1980s, and believe me, it was not easy to make human monoclonal antibodies in the mid-1980s. We were making antibodies to p24 and to gp41. This was about the same time as several people have mentioned today, that the V3 loop identified [00:11:30] as the principal neutralizing domain.

I started looking at the monoclonal antibodies to these three. Indeed, they were doing a great job of neutralizing the only viruses we had to work with in those days, which were the T cell-line adapted viruses. That was great until the early '90s when it became evident that these same antibodies were doing such a great job in the T cell line adapted viruses were really [00:12:00] not working very well in the primary isolates.

Why did I continue to look at V3 antibodies for a very long period of time? It was because these monoclonal antibodies that these patients we were making were cross-reacting with V3 peptides and gp120s from all clades of viruses as they became available. Having been trying trenches in immunochemist, [00:12:30] I wanted to understand how it was that a monoclonal antibody to a variable region could be so cross-reactive. I spent probably 10 years trying to understand this. Eventually came to the understanding as structural studies helped that V3 is variable in terms of amino acids but has a conserved structure, and [00:13:00] it’s that conserved structure that antibodies are recognizing. And it has a conserved structure because it’s involved with interacting with the co-receptors, and you had to maintain a structure in order to maintain the function. That structure was what was being recognized by these V3 antibodies.

Then one day it occurred to me, “Well, if that’s true for V3, what about V1 [00:13:30] and V2?” We started studying V1 and V2 and finding very much the same thing, that V1 and V2 are variable in terms of amino acids, and they are in fact much more variable in terms of length since it has insertions and deletions at particular points. But we were finding, and we had known since 1994 that V2 antibodies were also extremely cross-reactive. And so we began looking at the structure-function relationships and finding [00:14:00] the same thing in V1 and V2 that we had found in V3.

At this point, RV144 came along. Soon after the announcement of the RV144 results in 2009, (4) Bart [Haynes] and several other people called a meeting, I think the best meeting that I’ve ever attended, because everybody who was competing with everybody else came into the room to [00:14:30] try and figure out how we could understand how it was that we had gotten at least partial efficacy with RV 144.

To their credit, Jerome [Kim] and Nelson [Michael] announced and said, “Anybody who has a good idea, write a one-page proposal, submit it to us and you’ll probably get disbursements you want.” I submitted a proposal saying, “I would like to look at antibodies to V3 and to V1 and V2, because I knew that there was a conserved [00:15:00] structure there.” Needless to say, and as Glenda has mentioned, everybody thought that I was totally nuts all through this period of time, because it’s totally counter-intuitive to say that you want an antibody to a variable region that is going to protect against all the different strains in the world. But the cross-reactivity in the antibodies kept bringing me back to the idea that these variable loops were important.

Glenda: I’m going to give you one minute.

Susan: [00:15:30] Okay. We submitted the proposal. We did the studies. We sent the V1, V2, V3 antibody levels to Seattle. This was just before the meeting in Thailand. We were supposed to have a conference call to talk about the results. I was on vacation and I got a call from Bart. I was in a cabin in Woodstock, New York in the middle of [00:16:00] an electrical storm, I could hardly hear him over the telephone. He told me that the level of V2 antibodies were the only independent correlate of reduced infection.

I was utterly astonished. I was not astonished that there was a correlate, I was astonished that it was the only independent correlate. But I have to tell you, I don’t think it’s the only independent correlate. It’s the [00:16:30] only one that we measured. It’s the only one that we knew to measure. So I think antibodies to V2 were extremely important. I don’t think that they are going to be, and I’ve never thought that they’re going to be the only antibodies that are important.

I'd like to end by just putting in one controversial issue for discussion. I’m sorry that Bart isn’t here. It has to do with Robin [Weiss'] question, which is: Why is it that, since RV 144, which is the only human trial [00:17:00] that has given us an indication of a correlate of immune protection, why is it that RV 144 results with V2 are more or less been ignored to the priority of looking for and trying to elicit broadly neutralizing antibodies for which we have no precedent in the immunologic literature for being able to do?

Glenda: Sorry about that.

Susan: [laughs]

Glenda: [00:17:30] Any time you can separate the men from the boys is when you get into clinical trials. Larry in the early 2000s had a name. It was Mr. Dead, for a decade. There was a time [laughs] I joined the HVTN, and he had decided that the AVAC program had not met the immunological bar [00:18:00] and that if we didn’t do the Merck study (STEP study, 2004–2011), we would be dead for a decade. I’m going to now ask Larry to give his insight, and that the real thing that is to get into humans. Even if we find other things, I think it’s important to—like Emilio said, to make sure we get into humans for the ultimate understanding of our vaccines.

Larry Corey: Well, [coughs] she’s forcing [00:18:30] me into the hard part early. But I was going to at least give a quick overview of how I got into this field of HIV vaccines. I think my career is a little bit about—I'll call it a tale of two careers, the best of times, the antiviral times, I won’t say the worst of times. I'll just say, a much more difficult of times, which is the vaccine times. I was 29 years old when [00:19:00] Burroughs-Wellcome and Trudy Elion (1918–1999) came to me in Seattle and dropped this drug called the aciclovir in my lab. We rapidly put it through its paces. We were essentially the first person to give oral antiviral to healthy people.

One of my older colleagues by the name of Bernard Roizman (b. 1929) said that was the worst thing that I was ever going to do and I was going to kill people. It’s actually the best thing that I ever did so far, and that it opened up the entire [00:19:30] field of antivirals. With half the people in this room, Doug [Richman] and Paul [Volberding] and Tom Merigan (b. 1934) and Marty [St. Clair] went onto start the ACTG (AIDS Clinical Trials Group). I think Marty after about six months of been the Head of the ACTG approached me and said, “You should have this booby prize of being the first Head of the ACTG.”

That was pretty tumultuous time, shall we say. We did that, and—but the wonderful thing is that we actually really created the roadmap on how to license and how to develop antiviral drugs. At that point in time, for me, we had created that roadmap and it was time to move on. Mark [Harrington] actually was partially helpful to that, the sense of how difficult it was. [00:20:30] I think the hardest thing I had in the ACTG was getting the 076 trial (1991–1994) started. I'm not on that paper, but it was probably the thing I did most. (5) I made the Faustian bargain with the NIH that I would serve as the ACTG head for a year, if I could split off the obstetricians and the pediatricians, we were all together in the ACTG. I came up with that idea. That was the way to separate the advocacy for the babies from the African American women in Brooklyn, from [00:21:00] the MSM advocates, who felt that AZT was poison. It actually was the effective way to do it, and we got the 076 trial done.

That exhausted me and I went on sabbatical. Maurice Hilleman (1919–2005) had approached me about taking his glycoprotein vaccine from Merck and put it into people for HSV2. That got me into vaccines and immunology, and I started looking [00:21:30] at HIV vaccines and became part of the AVG.

That was a time where the government had these two separate organizations, but these gp120s made antibody and antibody was how HIV was diagnosed. In Africa, we were really having a problem getting any study through because, in fact, at that point in time, HIV vaccine study had to clear most African countries by going to parliament. That was going nowhere, and so, how would we—[00:22:00] You couldn't just drop a vaccine on a country that never heard about it. The goal was how to integrate this. And that was a really interesting career for me, because, I'm a Detroit boy like Sam Broder from the suburban Detroit, and I had not been to Africa yet. It was like, "Oh, gee, how do I do this? How do you become a global health maven very quickly?"

That was actually, not hard, was actually just to listen to people, [00:22:30] identify talent, listen to them, set up an organization that empowered the investigators in country. Glenda and Salim [Abdool Karim] are just one of our just great personifications of just that philosophy. We have, I think built a model organization and that's not me alone.

Glenda: One minute, can you skip to the real stuff?

Larry: Okay, get to the real point. The real story, [00:23:00] I think the real story has—maybe we should allow it to be, is that we have built the infrastructure to be able to test vaccines in humans. Now, when I look back at the field, I think that we can look at the—what I'll call the stages and the cycle of what's going on in HIV vaccines. And I will say to you, I think that part of the contrast I see between the antiviral field and the vaccine field [00:23:30] is the lack of risk taking. I don't mean risk taking that you're giving products that are risky to people. It's just the lack of risk taking in actually doing the definitive studies to actually decide how do this, and the very prolonged preclinical, pubescent, and conservativism that has permeated I think the entire vaccine field, but certainly the HIV vaccine field. [00:24:00] 

I think you also can see that we've been plagued a little bit by, what I will say is periods of time in which we listened to—almost the polemics of the preclinical work and not actually get to the definitive experiments. We've gone from G recombinant proteins, gp120 and the frustration of the vaccine failures, never really dissecting that. That's a very important thing because, no [00:24:30] dissection of why they failed ever occurred actually until actually the public sector got involved.

We then moved including me, into the belief that CD8 T cells in control of viremia would be an easier target for HIV vaccines. It turns out that actually acquisition is the better target and actually is maybe more approachable than actually reducing viremia.

If I look back at my own mistakes [00:25:00] in this field is that very first vaccine study I did was with recombinant vaccinia with a gp160 boost. We didn't get CDA T cells, but we got great CD4 responses and good binding antibodies. We would have had V1, V2 antibody and maybe we wouldn't be up here bemoaning the issue. We would actually be up here with much more success if we actually had not dropped that approach. We ended up dropping that approach and [00:25:30] I look back with remorse about that. Then we went from the, "It's all the vector"—and that hasn't been a bad thing because all the work that the vectors were doing in the HIV field have helped Ebola and Zika, and it's created the platform for those other things, because DNA, VSV, ADs, MVAs, foul packs, Al vac, [00:26:00] they all went through the HVTN first. Those platforms actually have paid off as it is, but I'm going to come back to say, it's okay.

Glenda: I'm giving you a little bit of less—

Larry: All right. To say that we went from the vectors, we looked for strong vectors and we're back to RV144, which I think the Veffa has brought out that in many respects. I'll maintain that I do believe about the correlates itself with RV144. Alvac is what I will call [00:26:30] the quiet factor. But is that insert, it's the 8244 insert that opened up the V1, V2 loop more than any other thing that we'd ever had, and maybe uniquely even that has created this opportunity that we picked up only in a human clinical efficacy trial. I think that it is essentially accepting what Emilio said, that we have to go into humans and do efficacy trials. We do elegant measurements. [00:27:00] We can measure all these wonderful things elegantly by the labs that we have but we have no sense of the biological meaning, what they mean until you actually go into humans in an efficacy trial.

Glenda: I'm going to cut you off. It seems that women are much more succinct than men.

[laughter]

Okay. I did give you some latitude and now we're going to have Dan, Dan is going to have some slides. I'm also going to ask Harriet [00:27:30] just to say one word afterwards. I'll allow after Harriet's gone, just allow a minute to rebuttal from each of the panel and then we we'll open it up to the audience.

Dan Barouch: So Bruce [Walker], Bob, and Glenda  asked me to say a few words about our personal perspective of our vaccine candidate that is [00:28:00] now being evaluated in clinical trials. This story actually began in 2004, it did not begin in 1981. I think I was still in kindergarten in 1981, but in 2004, I was no longer in kindergarten. I actually had finished my infectious disease fellowship training, clinical training as well as a research fellowship with Norm Letvin (1949–2012).

I started my own independent lab in 2004 and I was looking for a project to do. One of the first projects we started doing was to look at alternative CEO types of Ad (adenovirus) vectors [00:28:30] which were initially developed to circumvent the problem of high baseline Ad5 neutralizing antibody titers in human populations. In the first few years, it was a very crowded and busy field, with many collaborators and competitors alike. There was a general perspective that Ad5 was such a potent vector that this would all be fairly irrelevant in the end, anyway.

This all changed completely in 2007 when in the STEP study (2004–2011), an increased HIV acquisition was noted that it really led to a [00:29:00] reevaluation of a scientific basis of Ad vectors. Not only Ad5, but really all Ad vectors. Then, were some very difficult times where we really did some soul searching and tried to decide whether this program of alternative Ad vectors was really worth pursuing or not, or whether it was viable to pursue or whether it was wise to pursue. In 2007, 2008, it was not completely clear even to our team that this was something that we wanted to do or could do. [00:29:30]

But actually through constant NIH support and the support of many friends and colleagues in the field, including quite a number of people here in this room, then we did, pursue this program. We continued despite a lot of uncertainty, but we really focused—we really shifted the focus to studying basic vector biology. Perhaps one concept that has emerged from this is that vectors actually have a lot of biology in their own right, they are not simply blind delivery vehicles for interesting [00:30:00] antigens, but each one actually is different and actually very different from each other. Comparing Ad5 with other Ad vectors and certainly pox vectors and other classes, they have differences in virology, innate immunity, adaptive immune phenotypes. We looked at the specific question of T cell activation trafficking as well as a substantial number of clinical studies. Over the last four or five years, then Ad26 really has emerged as a lead alternative as Ad serotype vector actually, not only for HIV, but for other pathogens as well. [00:30:30] Through a series of NHP protection studies and human immunogenicity studies, then this is now moving forward.

In 2004 at the Stardust project is when we received our first NIH grant to develop actually not only Ad26 but a whole panel of Ad vectors, as well as chimeric Ad vectors as a partnership between BIDMC (Beth Israel Deaconess Medical Center) and a small biotech company in Holland called Crucell. We actually took three of these [00:31:00] into Phase I trials Ad26, Ad35, and a chimeric Ad5/HVR48 vector. This was after a series of vector evaluations in mice and monkeys to look at immunogenicity seroprevalence studies and also very importantly basic biology studies to make sure that we were not just simply moving different varieties of the same thing forward, but these actually all had very independent and discrete properties.

The first in human Ad26 prototype study Phase I study was launched in 2008, essentially, in the wake of [00:31:30] the findings from the STEP study, which was interesting in its own right. In 2010—actually, a couple years before 2010, we started working with Betty Korber as well as Norm Letvin and Bart Haynes on looking at a series of inserts to put into the vectors called mosaic antigens. Then through a series of NHP protection studies, we showed partial protective efficacy by Ad26 when boosted with MVA, in collaboration with Nelson Michael and MHRP [00:32:00] against both SIVmac and SHIV challenges.

Then through a series of discussions by a number of folks in the field, including Larry Corey and others, we decided to include purified proteins to try to boost antibody responses which appear to be the correlate of protection in the Ad26/MVA studies. Those protection studies then showed improved protection against both SIV and SHIV. Last year, Janssen, which had acquired Crucell at that time, then made a decision to sponsor [00:32:30] clinical development of our Ad26 envelope mosaic HIV vaccine and formed a consortium of partners to do so. (6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

In the next few months and through to 2017 will be Phase IIA clinical data and a Go/No-Go decision as to whether a Phase IIB efficacy study will begin. Do I have another minute, Glenda?

Glenda: You have one minute.

Dan: Okay. I think many people know that protection data here in SIV showing partial protective efficacy, a parallel study against a SHIV-SF162P3, [00:33:01] which is not yet published. The vaccine that's moving forward is Ad26 vector expressing mosaic gag-pol-env antigens and boosting with the vector combined with purified gp140 envelope proteins, which does not raise neutralizing antibodies but does raise other functional antibodies. This is the consortium of partners moving this forward. If things work well, then HVTN will start a study, perhaps approximately a year from now [00:33:30] to look at efficacy.

Glenda: It's a great timeline. Harriet, I'm going to ask you to say one minute then I'm going to allow the two women to just have a few more minutes because I think that they were disadvantaged. That's because we have a woman chairman.

Harriet Robinson: I'm going to be informational in my one minute. We've been working on a DNA/MVA virus-like particle expressing [00:34:00] vaccine. The DNA expresses virus-like particles that display gp160, and the MVA display expresses virus-like particles that display gp150. At this point, we've been in about 500 humans. We've made a detour express testing GM-CSF as an adjuvant, but we're going on with the un-adjuvanted form and HVTN 114 will start December [00:34:30] 1st, is scheduled this year, which is going to look at in AIDSVAX protein boost of our DNA/MVA, and we're going to do the MVA plus AIDSVAX, AIDSVAX alone and MVA alone. Then we are currently manufacturing to take the DNA/MVA in a DNA/DNA zero in two months MVA for in six months in 10 months. The MVA will either be [00:35:00] delivered alone or with a bivalent protein boost. Our bivalent boost will be a Bart Haynes transmitted founder gp120, and a Profectus Institute of Human Virology, FLSC. We've chosen those two have the transmitted founder to presumably boost the native elements that we've primed with our VLP and the FLSC will display the CD4 [00:35:30] induced form of gp120. And in our Phase I clinical trial, we'll test the MVA + B63 that's a transmitted founder alone and MVA + FLC alone and we'll do the two together so that we can get a good sense of how these proteins are contributing to our antibody response.

Glenda: The important thing is to—[crosstalk]

Harriet: We are going to go with now hydrogel adjuvant [00:36:00] with the protein.

Glenda: The important thing is to keep the pipeline going, and I'm glad to know that the pipeline is awake, and we're moving forward. I'm going to give you a chance after hearing what everybody had to say, a chance to put forward a statement or rebuttal or something that provocative thing that would keep the audience engaged for another 20 minutes. [00:36:30]

Veffa: Another 20 minutes, okay. Actually I would like to ask, Larry, what was the—so the data on the difference in non-human primates between alum (aluminum hydroxide adjuvant) and MF59 were actually transmitted by me to the P5 almost four years ago. Obviously, there was a lot of resistance at the beginning—that we degraded the protein so forth, I don't go to [00:37:00] the details of that, but the question that I have is, what was actually the mechanism that led to not consider the possibility of doing a better design trial in which you actually used in parallel also the alum hydrogel. Because that would really be a study that would help us because, as we discussed today, if the MF59 is doing the same thing that is doing in macaques [00:37:30] then you're going to end up having no protection and you don't know why and you did not do the Alvac alum control in South Africa.

Glenda: You're saying it's all about the adjuvant. It's not about anything else but adjuvant.

Veffa: I'm making an hypothesis that it is—in our studies, we had exactly the same vaccine. The only thing that was different was the adjuvant. We tested this hypothesis in human primate.

Larry: [00:38:00] I'll take the bite on this, the bait or whatever. I'm going to say both. We'll do a little fact-checking. Number one is, we have different data. There's the non-human—It's not like we actually ignored it. We actually have spent a lot of time on it. [00:38:30] Certainly, after your data became available, actually, there was commissioned a study to actually take the proteins that were going forward with in South Africa were made through clade C. One of them was a transmitted founder virus, and the other one is an older primary isolate. It has been put into MF59 because durability was felt to be a problem as it related to almost all the correlates that [00:39:00] were associated with RV144. A SHIV challenge study has been done with the clade C proteins associated, that are being used in South Africa between MF59 and alum. Actually, that study actually shows better protection with MF59, with the actual vaccine.

Now we then can get into the issue of the SHIV model versus the SIVmac239 model and then it becomes an interesting issue. What's the structure of the challenge [00:39:30] virus, which is the virulence of the challenge virus is either really the predictive model for non-neutralizing antibodies? I'll just say that I think that that's an unresolved area where people will have—of good faith and reasonable scientific acumen—will have somewhat different answers as to what are the factors. Yes, you have one model that says that alum [00:40:00] might be better than MF59. We have another model that actually says that MF59 is better than alum.

We actually have, probably I guess to say to you, an overriding issue to say that 30% is not good enough and we need durability. If there's something that is important to a vaccine on a population basis, its durability. I'd love to get to that question, I want to get to the durability question. First, [00:40:30] you need efficacy, then we can get some durability. But the reason we did what we did was A, we're trying to construct a vaccine that would be better and B, durability is an important part of it.

Now, if there is a mistake being made in the breadth of the immune response, with the type of immune response that's actually going to be handled by the adjuvant and not the protein—you know, we are looking at that now, we actually are looking at [00:41:00] the linear peptides in humans at the phase I trials between the clade C protein and comparing that to the RV 144.

I guess I'll just say, in fact-checking, we have a Heisenberg uncertainty principle here. I think we're taking the tactic as Emilio has outlined that we're going to do the experiment and do it as well as we can and it has been considered. I'll also [00:41:30] say that there are always ways of redesigning trials, as well as adding arms and doing other kinds, or starting another trial if it turns out that the evidence becomes overwhelming that it's resolved one way or the other thing. That's my answer.

Glenda: Just to say that these trials are monitored. We have sequential monitoring, we have an early look for harm, and so the participants are always protected. As we've seen, the STEP and [unintelligible], we're not scared to [00:42:00] pull the plug on studies and we will always make sure that the sequential monitoring takes into account both both harm and lack of efficacy.

Larry: And I think the worst thing to happen is to not do anything. It is just to continue to equivocate.

Glenda: We can't just sit around. We were already sitting around since 2009. We do need to get into advanced clinical development, at any time we see things. These studies are critical [00:42:30] to help us understand vaccine design and to understand what does work, so I do think, even though these are very expensive studies, I do think there's a huge amount of importance about understanding what happens in efficacy studies.

Veffa: Can I just say one thing only, is that the SHIV challenge that you are referring to, is a tier-1 virus, easy to neutralize, and the correlate is neutralization. [00:43:00] It's pretty clear that is a different kind of model. The second question that I have for you is that what is the evidence that actually MF59 is increasing the durability of the antibody response?

Glenda: We're going to ask Susie, to say something and then we're going to open up to—I see, Bob is jumping up and down. He's got, want to say something about the MF59, but let Susie and [00:43:30] Dan respond, and then we'll open up to the floor.

Susan: I have two things to say. One is that since you're asking us to rebut something that was said, I just want to say that I think it's a really low blow for Dan to tell us that he was in kindergarten—[laughter]—Really, Dan? Sadly true. [00:44:00] 

I would like to refer to something that the Larry said about the vaccine field being risk-averse, and us not plowing ahead with enough energy. I've certainly lived, as we've talked about, in an environment of skepticism of my work. And I find I'm living in it again, because [00:44:30] despite the fact that the V2 correlate has been confirmed in many different labs using RV 144 specimens, it's been confirmed in SIV model and it's been confirmed in SHIV model, there is still a lot of skepticism about whether RV144 protection was real or not. It was reflected by [00:45:00] Emilio's comment today. He said, "Well, RV144, if it's real." We won't know unless it's reproduced.

I worry a great deal about what's going, the new trial in South Africa. I hope that it shows efficacy. If it doesn't, I think people are going to say, "Oh, well, you see RV144 really didn't work." Almost everything that [00:45:30] was used in Thailand for the vaccine in 144 is different in the new trial. If it works, that's great. If it doesn't work, negative data doesn't tell us. We'll get a lot of information out of it, but it doesn't tell us that RV 144 did or didn't work.

Then in order to start some of the discussion, I want to go back to the point that I made [00:46:00] at the end of my remarks which has to do with having a much more aggressive follow up of RV 144, and the correlates that we did find—the ADCC, IgG3 antibodies, V2 specificities—versus the approach, which is getting the lion's share of the money and the attention, which is inducing broadly-neutralizing antibodies, [00:46:30] which no human vaccine has achieved in terms of the degree of somatic hypermutation that is necessary in terms of guiding the immune response from germline to these extremely mutated antibodies. And so I would like to see more of a balance in the field between innovative, maybe unusual [00:47:00] approaches that people are skeptical of, and this sort of almost fashion statement that because we have such gorgeous, potent, broad, neutralizing monoclonal antibodies that we can achieve them with a vaccine.

Larry: I'll just like to comment that I think the HVTN's portfolio at this point in time [00:47:30] is pretty equally balanced between the two concepts. What we call the 702 trial that Glenda is the head of, and starting in about 10 days, is the ALVAC gp120 non-neutralizing antibody V1/V2, non-neutralizing concept. As is the correlate stuff that comes from Dan's work. It's really non-neutralizing antibodies. It's proven very nicely that the protein boost is required. [00:48:00] That also has alum, so we have an MF59 versus alum. Yes, the vectors are different, but it is a non-neutralizing approach and that is going to start a year from now.

Then we have this enormous monoclonal antibody study in which we are giving IVV RC01 at two different doses, that is giving from 300 micrograms peak titers to the lower doses, 100 micrograms peak titers, every eight weeks [00:48:30] for 10 doses, for a 20 month period of time, to show the concept that neutralization is actually going to be effective, as well as what level of neutralization, both from a micrograms of antibody, as well as a neutralizing antibody activity, to actually prove the conceptual framework of this.

These are, frankly from a monetary point of view, almost equally balanced 50/50 [00:49:00] because of the the size and there's more cost than doing the IV monoclonal. I think we are at a place where we are finally taking the risks as a field to actually define which of these approaches, and will it be one way or the other? They're not mutually exclusive. It will be very interesting to see what happens if—I think if we can't protect [00:49:30]—

Glenda: I want to ask Dan to say something, and then I'll have to do the audience.

Dan: I'll reply to a few pieces of discussion, as well as a lunchtime, spirited discussion that several of us had about what's the role or predictability of the preclinical model. As someone with one foot in the preclinical world and one foot in the clinical world, having done dozens of large NHP challenge studies [00:50:00] I think that fundamentally, I really come down on the side of what Emilio, Glenda, and Larry said that we need to do the clinical trials.I think the NHP model is incredibly informative, and therefore very important, and probably in at least many cases, the NHP immunogenicity data, I think often predicts human immunogenicity data. But fundamentally, although the [00:50:30] NHP efficacy data is promising and encouraging. Then we simply, at this point in time, we don't know whether or not that will translate into human protection. And if so, whether low-dose, medium-dose, high-dose challenge SIV, SHIV, different clonal variants of challenge stocks, which one of those models is the most protective—sorry, is the most predictive. I think we really need [00:51:00] to have more concepts being brought into clinical efficacy trials, which will not only drive the field forward, but I think every clinical efficacy trial has also resulted in improvement of the preclinical models as well.

Glenda: I'm standing between you and one but I do want to—the audience has seen has been very attentive, so I do want some interaction from the audience. I think Bob's going to [00:51:30] be the first person.

Bob Gallo: This is not in disagreement or necessarily in agreement, but just want to say that for approximately 20 years, we've talked about the importance of the durability of antibodies. It's somewhat gratifying to see that within the past one or two years, it's being recognized. In the past five years, we've been writing about it, but at the same time, as the perspective [00:52:00] we wrote in PNAS says, "Durability and immune balance." Whether it's SIV, or SHIV, either SHIV or SIV, it didn't matter. We've got a small little window. We call it this real hotspot, that if we make no T cell activation, we don't get any help, we don't get the right antibodies, we don't get any protection. But if we edge over a little too much—you won't know it in man, you may have the world's best vaccine, [00:52:30] we don't get any efficacy at all. I am sure that's going to apply to humans too, and I feel sure that's what happened with adenovirus, and I said it to you, one night long ago. If we activate too much—I don't know anything about these adjuvants, but if you're moving to an adjuvant and you don't control serious activation, you may have a good vaccine and you'll never know about it.

I agree with both the comments. I agree with you that you that you are [00:53:00] covering it. You do have breadth but make sure you don't leave out full length single chain, right? You do have breadth in that program but I wanted to agree with Veffa and Sue, that I think everybody wants—the field is geared too much towards, "We've got to have the best neutralizing antibodies and we got to get there." Yes, maybe, but if you put all the eggs in that basket, you may be going right down a manhole with all the eggs in the basket that are called neutralizing antibodies. [00:53:30] We all wanted those antibodies. We all believe that's the best, but strangely, I don't understand it, we have seen levels of neutralizing antibodies that are above the levels that are supposed to protect that are in the literature, and we don't get protection. They don't correlate with protection. They correlated with Fc-mediated effector function. I don't understand, but that's the observation. We will follow the observations and I can't do those experiments in humans, we can't. We're taking this to where we think it must go [00:54:00] next. I just say, "Don't." You have to pursue the neutralizing antibodies but don't give up on those other things.

Glenda: Two eggs in one basket and one egg and other baskets. We've got two non-neutralizing approaches and one neutralizing approach.

John Mellors: I'd like to make some comments but I want as a disclaimer upfront. I'm not trying to rain on anybody's parade. I'm not trying to influence funding—

Veffa: [00:54:30] That sounds bad.

John: I work on a cure, which is pie-in-the-sky, vaccine's incredibly important. But sitting here this afternoon, my anxiety level has gone up steadily. Why is that? Despite everybody's best effort, incidence is flat. I have underlying anxiety that political turmoil, [00:55:00] economic abilities are going to result in us taking the eye off the ball and having a resurgence actually. I think the time we have to explore is limited.

I'm going to say that the greatest progress in HIV field has been made with small molecule [00:55:30] inhibitors of enzymes. We have treatments that's highly effective. We have PrEP that can be highly effective. The efficiency and effectiveness of both is not optimal. My feeling is that we should put as much resources into delivery of small molecules that are sustained over [00:56:00] time, as we do to any of the interesting science and biology. We're almost there. We're getting closer. The efficiency of ART is improving, one pill once a day, there's already injectable combinations that are effective—they're not ready to roll out. Then on the prevention side, we have 90-plus percent effectiveness in the IPERGAY studies (2012–2015) and other [00:56:30] studies. We have injectables and the bar is lower for an injectable for prevention.

I encourage the man who works for the richest man in the world, if he's still in the audience, to put a tremendous amount of resources into effectiveness, efficiency, and sustained delivery of what's got us [00:57:00] to where we are, which is small molecule inhibitors.

Glenda: Let me say something, that is to say that the South African government has done the investment case for universal test and treat and PrEP, and PrEP is incredibly expensive. The visibility of rolling out these interventions—

John: I'm going to tell you some really, really good news, and that is that you can make money in the United States from PrEP. [00:57:30] There's a positive economic model and we can speak with our colleagues from Gilead, but you can't get this reimbursed, you can make it profitable. That's the best news you could hear because that will draw other competition into the marketplace. What it costs now in South Africa is too high. You heard today from Bob Redfield that ART [00:58:00] is now $85 a year and that's just remarkable. If you sell product in the developed world, you could have the same model for ART.

Glenda: I'll ask David, and I'll ask Emilio after you, and Ruth.

David Baltimore: We listen to different things. The thing that I heard coming through from Salim [Abdool Karim] and from others is the very great [00:58:30] difficulty of adherence. That we have PrEP, we have ways, there's no question. If everybody behaved rationally, well we wouldn't have [Donald] Trump for one thing. At a time in young women's lives when they're most likely to acquire infection, at least in [00:59:00] South Africa, that they're at least adherent to PrEP regimens. Even ones that don't require a whole lot of their attention, I don't think that's going to get us there.

The eradication of HIV, I'll say this again tomorrow probably. The eradication HIV requires two things. It requires breaking the transmission and it requires treating people who are infected [00:59:30] so that they don't infect others. I think we can do the second, and I think we have to put our focus on the first. I don't really see any hope, but something that people don't have to adhere to, that takes care of itself.

It's the issue with vaccines. The vaccines have to have durability. In fact, they have to have durability at a very high level as fa,r as we know, [01:00:00] and it's really scary to see how long it may take before we get to the durability. I think when we're looking at the trade-off between V2 and neutralizing antibodies, and there are lots of other trade-offs, durability has got to be one of the most important issues. [01:00:30] We don't know a whole lot about that yet and I hope we learn from these trials a little about that.

Glenda: Well said. Ruth and then Emilio.

Ruth Ruprecht: Thank you. Please allow me to use a phrase from real estate. Location, Location, Location. Basically, 90% of all HIV transmissions occur mucosally [01:01:00] which are by viruses. The human body makes more IgA per day than all other classes of immunoglobulins combined. Where does it go? Into the mucosal–lumina. Right now we have actually not heard in this panel discussion anything about the location and IgA. I would like to point out that there is an other mechanism of prevention [01:01:30], and that is called immune exclusion. We've actually given proof of concept with dimeric monoclonal IgAs in collaboration with Robin Weiss, Antonio Lanzavecchia, and Davide Corti, that immune exclusion works. You have to have the dimeric IgA1s at the right location, and you can trap the virions before they even get anywhere close to the mucosal barrier. There is something that can be done [01:02:00] to drastically decrease the number of infectious virions that approach the mucosal barrier.

We've also published a second study where we have again, with Robin and Antonio Lanzavecchia and Davide Corti, we have combined monoclonal IgG and a monoclonal dimeric IgA2 version with the same specificity, namely the crown of the V3 loop, you'd like that, the conserved [01:02:30] crown of the V3 loop and we got an amazing synergy in the mucosal compartment. 100% protection when the deliberately low dose of IgG that we gave intravenously, by itself didn't give any protection, and the dimeric IgA2 version of the monoclonal antibody by itself only gave 17% protection, but combined 100% protection. [01:03:00] There are interactions happening in the mucosal lumina with mucus, with these antibodies, that we don't understand, but they can be highly protective. I would like to make the point. Location, location, location, and please don't forget about IgA, because the human body bothers to make more of it than all of the other immunoglobulin classes combined.

Glenda: [01:03:30] Okay, I'm going to ask Emilio. I think we need the guy who works for the man who has the most money close the conference, I mean close the evening.

Emilio: No, this is obviously responding to John's point. I mean David said it perfectly. You have to remember that none of the options that you put on the table John are mutually exclusive of each other. We're at a point where we absolutely need to do them all. We need to look at the vaccine approaches, we need to look even at passive antibody approaches, we need to take a look at a passive [01:04:00] prophylactic small drug approaches. However, as David said, very importantly, you got to remember the populations in which these approaches need to be used. They've got to be simple to use, they've got to be easy, they've got to be relatively cheap and low-cost, and most importantly, they have to be in essence, passive. Duration is important. Long-acting prophylactic antibodies, if you decide, if we ultimately go that road, who knows, they have to be delivered in a way in which you get a rather extended [01:04:30] period of window of efficacy.

The same thing is going to be true for small molecules. Therefore either, parental administrations, long-acting implantables, whatever the case is. Coming back to vaccines, it's absolutely right. Durability. If you see protection whatever it is, if we see it collectively, durability is important. A vaccine that gives you 40% protection for 6 months is not going to be that usable. You need something which is much better than that and much longer than that, or otherwise [01:05:00] it's just simply not going to have the epidemiological effect that we're all hoping to get ultimately in the end. We got to keep focused on remembering who the populations are and where we need to do this. None of the approaches are exclusive.

John: Of course, you're talking about one pill, once a day.

Emilio: Yes, that's fine.

Glenda: What you're saying is that [unintelligible 01:05:19] it must work in the vagina and that must work in vagina for long term. I'm letting you go first and then.

Wasif Khan: I just want to support what we just heard about IgA [01:05:30]. I'm sure a lot of us are aware of it but microbiota influence on what type of IgA is produced and how much, and alteration in microbiota may be part of mucosal immunity which should be considered in vaccine design.

Glenda: Shall we let him have the last the—?

John Mellors: With all due respect, David I'm not talking about something that requires daily or weekly [01:06:00] or even monthly adherence. In that regard, I totally agree with you. I'm talking about pushing the envelope for delivery of a year, or two years in between interventions. To the guy who spends the most money of the richest man in the world, put out a grand challenge for sustained delivery.

Glenda: I think Merck could speak about sustained delivery, [01:06:30] they're working on it. I'm going to close this because I think there's one outside. The conversation is rich and we can continue. All I want to say is that vaccine development and advancing products into advanced clinical development is critical for us to move any anything forward. I look forward to the next 10 years.

[applause]

[01:06:59] [END OF AUDIO]

Citations

1. Pillay-van Wyk, Victoria, William Msemburi, Ria Laubscher, Rob E Dorrington, Pam Groenewald, Tracy Glass, Beatrice Nojilana, et al. “Mortality Trends and Differentials in South Africa from 1997 to 2012: Second National Burden of Disease Study.” The Lancet Global Health 4, no. 9 (September 1, 2016): e642–53. doi:10.1016/S2214-109X(16)30113-9.
2. Burton, Dennis R., Ronald C. Desrosiers, Robert W. Doms, Mark B. Feinberg, Robert C. Gallo, Beatrice H. Hahn, James A. Hoxie, et al. “A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials.” Science 303, no. 5656 (January 16, 2004): 316–316. doi:10.1126/science.1094620.
3. Belshe, Robert, Genoveffa Franchini, Marc P. Girard, Frances Gotch, Pontiano Kaleebu, Marta L. Marthas, Michael B. McChesney, et al. “Support for the RV144 HIV Vaccine Trial.” Science 305, no. 5681 (July 9, 2004): 177–80. doi:10.1126/science.305.5681.177b.
4. Rerks-Ngarm, Supachai, Punnee Pitisuttithum, Sorachai Nitayaphan, Jaranit Kaewkungwal, Joseph Chiu, Robert Paris, Nakorn Premsri, et al. “Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand.” New England Journal of Medicine 361, no. 23 (December 3, 2009): 2209–20. doi:10.1056/NEJMoa0908492.
5. Connor, Edward M., Rhoda S. Sperling, Richard Gelber, Pavel Kiselev, Gwendolyn Scott, Mary Jo O’Sullivan, Russell VanDyke, et al. “Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment.” New England Journal of Medicine 331, no. 18 (November 3, 1994): 1173–80. doi:10.1056/NEJM199411033311801.
6. Liu, Jinyan, Kara L. O’Brien, Diana M. Lynch, Nathaniel L. Simmons, Annalena La Porte, Ambryice M. Riggs, Peter Abbink, et al. “Immune Control of an SIV Challenge by a T-Cell-Based Vaccine in Rhesus Monkeys.” Nature 457, no. 7225 (January 1, 2009): 87–91. doi:10.1038/nature07469.
7. Barouch, Dan H., Kara L. O’Brien, Nathaniel L. Simmons, Sharon L. King, Peter Abbink, Lori F. Maxfield, Ying-Hua Sun, et al. “Mosaic HIV-1 Vaccines Expand the Breadth and Depth of Cellular Immune Responses in Rhesus Monkeys.” Nature Medicine 16, no. 3 (March 2010): 319–23. doi:10.1038/nm.2089.
8. Santra, Sampa, Hua-Xin Liao, Ruijin Zhang, Mark Muldoon, Sydeaka Watson, Will Fischer, James Theiler, et al. “Mosaic Vaccines Elicit CD8 + T Lymphocyte Responses That Confer Enhanced Immune Coverage of Diverse HIV Strains in Monkeys.” Nature Medicine 16, no. 3 (March 2010): 324–28. doi:10.1038/nm.2108.
9. Barouch, Dan H., Jinyan Liu, Hualin Li, Lori F. Maxfield, Peter Abbink, Diana M. Lynch, M. Justin Iampietro, et al. “Vaccine Protection against Acquisition of Neutralization-Resistant SIV Challenges in Rhesus Monkeys.” Nature 482, no. 7383 (February 2, 2012): 89–93. doi:10.1038/nature10766.
10. Barouch, Dan H., Kathryn E. Stephenson, Erica N. Borducchi, Kaitlin Smith, Kelly Stanley, Anna G. McNally, Jinyan Liu, et al. “Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys.” Cell 155, no. 3 (October 24, 2013): 531–39. doi:10.1016/j.cell.2013.09.061.
11. Barouch, Dan H., Galit Alter, Thomas Broge, Caitlyn Linde, Margaret E. Ackerman, Eric P. Brown, Erica N. Borducchi, et al. “Protective Efficacy of Adenovirus/Protein Vaccines against SIV Challenges in Rhesus Monkeys.” Science 349, no. 6245 (July 17, 2015): 320–24. doi:10.1126/science.aab3886.
12. Barouch, Dan H., Jinyan Liu, Lauren Peter, Peter Abbink, M. Justin Iampietro, Ann Cheung, Galit Alter, et al. “Characterization of Humoral and Cellular Immune Responses Elicited by a Recombinant Adenovirus Serotype 26 HIV-1 Env Vaccine in Healthy Adults (IPCAVD 001).” The Journal of Infectious Diseases 207, no. 2 (January 15, 2013): 248–56. doi:10.1093/infdis/jis671.
13. Baden, Lindsey R., Stephen R. Walsh, Michael S. Seaman, Robert P. Tucker, Kathleen H. Krause, Alka Patel, Jennifer A. Johnson, et al. “First-in-Human Evaluation of the Safety and Immunogenicity of a Recombinant Adenovirus Serotype 26 HIV-1 Env Vaccine (IPCAVD 001).” The Journal of Infectious Diseases 207, no. 2 (January 15, 2013): 240–47. doi:10.1093/infdis/jis670.
14. Baden, Lindsey R., Jinyan Liu, Hualin Li, Jennifer A. Johnson, Stephen R. Walsh, Jane A. Kleinjan, Brian A. Engelson, et al. “Induction of HIV-1–Specific Mucosal Immune Responses Following Intramuscular Recombinant Adenovirus Serotype 26 HIV-1 Vaccination of Humans.” The Journal of Infectious Diseases 211, no. 4 (February 15, 2015): 518–28. doi:10.1093/infdis/jiu485.
15. Baden, Lindsey R., Etienne Karita, Gaudensia Mutua, Linda-Gail Bekker, Glenda Gray, Liesl Page-Shipp, Stephen R. Walsh, et al. “Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention.” Annals of Internal Medicine 164, no. 5 (February 2, 2016): 313–22. doi:10.7326/M15-0880.

Index

• 1.4 Robin Weiss — Retrovirus History and Early Searches for Human Retroviruses 
• 2.1 Paul Volberding — The First Patients 
• 2.3 Mark Harrington — The Importance of Activism to the US Response 
• 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents
• 3.1 Marty St. Clair: Discovery of AZT as the First Anti-HIV Drug 
• 3.2 Samuel Broder: The First Clinical Trials of Antiretroviral Drugs 
• 3.3 Douglas Richman: Antiviral Drug Resistance and Combination ART 
• 4.0.2 Ruth Ruprecht — Session 4, Introduction 2 
• 6.3 Bruce Walker — Role of T Cells in Controlling HIV Infection 
• 6.4 Barton Haynes — Development of HIV Vaccine: Steps and Missteps 
• 6.5 Emilio Emini — Issues in HIV Vaccine Development: Will the Future be any Easier than the Past? 
• 6.6 Robert Redfield — The PEPFAR Program to Treat HIV in Africa 
• 6.7 Salim Abdool Karim — Stopping the Spread of HIV in Developing Countries 
• 8.1 John Mellors — MACS and Beyond: Epidemiology, Viremia and Pathogenesis 
• 8.6 David Baltimore — Bringing it to an End (And Where Are We Going?) 
• aciclovir (ACV) 
• ACTG trial 076 (1991–1994) 
• adenovirus 
• adherence, patient compliance 
• adjuvant 
• Africa, sub-Saharan Africa 
• AIDS Clinical Trials Group (ACTG) 
• alum (aluminum hydroxide adjuvant) 
• antibody, immunoglobulin (Ig) 
• antiretroviral therapy (ART) 
• AZT (azidothymidine) 
• Beth Israel Deaconess Medical Center (BIDMC) 
• Burroughs-Wellcome & Company, Glaxo Inc., GlaxoSmithKline 
• capsid, capsid protein (p24) 
• cell culture, tissue culture, immortalized cell line 
• chemistry, chemists 
• clinical trials (phases of clinical research) 
• demographic cohort
• Ebola 
• education and early career 
• Elion, Gertrude B. "Trudy" (1918–1999) 
• env 
• Friedman-Kien, Alvin E. 
• funding and grants 
• gag 
• Gilead 
• gp120 
• gp41 
• herpesviruses 
• Hilleman, Maurice (1919–2005) 
• HIV vaccine 
• immunology 
• implants, drug delivery implants, implantable antiretroviral therapy 
• infectious disease (medical specialty) 
• IPERGAY Trial (2012–2015) 
• Janssen Pharmaceuticals 
• Kaposi's sarcoma (KS) 
• Kim, Jerome 
• Korber, Bette 
• lab vs. clinic 
• Letvin, Norman L. (1949–2012) 
• macaque, rhesus macaque 
• Mbeki, Thabo (b. 1942) 
• mechanism 
• medical school, residency, and fellowship 
• Merck & Co., Inc. (Merck Sharp & Dohme) 
• Merigan, Thomas C. (b. 1934) 
• MF59 
• mice 
• Michael, Nelson L. 
• models (model systems, model organisms, modeling) 
• monoclonal antibody 
• mother-to-child transmission of HIV 
• MSM (men who have sex with men) 
• National Institutes of Health (NIH) 
• non-human primates 
• NYU (New York University) 
• patents and intellectual property (IP) 
• pediatrics, pediatric AIDS 
• PNAS (Proceedings of the National Academy of Sciences) 
• pol 
• pre-exposure prophylaxis (PrEP) 
• Robinson, Harriet 
• Roizman, Bernard (b. 1929) 
• RV 144 (2003–2009) 
• scientific competition and collaboration 
• scientific controversy and consensus 
• Seattle 
• simian immunodeficiency virus (SIV) 
• simian-human immunodeficiency virus (SHIV) 
• South Africa 
• Stanford University, Stanford University School of Medicine, Stanford University Medical Center 
• STEP study (2004–2011) 
• structural biology
• Thailand 
• Trump, Donald (b. 1946) 
• tuberculosis (TB) 
• vaccinia 
• vagina 
• viremia
• women in science 
• Zika