Descriptive Transcript
music // Title card reads Back to Basic Toronto, 2014. Dr. Ken Rosenthal. Combination HIV Prevention. Ken Rosenthal delivers a per-recorded talk, speaking into a webcam from an office. An on-screen graphic identifies him as Professor, Pathology and Medicine, McMaster Immunology Research Centre, McMaster University.
Rosenthal displays a slide containing an image of several blocks stacked on top of each other. Each of the blocks is labelled with an HIV prevention method (from top to bottom: treatment as prevention, PrEP, PMTCT, STI treatment, Male circumcision, microbicides, testing/counseling, education, drug/alcohol treatment, condoms, harm reduction, blood screening). In the top centre row, a block labelled “vaccine” is highlighted and stands out from the rest.
Ken Rosenthal: I think the first point I want to make is that, shortly after arriving here, in Cape Town, I had the pleasure of attending the HIV Research For Prevention meeting, which was given the hip-hop name of HIVR4P. I now appreciate, as you should, that, in fact, many advances have been made in preventing or trying to control the HIV epidemic. These include a number of methods to prevent the acquisition of HIV.
So, there are lots of tools, now, in our toolbox to try to protect individuals. For example, male circumcision, we know, protects 60% of circumcised men, so many men in Africa have voluntarily stepped forward to have voluntary circumcision. This certainly will have an impact. With prevention of mother-to-child transmission, we’ve seen the roll-out of ARVs — that’s significantly reducing the number of infected infants in the developed world from getting HIV. There’s treatment as prevention, which, as you know, can be used to protect individual partners who have partners that are infected from getting the drug, and PrEP the use of antiretrovirals for prevention. Microbicides are moving along, particularly the vaginal rings with antiretroviral drugs in them. But, ultimately, a safe and effective prophylactic vaccine will be essential for the ultimate control of HIV within the context of these other prevention technologies. So, even though there are a lot of tools, we we still will need an HIV vaccine.
Rosenthal displays a slide containing a screencap of a diagram depicting how vaccines work. The diagram and accompanying text are largely unintelligible from the audience, but Rosenthal describes the major points below.
Now, I know that many of you may not be well aware of how vaccines work. And, this is a slide — a busy slide, and I apologize for it — for how vaccines work. But, in a nutshell, the point I want to make is that, in essence, vaccines take whole, or sub-units, or parts of microbes, or viruses — these can be inactivated; they can be put into a vaccine with an adjuvant, perhaps, particularly if they’re non-replicating; they can be administered by a variety of routes, including a shot, or mucosally. And once these vaccines are introduced, the antigens — the viral antigens, for example, can get picked up by antigen-presenting cells. This will induce, initially, an innate immune response — which we won’t discuss immediately, here, now — but, ultimately, those in native immune responses protect early after exposure, and, in the meantime, the B-cells will be activated to produce antibodies, which may have neutralizing or antibody-dependent cytotoxicity activities, and the T-cells will be activated.
And, there’s a variety of T-cells: T-cells that help, T-cells that suppress, T-cells that regulate. And, ultimately, what is done is, after these immune responses are initiated, after a period of time, we end up with memory cells — in this case, central memory cells — that, on re-exposure to the pathogen, will re-turn on the immune responses to try to control that infectious agent.
The video jumps forward to a later point in Rosenthal’s presentation. Rosenthal displays a slide titled “Holy Grail: Broadly Neutralizing Antibodies (bnAbs).” The slide contains an image from Burton et al. published in Science in 2012, showing a model of an HIV envelope spike bound to broadly neutralizing antibodies. In plain terms, a wire-frame image of a sphere rising from a flat surface with several brightly-coloured, irregular masses attached to it. The masses have a crumbly texture and a malleable appearance.
I think all of you may be aware that one of the Holy Grails of trying to control HIV is to generate broadly neutralizing antibodies. There are now more than 30 broadly neutralizing antibodies that have been identified, and that are specific for conserved neutralizing targets on the envelope of HIV. But, importantly, all of these broadly neutralizing antibodies require an extraordinary level of somatic hypermutation. What this means is that the B-cells that produce these antibodies take a very long time and have to go a lot undergo a lot of mutations in order to generate these antibodies that can broadly neutralize HIV.
The other thing is, is that these antibodies tend to be auto-reactive against host molecules, raising questions about their real utility, because they will interact and affect host molecules. And, also, these broadly neutralizing antibodies, so far, for the most part, seem to have very long arms.
Rosenthal rolls his chair away from the camera and raises his arms high above his head.
They’re almost like extended antibodies that glomp onto things. So, they have a very unusual structure. And they’re very — they function in a way that they can access recessed antigenic determinants.
The other important thing is that the individuals who generate these broadly neutralizing antibodies, after many years, and many mutations and changes in these antibodies — they don’t protect the people that generate them. So, these — but nevertheless, these monoclones may be useful as passive antibody protection.
The video jumps to another part of Rosenthal’s presentation. He presents a slide listing recommendations to accelerate clinical efficacy trials, which he outlines below.
We’re also concerned that there has to be a speed-up of clinical efficacy trials to test these next generation of HIV vaccine candidates. This will require cooperation of industry. It’s hoped that industry will help advance clinical development, manufacturing, regulatory affairs, product development, and downstream licensure, and the capacity to produce and deliver an HIV vaccine, to mobilize resources including industry, government, and additional dollars from philanthropic people or groups.
We need to expand the current vaccine pipeline against HIV. And we need robust pre-clinical challenge studies to prove that these work.
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