Since you're adding the envelope protein gene into the PAVE vaccine, is there a chance that vaccine could be both preventative and therapeutic?
It likely would be some antibody effect, but unlikely would be neutralizing antibodies, because the envelope is presented in that conformational form that doesn't reveal very well its component that would induce that neutralizing antibody. So, yes, there would be some antibody response—and hopefully it will add to the benefit. But, it is more likely that it would elicit a T cell response rather than an antibody response.
To your decision to reject this vaccine trial, there must have been some point where, in smaller trials, the PAVE vaccine proved to be safe and at least somewhat effective. It would have had to in order to get to a large trial, right?
No efficacy at all, because it wasn't done in a large enough trial or among at-risk people, who would allow enough infection to occur to see if it would work. All it showed was safety to some degree—I mean, we didn't do a lot patients—but safety in those we looked at. And the fact that it induces an immune response, which one would argue was somewhat better than what you saw in the STEP trial.
There was some argument about that at several meetings. "Somewhat better" is what? A lot better? I didn't think it was a lot better. That gets back to the point I made at the beginning of our conversation: So it elicits a similar immune response [to STEP]. Well, we know that immune response was not associated with protection [from the virus] in the STEP trial, so I'm not even sure that those immunological correlates are the relevant ones. So it really is sort of like we're swimming in the dark because we don't really know what the immunological correlates are. So, that's why I said I don't accept the original proposal for the PAVE trial. It's powered large enough to give you a whole bunch of immunological correlates, which, to me, are irrelevant if the vaccine doesn't work.
First show me a lean, mean trial with as little risk as possible to the people, as few samples as you possibly can to statistically give me a "yes" or "no" as to whether it lowers the viral load. If the answer is yes, then I definitely want to pursue it by getting many more people to see if we can get a good correlate.
So, that brings us to your piece in Science, outlining the way forward for vaccine research...
That was based fundamentally on the summit that we had in March of this year, in which we looked at the basic fundamental role of discovery versus development, animal models, clinical research. We addressed each of those. So, we outline some of the critical issues: Why don't we get a neutralizing antibody response? How will we be able to elicit it? What is a correlate of immunity? What about nonhuman primate models?
Nonhuman primate models can be very valuable, but right now we've got to link them closer to what goes on in the human. For example, the challenges in the nonhuman primate model are homologous challenges, which means you inject them with the same virus that you vaccinate them with. That's not the way it works in the real world. If you vaccinate somebody with a particular strain or a particular component of a virus, it is overwhelmingly likely that they are going to get exposed to something that's a little bit different. So, if you can't protect against a heterologous challenge, we've got to perfect the monkey model a little more, so that we use heterologous challenges.
Also, we need to totally reexamine what we're calling "potential correlates of immunity."
So, there are some basic definitions of success that need to be agreed upon before moving forward?
We need to have answers to some concepts first before we embark on large, empirically based clinical trials. Clinical trials, as we admit in Science, can be an important part of discovery research. You can get discovery doing clinical research. But, we are going to set a much higher bar for going into a very large empiric-type of efficacy trial. We need to have some really good reason to think that there's a reasonable chance that [a vaccine] will work.