Interview: Dr. Regina Rabinovich

This interview of Dr. Regina Rabinovich by Nancy Tomich first appeard in the December 1999 issue of U.S. Medicine (vol. 35, no. 12) and is reprinted with permission.

What made you decide to leave NIAID and take this position?

I wasn't searching for positions outside of the NIH. I was employed full-time, I had a great job, good people to work with. I had been talking to Ripley Ballou, who wrote the original proposal for the project. [Dr. Ballou, formerly of Walter Reed Army Institute of Research, has retired from the Army and now is with MedImmune]. When it became clear that he would not be able to take the project into its implementation phase, there were several suggestions that I should consider putting my hat in the ring for it.

Fifty million dollars is real money, if you can work effectively with all the partners that are in place. You cannot develop a vaccine for $50 million. You can't develop even one -- and with malaria there is going to have to be multi-antigen or multi-technology vaccine. But you can certainly leverage, and you can certainly facilitate and move things forward much more rapidly.

The real challenge is that it has to be done well. I looked around and said, "I can do this." And I really want it to be done well.

I have this pin with three kids on it. I bought it because it's the perfect logo -- it's the three kids per minute that die from malaria.

At this point I feel this is why I went to medical school, to do this project. My whole training at NIH has been in preparation for taking this project on. So, it's perfect timing, actually. I'm very excited about it.

What specifically have you been working on at NIH that transfers into this project?

I came to NIH in an epidemiology training position. I was a pediatrician with some administrative experience, teaching experience. I had decided I wanted to do research and did a master's in public health and realized very naively that you can't do research on a master's. NIH offered me a training position in which to complete my PhD.

I was working on acute respiratory infection, which was an interest of mine because it's the leading killer of children in the developing world. As I was finishing a mostly computer-driven analysis of a large database of asthma hospitalizations for the entire state of New York, I got a phone call from John La Montagne [now NIAID deputy director], who was division director at the time, and he said, "Have you thought much about vaccines?"

Within a month I basically had left everything else behind and jumped into a fascinating world of national vaccine policy. This covered three years, working with different federal agencies -- the National Vaccine Program Office -- and at the time, about five years ago, they were consolidating our vaccine unit.

Our vaccine unit has units under contract at universities across the United States that conduct phase I through phase IV trials. I was asked to manage those units. At that point I had two kinds of activities under me as part of our group -- vaccine evaluation, the clinical development, working with biotechs and big companies, worrying about what was ready for phase I, working with our regulatory group, as well as the DMID vaccine production contract. We had gotten, previously, funding to support some projects at the Salk facility [in Pennsylvania], we had an interagency [agreement] with Forest Glen [WRAIR's pilot production facility], and we had another contract that went through the re-award process.

So, I had vaccine production, clinical evaluation, and then I took on the branch chief position, which includes clinical and regulatory affairs. That included the group which manages regulatory affairs with the FDA, as well as the clinical trials component of regulatory affairs.

How to conduct clinical trials under good clinical practices in the United States is changing. It's advancing. We're worrying about things now that we weren't worrying about ten years ago, or not at that level of detail.

Do you have an idea as yet where will the emphasis be with the malaria vaccine initiative?

Actually, that's the first phase -- understanding who all the players are. It's a relatively small group. So, it's not as hard as you would think, and it's not just a U.S. initiative. We're looking broadly. People have been asked to conduct site visits abroad at specific laboratories.

We're not going to replace what people are already doing. We have to go beyond the initiatives that are in place. There are groups that are worrying about field sites for testing malaria vaccines. We're very interested in those field sites. The Vaccine Treatment Evaluation Units in DMID will be very useful in safety trials. That capability also exists in the Department of Defense, with the things that they're interested in.

So, one thing is, who are the players working in malaria? The other element of this overall matrix is, who has the best vaccine technologies? Are there vaccine technologies that aren't pursued for malaria vaccine specifically that should be? Are there opportunities that could be more aggressively pursued?

We're looking on both sides.

Will this initiative help Army and Navy researchers, whose malaria work is not robustly funded, take things a step further?

It certainly could. We're working to set up agreements with the major players, but focused on the kind of things we want to move forward on. Their programs are by necessity defined as development of vaccines for prevention of disease in the field. Our focus is on children.

In some ways it's a natural extension. You can't tell what's going to work for children and what's not. On the other hand, it's a little bit different focus. Different technologies in the final analysis could end up being very compatible with each other. In the DNA vaccine field, for example, one concept that is really hot right now is the concept of priming with one type of vaccine and boosting with another. These studies need to be conducted, and actually collaborations are being formed to figure that out.

Will you have any sort of advisory group that you'll be working with?

Yes. You can't do this without support from the field. We have two groups. One is a strategic advisory council that advises the entire children's vaccine program managed by PATH. We have a number of people on it with expertise in malaria, which will be very helpful. The other is a more technical advisory group which we will ask to give us advice on more specific projects and selection of approaches that we will be pursuing.

Do you have any idea yet how many projects you'll be dealing with?

How many projects we'll create? Whatever it takes.

In the past there has been excitement that we were on the verge of a breakthrough on malaria vaccine, but it never quite materialized.

It was very exciting when polio vaccine was developed, and I think that's an interesting model. It happened externally to big industry and definitely external to government. It was driven by an overwhelming perspective of public health need.

The story is that the trial finished one week and the next week they began immunizing. That's the kind of orchestration I don't think is possible in this day and age. I think that as tough as polio was to crack -- right now we're using a third-generation polio vaccine, an enhanced inactivated polio vaccine -- malaria is going to be a lot harder. It's a parasite.

We have to work in recognition that even if we had the best vaccine cheaply available, manufactured in large quantities, in our hand right now, we could not deliver it effectively to the children who are dying from it.

So, the linkage across PATH between the malaria vaccine initiative and the rest of the children's vaccine program is very focused on developing strategies to purchase and deliver the vaccine to children.

That being said, yes, there have been other five-year initiatives to develop a vaccine. I don't think we're going to have a licensed malaria vaccine in the first generation available in five years preventing disease in the field. I think we'll have several vaccines that we will try in the target population, and I think we're going to be able to move things forward.

Obviously, with $50 million -- it is a lot of money, and I don't want to make it seem smaller than it is. It's something that the malaria community is looking to. It has to go along with increased resources for the federal agencies and industry.

It's still an orphan vaccine. There are many players in the field who aren't convinced that the path is clear to developing a vaccine. There are many players in the field who don't feel like there's a market. We haven't convinced them that we could figure out how to get the vaccine delivered. We have no way of delivering it right now.

So if you will, it's a triple orphan. I think that the science and tech base is there to make significant advances, and I'm betting my career -- I'm leaving a tenured position at NIH -- to do this.

But I think it's a very exciting time. You're going to see more and more different types of malaria vaccines going into field trials. I think that will draw the credibility. We have to rest it upon results in humans, not in mice.

You have a lot of immunologists who are used to working in very specialized animal models who have come upon a technology or a way of manipulating an antigen that is relevant to malaria, and their hearts are in the right place, but you've got to get it out of mice. If you look at the vaccines that are furthest along, whether it's RTSS that the Army has developed or even the DNA vaccines, and the mouse stuff looks very promising. (The RTSS vaccine has been in Phase II testing in Gambia.)

The whole DNA vaccine field rested initially on the fabulous ability of tiny doses of plasmid DNA to generate great immune responses in mice. But it's not a primate. Clearly, they are less complex and more easily tricked.

If all we do is spend $50 million wisely and advance the field, we'll have done part of our job. But I think the greater part is to bring credibility and enhanced commitment from other partners. It's going to take more than $50 million.

Do you have indications that industry wants to be a player in this?

I've been talking to industry about different kinds of orphan vaccines for a number of years as part of the National Vaccine Program Office and the National Vaccine Advisory Committee that have been looking at these issues for a long time, as well as negotiations with industry, so I've had ample opportunity to get an understanding of how they make decisions.

If you go to one of the really big players that's a pharmaceutical company, not necessarily a vaccine company, and ask them how they make decisions, they will give you certain cutoff figures, like they need to look at $500 million in profit or they're really not interested. Within the vaccine community, you go to the people who are responsible for developing vaccines on a commercial level, I don't think the figures are quite like that, and I think that what we have to convince them of is that there is a market.

If you look at hepatitis B vaccine, which is the number one moneymaker of the new vaccines compared to the ones that have been in place for 40 years or so, it is driven by both a U.S. market and a developing world market. It's into its third-plus generation, from a plasma design to a recombinant to better and cheaper ways of producing a recombinant. So that gives you the production capability, the efficiency of scale, and there have been a lot of players. You have major manufacturers.

You don't have that in malaria at this time. You have biotechs that see malaria as a useful and interesting model to explore their technology, whether it's an adjuvant or delivery technology, but don't have the wherewithal to make a commitment to advanced development leading to production.

You have big companies -- some of them have historically been interested in research and development but don't have the commitment at this time to take it forward. I think SKB [SmithKline Beecham] has supported under a CRADA [cooperative research and development agreement] RTSS. It has been a great tool for them, and there's been a commitment for 14 years. I certainly can't complain about that.

But the question is, is this the right time to put this into a production effort? And I don't know what the answer is. Effectiveness in field studies will help.

What is unique about malaria vaccine is that there will be a small travelers' market, there will be a military market, but there is not going to be a huge developed country that will drive the development or the production base that would then allow marginal production for the rest of the world. We have to think differently about this.

Unless global warming brings it to the U.S. again.

The concept of emerging diseases -- malaria in the U.S. is not something I would want to wish upon anybody. However, a couple of years ago we looked up the statistics for Montgomery Country [Maryland, in which NIH is located]. It must have been in the early '90s. There were more cases of malaria reported in Montgomery County than there were of measles.

Now, it has major airports in the area and travelers coming in, so I think that's what it was. And there were actually even on the national level very few cases of measles, so you have to take that into consideration. But there are sporadic cases. And this thing of West Nile virus that was found in a vector in New York and now a dead bird in Montgomery County carrying the virus.

It really does point out the lack of geographic and national boundaries for emerging diseases. But I'm not going to raise the global warming flag as a cause for malaria. The three kids per minutes does it for me.

How will you try to approach industry?

Well, I think there are several ways that we will be pursuing to try to figure out how to change the balance of interest and the profit they need to make to draw them in as well as the limits to the costs that the world can afford to pay for a malaria vaccine.

Will you dovetail at all with the World Health Organization's "roll back malaria" campaign?

We will dovetail with whatever groups are interested and it will be helpful to do so. We will not be supporting or focus on drug development, and at this point it's not an issue of having a product that is ready to be utilized in effective prevention programs.

We will look upon it with interest. We will consult with appropriate groups. There are a number of different players that we will be talking to.

I've made two points very clear. I said, "If you have sold this initiative as something that will have a licensed produced in the field five years, I'm out of here." We will definitely work to accelerate things, but we must be realistic. The other is that we can't take credit -- we're the new kids on the block -- we cannot and will not take credit for other groups have been working on for decades.

Everyone wants this to work. They want to be able to move things forward. The funding base for malaria vaccine development for any of the players is not as robust as it could be. So, I think there will be effective partnerships, and that's definitely what we're looking forward to.

Are you comfortable that funding will be renewed after five years?

I think that we will be looking to leverage and bring in resources as needed from a number of different sources. I'm confident the foundation understands the complexity of this endeavor. Can I count renewal? Of course not. But I think the program will do well if we bring credibility to it.

Do you know yet how large your immediate staff will be?

I'm not looking toward creating a huge staff at this point. There will be a small management group of people with different kinds of vaccine expertise that will draw from malaria expertise in the field. I think that vaccine development expertise could be a benefit.

Will successful sequencing of malaria make a difference in the speed of your program?

It's definitely going to be useful for drug development. And there are some models that are in place for different kinds of organisms that could prove very useful for vaccine development. I'm talking and meeting with those groups. I'm very excited about it.

I'm not sure that that will yield the vaccine we need to have in the field in five years, but it may yield the vaccine we need to have in the field in ten years. I'm looking at what's been done with other relatively complicated organisms that have gone from genomic information to identification of specific antigens that are very likely to yield a relevant immune response.

Did you have difficulty making the decision to take your new position?

Taking the position wasn't a tough decision, but leaving my position was. I go with a lot of good feelings about the program at NIAID. But this is more of a personal commitment.

Do you have children yourself?

I have three -- a 7-year-old boy, who has figured out that malaria is a parasite that kills three children a minute, and my mother is going to work on it; I have a daughter who is 13, who said I should take this job because it's so cool and I will get to meet Bill Gates; and I have a 14-year-old son, who asked, "Does this mean you'll have to travel more?"

Have you met Bill Gates?

Not yet. I've met Bill Gates Sr. Both he and Melinda run the foundation. He asks very good questions about malaria. He does his homework.