An Interview with José Esparza

HIV vaccine developments

José Esparza MD, PhD has been a leader in the international HIV arena for almost two decades and for much of that time has been a consistent champion for AIDS vaccines, particularly for developing countries. He currently wears two hats, one as Senior Advisor on HIV Vaccines at the Bill & Melinda Gates Foundation, as well as head of the interim secretariat for the Global HIV Vaccine Enterprise.

Esparza began his research career at the Venezuelan Institute of Scientific Research in Caracas, Venezuela, where he rose from graduate student to full professor. During that time he completed his PhD at Baylor College of Medicine, Houston, Texas, and managed a two-year spell as a visiting professor at Duke University, North Carolina. His research interests have encompassed epidemiology to molecular biology in human virology, including herpes simplex viruses, Venezuelan equine encephalitis virus, and rotaviruses.

In 1986 he joined the World Health Organization in Geneva, and soon became a leader in that organization's HIV/AIDS programs, with an emphasis on vaccines. Esparza then moved in 1996 to the Joint United Nations Programme on HIV/AIDS (UNAIDS) to lead their HIV vaccine programs. In 2004 he joined the Bill & Melinda Gates Foundation and has been an important figure in establishing the nascent Vaccine Enterprise. IAVI Report Editor Simon Noble recently spoke to Esparza about the Gates Foundation, the Vaccine Enterprise, and recent developments in the field of AIDS vaccines.

The Gates Foundation is now a leading global health organization. Consequently it now has a very wide scope of activities—in comparison to other diseases, what emphasis does the Foundation place on HIV?

The Gates Foundation is a family foundation and our mission—which reflects the vision of Bill and Melinda Gates—is to help address fundamental inequities in the world, something that Bill has referred to as the random geography of birth: A child born in the US or Europe has a totally different perspective in relation to access to health, education, housing, the future in general, when compared to a child who is born in, say, the middle of Africa. They have identified that two of the major factors of this inequity has to do with lack of access to education and healthcare. Because of that, global health—the emphasis is to develop interventions that can be used in developing countries—takes about 60% of our funding at this time.

When AIDS appeared 25 years ago, it not only created major inequities but also helped to identify existing major inequities, including inequities to do with access to education that helped prevent many people in the North from becoming infected but that wasn't widely available in the South. And that inequity between the haves and the have-nots was then increased when antiretroviral drugs were developed.

I hope that once an HIV vaccine is developed it will not contribute to further increasing the gap between the North and the South. If the vaccine that is developed is not appropriate for developing countries because of the cost, because of the regimen for administration, because of the sub-type specificity, or for some reason it's not available in developing countries, then that would be the ultimate tragedy.

About $1.1 billion of the $6 billion in global health grants to date have gone towards HIV. This proportion may change as we find where the strategic opportunity arises, so we can move there and make a difference.

How much emphasis is placed on HIV prevention versus treatment?

Today, in 2006, we don't see a dichotomy between prevention and treatment. Both are important components of our response to AIDS, they have to go hand in hand. But ten years ago, there was confrontation between prevention and treatment. When I was at the WHO I remember making the point that an organization that focuses on prevention can't disregard those who are infected.

We're very encouraged by the recent progress on treatment, but there's still a long way to go on prevention. We are developing a broad prevention portfolio, including microbicides, vaccines, pre-exposure prophylaxis, behavioral components like the Avahan initiative in India to empower disenfranchised populations, and others. We work with other partners to ensure that the response to the epidemic is not skewed in any direction but remains comprehensive, rational, and durable.

There have been major efforts in the last three years, like PEPFAR and the '3 by 5' program, to increase access to therapy. That's wonderful, and it has facilitated the work of organizations like IAVI that focus on prevention.

You used to work on rotavirus, it must be exciting to finally see an effective vaccine come to market. Does this example have lessons for AIDS vaccine development?

Yes, I started working with rotavirus soon after it was discovered, in 1974. The ultimate goal was the development of a vaccine, and I am thrilled that now we have one, or maybe even two. I often use rotavirus as a paradigm for HIV vaccines. The development of the vaccine took over 30 years of hard work, with multiple efficacy trials conducted in industrialized and developing countries. A key strategic decision was when the end point to measure vaccine efficacy was changed from prevention of infection to prevention of disease, which is a current discussion in the HIV vaccine community, although there are important differences.

In rotavirus, there is not natural immunity after infection, children who are infected with rotavirus can be re-infected and re-infected. Conventional wisdom will tell you that if there is no post-infection immunity, forget about a vaccine. The eureka moment came when Al Kapikian at the NIH and others realized that the primary infection was the more pathogenic, and when a child was re-infected the disease was generally very mild. That actually led to a change in the paradigm: A vaccine may not be able to prevent infection, but let's measure instead the severity of disease. And voila—there was a clear difference.

There are other parallels with HIV vaccines. There are many rotavirus types—although the problem of rapid mutation does not apply—and one vaccine is based on one type, and the other vaccine on four types. How much cross-protection between types exists? With correlates of protection, the rotavirus vaccine protection seems to be better than the level of circulating and mucosal antibodies would predict. So the immune correlates of protection are not very clear. Also, the rotavirus vaccine was developed without a good animal model.

The other lesson for HIV vaccines of course is the need to conduct multiple, multiple Phase III trials. To some extent, it was an empirically-developed vaccine. It wasn't this approach that scientists tend to have, that you do a trial or an experiment to prove that your hypothesis was correct. It was actually a very exploratory, empirical approach to vaccines that they learned by doing. Overall, the rotavirus vaccine gives us some good lessons for HIV, including the need to maintain a balance between rational development and empirical testing. There is no substitute for clinical trials.

Do you think that within the AIDS vaccine field people are seeing that prevention of infection, sterilizing immunity, is such an elevated goal that perhaps we have to lower the bar and go for prevention of disease? Do you think that's being tacitly agreed upon?

I don't think so, or at least for me it's not clear. I think that the intermediate goal of a vaccine may be prevention of disease rather than infection. But we don't have the information to conclude that this should be the ultimate goal of a vaccine. Experience is that people who become infected will, sooner or later, progress to disease. And accepting this intermediate goal too early could actually prevent the research that is needed to see if we can develop a vaccine that confers sterilizing immunity. There are many, many opinions in this field and I think we need more than opinions; we need facts. Science is not what you believe but what you know.

I think that debate is still ongoing. I would caution against premature agreement in the scientific community that the goal should be a vaccine that just prevents disease. This is work in progress; we don't yet know the limitations.

An effective rotavirus vaccine was introduced into the US in 1999 but was subsequently associated with intussusception (a folding of the intestine) in fewer than 1:10,000 children given the vaccine, leading to its withdrawal. In industrialized countries rotavirus is a fairly innocuous infection but in developing countries almost half a million children die each year from dehydration caused by rotaviral diarrhea. Do you think this has any relevance for AIDS vaccines, that perhaps we have to look at the risk-benefit analysis of a vaccine in the context of a particular country?

I'm very familiar with the intussusception story, and we lost an opportunity there. The strategy for introducing most vaccines, still in use today, is introduction first in industrialized countries to try to recoup some of the development costs and then move it to developing countries. The conversation about rotavirus vaccine took place after the intussusception issue was identified in the US, when the vaccine was not actually in use in developing countries.

There is a very, very heavy political component to this. It's very difficult for decision-makers in developing countries to justify using a vaccine that was found not to be safe enough for the US. I've seen all the calculations of how many lives will be saved, because intussusception, as you say, is a very rare phenomenon, but from the very beginning I knew that it would be too much to ask for decision-makers in developing countries to accept a vaccine that had been found unsafe.

Now, had the rotavirus vaccine been simultaneously tested and introduced into industrialized and developing countries, I think the discussion would have been different. Developing countries may have different risk-benefit decisions than industrialized countries. A risk-benefit analysis takes into account burden of disease, the cost of the product, its ease of use, and many other factors that typically differ from country to country. But the value of life is the same anywhere in the world, and if the perception is that you are proposing a substandard vaccine in developing countries, that will not fly.

So that's a lesson to learn for HIV vaccines: Simultaneous testing and simultaneous introduction of the vaccine in developing countries, and allowing developing countries to make their own risk-benefit analysis. A major priority for the Foundation is helping to ensure that health products that could save lives reach the people who need them the most as quickly as possible.

Given those provisos, do you think there is a global perception now that HIV/AIDS within developing countries has become such a crisis that perhaps these conversations can now be broached again?

Yes, I think so, and the reason is that there is far greater research literacy in developing countries today than ten or 15 years ago. Then it was very difficult because basically you went to developing countries to ask them ‘Please trust me. Trust the NIH. Trust the WHO.' It's very difficult to have a rational and pragmatic discussion when you're asking people to trust you. Today, I think that thanks to the work of many people, IAVI included, vaccine literacy is much higher.

What do you think sets apart the Enterprise's way of doing business? What does it offer above and beyond the collaborative efforts already underway?

I have been observing the field of HIV vaccines for many years, and I saw a major strategic shift after the results from the recent Phase III trials. On one hand, the research community realized that developing an HIV vaccine was one of the major scientific challenges we were confronting and that a much more intense and rational effort was needed to complement the more or less empirical approach taken up till then. The other shift was what I call from the "solitary hunting approach" to "pack hunting," as prehistoric man did when he shifted from hunting small animals to mammoths. If we want to succeed on this hunt, we need to reorganize ourselves in a more purposeful and targeted way, as that proposed by the Enterprise. Collaborative efforts should expand beyond exchanging reagents and talking in meetings, to a more structured and accountable way—perhaps we should look at how collaboration is structured in industry.

But I want to clarify that the Enterprise does not propose to replace the creativity of individual investigators, which we consider essential. The Enterprise proposes to supplement that creativity with systems and structures that provide the critical mass, a clear blueprint for research that may lead to discovery and product development, access to information and resources, a supportive political and community environment, and the financial resources to achieve success.

I recently had a conversation with Rino Rappuoli, who for me is the quintessential, practical vaccinologist, and he thinks the industrial model is very much an engineering approach. If you want to put a man on the moon, you know the laws of physics that will govern how a rocket will fly from the earth to the moon, so it's an engineering problem, an industrial problem. The problem we have with HIV vaccines is that we are to some extent in a pre-industrial stage, because we don't have a solution, and we have to explore many avenues, we have to build many small space probes rather than one big spaceship. However, if the industrial model means a more targeted effort with clear milestones, with clear go-no go decisions, in which the different partners are accountable for their contribution, then I like the industrial model.

A number of people believe there is a strategic gap in the field of HIV vaccines. We can divide the vaccine development process, from an idea to injection into the arms of people, through four phases. The first is the discovery phase, creation of new knowledge, and the NIH is the driving force. Most NIH-funded scientists stop at that level, publication is basically their goal. The second is the translational or, as I like to call it, maturation phase. The third phase is the manufacturing phase, the typical industrial approach, the engineering phase. And the fourth phase is the delivery of the vaccine, we have a vaccine, how do we make it available to people around the world?

My feeling is that we have a strategic gap in the second phase, and that is one of the areas where the Enterprise can make a major contribution and help mature ideas so that they become interesting leads for industry to follow, and then work together with industry as real partners, because we need industry for their process development and manufacturing expertise.

What are your initial impressions of how CHAVI is developing?

I think that the success of CHAVI is related to the success of the Enterprise: We need to improve the way scientists interact with each other and CHAVI represents a new model for increased collaboration. CHAVI and the NIH decided to first identify the core leaders and then asked those leaders to develop the network. The foundation is taking a similar approach, although we first identified the members of the network, and now we are working with them to establish a collaborative group.

What I see from CHAVI is that they are making a very serious effort to do two things. One is to bring new partners to the field. Now, of course many of the leaders are veterans of the HIV vaccine effort, because you have to go to those people who have the knowledge that we need to tap. The trick is getting the same players to play a different game, a more cooperative game. But CHAVI is also making an effort to bring in new players, and in their list of collaborators you see more people from developing countries, more strategic alliances being created with people who are actually newcomers to the field.

The second is to bring new money to the field, and the NIH has pledged up to US$350 million for CHAVI. That is additive money, and hopefully it'll create a culture of more collaborative work than the typical NIH R01 grants. We are eager to see CHAVI's progress: I'm very optimistic that CHAVI is a critical contribution to the Enterprise.

It seems that the Enterprise's strategic scientific plan has been quite a step forward, and that at least the broad scientific questions, have been agreed upon.

I'm going to say something you may not be expecting: While the plan is important, in fact what's more important is the process that led to the development of the plan. That's a process of bringing people together and challenging them to identify the key questions and potential ways to address those questions, and I think that discussion between 150 scientists from around the world was very helpful.

The plan was agreed upon by everybody. Why? Because it basically represents what we would call the current paradigm. I wrote an article (International Microbiology 8, 93, 2005) on the Enterprise where I address the issue of group think versus individual thinking, and I refer to one of my favorite philosophers, Thomas Kuhn, who said that in the scientific community knowledge moves not by gradual increment but by scientific revolutions.

Thinking within the scientific community is defined by the current paradigm because the individual thinking that the scientific community values so much is constrained by preexisting data and available tools, but also by the ability of getting grants or getting published, by the peer review system in general. If you are a very innovative, creative person, maybe you will not get the grants and your papers will not be published. So the scientific plan that we have today is mostly a current paradigm plan, but still have to explore harder how to bring in new paradigms, real innovative ideas.

Kuhn proposed that when the current paradigm doesn't provide a solution to a scientific problem, then the scientific community jumps to a new paradigm. Now, when you try to jump to a new paradigm, you're trying to jump with ideas that are not supported by data, because they are new. Most of the time those new ideas outside of the paradigm are wrong. So jumping to a new paradigm will require taking risks to a level that most organizations cannot accept.

Although the solution for an HIV vaccine may come out from the current paradigm we need to be constantly looking at innovative research, how to bring really new science, not only theoretical knowledge but also even instrumentation and bioengineering tools.

What do you see as the next big step in the Vaccine Enterprise?

A year ago the Gates Foundation issued a Request for Proposals, inviting the scientific community to submit innovative ideas and approaches to accelerate HIV vaccine development focusing on vaccine discovery, both antibody and T-cell inducing vaccines, and laboratory standardization. We're planning to make an announcement within the next few months. We're structuring these projects as an interactive and collaborative network that shares information, reagents, and ideas, not only among themselves but with other key partners of the Enterprise, including CHAVI, IAVI, and others.

Our major priority is expanding the research agenda to implement the scientific priorities identified in the Enterprise plan. Also, the Enterprise is almost ready to appoint its first Chief Executive and to establish its permanent secretariat. In the short term, our other priorities are to update the current scientific plan and establish approaches to monitor its implementation by the Enterprise partners, start the implementation of activities in the areas of clinical trials capacity, have a reality check on our approaches to working with industry in areas of process development and future manufacturing, fine-tune our investment menu—a list of financial needs to implement the priorities identified in the scientific plan—and use it to raise the necessary funds for the Enterprise partners and for the secretariat.