Accelerating Development of Bioterrorism Vaccines

An Interview with Philip Russell 

Since October 2001, Dr. Philip Russell has been a senior advisor in the US government’s scaled-up program to stockpile vaccines against the most threatening bioterror agents, and to develop a new generation of safer, faster-working products. The program sits within a newly created Office of the Assistant Secretary for Public Health Emergency Preparedness in the Department of Health and Human Services (HHS).

Russell’s career in vaccine development and infectious disease research spans over 40 years. An MD certified in internal medicine, he held leading positions at the Walter Reed Army Institute of Research in Rockville, Maryland and conducted medical research in Pakistan, Thailand and Vietnam. After retiring from the military in 1990, Russell joined the faculty of the Johns Hopkins School of Hygiene and Public Health, and was named Professor Emeritus in 1997. He also served as special advisor to the Children’s Vaccine Initiative from 1990-1994, was a founding member of the Albert B. Sabin Vaccine Foundation, and is now on IAVI’s Board of Directors.

Here Russell speaks with IAVI Report editor Patricia Kahn about new vaccines in the pipeline, how the R&D is being fast-tracked—and what lessons this might offer the AIDS vaccine field.

What does your role as special advisor on vaccines entail?

My basic responsibility is to coordinate efforts of the public health service agencies in bringing the new vaccines we need into the inventory, starting with smallpox and moving onto others.

One of the reasons for creating this office was that HHS did not have what in government parlance is called an ‘acquisition mechanism.’ HHS has never had a continuing program for research, development, stockpiling and use of vaccines. It’s done all of the pieces, but one at a time. So there wasn’t any process in place for defining requirements, contracting for research and development of a state-of-the art vaccine, purchasing the product, seeing to licensure and so forth. Those are the issues we’re coordinating from this office, starting with the new smallpox vaccine.

What strategies are being used to make improved smallpox vaccines?

The first thing is that we’re re-manufacturing the old vaccine in cell culture, under a contract with Acambis, a US-British company. [Editor’s note: Traditional smallpox vaccines contain live vaccinia virus harvested from the skin pustules of infected calves.] That’s not scientifically very novel, but it’s a major step forward in terms of developing the production, purification and testing techniques for this vaccine. Over time, we will replace all old vaccine with this new product. It’s the same virus in the vaccine, just a more efficient production and a much purer product.

But the big problem with the current vaccine is that it’s dangerous for certain people [due to replication of the vaccine virus]. It’s very dangerous for those with eczema, especially kids. It’s dangerous, or even lethal, for seriously immuno-suppressed individuals—people with HIV, transplant recipients, those undergoing cancer chemotherapy. That’s a substantial population.

So the next big task is to find a safer way to immunize than with the current vaccinia strain. The preferred short-term option is to use MVA [modified vaccinia Ankara, a highly attenuated vaccinia strain]. NIH is now soliciting proposals for potential contractors to develop and manufacture an MVA-based smallpox vaccine.

Why MVA?

There is 1970’s data from Germany showing that intramuscular injection of MVA at high titer was a very good way of modifying subsequent immunization with standard vaccinia vaccine. So the idea is to rapidly develop an MVA strain as a first vaccination for people where vaccinia is contraindicated. If MVA works well, maybe it could even replace a follow-up vaccinia immunization. Both options—MVA and then vaccinia, or two doses of MVA—will be tested.

How can the efficacy of smallpox vaccines be tested, and what proof of efficacy will be required for licensure?

For this first Acambis vaccine, we don’t a problem proving efficacy. All we have to do is prove that it gives the same types of clinical and serological responses as the current vaccine. The large-scale trials are merely safety trials.

But licensing the next generation of smallpox vaccines will test the FDA’s new animal rule. According to this rule, if there’s no ethical way to test a new vaccine in humans—for example when it’s against an eradicated disease—we have to show that the vaccine produces similar immune responses in both humans and an animal model, and then demonstrate that it induces protective immunity in this model.

Smallpox doesn’t infect monkeys except in very high intravenous doses, so there isn’t a good monkey model of variola [the virus that causes smallpox]. But there is a closely related monkeypox virus, which produces a serious pox disease in monkeys. There’s also rabbitpox, camelpox—almost a pox virus for every animal. They are all orthopox viruses, a family of viruses closely related to smallpox.

The immune response to vaccinia is focused on structural proteins that are highly conserved between variola and the orthopox viruses, which is why Jennerian vaccination works. [Jenner’s original smallpox vaccine used cowpox.] We also know that vaccinia protects against monkeypox, mousepox, rabbitpox and so on.

So for licensing, we will test whether MVA can protect in these animal surrogates. And we’ll need to show that the vaccine generates anti-variola neutralizing antibody. It’s going to be difficult because we are breaking a lot of new ground here: new tests of the animal rule, and with an indirect model [using a different virus than the vaccine’s intended target].

Will you also look for cellular immune responses, and with what assays?

We’ll look for everything we can measure, but focus on the antibody response. Not because it’s necessarily more important, but we know that if you don’t get an antibody response, you’re unlikely to have protective immunity. In terms of assays for measuring cellular immunity, we’re going to lean on the HIV and cancer vaccine communities for guidance.

What’s known about immune correlates of protection for smallpox?

Despite the huge amount of experience we’ve had using vaccinia-based vaccines to protect against variola, the exact correlates of immunity aren’t well-understood. We know that both cellular and humoral components are important, and that immunization with vaccinia produces neutralizing antibody against both vaccinia and variola.

MVA is also being used as a vector for candidate vaccines against HIV and malaria. What would it mean for these efforts if there’s a new MVA-based smallpox vaccine?

That’s a very good question and I can’t answer it. Widespread use of MVA, or any smallpox vaccination program, would seriously interfere with the use of these vectors for other vaccines. That’s a significant worry. The whole issue of widespread vaccination against variola has to be factored into decision-making.

But the probability of widespread global vaccination with vaccinia or MVA is very low, especially in the developing world. So there’s no justification at this point for changing course and not pursuing MVA-based vaccines for HIV and other diseases.

What about the US?

How widely we’re going to vaccinate is still an open question.

Is it far-fetched to ask whether MVA could be used to make a vaccine against multiple diseases?

No. I think the work of NIH and its contractors on MVA will enhance knowledge of how this virus functions, both as an immunogen and as a vaccine platform. It may well be that a national strategy downstream is to include other antigens.

It usually takes some time after vaccination until protective immunity is established. Why is smallpox vaccine effective even when it’s given shortly after exposure?

The data are pretty clear that vaccination within a few days of exposure to smallpox has a dramatic impact. It is a unique situation; maybe the only vaccine that works this way.

The pathogenesis of smallpox involves a long incubation period. Infection occurs by inhalation, which gives primary replication in the oral pharynx. Then there’s a viremic spread that seeds the skin. During this period, the patient is asymptomatic. Finally there’s viral replication in the skin, which produces the serious illness.

But the vaccine grows a lot faster—when vaccinia is injected into the skin, it immediately starts an infection. The cellular response begins very quickly, although antibody doesn’t come up very fast.

There’s also a lot of attention now on anthrax vaccines. What is being done?

NIH recently gave two contracts for the rapid development of a second-generation anthrax vaccine, which will be a recombinant vaccine against the so-called protective antigen of anthrax [a protein that helps anthrax toxins enter cells]. Antibody against this protein has been shown to be the dominant—perhaps the only—important factor in the current anthrax vaccine and the contracts went to VaxGen and to Avecia in the UK [see Industry Insider]. A recombinant vaccine would be an important step forward, since it could be produced and highly purified on a large scale. And it would be a very safe vaccine, and easy to control quality.

How will it be tested for efficacy?

Again, through the animal rule. In this case, the animal models, especially the monkey, are very good.

What other new vaccines against potential bioterror agents are being developed?

There’s been a very rapid surge in the bioterrorism business at NIAID.

For smallpox, MVA is a first attempt at a safer vaccine. I think it will probably succeed. But I don’t know if it will be the final answer. There’s obviously going to be more work on how to better protect against smallpox.

Then there’s a whole set of vaccines that are less urgent for civilians, but are needed to protect laboratory workers and the military. We need a plague vaccine, a Rift Valley Fever vaccine, encephalitis virus vaccines. And I would assume that there’ll be some serious efforts soon on what we used to call orphan vaccines.

Let’s talk about vaccine supply and manufacture. We often hear that the vaccine market is much smaller than that for drugs. What are the financial incentives for industry to develop and mass- produce these new vaccines, especially with pressures to keep prices low?

Very simple. Money.

But isn’t the profit for vaccines relatively low?

I can’t answer that. I have no insight into what the profit margin is for Acambis, for example. But obviously they’re business people. They made a bid, came in with a price, and it was acceptable to the government.

What got Acambis involved initially was a long-term contract that called for research and development first, then for an initial production and finally annual production of a certain amount for 20 years.

I suspect that a major incentive was that this is a virtually guaranteed market for a long time. In the second Acambis contract, I think the size of the order was enough of an incentive: 154 million doses.

So you’re talking hundreds of millions of dollars. Somewhere in there is some profit—enough that companies bid on it. They were probably also betting on the fact that this would give them an entree into the international market.

Do you think that advance purchase commitments like these would also be an incentive for AIDS vaccine developers?

Yes. For anthrax, and for all the accelerated development programs, we’re including promises of a substantial initial purchase. So even if there’s more than one company involved, the companies are assured of at least a certain size market. To the extent that they see it as big enough to justify their opportunity costs, they’ve bitten.

Is there enough existing capacity to produce the new vaccines we need, or will more need to be built?

Some of both. We’re taking maximum advantage of existing capacity but also building new capability, especially where there’s new technology. The smallpox vaccine from Acambis and its partner, Baxter International, is a mixture. The bulk manufacturing took advantage of an existing plant that makes flu vaccine, but had a down period. So it was available to produce the bulk of the Acambis smallpox vaccine.

On the other hand, for later manufacture using a new process, Acambis has to either build or renovate a plant.

There are now serious shortages of certain basic childhood vaccines for the developing world. Will the new production demands for smallpox and anthrax vaccines make this worse?

I don’t think so. The short supplies of existing childhood vaccines has a mixture of causes. Some of it is capacity. Some is regulatory, and the economic requirements to meet more stringent regulatory standards.

As far as we can tell, we’ve avoided any impact on basic vaccines. The only one that came close was that we had to work around Wyeth’s influenza manufacturing capacity to process the stored material for the Wyeth DryVax. But we were able to work around this.

How does Acambis have enough capacity to produce hundreds of millions of doses of a new smallpox vaccine?

Partly by teaming up with Baxter, and partly because they were a startup vaccine company. They’ve been working on several vaccines, so they had internal capability and purchased manufacturing capacity. Some of the work, for example bottling, lyophylizing and labeling, is being subcontracted.

How is liability being handled in these large contracts?

With great difficulty. It’s a complex issue and frankly, one I’ve left to the lawyers.

Acambis was able to get insurance to cover liability for the first parts of its contract. But the issue shifts when you get into large-scale vaccination, and that’s where the government will have to provide some liability protection.

Are there any plans for speeding up FDA review?

For these high priority projects, the FDA has made special efforts to manage the review and regulatory aspects very rapidly. They are having frequent meetings with the companies and scheduling the submissions. So when the submissions come in, the FDA is immediately poised to respond.

They have also been incredibly responsive on manufacturing issues. There are none of the usual delays—bioterrorism issues jump the queue. The process is just as complete, but it’s a lot faster.

What else is being done to move things more quickly?

A lot of things we’re doing to compress the timeline involve enormous risk-taking. Acambis and Baxter manufactured maybe 200 million doses of bulk vaccine before submitting the initial file, and before there was any clinical data. No company in the world would take that risk under ordinary circumstances. Normally they don’t do large-scale manufacturing until they’ve had lots more experience, and more feedback from the FDA.

But we’ve had to start doing things based on what we predict will happen. We now have between 25 and 30 million doses, bottled and lyophilized, of Acambis smallpox vaccine, even though the first clinical trial doesn’t start until about mid-October.

In this case it wasn’t an inordinate risk. From the preclinical data, this looks just like the old vaccines. And the seed viruses were derived from the Wyeth vaccine, so there’s a high level of virologic confidence that allows us to take that risk. Nonetheless, from a regulatory and manufacturing point of view, it’s a very high-risk business.

It’s striking how many ways there are to accelerate vaccine development when there’s enough push. Do you think some of this will spill over onto AIDS vaccines?

I hope we’ve learned things that are generalizable in terms of driving programs faster. It all comes down to money in the end. If you have enough to guarantee a large first buy, then you can provide the incentive for a company to move fast. And if the developer is willing to accept risk, there are ways of short-cutting the usual process—for example, manufacturing at risk, as we’ve done, and doing things in parallel rather than serially.

The huge question with an HIV vaccine is how much risk to take before you have solid information on efficacy. When do you invest in scaling up and manufacture?

Actually there are two risks. One is if you do a Phase III trial, prove efficacy and then it takes two years to scale up and manufacture. That’s a terrible scenario. The other risk is that you manufacture the vaccine but the Phase III trial bombs, so you’ve blown a lot of money.