Vaccine Renaissance

With the very latest in x-ray crystallography, structure-based design and advances in cell-culture technology, it’s a renaissance period for vaccines, believes Dr. Gary Nabel, Director of the Vaccine Research Center within the National Institute for Allergy and Infectious Disease.

NGP. What is it about vaccines that makes it so difficult to create them?
GN. The fundamental difference between working on the development of vaccines and probably almost any other medicine is that you’re administering vaccines to people who are otherwise healthy. There’s an axiom in medicine: above all else, do no harm. And so, when you have a vaccine that you’re giving to a healthy person, there’s great value that we place on safety. Where side effects are often tolerated for medicines, with vaccines we have a very low tolerance for them. We’re faced with having to do a lot of safety and regulatory testing that meets our standards and the standards of the regulatory bodies.

In addition to that, we’re often dealing with infections that are very difficult to control immunologically. For so many of the traditional vaccines, there are well-established examples that are followed for how humans normally control those infections. When you talk about diseases like HIV, where there’s little precedent for immune control or protection from disease, we’re trying to do something that’s never been done naturally. And so, there are aspects of the biology of some infections that make them difficult vaccine targets as well.

NGP. One classical way of making vaccines is to use an inactivated viral particle of some sort. What are the disadvantages of this approach?
GN. There are two classical ways of making vaccines. One is to take an inactivated particle, as you say. The other is to attenuate a virus and to use the same virus but one that won’t cause disease, one that’s been modified biologically or genetically. There are advantages and disadvantages to each.

The inactivated virus doesn’t really give you a true infection. It tends to encourage one type of immune response, the antibody response. But it tends not to stimulate the cellular immune response, which is often very critical in controlling infections. The live attenuated one often does better, but there are safety issues with live attenuated vaccines. If they should start to replicate, they can cause problems in some individuals – like the smallpox vaccine does in people who have psoriasis or other skin conditions, or in asthmatics.

More and more, people are moving away from live attenuated vaccines and as a whole, the field is moving to newer technologies that involve recombinant DNA technologies and use of newer delivery approaches, like DNA or replication defective viruses; though you have to figure out whether or not they have the efficacy that you need.

NGP. What do you consider the most promising ways to create antiviral vaccines?
GN. One that I find most promising and that we put most of our effort in is gene-based vaccination, where we take specific genes from viruses that cause disease. We insert them into vectors that will express them when they’re injected into the body. Those vectors express specific viral genes that elicit immune responses against them. It’s a nice way to stimulate the response because you’re getting some aspects of the natural delivery of the virus. In other words, the cell that receives the vectors makes these viral genes, so it’s a more physiologic presentation of the proteins, but you avoid the consequences of infection that you would have with a normal virus. And so people use a variety of different vectors: DNA, adenovirus, poxviruses, adeno-associated viruses, and there are others as well. We’re focused more on DNA and replication-defective adenoviruses because that combination seems to do very well immunologically, both in animal models and in people.

There are other approaches as well, though. For example, some take advantage of newer techniques in molecular biology. There are recombinant proteins that can be made. They can be engineered to look more like the natural viruses. There are artificial viruses that look like viruses but can’t grow after injection into recipients.

One of the exciting things that’s happening now in vaccines is that we have been able to use some of the advances in molecular biology, molecular genetics, and molecular immunology to develop more effective and safer vaccines.

NGP. As far as your research efforts are concerned, are you happy with the progress you’re making?
GN. We’ve been encouraged by the progress we’re making. We are hoping to start an efficacy trial for an AIDS vaccine next month. We began developing that vaccine in 2001. So to have gone from a theoretical concept to the beginning of an efficacy trial in short period of time, probably more quickly than has ever been done before. We’re just getting data from the phase II trial, and we’re encouraged by what we’re seeing. And with our Ebola vaccines, at least in animal models and early human studies, we’re seeing the kind of immunogenicity that we were hoping to see.

Having said that, we’re not across the finish line, and in the case of HIV it’s important to recognize that this will be an incremental process. It’s very unlikely that the first vaccine that we test in efficacy will be the one that will be highly efficacious and ready for immediate use. But if we can derive basic knowledge about how to achieve efficacy from the trial, it will guide us in the future. Then there will be a good chance for getting the HIV vaccine.

NGP. What are some of the challenges, expected or unexpected, that you’ve come across?
GN. There are challenges at all levels, for example, at the level of production. Even when it’s easy to make a reagent at a laboratory bench, it can be be a challenge to translate it into something that can be scaled up and meet all of the safety and manufacturing requirements. We’re very lucky to have some excellent expertise, both within the VRC and within our industry collaborators.

With HIV, scientifically there are great challenges in trying to cover the diversity of viruses that you see in the world. What’s different about HIV from any of the other viruses we work with is that it’s not a single virus. It’s literally millions of different viruses each with slightly different genetic sequences. So instead of making a vaccine against a single virus, we’re making it against this swarm of viruses. It’s a lot harder to identify common points of vulnerability and to give the breadth of protection that we would like. It’s also very resistant to neutralizing antibodies, at least broadly neutralizing antibodies, so those clearly are challenges with which we have to deal.

NGP. What are the advantages of DNA viral vaccines over non-DNA viral vaccines?
GN. DNA vaccines are not viruses, they’re synthetic pieces – pieces of DNA grown in a plasmid – and so they are easy to grow. But they don’t have any of the natural targeting mechanisms that viral vectors would have. Viral vectors, if you chose the right one, can target you more effectively to the right cells to stimulate an immune response. But they carry some extra baggage with them: they carry proteins on their surface that can also be the targets of the immune system. And so it’s possible particularly in the case of adenoviruses that pre-existing immune responses against related viruses could diminish the efficacy of those vectors. That’s not been a showstopper for us, but it’s been something that we’ve been concerned about.

NGP. How will the pharmaceutical industry benefit from your research efforts?
GN. The pharmaceutical industry is very important in this whole process because ultimately, to distribute a vaccine on a mass scale to people who need it, we need their manufacturing capacity. They benefit from what we do because we take on much of the upside risk in terms of developing it and showing that it works. And we bear those expenses as well, so particularly for diseases like HIV, TB or Malaria, where there’s not as much of a market, we can defray some of the risk to them, which it makes it easier for them to step in later with a product that’s likely to be successful. So partnerships are really quite important. And from our perspective, if we want to see the vaccines developed and used, unless we can make the hand-off to them, it won’t happen. It’s very important that we have good lines of communication and careful coordination as we proceed through the development process.

NGP. The adenoviral production is cell culture based. What are advances that are being made in cell culture technology?
GN. There’s been very good progress with cell culture based technologies. It’s very important particularly if you have a disease like avian flu, where you are dependent on chicken eggs to grow your vaccine. Avian flu could potentially wipe out these chickens, and there would not be a vaccine.

If it’s done properly, there’s more control over adventitious agents, purity and reproducibility with cell culture vaccines. Acambis developed one for smallpox that looks like it’s performing very well, and Novartis has developed a cell culture method for flu vaccine. There are other companies that are developing them. It’s an important advance in the product technology, so I’m very happy to see it.

We’re basically in a renaissance period for vaccines. A few years ago, they were regarded as something that we took for granted, where there was thought not to be a lot of science behind it. Now, it’s the opposite. You’re seeing the very latest in x-ray crystallography, structure-based design, immunology, virology and production technology. With that combination of tools, we’re poised to make good progress on some very difficult targets.

NGP. Where will you concentrate your efforts in the future?
GN. HIV is our primary goal. Ebola and Marburg, the hemorrhagic fever viruses, are next. We’ve also taken a pretty active role in influenza virus vaccines with an eye towards making universal vaccines and also with preemptively preparing for avian flu.

Dr. Gary Nabel undertook the position of Director of the Vaccine Research Center (VRC) within the National Institute for Allergy and Infectious Disease at the NIH in 1999. He is well known as a molecular virologist and immunologist for his work in the fields of HIV, cancer, and Ebola virus research. His laboratory has studied mechanisms by which cells coordinately regulate the expression of genes during viral infection and development.