Important note: Information in this article was accurate in October 2001. The state of the art may have changed since the publication date. One of the conflicts associated with developing vaccines that people don't think about is why it takes so long for vaccines to be developed. Basically, there are two types of vaccines: There are vaccines that prevent infections -- those are called preventive vaccines. Then there are vaccines which treat infections, which are therapeutic vaccines. When you hear people saying that President Clinton challenged us to develop a vaccine in ten years, they're talking about developing a vaccine to prevent infections. And that's really where the bulk of the research effort is going these days. Some of these vaccines may also be able to be used as treatment vaccines. The vaccine that I've been working on actually started out being developed as a therapeutic vaccine, and we will continue to do that. But its first use is going to be as a preventive vaccine.
Four years ago, President Clinton said, "You know, we're 16 years into this epidemic, and we really need to have a vaccine," and a lot of effort was put behind that. We've heard a lot about vaccines in the news lately, and a lot of people wonder why it is we don't have a vaccine. The reason is that, first of all, when we first started talking about this epidemic twenty years ago, we knew nothing -- we were starting from scratch. And we've really taken quite a bit of time to understand what it is that we're trying to target when we make a vaccine.
One of the problems with viruses, and one of the reasons why we need a vaccine, is that we don't have drugs to treat viruses, in the way we have antibiotics to treat bacterial infections. When you were a child and you were vaccinated, the vaccines that you got were mostly against viruses: They were against polio, they were against measles, mumps, rubella. They were against viruses for which we have no treatment. The goal was to either prevent an infection or to make an infection that you get not quite so bad. People will sometimes say, "Oooh, I had the flu vaccine last week and then I got the flu, and I must have gotten it from the vaccine." What really happened was probably that the flu vaccine was given during flu season. They got the vaccine and they probably got the flu, because what the flu vaccine does is make the flu less bad. So, instead of getting the flu for a week, you get the flu for two days. The misconception is that it's the vaccine that gave them the flu, when the reality is that the vaccine made the flu less bad. When you ask if you can take a drug to treat it -- there are really very few drugs for viruses. There are a couple of new drugs for the flu that have come out in recent years, and that's pretty much it. So basically vaccines are our only hope for dealing with viruses.
A vaccine is a preparation that stimulates an immune response to protect against a foreign substance. The immune response prevents developing an infection. There are antibody responses which prevent cells from becoming infected, and there are cellular responses that remove infected cells from circulation. A vaccine can target either or both parts of your immune system.
B-cells are responsible for secreting proteins which are called antibodies, and these prevent cells from getting infected. They coat the virus and then it gets taken out of circulation. If, however, something makes it past that first line of defense, then you've got an infected cell. And now you need to get rid of the infected cell, and that's where the cytotoxic T-lymphocytes come into play. Their play is to remove the infected cells from the system. In looking at a magnification of the HIV virus, there are a lot of different parts of the virus -- and each one of those parts of the virus can be targeted by a different immune response. And each one of those parts of the virus makes it vulnerable to us as scientists to try and develop vaccines.
There are human costs that make us need a vaccine, and there are economic costs. What are some of the human costs? There are 36 million people who are living with HIV and AIDS in the world. There were 18.8 million cumulative deaths as of the end of last year. There are 16 thousand new infections in the world every single day. Thirteen thousand of these are people between the ages of 15 and 49. We're losing an entire generation of people to this epidemic. In the United States, almost two teenagers are infected every hour of every single day. The epidemic is at its worst in sub-Saharan Africa, and in Southeast Asia.
According to UNAIDS estimates, a million new infections occurred last year. These are estimates, because in a lot of places infections aren't recorded. But, again, the bulk are in sub-Saharan Africa, and in Southeast Asia, where there isn't access to antiretrovirals.
As to economic costs associated with the epidemic, the United Nations estimates that medical and human costs have stifled economic and social development in fifteen countries so far. And highly active antiretroviral therapy, which has been an amazing phenomenon, costs between $15,000 and $30,000 per year. This is not a viable alternative for the developing world.
As I said, there are different vaccine types: There are preventive vaccines (sometimes called prophylactic) to prevent new infections. There are therapeutic vaccines, and those are used in the treatment of people already infected. As a concept, therapeutic vaccines really didn't exist until about three or four years ago. So when you hear people talk about vaccines, you've heard people talk about preventive vaccines.
At a vaccine meeting I attended three years ago, someone said they wanted to talk about therapeutic vaccines. One of the old-time vaccinologists said "There's no such thing as a therapeutic vaccine," and he turned and walked out of the room. It really wasn't until people started doing trials for cancer that we started talking about therapeutic vaccines. They're not necessarily the same sorts of vaccines that you think about for a virus. In that case, they're giving people back cells that might be able to protect them, and we're calling that a vaccine because it's stimulating an immune response. Therapeutic vaccines are in their infancy, but they have great potential -- such as the possibility of re-exposing somebody to a safer version of the virus so that the body can try to fight it off, and so that maybe the structured treatment interruption periods could be longer. Our initial goal isn't to use this therapeutic vaccine to eradicate the virus -- our goal is to use it to allow for treatment interruption. I think the vaccines you will see in the next few years will not be just one thing or another, therapeutic or preventive.
There are education and behavior modification, which we have done and continue to do since the beginning of the epidemic. There's drug abuse treatment to try to prevent people from needing to use dirty needles. There are condom usage; topical microbicides (an area which has very active research right now); the treatment of other sexually transmitted diseases (we know that STDs are a risk factor for getting infected with HIV); and the interruption of transmission from mother to child.
But the single best approach to prevention is going to be vaccination.
So what are the concepts that we want for an ideal vaccine? An ideal preventive vaccine would be effective regardless of the nutritional and health status of the target population, or its ethnicity. Think about this: where are we going to need to deliver the vaccine? It's going to be delivered to the developing world, to Europe, to everywhere. So you need that not to be a factor. You want the vaccine to protect people against all types of HIV, since different types of HIV circulate in different parts of the world. An ideal vaccine would be a single vaccine that would protect everybody.
You would want it to protect against any route of HIV infection, whether it's sexual transmission, mother-to-child, or by needles. You would definitely want it to be inexpensive to manufacture. You would want it to be easily transported and administered because you'll need it in remote regions of the world in an effort to deliver the vaccine. It would need to be stable under field conditions and also provide long lasting protection so that, if possible, you would only need to give a single vaccination -- and this is really important to keep in mind. We'll talk about it a little bit at the end, but there's only one viral disease that's ever been cured and eradicated from the world, and that's smallpox. That was eradicated by a vaccine. The very last parts of the world where people went in with that vaccine -- they went into villages and held guns to people's heads and said, "You will take this vaccine." If you had to go back and do that again, do you actually think that they would have been able to pull that off? It's not that I think that they should have done it, but my point is that we want a vaccine that you only have to deliver once.
So there are different objectives for a vaccine. One would be what we call "sterilizing immunity" -- you would prevent everybody from getting infected. You could also say, well, that's not really realistic -- I'm going to go for what most vaccines do, which is that someone can become infected but there will be no disease. Or they'll become infected but there will be a longer time period before somebody gets sick. Or somebody can become infected but will have a low risk of transmitting the disease to somebody else. And these are all issues that people who are doing vaccine research struggle with every day.
Another question is, how much efficacy is acceptable? Would you want 90% protection against repeated exposure? Would you want 98% against a single exposure? How about 57% against ten exposures? These are all issues that we still haven't dealt with, and that still really need to be dealt with, in terms of the field of vaccinology.
I'd like to give you a very brief description of what it takes to bring a vaccine from an idea to something that can be delivered to people, so you can understand why it takes so long. What are the phases for vaccine development? They're actually the same phases that are involved in any kind of drug development. The first thing is to have someone like me walk into a laboratory and have an idea, and we do what's called pre-clinical testing. You do that to design and produce a vaccine or a drug, and we do a bunch of testing in the laboratory to see if it works. If it works in the laboratory, then we do some testing in small animal models. Then, if we see anything in the small animal models, which are really not that relevant, then we do studies in monkeys, which are unfortunately not perfect models, but are the best animal model that we have so far. And this is all pre-clinical -- this is before the drug goes into any person.
Then, if it makes it through this, the next phase is what's called a Phase I trial. A Phase I trial is generally done with fewer than fifty people per dose of whatever it is that you're testing. Generally, you choose a low risk population, and what you try to do in a Phase I trial is simply measure the safety of how your drug or how your vaccine is tolerated. Is giving it to a person safe? That is really the goal of a Phase I trial. It takes about eight to twelve months to complete. Sometimes a scientist can sneak in a little data that tries to see if the substance is effective, but that's not really the goal of a Phase I trial. This group is not large enough to determine if something works; you just want to know if it's safe.
If it's safe, then we can move to Phase II testing. In Phase I you've spent one year, and you've probably spent three years in pre-clinical development, so now you're up to four years. Phase II has hundreds of subjects, and people can be of low and high risk. We will do expanded safety testing -- in every single phase, safety is an issue. At this point, we start to measure immune responses. These trials take longer -- they take two years -- so now you're up to six years.
If you make it past Phase II -- and only one vaccine has made it past Phase II in twenty years of this epidemic, you move to Phase III. Phase III involves thousands of participants. You usually need thousands of people because you need to ask how many people would get infected naturally, in the absence of the vaccine. People can be of moderate to high risk. Again, we do more safety testing. With all of the Phase III trials, we try to determine efficacy and immune response. These generally last anywhere from three to five years. So now, just adding all that up, if everything is working, from the day that you have an idea to the day that you finish Phase III, where you can then apply to the FDA to market the vaccine, ten to twelve years have passed. And that's why it takes so long.
Now, I've spent the last three weeks writing a grant to study my vaccine, and one of the big goals of my grant is to try to move this faster, to try to make the pre-clinical stage go much faster so that we can get to these Phase I and Phase II trials without sacrificing safety. If it's going to take twelve years for everybody who has an idea to bring a vaccine to market, it's going to be a very long time before we have a vaccine.
Let's look at government sponsored HIV vaccine trials. About forty-five vaccines have made it into Phase I; three made it into Phase II; one made it into Phase III. It's been twenty years since the beginning of the epidemic; well, let's say eighteen years since we knew it was a virus. Only one made it to a Phase III trial. [See "Vaccine Update" on page 3.] And, unfortunately, this vaccine is using information that we knew eighteen years ago. We know a lot more now -- we can design a much better vaccine, and have. Those vaccines are beginning to wend their way through the process now. There are other trials in other countries; these are trials that have been sponsored by the National Institutes of Health.
Then the question becomes: When do you begin a clinical trial? Let's assume that we have one million people in our mythical country, and 10% of those people are infected today. We have 5% new infections every year. A 60% effective vaccine, if it were started today, would prevent 125,000 new infections over ten years in this mythical country. If we waited five years, until we had a 90% effective vaccine, only 87,000 new infections would have been prevented at the end of that period. So starting sooner with a less efficacious vaccine would have prevented more infections than waiting until we had something better. And that's why it's really important to get things out of pre-clinical testing and get them into clinical trials, because we really can't shorten those time periods. It takes time for immune responses to develop and we need to make sure that what we're doing is safe, but what we need to do is get ideas to the clinical trials faster.
We have made some scientific advances -- I don't want it to seem like this is all doom and gloom. We have in the past eighteen years learned that there are new ways to produce antibodies, and we want to produce antibodies because they're going to be important to prevent infection. We've learned a lot about the immune system from HIV. We actually knew practically nothing about the immune system, we realize in retrospect, until this virus came to be. And we've now learned the role of cytotoxic factors and how important it is to include these sorts of things that we want to target for a vaccine. In the beginning of the epidemic, cellular immunologists said, "It's the cells," and the antibody people said, "No, it's the antibodies," and there were fights at meetings. We've really now learned that we need to take both of them into account when we develop a vaccine. We've made animal model and efficacy improvements. We've improved some processes that we can do in the laboratory as well.
So what are some of the technical obstacles that are still in front of us? We still don't really know what all the immune problems of HIV disease are. We know HIV causes AIDS, but how you get from point A to point B, we still don't know everything. And unless we know what's important, we really don't know what to target with a vaccine. As I said earlier, there are a lot of different strains of viruses circulating in the world -- within one person there are a lot of different strains of the virus. We don't know how important those issues are going to be until we start looking at vaccines that are developed in Country X or in Country Y. We've got some animal models, but as I said, they're not perfect, and that makes it difficult to judge what should go into the clinical trials.
We have only in the last couple of years come to appreciate that there's a whole part of the immune system that we never paid attention to, and that's the mucosal immune system. Think about it: the greatest means of transmission is through sexual routes, meaning the virus has to pass over what we call mucosal borders, either in the rectum or the vagina. We didn't understand anything about mucosal immunity until a few years ago, and now we're beginning to. As I said, we still don't really know what causes pathogenesis.
There are some logistical and ethical issues as well. There are behavioral factors in exposure. There are things that might work in one population that won't work in another population. If we conduct efficacy trials in the United States, then we need to conduct efficacy trials in the developing world. If we go into the developing world, does that mean that we are taking advantage of people who are not in a position to defend themselves? There's a lack of consensus on that, as well as on treatment. Do we provide treatment for people who are in vaccine trials? That's a real issue with a lot of pharmaceutical companies. There's a lot of money that goes into developing a vaccine, and then on top of it, there's pressure brought to provide drugs in case somebody becomes infected, and that's been part of the reason the pharmaceutical companies have been very late to the plate to join in this effort.
There are also potential social harms to volunteers. What if you're enrolled in a vaccine trial and then test positive for the virus -- can someone then discriminate against you? Interestingly, California is the only state in the union that has a law on the books making it illegal to discriminate against someone participating in an HIV vaccine trial. It's only been in the last year or so that people have thought about that. These are major issues that need to be addressed.
There are other potential obstacles. There are market forces and these are things that really come to bear, less for scientists in universities and more for people at pharmaceutical companies. How much profit is going to be acceptable? How much liability is there associated with a vaccine? What if you make a vaccine that doesn't work and somebody sues a company for making a vaccine that doesn't work?
There are pricing issues as well. One of the things that I think that's the most amazing that's happened: The International AIDS Vaccine Initiative (IAVI) has put a rule out that anybody that they give funding to develop a vaccine can only market that vaccine for 10% above what it costs to make it. And that's really something that's going to need to be looked at, because otherwise there's a huge disincentive for pharmaceutical companies to make a vaccine. But people like me can't make vaccines by ourselves -- we need the infrastructure. So we need to attract big pharmaceutical companies to work with people at universities that have ideas, to bring things forward.
And then there are the regulatory issues -- and there are a lot of regulatory issues. The application that we're filing with the Food & Drug Administration for our vaccine is going to be about the size of a phone book -- not a little phone book, a big fat phone book. There may be one sentence that the FDA wants to see in the middle of that phone book. I don't know what it is, but if it's not there -- my vaccine's not going anywhere. So we need to educate people like me who are making vaccines to understand how to work with the FDA, and we're starting to do that. And then there are issues -- again, getting back to market forces -- such as antitrust issues that need to be addressed.
So there are challenges ahead. What I want to show you is what I started out with, which is how long it takes to make a vaccine. There are some vaccines that you commonly get during childhood. For instance, polio: the disease was discovered in 1908, the vaccine was developed in 1955—47 years from the time that we knew the cause of the disease to develop a vaccine. Hepatitis a -- 20 years; hepatitis b -- 15 years; measles -- 30 years. We're 18 years into knowing what causes AIDS, and we still don't have a vaccine. This is what I talked about with smallpox. From the time we knew what caused smallpox until we eradicated it, 200 years passed. From the time in the 1940s that we were able to make a vaccine that we could deliver around the world, it took another 40 years to eradicate smallpox. And, again, smallpox was eradicated by people going into villages and holding guns to people's heads. We've been trying to eradicate polio. We were supposed to have polio eradicated in the world three years ago, but to vaccinate people in remote regions now, we have to negotiate peace treaties so that scientists can go and administer the vaccine. These are issues that need to be taken into account when we design vaccines, and when we design vaccine trials.
People need to understand that we're going to try to make vaccines, and I hope that you'll do your part. But it's going to take time. I think it's great that President Clinton stood up and said that we should have a vaccine in ten years, and boy, do I miss President Clinton. But we have to understand that that's not a realistic goal. It's just not enough time. In ten years, if we're lucky, we'll have five or six vaccines in Phase III trials, which would be spectacular.
So what's our history in HIV vaccine development? We started out thinking that we could just take a little piece of the virus and that would be enough to make a vaccine. Well, that really didn't work. Unfortunately, that's what's in Phase III trials now because in 1988 that's what we thought was all we needed to do. Then in the 1990s we started to pay attention to the cell-mediated immune system and thought we should probably consider using something that would deal with that as well. And now, in the last few years, we've come to a point where we can take all of the knowledge that we've got, and by taking advantage of what we know, make a vaccine that's going to be capable of providing an immune response and targeting the most areas.
Many people want to know, "What can I do? How can I help?" Whether you enroll in a vaccine trial or not is a very personal issue, and people have different reasons for doing it. We certainly want to encourage people to enroll in vaccine trials, but we want you to be very well informed about what you're doing when you sign up. There are risks that are going to vary with each clinical vaccine, and each method of administering the vaccine. It's extremely important, if you're thinking of enrolling in a trial, that you understand what the risks are. Before you enroll, you discuss it with people you trust -- with your partner, with your doctor, with your parents -- you really need to know everything that you're getting into.
The most important thing you need to do is ask a lot of questions so that you can make a really informed decision. You may enroll in Vaccine Trial X and you might never be able to enroll in another vaccine trial again. So you want to make sure that you really believe that Vaccine Trial X is important -- whether you believe it's important because it's going to work, or whether you believe it's important because it's just time to see whether something is going to happen or not. And that's why a lot of people have enrolled in the vaccine trials that are ongoing, not because they necessarily believe that it's going to work, but because it is time for us to show that we can do a Phase III Trial. It's time for us to start to address some of the issues that need to be addressed -- things such as how to protect people from discrimination in vaccine trials. There are a lot of different reasons why one person might choose to be in a trial, and you need to really examine those reasons before you sign up.
I'd like to give you an idea of the process that I have been involved in developing at UCLA. Basically, what I did was sit down and ask myself what was needed. As I mentioned earlier, I think we need to make a vaccine that will produce the broadest response. So how can we do that? I think in order to do that, and this is my personal opinion, we need to have as much of the virus there as possible. But again, you don't want to have something that's not safe. So what we did was to take the whole virus and say, "How can we kill it?" Well, we know we can pasteurize milk and we can kill everything in milk, so let's take the virus and see if we can kill it with heat. And it turns out we can. So then we ask, if we do that, can the envelope, the outside portion of the virus, still bind to antibodies? And can the portion of the virus that has antibodies still bind to antibodies? If it can't, then we can't use this method. As it turned out, it worked even better. The next thing we asked was, could cells in people who are already infected with the virus make the immune response against it? And you know what -- yes, they could! So that showed that, even though we started out to make a preventive vaccine, it was possible that we could use this method as a treatment as well. At the time that we decided that this was the path we were going to take, which was about a year and a half ago, nobody was really talking about treatment vaccines. As I said, there's only one vaccine that's currently being used as a treatment. And we really felt that this was an area that needed to be pushed in terms of the research.
So basically what we have done -- and there are days that I wake up, and I'm stunned and amazed -- we have actually raised the money, and we can see our way to start production of this vaccine. This will involve myself and three people who work for me going into a lab, living in a hotel next to the lab for months, to make this vaccine by ourselves, so that we can make enough of it that we can test it to be sure that it's going to be safe enough that it's ready to be put into people. At that point, we will apply to the FDA for them to allow us to conduct this clinical trial. I found out that we were going to do this and thought, "oh my god, I'm going to make this vaccine! This is so exciting!", and then I thought, "oh my god, I have to make this vaccine -- there's a lot of pressure!"
I started at the very beginning of the epidemic and all I've ever wanted to do is make a vaccine. For somebody who's wanted to do this from the very beginning, it's been just a remarkable ride. And I've learned so much. What I really want people to understand is that this is a very complex issue, and there are a lot of things that need to be thought about, and talked about. Maybe you don't want to participate in a trial -- maybe you want to come to UCLA to help us figure out how to design trials, so that we can go into communities more effectively. We don't have all the answers -- we need people to help us figure out how to do these sorts of things. We're having think tanks just to figure out what the questions are that we need to ask, to design these types of trials.
Question from the audience: Given that hundreds of millions of people are dying, why can't the FDA move to institute the same sort of fast-track approval for vaccines that AIDS activists brought about in the '90s for drugs?
Dr. Grovit-Ferbas: The sad thing is that those numbers I presented to you are the fast-track numbers. If you add it up from when you went into Phase I until you came out of Phase III, in a trial that progressed all the way through (I added about three years for pre-clinical testing) it's seven years -- as opposed to forty years, or twenty years. One thing to keep in mind: While I hate the paperwork that I'm filling out, the FDA certainly has a place, and we need to work with the FDA rather than look at them as our enemies. The FDA came to be because of the polio vaccine, because there was no FDA when Salk and Sabin developed the polio vaccine.
Salk developed an inactivated vaccine, which is actually the vaccine that we use today in this country. There was an unfortunate incident, referred to as the "Cutter incident," in which the laboratory making the vaccine didn't completely inactivate the virus, so people became infected with polio from having taken the vaccine. And at that point, we figured out that this country needed some sort of regulatory clearing house for treatments to go through -- and things began to go through too slowly. I really think the vaccine field has benefited from fast-track. The FDA hasn't really had an adversarial role -- they want to help us, but it's very important that we bring something to market that's safe -- especially with a virus for which therapies are not available for everyone.
I agree that it needs to be fast. IAVI is working very hard to come up with ways to streamline the process, and one of those ways is that we need to have the most people involved. We need to have scientists who are working in the lab that want to do this, who want to take a chance, because if we do this, if you invest five years of your career and it doesn't work, you've lost five years of your career. There needs to be a method for people to come in and say, "I don't care about losing five years of my career -- it's not going to prevent me from being paid next week." And that's a big issue: we need to fund the basic development because it's the development phase, I think, that's been the slow part. It's not just getting through the clinical trials, which you can't really make go faster. It takes a certain number of weeks to develop an immune response. You can't change that; that's just biology. So we really need to put money and effort into the research part. And we need to attract pharmaceutical companies that will come to somebody like me and say, "If you prove that this work, then we're going to take it off your hands, and we're going to make it on a large scale." Because I can't. So what we need is to develop partnerships on the front end rather than pushing the FDA any more, I think, than they've already been pushed.
Kathie Grovit-Ferbas, Ph.D. is an Assistant Professor of Medicine at the UCLA School of Medicine. The Medical Update took place on August 28, 2001.
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