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Are two really better than one?

Researchers are testing to see if two different vaccine candidates can together induce improved immune responses against HIV

We all use things every day even though we have little appreciation of how they work. Cars, cell phones, and computers come to mind. But usually someone somewhere knows exactly how they function. This isn't the case with many of the vaccines that are routinely administered to children and adults throughout the world. For many of these licensed vaccines scientists don't know exactly how they work.

This is also true for AIDS vaccine candidates that are in various stages of clinical testing. Researchers are yet to find a candidate that protects people from HIV infection, although many different approaches are currently being explored. Some candidates in clinical trials use HIV proteins, viral vectors (see VAX September 2004 Primer on Understanding Viral Vectors), or DNA to deliver fragments of HIV to the immune system with the intention of inducing an immune response against the virus. Each of these induces an immune response to some extent but to improve upon these responses researchers are now testing different approaches in combination—a strategy known as prime-boost—to see if delivering different candidates in sequence can augment immune responses against HIV.

Although researchers don't know exactly how the prime-boost strategy works, the rationale for it is simple. The first administration (the prime) generates a collection of immune cells that recognize HIV, and these cells then allow for a quicker and stronger immune response to the second vaccination (the boost). And this prime-boost approach seems to work. "Essentially, most vaccination strategies are primes and boosts," says Larry Corey who leads the HIV Vaccine Trials Network (HVTN) in Seattle. However, usually the same exact vaccine is given multiple times, as is common practice with vaccines against chickenpox and measles.

But using different vaccines for the prime and boost is now the regimen of choice for many AIDS vaccine candidates that are in clinical trials. The hope is that the combination will lead to increased immunogenicity (see Primer) and could also result in a broader immune response because each vaccine component might stimulate a different type of immune cell. Hildegund Ertl of the Wistar Institute, a research institution in Philadelphia, thinks a successful AIDS vaccine is likely going to consist of two different candidates administered in a prime-boost regimen. "That's where I'd put my money right now," she says.

Trial and error

Many of the prime-boost regimens now undergoing evaluation combine a DNA-based vaccine with a viral vector such as adenovirus or modified vaccinia Ankara (MVA) to deliver fragments of HIV to the immune system. Several different combinations have been tested and still more are planned—about half of the 30 or so ongoing AIDS vaccine trials use such combinations. Even so, there is surprisingly little known about how prime-boost works or the reason that some combinations work better than others. Finding the right combination often comes down to trial and error.

One of the first questions researchers tackled was which candidate to use as the prime and which for the boost. This was primarily determined by experimentation, says Tomas Hanke of the University of Oxford, UK, who did some of the earliest work with DNA and MVA-based vaccine candidates. "We wanted to try their combinations, first without really thinking why we should use this one first as opposed to the other," he says.

Deciding which vectors to use for prime and boost still involves a lot of guesswork. Peggy Johnston of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID) refers to this approach as "thoughtful empiricism." "Try it and see what happens, but there is some thought behind it," she says.

Lost in translation

There are data that show prime-boost regimens work in animal models, but this doesn't guarantee that they will also work in humans. Some of the first DNA/MVA regimens, for example, worked well in mice and monkeys but not so well in humans. Clinical trials with some of the early DNA/MVA prime-boost combinations developed by Hanke and Andrew McMichael, also of Oxford, showed that few of the volunteers had substantial immune responses to HIV.

David Ho of the Aaron Diamond AIDS Research Center in New York is currently testing a different DNA/MVA prime-boost regimen in clinical trials. In pre-clinical studies in mice and rabbits the combination works about 10 times better than when either candidate is administered by itself, and Phase I trials have already shown that each individual component is both safe and immunogenic. Ho will soon test this DNA/MVA combination in Phase II trials and is optimistic.

Other groups are working on prime-boost regimens that combine different viral vectors, rather than using DNA-based candidates. Dan Barouch at Harvard University is testing different combinations of adenovirus-based candidates in non-human primates. He has found that certain combinations of different strains or serotypes of adenovirus are much more immunogenic than others. Researchers at the Vaccine Research Center (VRC), part of NIAID, are now testing a prime-boost regimen with two different adenovirus candidates—adenovirus serotype 5 (Ad5) and Ad35—in a Phase I trial (see VAX June 2007 Global News).

Early results

Although most of the evidence supporting use of a prime-boost administration of two different vaccine candidates comes from pre-clinical studies, some regimens have already proven safe in humans and appear to be immunogenic in Phase I trials. Giuseppe Pantaleo of the University Hospital in Lausanne, Switzerland, is one of the coordinators of a Phase I trial in Europe that uses a combination of a DNA-based candidate and a poxvirus-vector candidate known as NYVAC. This combination induced much better immune responses than when the poxvirus candidate was used alone. A Phase II trial with these candidates has already started enrolling volunteers.

Another regimen that appears promising uses DNA as a prime and Ad5 as a boost. According to Corey, results from Phase II studies with the DNA/Ad5 vaccine candidates developed at the VRC suggest that more than 70% of the recipients develop immune responses to HIV. The regimen will soon be tested in a Phase IIb test-of-concept trial called PAVE 100 (see VAX September 2005 Primer on Understanding Test of Concept Trials). This trial will take place at multiple trial sites affiliated with HVTN, the United States Military HIV Research Program (USMHRP), and IAVI.

These preliminary clinical trial results are encouraging, but not everyone has observed that prime-boost combinations with different candidates work better in humans than using the same vaccine repeatedly. "We haven't found anything that shows that prime-boost adds a synergistic effect in people, and we have tested probably more things than anybody else," says John Shiver of Merck. The company is currently conducting two Phase IIb trials in North and South America, the Caribbean, Australia, and South Africa that use repeated injections of their Ad5 vaccine candidate.

Mysterious mechanism

Given that, in many cases, prime-boost appears to induce stronger immune responses, the question remains how. "Exactly why it's better, I don't think anybody knows," says Rockefeller University's Sarah Schlesinger, who collaborates with Ho. Part of the mystery may be because it's difficult to directly measure the effect of the prime, she suggests.

Pantaleo thinks the enhanced immune responses occur because each candidate does something very different—perhaps targeting different types of immune cells. And there is some evidence suggesting that using two different candidates in a prime-boost strategy does induce more varied types of cellular responses to HIV than using the same vaccine more than once.

For many of these prime-boost combinations it is very difficult to know the precise mechanism of how they induce an improved immune response, especially since researchers know very little about why the individual components are immunogenic. "We don't know a lot about the mechanism of how DNA is immunogenic," says Gary Nabel, director of the VRC.

Apples and oranges

Another challenge facing researchers is that it is difficult to understand which combinations of vaccine candidates work better than others because comparing the results from different studies isn't straightforward. Research groups often use slightly different viral vectors or different fragments of HIV (antigens) within the viral vector or DNA-based candidate. This makes the comparison between trials that appear to be using similar candidates more complicated. "I think there is a false assumption that a DNA is a DNA and an MVA is an MVA," Johnston says. "That's just not true."

These slight variations could, in part, account for the widely-disparate results from studies that use similar prime-boost combinations of vaccine candidates. For this reason Nabel and others are promoting use of a standardized genetic insert containing the same fragments of HIV, which can be included in different DNA or viral vectors. This could help eliminate one of the variables between related vaccine candidates and help researchers decipher exactly which prime-boost combination is the most effective. Nabel says the HVTN just started a series of trials using different viral vectors that are all carrying this standardized genetic insert.

Another concern is that if a prime-boost combination of two different vaccine candidates is found to be superior, administering it will likely be more complicated and costlier than if it were just a single component. There is currently no licensed vaccine against any other disease that consists of two different vaccine components. "Ideally you would have a single product," says Schlesinger. "The only reason we are doing prime-boost is that we don't."