What are replicating vectors, and why might they be important to AIDS vaccine research?
What is a viral vector?
How do viral vectors work?
What are viral vectors derived from?
Can viral vectors cause HIV infection?
What is a replicating viral vector?
Why use replicating viral vectors?
What evidence is there that vaccines based on replicating viral vectors will have any of these benefits?
Would replicating vectors be safe?
Which replicating vectors is IAVI helping to develop?
What is a viral vector?
Vaccines teach the body to recognize and neutralize invading pathogens. Most vaccines against viruses accomplish this in one of two ways. They either expose the immune system to a killed or largely innocuous (attenuated) version of the virus they are devised to protect us from, as do the measles and polio vaccines. Or, like most flu vaccines and the hepatitis B vaccine, they expose the body to molecules derived from the targeted virus. These molecules, known as antigens, basically teach the body how to detect and destroy the offending pathogen.
Unfortunately, neither of these strategies is practical for the design of an AIDS vaccine. The first approach is perceived to be too risky (a small fraction of the HIV used to make the vaccine might escape attenuation or killing). And traditional antigen-based approaches, meanwhile, have not worked because antigens derived from HIV have not triggered appropriate immune responses.
Because of these difficulties, researchers have taken an entirely different tack in devising candidate AIDS vaccines: engineering alternative viruses—or viral vectors—to produce HIV antigens. These modified viruses contain, along with their own genes, several genes that code for HIV antigens that researchers believe might provoke a protective immune response. This vaccination strategy relies on the viral vector infecting a cell and subsequently directing the production of antigens that should trigger an immune response. No licensed human vaccine has been made this way, but this approach has been successfully used in the veterinary field.
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How do viral vectors work?
Viral vectors carry, along with their own genes, copies of one or more HIV genes encoding antigens that might be able to induce immunity. When used this way, the antigens are known as immunogens. Once introduced into the body, the vectors shuttle the HIV genes into a relatively small number of cells, directing the cellular machinery to produce HIV immunogens along with their own proteins. The hope is that the HIV immunogens produced by the cells will provoke an immune response capable of preventing HIV infection.
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What are viral vectors derived from?
The vectors themselves are often derived from viruses that do not normally infect humans. For example, the canarypox virus, which does not ordinarily infect or sicken humans, has been used to make candidate AIDS vaccines. In fact, the canarypox vector was used in one of the components that was tested in the RV144 trial in Thailand, in which a combination of two AIDS vaccine candidates demonstrated modest efficacy in preventing HIV infection. Vectors may also be derived from viruses that cause mild human ailments, such as the common cold. In either case, the vast majority of viral vectors tested to date in humans have been further modified to make them incapable of replicating themselves. What this means is that each viral vector particle can infect only a single cell and present the HIV immunogens it carries to the immune system only once before the infected cell—and the vector it contains—is destroyed. While limiting the ability of the vectors to replicate may make them safe, it also limits their potency as vaccines.
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Can viral vectors cause HIV infection?
No. As with all AIDS vaccine candidates, those based on viral vectors encode only fragments of HIV. They cannot cause HIV infection.
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What is a replicating viral vector?
Replicating viral vectors are similar to other viral vectors in that they are derived from relatively innocuous viruses. The difference, as the name implies, is that they retain the ability to multiply. Once introduced into the body, these vectors proceed through the steps of a natural viral infection, using cells to make multiple copies of themselves that in turn go on to infect other cells. In doing so, they mimic with greater fidelity the natural course of a viral infection and so may be able to generate a stronger immune response.
To develop a replicating viral vector, researchers use viruses that are unable to replicate at their full capacity (they are attenuated) and never reach the numbers needed to cause illness. Slowing them down allows the immune system to detect and respond to the infection, typically within a few weeks, and rid the body of the viral vector before it can cause symptoms . To make vectors that are attenuated, researchers can manipulate the virus to reduce its ability to replicate. They are also trying to make replicating vectors from animal viruses that do not naturally infect humans and so are not able to replicate very swiftly in human cells.
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Why use replicating viral vectors?
Although completely stripping vectors of the ability to replicate may make them very safe to use, it also limits their potency as vaccines. This is because their inability to multiply drastically lowers the immune system’s exposure to the HIV immunogens they carry and, in consequence, lowers the magnitude of the HIV-specific immune responses they provoke. When a replicating viral vector is used, many more cells are exposed to the virus used in the vaccine candidate. The hope is that the immune system’s response to the HIV immunogens becomes stronger and more sophisticated with greater and longer exposure to them. Replicating vectors should therefore provoke a fiercer—and broader—immune response to candidate vaccines.
Indeed, many vaccines that have been used safely for decades to prevent highly infectious viral diseases (such as polio, measles, mumps, rubella and chickenpox), are based on attenuated live viruses. It is thought that such vaccines are highly effective because they can still infect cells and spread in the body (to a limited extent), thus mimicking what happens after natural exposure to a viral pathogen. This process, researchers suspect, trains the immune system to produce the types of immune responses associated with a natural viral infection–in other words, one that protects people upon subsequent exposure.
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What evidence is there that vaccines based on replicating viral vectors will have any of these benefits?
Many scientists believe that the ability of live attenuated vaccines to multiply contributes significantly to their typically impressive potency. And there is evidence from outside the AIDS vaccine field that supports the promise of vaccines based on live viral vectors. A replicating vector derived from a live attenuated yellow fever virus vaccine, for example, has been modified to carry two Dengue fever virus genes. The resulting vaccine candidate has been safely tested in people and found to induce the production of antibodies that neutralize the Dengue fever virus. This vaccine candidate is currently being tested for efficacy in large-scale human trials. Further, the yellow fever virus vector is already in use in the veterinary field: a vaccine that uses the vector to carry two West Nile virus genes has been licensed for use in horses.
Studies conducted in non-human primates indicate that live vectors might prove to be effective tools for the control and prevention of HIV as well. Inoculation with a live attenuated variant of simian immunodeficiency virus (SIV)—which is the simian version of HIV—protects non-human primates from disease caused by infection with a pathogenic SIV. Adding to this evidence, researchers working with the International AIDS Vaccine Initiative (IAVI) have developed an SIV vaccine construct using a replicating vector based on cytomegalovirus (CMV) that provokes an immune response that significantly suppresses the amount of SIV in the blood of non-human primates later exposed to the virus. Although this vaccine does not prevent infection, its suppression of SIV indicates that candidates based on replicating vectors indeed provoke a relatively strong immune response.
So far, one AIDS vaccine candidate constructed using a replicating viral vector based on the vaccinia virus strain Tiantan—essentially a smallpox vaccine modified to carry HIV genes— has been tested in Phase I human trials conducted by the Chinese Center for Disease Control and Prevention (Chinese CDC). Researchers at the Chinese CDC found it to be well tolerated and safe, and to generate immune responses that justified further investigation of the candidate vaccine in a larger, Phase II clinical trial. Further, another vector, based on a replicating vesicular stomatitis virus and a product of a partnership between Profectus Biosciences and the National Institute of Allergy and Infectious Diseases, is slated to enter human trials in 2010.
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Would replicating vectors be safe?
As with all research and development initiatives, IAVI and its research partners will conduct comprehensive studies to rule out potential safety risks with replicating vectors. These include investigations of where in the body the vector goes—for example, to determine if it goes to any major organs, and whether that has any effect on the organs. IAVI will also evaluate what effect, if any, these vectors might have on those who have weak immune systems. Further, we are proactively designing replicating vectors to minimize the potential risks associated with them. We are weakening the vectors so that they do not have the ability to replicate fast enough to spread extensively in the body and cause a major infection. Many of the candidates are also derived from viruses that infect animals and tend to multiply inefficiently in humans in the first place. Finally, none of the replicating vectors IAVI and its partners are developing has the ability to slip into the human genome—as does HIV—or, for that matter, to modify human DNA in any way.
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Which replicating vectors is IAVI helping to develop?
In collaboration with laboratories of the Vectors Consortium that it oversees, and which is supported in part by the Bill & Melinda Gates Foundation, IAVI is designing a number of replicating vectors that address three distinct hypotheses:
- The first posits that an AIDS vaccine built using a vector that persists for some time after it has been introduced into the body is more likely to generate immunity to HIV than one carried by a vector that is cleared relatively quickly.
To address this hypothesis, members of the VEC are designing vaccines built on CMV, which naturally infects the vast majority of people and, in most cases, causes only a transient illness if any at all. In other words, people have essentially learned to live with this virus. Researchers have stitched SIV genes into this vector and shown that, when given to monkeys, it induces very strong immune responses against SIV immunogens.
- A second hypothesis suggests that vaccines might be made more effective if they are designed to target the tissues preferentially infected by HIV, such as lymphoid tissues in the gut.
To develop replicating vectors that address this need, IAVI and its partners are working with the canine distemper virus, a relative of the measles virus that is not known to cause disease in humans. This virus initially infects the respiratory tract but quickly moves to lymphoid tissues as the infection progresses. IAVI is building its experimental vector from a virus used in a veterinary distemper vaccine that has been given safely to dogs for decades.
IAVI is also working on two chimeric virus vaccines, in which one or two genes from the viral vector are substituted with genes from HIV. These vaccines are designed to target immunogens to the lymphoid tissues that are natural sites of HIV replication. One is being derived from a vaccine strain of the Venezuelan equine encephalitis virus, which is similar to a live vaccine used to vaccinate horses in some countries and is being tested by the U.S. military as a human vaccine against encephalitis.
A second is being built on the vesicular stomatitis virus—which naturally infects pigs and horses but does not generally make humans sick. Researchers are removing certain genes from these viruses and replacing them with HIV genes. In the process, the virus becomes very weakened yet able to selectively target lymphoid tissue at the same time.
In both chimeric vector approaches, cells infected with the vaccine produce viral particles that look, structurally, very much like HIV. So aside from testing the effects of targeted replication with the use of these vectors, researchers will be able to assess whether production of virus particles that physically resemble HIV stimulates strong immune responses.
- A third hypothesis IAVI and partners are testing holds that the generation of immunity in mucosal tissues—the lining of body cavities—is likely to prove critical to stopping the virus before it can cause lifelong infection. These mucosal surfaces, which include sites where HIV often makes first contact with the human body, serve as barriers against all sorts of pathogens and are one of the body’s first lines of defense.
IAVI is involved in a few projects to develop vectors capable of inducing immunity in such tissues. All of them assume that the generation of immunity in one kind of mucosal surface—say that of the respiratory tract—is likely to result in similar immunity in others, such as the lining of the vagina or the intestines. This assumption has been supported by studies in mice.
IAVI is working with a biotechnology company in Japan named DNAVEC to develop a replicating vector derived from the Sendai virus—which ordinarily causes upper respiratory tract infections in mice.
Researchers at IAVI’s AIDS Vaccine Design and Development Laboratory in New York are also building a replicating vector from the Newcastle disease virus, which ordinarily infects poultry through the upper respiratory or oral cavity. Again, the vector, still in the earliest stages of vaccine design, is derived from a strain of the virus that is used in a veterinary vaccine.
Both of the vaccines above would be delivered through the nostrils. The hope is that such delivery would stimulate more vigorous mucosal immunity.
IAVI is also supporting a project to develop replicating vectors based on the reovirus, which infects the gastrointestinal tract of many different mammals but does not generally cause illness in humans. Taken orally, a vaccine based on a reovirus vector might generate a vigorous immune response in the rectal mucosal surfaces.
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