The Aaron Diamond AIDS Research Center (ADARC) in New York City and University of Rochester Medical Center at Rochester, NY recently began enrolling volunteers for a Phase I vaccine trial. The trial will test the safety and immunogenicity of a vaccine candidate in 48 healthy volunteers.
The vaccine candidate is called ADMVA and is based on a Modified Vaccinia Ankara (MVA) viral vector. This vector is developed from a virus that is similar to the virus used for the smallpox vaccine.
This vaccine candidate was developed at ADARC and contains genes from clade C HIV, which is prevalent in China, India, and sub-Saharan Africa. "We're particularly excited about this. The epidemic in China is burgeoning and really the only hope for some people is a vaccine," says Sarah Schlesinger, a Research Associate Professor at ADARC, a partner of IAVI and Rockefeller University.
A Phase II trial of an AIDS vaccine candidate developed by the US-based company Merck began enrolling 1,500 volunteers in December at sites in the US and Canada. Enrollment will continue in the coming months in Peru, the Dominican Republic, Haiti, Puerto Rico, and Australia.
The vaccine candidate uses an adenovirus called Ad5. In its natural form adenovirus can cause severe colds but a weakened version is used to make the vaccine. The adenovirus vector delivers three different HIV genes to the immune system. None of the vaccine components can cause HIV infection. For more about the use of this viral vector see the Primer in this issue.
Scientists are hopeful that the vaccine will cause the immune system to raise a strong response against HIV by producing killer T cells to attack HIV-infected cells. The trial is the first large-scale study to test the ability of this vaccine candidate to protect people from infection with HIV. The study will also follow volunteers who later become infected with HIV during the trial follow-up period (four and a half years) to see if the vaccine can help control disease progression.
India began enrolling volunteers for the country's first preventive AIDS vaccine trial in February. The Phase I study will evaluate the safety and immunogenicity of a single shot vaccine candidate in 30 healthy men and women.
The vaccine candidate, called tgAAC09, uses a modified adeno-associated virus (AAV) vector to deliver a small part of HIV's genetic material into the body. The small fragments of HIV used in this vaccine candidate cannot cause infection. The AAV vaccine was developed by Phil Johnson, formerly at the Columbus Children's Research Institute and currently with the Children's Hospital of Philadelphia, and is now licensed and manufactured by the US-based company Targeted Genetics.
The vaccine candidate is now being tested in a joint Phase I clinical trial in Germany, Belgium and India. The clinical trial is sponsored by IAVI and conducted at the National AIDS Research Institute in Pune, an affiliate of the Indian Council of Medical Research (ICMR). The start of the study is an important scientific advancement in a country with the second largest number of people living with HIV in the world.
"With this first trial, Indian scientists are making an important contribution that will bring the world a step closer to an AIDS vaccine," said N.K. Ganguly, Director General of ICMR.
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All articles written by Kristen Jill Kresge
What is pre-existing immunity to a vaccine vector?
When a person is infected with any disease-causing agent (or pathogen, such as a virus) the immune system makes antibodies and immune cells that recognize the pathogen and control the infection. Many of these antibodies and immune cells disappear after the infection is over. But a group of immune cells remain that are called memory cells. These cells stay inactive in the body until the person is exposed to that same virus again. The memory cells can then quickly recognize the virus and make more antibodies or immune cells to limit and clear out the infection.
A vaccine tries to get your immune system to produce the same immune response as in a natural infection by using immunogens (pieces of viral protein). These small pieces of virus generate memory cells that can rapidly respond if the person is later exposed to that virus. (For more information see the February and March 2004 Primers onUnderstanding the Immune System, Part I and II).
In order to generate an immune response against HIV, an AIDS vaccine will have to contain some immunogens that are copies of pieces of the genetic material of HIV. Because only a part of the HIV genetic material is used, this type of vaccine cannot cause HIV infection. Researchers are trying to design a vaccine so that the protein of HIV will cause an immune response strong enough to protect people if they are later exposed to HIV.
First, the immune system must ‘see’ the vaccine. Many current AIDS vaccine candidates use a vector as a carrier to get to the immune system. The vector is a weakened virus (or bacterium) that is safe for use in humans. Sometimes the vector is developed from a vaccine against another disease. Scientists are working with a number of different vectors for AIDS vaccines (for more about vectors, see the September 2004 Primer on Understanding Viral Vectors). Vectors made from other viruses are called viral vectors.
When a common virus or vaccine is used as a vector, some people will have been previously exposed to this virus either naturally or through immunization. Some people will have an immunity to the vector; this is called pre-existing immunity.
When someone has pre-existing immunity to a virus or to a harmless vector, they have immune memory cells or antibodies specific to that pathogen or vector stored in their body. If the vaccinated person’s immune response is directed towards the vector, it might limit the immune response to the HIV immunogens. This could make the vaccine less effective. So for each vector it is important to figure out whether preexisting immunity to it could prevent the vaccine from working.
Current vectors
Several promising AIDS vaccine candidates are using a modified human adenovirus called Ad5 as a vector. Human adenoviruses naturally cause severe colds. After the infection is cleared the infected person has memory cells and antibodies specific to that adenovirus. There are about 40 different groups (called serotypes) of human adenoviruses. About 35% of people in Europe and the US, and as many as 90% of people in some countries (South Africa, Zambia, Botswana, and Thailand), have previously been infected with Ad5. So pre-existing immunity to this vector is common.
An important AIDS vaccine trial is now ongoing with Merck’s Ad5 vector, called MRKAd5. This trial will test the ability of the vaccine to either prevent infection with HIV or control disease progression in people who do later become infected with HIV. Researchers hope that the vaccine will stimulate the immune system to produce killer T cells that can kill HIV-infected cells. This is called a cellular immune response.
This vaccine is being tested in 1,500 volunteers in eight countries. Only people with a low level of pre-existing immunity to Ad5 are enrolling in this trial. Without the problem of pre-existing immunity, researchers can fairly assess how effective the vaccine candidate is against HIV. But the results of this trial are not due for about four years. In the meantime researchers are exploring different approaches to improve the adenovirus vector. Some of these approaches include using higher doses of vaccine or using more than one vaccination (what is called a prime-boost strategy). Another approach would be to use a different serotype of adenovirus for which there is less pre-existing immunity, like Ad11 and Ad35. These serotypes are currently being developed as vectors for AIDS vaccines and could be used to get around the problem of pre-existing immunity to Ad5 if the current trial shows promise.
Other viral vectors now being used or developed for preventive AIDS vaccines may also face the problem of pre-existing immunity (such as measles or polio vaccine viruses) but each new vector must be studied to determine the importance of pre-existing immunity. Researchers are yet to determine whether pre-existing immunity will be a problem for the different vectors being developed as AIDS vaccine candidates.
The Modified Vaccinia Ankara (MVA) vector is one example where pre-existing immunity does not seem to be a problem. This vector is part of several ongoing trials, including one that began in January (see Research and Trials). MVA is similar enough to the virus used for smallpox immunizations that pre-existing immunity to the smallpox vaccine could possibly affect the efficacy of an MVA-based AIDS vaccine candidate. But this vector may have less trouble with pre-existing immunity because smallpox vaccinations ended in most countries in the mid-1970s. People enrolling in vaccine trials are typically aged 25-40 and therefore pre-existing immunity will be unlikely. It is also no longer a naturally-circulating virus because of the successful worldwide immunization campaign. So far no effect of pre-existing immunity has been seen for MVA vectors but more information is needed.
Until researchers have more data on pre-existing immunity this is just one of the many considerations that vaccine developers must face.