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Understanding Pre-existing Immunity

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.