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Understanding AIDS Vaccine Pre-clinical Development

How are AIDS vaccine candidates tested for safety and immunogenicity before they enter clinical trials?

Clinical trials are a stepwise process to determine the safety and immunogenicity of AIDS vaccine candidates in human volunteers. The earliest trials (Phase I and II) are designed primarily to evaluate safety, while the later stage trials (Phase IIb and III) are when researchers determine if the vaccine candidate is effective. Each Phase involves a progressively larger number of volunteers and conducting clinical trials is a time-consuming and expensive process. The conduct of these trials is closely monitored by regulatory agencies, like the US Food and Drug Administration or the European Union's European Agency for the Evaluation of Medicinal Products, to ensure that a vaccine candidate meets necessary safety standards.

Prior to testing in humans, vaccine candidates are developed and tested extensively by researchers in the laboratory and then in different animal models. Data from these pre-clinical studies give researchers important information about how vaccine candidates might work in people and are carefully reviewed by regulators when they are granting approval to an organization or company to proceed with a Phase I clinical trial.

Vaccine development

Before a vaccine candidate is tested using animal models, researchers fully characterize the engineered vaccine in the laboratory—whether it is a viral vector, protein subunit, or DNA-based vaccine that will be used to present HIV protein to the immune system. For candidates that use viral vectors (see VAX September 2004 PrimerUnderstanding Viral Vectors), scientists will already have an extensive body of knowledge about how the naturally-occurring virus acts both biologically and immunologically so that they have an idea of how it will act in humans. This allows researchers to generate a well-informed hypothesis about the types of immune responses the vaccine candidate might induce in humans.

Other pre-clinical evaluations

Even with a strong hypothesis, laboratory studies can only give researchers a vague idea of how the vaccine will work in the complex environment within the human body. To try to gauge the safety and immunogenicity of a vaccine candidate, therefore, scientists have to conduct research in animal models. Usually the vaccine candidate will first be tested in mice and then in non-human primates, most often rhesus macaques.

Researchers start by administering the vaccine candidate to macaques and then characterizing the immune response it induces. This includes a detailed analysis of the cellular responses, especially in T cells, and measuring the level and type of antibody responses. Based on these results researchers can alter the vaccine candidate to try to enhance its immunogenicity and then re-test it in macaques. Working with animal models allows researchers to obtain extensive data that would be impossible to collect from human volunteers.

Next researchers usually use challenge studies to evaluate vaccine candidates. In these studies the vaccine candidate is administered to macaques that are later infected with simian immunodeficiency virus (SIV), which naturally infects many species of non-human primates. Challenge studies are only conducted in animal models, never in human volunteers. In this type of study researchers can determine how many macaques are protected by the vaccine candidate from becoming infected with SIV. They can also determine how long this protection lasts by challenging the macaques again later. Challenge studies may also provide clues on what type of immune responses (specific types of antibodies or cellular responses) are responsible for this protection, an idea referred to as correlates of protection.

This data gives researchers critical information about the vaccine candidate and helps them determine if it is safe and immunogenic enough to move into clinical trials involving human volunteers. Many of the vaccine candidates that are evaluated in pre-clinical studies never actually advance into clinical trials because they are not immunogenic enough to explore further.

Limitations

One important limitation with these animal studies is that the vaccine is not being tested against an HIV challenge. Researchers must evaluate the vaccine candidate's immunogenicity against SIV, which is a closely-related but different virus, because HIV does not infect non-human primates. To more closely mimic HIV infection in humans, researchers have tried running challenge studies with an engineered virus that contains both SIV and HIV genes—known as SHIV—but this is generally seen as an even less satisfactory model than SIV for predicting how a vaccine will work in humans.

Another limitation is that researchers have to also modify the vaccine candidate to carry SIV genes, rather than HIV genes, to match the virus being used in the challenge studies. Using a different challenge virus and a different vaccine candidate in a different animal species makes pre-clinical evaluation more difficult. This is just one of the many complications researchers face in developing an effective AIDS vaccine.

For many years, therefore, researchers have sought ways to improve their ability to evaluate candidates in pre-clinical studies and find a better animal model for HIV infection. Recently researchers have developed an engineered mouse model where human cells are transplanted into mice that have their own immune systems depleted. This allows mice to grow human immune cells that can be infected by HIV. With refinement this type of model may be useful to researchers as an initial screen for AIDS vaccine candidates to help determine if a candidate is immunogenic enough to pursue in human clinical trials.

Scientists are also studying the genetic factors that allow non-human primates to fend off HIV infection. This research might one day enable scientists to engineer an HIV strain that can productively infect an animal model and therefore more closely mimic human infection.