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Understanding Vaccine Development

How are vaccines developed?

Vaccine development is a lengthy process of testing ideas and candidates with the goal of identifying a safe, effective vaccine that can be reliably and affordably produced and distributed to all who need it. The development process can be divided into five overlapping stages. These stages are common to all medicines, vaccines and microbicides. Scientists, manufacturing experts, policy makers and advocates work on many of these stages simultaneously with different candidates. It can take 10 years or more for one candidate to complete the first three phases and even longer to identify an effective candidate for licensure and widespread use. The five stages are described below using AIDS vaccines as an example.

Idea generation and basic science

Vaccine development begins with "basic science," which includes experiments on and observation of various aspects of HIV and the immune system. Basic science research is carried out in laboratories in universities, research institutes and private companies. Scientists use various techniques to isolate the virus and human immune cells and to study the types of cells HIV infects, how it kills those cells, and what effects this has on other cell types. One general term for these studies is "in vitro assays." (In vitro means "in glass" in Latin and it is used for studies that are conducted outside of a living organism.) In vitro assays give scientists a chance to observe processes that usually happen inside the human body. Some basic science experiments study immune responses to HIV in small animals like mice. Basic science provides clues about how to develop better vaccines.

Pre-clinical development

Pre-clinical tests include tests of the purity and composition of the candidate, as well as very early measures of vaccine effects against HIV. Some of these tests are done in vitro and some have to be done in animals. (Tests in animals or humans are called "in vivo" experiments.) For example, scientists might try to design a vaccine that causes immune responses that effectively control HIV growth in cells. This can be tested by immunizing mice, then testing their immune cells in vitro to see if they stop HIV from growing. These and other experiments are used to gather early information about "immunogenicity," which is a measure of the types and strength of the immune response caused by the vaccine. If the candidate appears promising, additional tests are done in monkeys. Researchers give the monkey the experimental vaccine and later "challenge" the animal with a monkey version of HIV called simian immunodeficiency virus (SIV) to see whether the vaccine provides any protection. Pre-clinical studies also gather extensive information on product safety. Only a small percentage of the vaccines that make it to the pre-clinical development stage move forward to the next stage.

Clinical trials

A clinical trial is a research study in humans used to answer a question about an experimental drug, vaccine or other medical intervention. Clinical trials are conducted in sequential steps or "phases," each answering a different question. Small Phase I safety trials of AIDS vaccines ask: Is the vaccine safe in a small group of HIV-uninfected people who have undergone an extensive health screening process? Phase I trials may also look at vaccine immunogenicity. Phase II AIDS vaccine trials ask: Is this vaccine safe and immunogenic in a group of hundreds of HIV-uninfected people, who are known to be generally healthy?; and What is the best dose, dosing schedule, and route of immunization for the vaccine? Phase III AIDS vaccine "efficacy" trials usually enroll thousands of volunteers to ask: Does this vaccine provide protection against HIV infection, or reduce the severity of illness in people who receive the vaccine and later become infected with HIV through high-risk contact? If a Phase III trial shows that a candidate has either benefit then it may advance to the licensing and approval stage. The trial sequence may sometimes include large Phase IV trials after licensure.

Licensing and approval

If a Phase III vaccine trial shows that the candidate has positive effects, then vaccine developers may submit an application to regulatory agencies for licensure. In the US the regulatory agency is the Food and Drug Administration; in the European Union it is the European Agency for the Evaluation of Medicinal Products; in South Africa it is the Medicines Control Council.

Regulators review everything about a product: all of the details of the manufacturing process, what it is made of, the benefits and risks of use, and the label and packaging that will be used to inform the public about the product. It is their task to determine whether the product is safe and of sufficient benefit to be made available to the public.

Several factors could influence decisions about whether to license AIDS vaccines. These include the level of benefit or efficacy observed in the Phase III trial, and the type of population that was enrolled in the trial. Some regulatory agencies may require a second "confirmatory" Phase III trial that may test the product in a different population, perhaps in a different age range or different part of the world.

Policy makers and health advocates are now working to develop and strengthen expertise in the regulatory agencies in the developing nations and to identify strategies for rapid licensing and approval processes.

Manufacturing and delivery

Once an effective vaccine has been developed, it must be made in sufficient quantities to meet the global need. These supplies can only be made in large-scale manufacturing facilities which are costly and time-consuming to build. This is why vaccine developers begin planning manufacturing facilities long before they have a licensed product and even before they have results from a Phase III trial.

It is also essential to have systems and strategies to deliver the vaccines to people who need them. These systems require storage facilities and equipment and trained personnel who can safely administer the vaccine. The strategies include outreach and education campaigns to explain to people how the vaccine works, who should use it, and why the vaccine should not replace condoms or other strategies to avoid HIV, since all of these strategies must be used together.

Adapted from the December 2003-March 2004 Uganda AIDS Vaccine Update, the newsletter of the Uganda Virus Research Institute-IAVI HIV Vaccine Program. For more information or a copy of the newsletter: www.iavi.org/uganda