Emory scientists provide new details about long-term immune memory boost vaccine development

New discoveries about how individuals acquire long-term immunity against diseases are proving essential for the development of new vaccines for complex and persistent diseases such as HIV, malaria and tuberculosis. Rafi Ahmed, Ph.D., director of the Emory University Vaccine Center and a Georgia Research Alliance Eminent Scholar, will discuss the links between mechanisms of long-term memory and vaccines in a lecture at the Experimental Biology 2001 Meeting in Orlando on April 3.

Dr. Ahmed is one of three immunologists selected to deliver the American Association of Immunologists Distinguished Lecture at this year’s meeting.

In the past, scientists used a hit-or-miss approach to the development of vaccines for diseases like polio, yellow fever or measles.

Vaccine development for diseases such as HIV, however, which are expert immune-system evaders, require a detailed understanding of exactly how the immune response works.

Acute viral infections produce two types of long-term memory – humoral immunity, in which B cells produce antibodies to prevent infection by viruses, and cellular immunity, in which T cells activated by specific viral antigens kill the virus-infected cells and also produce cytokines –– proteins that prevent the growth of viruses and make cells resistant to viral infection.

Dr. Ahmed and his colleagues previously found that plasma cells, the B cells that produce antibodies, live for quite a long time––sometimes for the entire life of an organism ––which helps explain why humoral immunity is capable of such long-term persistence. The other aspect of immunity – the response of T cells to viruses – is much different than the B cell response, Dr. Ahmed explains. CD4 T cells and CD8 T cells, which kill virus-infected cells, are of three types: naïve cells, effector cells or memory cells. Following exposure to virus or vaccination, T cells respond in a phase called "antigen-driven expansion," in which naïve T cells are activated and undergo a dramatic 50,000- to 100,000-fold increase in number, resulting in an expanded population of cells. These effector cells kill virus-infected cells or produce cytokines. The effector-cell response lasts for only a few weeks, then the majority of effector cells die and about 5-10% become memory cells. When memory cells come into contact with the original virus, they mount an immediate, strong and rapid immune response.

Dr. Ahmed and his colleagues believe their recent findings about long-term memory hold the keys to successful vaccine development:

The effectiveness of the long-term memory-cell response to infection or vaccination depends on the size of the initial antigen-driven expansion. A strong initial T-cell response is critical to generating a large pool of memory T cells and maintaining strong, long-term immunity. This means that in vaccine development, the initial stimulus is a critical component of the effectiveness of the vaccine.
Memory T cells do not show the same signs of aging as do most other cells, and may possibly even outlive their hosts. Normally, as cells undergo division after division, the ends of their chromosomes – called telomeres – gradually shorten, eventually causing the problems of aging. When T cells are activated and become effector cells, however, they upregulate an enzyme called telomerase that lengthens chromosomes. In the resulting pool of memory cells, telomerase activity also is high, indicating that memory T cells can maintain their telomerase length and not succumb to "aging."
Even under the most optimal conditions of vaccine-induced immunity, vaccines are usually not capable of completely preventing an initial viral infection; however, they can blunt the infection, then work on eliminating it.
Even when an infection is of very short duration and mobilizes only a few T cells, those cells go on to become effective memory cells and do not depend on repeated exposure to either the virus or a vaccine to maintain a stable pool of memory cells. The immune system has a special program that directs T cells, when they are optimally stimulated, to continue to divide a certain number of times, then differentiate into memory cells, no matter how brief the initial exposure.
The pool of total memory cells is maintained through the principle of homeostasis, in which the memory cells undergo a slow proliferation coupled with a slow death rate to maintain a constant, stable base of cells. Since homeostatic proliferation does not depend on repeated exposure to disease or vaccination, however, it is important to solve the mystery of which regulatory signals drive homeostatic proliferation.

As scientists struggle to create long-term, effective vaccines for difficult diseases, they need a detailed understanding of the mechanisms of long-term memory, Dr. Ahmed points out. "Understanding immune memory is the necessary basis for developing any effective vaccine. No matter what type of vaccine you are working on, or for which disease, you need to understand the details of immune memory."

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Dr. Ahmed’s research was funded by the National Institutes of Health (NIH).

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