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Vaccines:

Immunologic memory, the ability of the immune system to respond in a more rapid and

effective manner to antigens that have been encountered previously, forms the theoreticalbasis for vaccination.

Following viral expansion there is a dramatic expansion of CT specific for the relevant

virus. !any of these cells die, but a fraction of them survive, go bac" to a resting state,and persist as memory CT capable of responding rapidly to subse#uent exposures to the

same virus.

In considering immunologic memory, it is important to note that clonal expansion is notthe whole story. !emory cells are also #uantitatively different from their na$ve

counterparts. They have different properties with respect to fine specificity, triggering

re#uirements, tissue distribution and traffic"ing patterns and effector functions.

For % cells, the structure of the antigen receptor itself provides clues to previous exposure

to antigens. &hile na$ve % cells express surface Ig! and Ig', memory % cells may

express Ig( or Ig) and show evidence of having undergone somatic mutation. This

process occurs in a distinct microenvironment, the germinal center of the lymph nodes.*omatic mutation occurs in a rapidly proliferating population of antigen+activated % cells

in the germinal centers. These cells are "nown as centroblasts. !ost of the cellsproduced by this proliferative process will die unless rescued by signals such as the

crosslin"ing of surface Ig by antigen that is attached to F'C by Fc and complement

receptors. % cells whose receptors have mutated to form with higher affinity for antigenwill have an increased chance of survival.

Critical for this process may be the capacity of the % cells to ta"e up antigen via

surface Ig, process it, and present it to T cells leading to direct interactions of antigen

specific % and T cells. These interactions involve C'- on activated C'-/ T cells andC'- on % cells. )ntigen stimulated % cells will become memory cells or undergo

terminal differentiation into plasma cells.

For T cells, the antigen receptors expressed by na$ve and memory cells are the same, but

the cells differ in the expression of a number of other surface molecules. ) variety of

adhesion molecules are upregulated on memory T cell, while +selectin isdownregulated. The most reliable mar"er for memory vs. na$ve T cells is the expression

of different isoforms of C'-0, an integral membrane protein whole cytoplasmic domain

has tyrosine phosphotase activity. C'-0 is "nown to play an important role in signaling

through the T cell antigen receptor. In C'-0+negative T cell lines, cross lin"ing of the Tcell receptor does not induce turnover of 1I derived 23 messengers or changes in

intracellular Ca//. )t birth, most T cells express C'-04). This is characteristic of

na$ve T cells. Following antigen driven activation, a different isoform, C'-045, isexpressed.

There are two other important differences b6t na$ve and memory T cells. 78 the

cells show different traffic"ing patterns. 9a$ve cells can efficiently traffic from bloodinto the lymph nodes because of their expressions of +selecting C';28, the lymph

node homing receptor. This protein interacts with a C

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cells, by contrast, accumulate in the spleen and at sites of inflammation. 28 9a$ve T cells

produce I2 upon activation while memory T cells produce a wide variety of cyto"ines.

1ersistency of memory lymphocytes may be due to 78long term survival of memory %

and T cells in the absence of antigen stimulation. 28restimulation of memory % and T

cells by cross reacting environmental antigens or by cyto"ines. >8restimulation ofmemory % and T cells by low levels of persistent antigen.

1ersistent antigen is responsible for long term memory, except for in CT, where for at

least Cd?/ CT, long term survival of memory cells may be possible in the absence ofantigen

Vaccines for tetanus and diphtheria protect by inducing antibodies that react with and

neutrali@e the relevant bacteria toxins that actually produce disease. Vaccines forpneumoccoccus and influ, induce abs that react with the capsular polysaccharide and

trigger Fc dependant effector function including upta"e of phagocytic cells and in same

cases, complement dependant lysis of the bacteria.

For viral infections, it is important to note that only antibodies can prevent initial

infection. CT can only act on host cells once they are already infected.

2 mechanisms by which abs mediate neutrali@ation: 78saturating binding that bloc"s

attachment of the virus to host cell 28 induces some conformational change that preventsviral entry.

!any neutrali@ing antibodies to 8 can be given orally, which eliminates the need for sterileinAection e#uipment and has the further advantage that it induces mucosal immunity,

resulting in the secretion of specific Ig) abs into the alimentary tract. This helps reduce

the spread of infection.'isadvantages: 78 there is a possibility of reversion to a virulent form

28 can produce serious and sometimes fatal disseminated

infection in people who are immunodeficient.

*ubunit vaccine: involves the inAection of individual components of the relevant

microorganisms, components which will elicit a protective immune response. It has a

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safety advantage but is dependant upon the ability to identify and to produce large

amounts of the relevant component.

Inactivated whole organism vaccine is a third approach which has been successful in

polio, influ, and pertussis.

9ewer strategies for the development of vaccines ta"e advantage of current "nowledge

about mechanisms of antigen presentation and memory cell generation. 5ne appraoach is

the use of established vaccine vectors to express genes from another pathogen viahomologous recombination. 5ne advantage of this approach over immuni@ation with

purified recombinant envelope protein is that the vaccine vector approach allows the

generation of C'?/ CT. The vaccine vectors infect host cells which express the

relevant foreign genes in the cytoplasm of the cells, enabling processing for associationwith class I !

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irradiated non+transduced tumor cells. (!+C*F is a growth factor for the most potents

)1C, 'Cs.

)ntigen presentation can occur either directly by the tumor cell, or indirectly viaprofessional )1Cs such as 'Cs. 4ecruitment of the )1Cs appears to be more efficient in

activating potent systemic immunity since it provides a mechanism by which to activate

both C'-/ and C'?/ effector cells.

Future cancer vaccines will be composed of recombinant antigens in the form of proteins

or genes that encode for proteins. There are three main re#uirements for the successfuldesign of recombinant vaccine strategies that target specific antigens expressed by

tumors. 78 identification of common T cell antigenic targets that are expressed by the

maAority of patient tumors 28 the demonstation that a single antigen can serve as an in

vivo tumor reAection target. 8 the development of recombinant vaccine strategies that can successfully

generate antigen specific immunity.

Identification of tumor antigens: Tumor antigens fall into three main categories: 78 genes

that are silent in normal cells but are reactivated in the tumor cell 28 tissue associatedantigens in which the tumor cell overexpresses a normal tissue specific gene relative to

the normal cell from which the tumor derives. >8 the products of a mutant gene.

1eptide+peptide based vaccines: =xp using peptide antigens which have been treated in

such a way that they target both the !