ReviewRole of T lymphocyte replicative senescence in vaccine efficacy
Introduction
The original “proof of principle” vaccination experiment was performed over 200 years ago by Edward Jenner, yet, there is still an ongoing debate among immunologists regarding the optimal vaccine strategy. The undisputed goal of vaccination is to protect the host against disease, yet, the specific characteristics of immune responses to the vaccine that will confer optimal protection are often not known, and in fact, may vary among different pathogens. Neutralizing antibody has been the traditional gold standard used to evaluate vaccine efficacy, but it is becoming increasingly clear that for many pathogens, other components of the immune system may be required to confer long-term protection. Indeed, there has been a gradual paradigm shift among vaccinologists, with an increasing realization of the importance of eliciting cell-mediated immunity in addition to, or even in place of, antibody [1], [2], [3], [4], [5], [6].
A second general issue that presents a challenge to vaccine development is the heterogeneous nature of the population requiring inoculations with respect to overall physiology, history of previous infections and immune system variables. It is clear that what constitutes a successful vaccine in infants may differ dramatically from the features required to protect the elderly. Unfortunately, the process by which vaccines are developed does not necessarily take these factors into account. The animal studies that usually precede human clinical trials are rarely aimed at optimizing and fine-tuning vaccine preparations to address the immunological deficits associated with aging. Moreover, even when aged animal models are incorporated into vaccine research, it is not possible to reproduce in old rodents, or even primates, the unique and complex immunological history of an aged human, which includes such variables as the spectrum and frequency of pathogen encounters, specific infectious episodes, previous vaccinations, and latent infections. Indeed, previous immunological experience is one of the key factors in determining the quality of the T lymphocyte pool in aged humans. This review will summarize some of the general issues relating to vaccination in the elderly, then focus on the potential role of senescent CD8 T lymphocytes on the reduced responsiveness to vaccines, and conclude with possible strategies to prevent the generation of these cells.
Section snippets
Elderly persons show reduced responses to vaccines
It is well documented that aging is associated with markedly reduced responses to vaccines. One of the major current concerns is the protection of the aged population from influenza outbreaks in general, and, specifically, from a possible avian flu pandemic. Indeed, during influenza epidemics, up to 90% mortality can occur in the elderly [7]. Furthermore, although influenza immunization of young adults provides 65–80% protection against illness caused by a virus present in the vaccine [8],
Replicative senescence
Replicative senescence (sometimes called cellular senescence) describes the natural barrier to unlimited proliferation that is characteristic of all normal human somatic cells, and which is believed to be regulated by telomere shortening. The process has been studied extensively in cell culture, using cells of human rather than murine origin, due to major species differences in telomere biology [32]. Although the term replicative senescence highlights the proliferative aspect of the process,
CD8+CD28− T lymphocytes as suppressor cells
There is accumulating evidence from a variety of systems that CD8+CD28− T lymphocytes may have suppressor cell activity. It has been reported that a population of MHC class I-restricted CD8+CD28− T lymphocytes generated in the course of in vitro and in vivo immunizations functions to suppress immune reactivity by inducing antigen-presenting cells to become tolerogenic to helper T lymphocytes with the cognate antigen specificity [42]. Interestingly, this same subset has been specifically
Which pathogens should the elderly be protected against?
Whereas influenza vaccination of the elderly has received a great deal of media attention, development of vaccines directed at other pathogens affecting the health of the elderly is also an active area of research. For example, varicella zoster virus (VZV) establishes a latent infection in the dorsal route ganglia in previously infected persons, and can re-emerge as painful “shingles” in persons with reduced cell-mediated immune function. Vaccination with a live attenuated form of VZV has been
Strategies for retarding the generation of senescent CD8 T lymphocytes
Given the multiple deleterious effects associated with the presence of high proportions of CD8+CD28− T lymphocytes in the elderly, it has been suggested that therapeutic approaches directed at these cells might have pleiotropic beneficial outcomes on health. As noted above, one possible approach to preventing the generation of at least some of the senescent CD8 T lymphocytes would be prophylactic vaccination against CMV early in life. However, the development of childhood vaccines against a
Concluding remarks
The aging immune system presents a formidable challenge to researchers involved in vaccine development. The urgent nature of the problem is underscored by the estimation that persons over age 65 will constitute approximately 25% of the U.S population by the year 2050. The potential threat of bioterrorism further accentuates the timeliness of devoting increased resources to improving vaccine efficacy in the elderly. A two-pronged approach--specifically tailoring vaccines for the elderly,
Acknowledgements
The research reviewed in this manuscript was supported by NIH AI060362 and AG023720.
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