Robust modern forms of vaccination that were developed in the 20th century remain one of the most important forms of medical technology. Infectious diseases are not going away any time soon, and continue to cause a sizable fraction of human mortality, even though that fraction is much reduced in our era. Unfortunately, effective vaccination depends on an effective immune system, and thus vaccines tend to perform increasingly poorly with advancing age. As we age our immune system becomes ever less capable, a decline into immunosenescence caused by a range of contributing processes: involution of the thymus, where T cells of the adaptive immune system mature; a growing presence of senescent, exhausted, and malfunctioning immune cells; a shift in cell populations of the bone marrow to produce more myeloid and fewer lymphoid cells; and so forth.
As today’s open access paper points out, the approach to improving vaccination in the old has long been to find ways to work around the growing incapacity of the aged immune system. Developing better adjuvants to vaccines, for example. This produces only incremental gains. The yearly toll of influenza deaths is much larger than the estimates of prevented deaths due to widespread vaccination. For the 2022-2023 season those numbers show 21,000 estimated deaths versus 3,600 estimated prevented deaths. Most of those deaths are old people, not only less able to defend against an infectious pathogen, but also less able to benefit from vaccination. Something must change! That change must be to focus on ways to repair the aged immune system, restore its function to more youthful capabilities.
There are any number of approaches presently under development that show promise. Restoration of active thymic tissue would help by providing a supply of new T cells. Use of CASIN can produce lasting improvements in hematopoietic stem cell function in the bone marrow following a single treatment. Clearance of populations of malfunctioning immune cells has been demonstrated to improve immune function in animal models. Clearance of senescent cells can reduce the burden of unresolved inflammatory signaling that puts stress on the aged immune system. There are more in various stages of development.
The global population is entering an era of aging. Older people are more susceptible to pathogens and have higher rates of morbidity and mortality. Despite the significant success of current vaccine products, many commercial vaccines fail to generate effective and long-lasting immune protection in elderly individuals. With increasing age, the reasons for the decline in vaccine potency are multifactorial. Age-related dysregulation of lymph nodes, and crucial immune cells jointly reduces the efficiency of vaccination. With the continuous emergence of new pathogens, it is urgent to create strategies to improve vaccination-mediated protection for elderly individuals.
The existing approaches are primarily aimed at optimizing the vaccine delivery system rather than inhibiting the immunosenescence of the immune microenvironment in elderly individuals. Inhibiting the immunosenescence of elderly individuals can evoke strong and long-lasting immune protection, which serves as a critical measure to improve vaccine-induced immunity. Although inhibition of immunosenescence most likely requires continuous intervention/treatment and is complicated to achieve, we believe that sustained-release vaccination/adjuvants or booster immunizations may sustainably ameliorate immunosenescence in the elderly. Once the immunosenescence of the elderly is corrected, their immune efficacy against various antigens can be improved.
An attractive research direction will be discovering immunomodulators and vaccine formulations that can inhibit immunosenescence. The selection of adjuvants can greatly impact the type and magnitude of the immune response. Considering the special immune status of elderly individuals, designing tailored vaccine adjuvants is indispensable for the development of next-generation vaccines for older individuals. A chronic inflammatory state also accompanies immunosenescence. However, the common opinion is that adjuvants promote immunity by inducing local inflammation. Therefore, more in-depth studies are needed to explain the role of inflammation in vaccine-induced immunity and tune the contradictory perspectives.
Most studies focus on one or several cell types or certain processes of the immune response. However, our immune system is a complex and coordinated comprehensive network. More new technologies and advances will help reveal the complexity underlying the human immune system. We must pay more attention to the impacts of versatile cells or multiple immune cascade processes. Future research should focus on developing scientific methods to build more convincing models of aging and study the profound mechanisms underlying age-related alterations that impact the immune responses of older people.
