ReviewThe effects of exercise on vaccination responses: A review of chronic and acute exercise interventions in humans
Introduction
Vaccination programs have become a major strategy in reducing the mortality and morbidity rates for many infectious diseases, currently making them the most effective and cost-efficient method of disease prevention in humans (Nicholson et al., 2003). Despite having an influential role in disease prevention, there is great variation in the efficacy of some vaccinations (Hilleman, 2000, Villari et al., 2004). For example, there is significant variation in the response to influenza vaccinations, where clinical vaccine efficacy is estimated to be 70–90% in young adults, whereas the corresponding efficacy in the elderly is only 17–53% (Goodwin et al., 2006).
The immune response to vaccination is a complex process, which is important to understand if the potential for exercise to alter the response is to be investigated. Vaccines can be classified according to the involvement of T lymphocytes in the generation of the response; as thymus dependent (T-dependent) or thymus independent (T-independent). The majority of vaccines are T-dependent, comprising of antigens which are soluble proteins. The initial process in the response to vaccination is antigen uptake and presentation, performed by specialised antigen presenting cells, including macrophages and the highly efficient dendritic cells, or by B cells themselves. In T-dependent responses, naïve B cells recognise the presented antigen, and mature after cognate interaction with T helper cells, whilst in T-independent responses the B cells do not need interaction with presenting cells or T cells. Matured B cells include plasma cells which secrete antibodies, and long-lived memory cells. The measurement of the vaccination response can be quantified in two main ways: the plasma cells’ production of antibody (measurement of serum antibodies) and the response of memory lymphocytes to stimulation with the antigen (e.g., measurement of proliferation or cytokines released by in vitro stimulation of peripheral blood mononucleocytes). The term seroprotection is used when a dichotomous endpoint reflecting clinical protection is identified; most commonly for influenza a heamagglutination inhibition (HI) assay is often used to determine antibody concentration. The titre represents the dilution at which sufficient antibody is present to prevent agglutination of red blood cells when virus is added, this a higher titre represents a greater concentration of antibodies, a titre of >1/40 is referred to as seroprotective for influenza (Coudeville et al., 2010). The response to an antigen may be primary, the first encounter, or secondary, subsequent encounters. The primary response peaks at approximately 30 days, with secondary responses showing faster and greater magnitude peaks. The use of completely novel antigens such as the benign protein keyhole limpet haemocyanin (KLH), allows investigators to ensure they are examining a primary T-dependent response but the specific clinical relevance is unclear, whilst the use of prophylactic infectious disease vaccines allows investigation of a clinically relevant response.
The importance of understanding vaccine efficacy has led to investigation of factors which may influence the immune response. There are several well-established demographic and behavioural features that are known to be associated with reduced vaccine responses. Chief amongst these is chronological age (Aspinall et al., 2007, Bender, 2003); immunosenescence, which is the gradual deterioration and chronic inflammation of the immune system that occurs with age, includes alterations in both the innate and adaptive immune systems, resulting in an increase in susceptibility to infection and reduced ability to clear pathogens as well as reduced responses to vaccinations (Grubeck-Loebenstein et al., 2009, Lang et al., 2011). Many disease conditions are also associated with reduced responses to vaccinations; these include malnutrition, type 2 diabetes, cardiovascular disease, rheumatological diseases, certain cancers and osteoporosis (Feikin et al., 2000, Nicoll et al., 2008). Furthermore, lifestyle factors such as chronic stress, depression, caregiver burden, excessive alcohol consumption, dietary restriction or weight loss, and smoking are known to diminish the efficacy of the immune response to vaccinations and/or alter susceptibility to infection (Powell et al., 2011). Thus, the problems of low vaccine efficacy are far-reaching and the search for adjuvants to boost responses and improve protection from disease is of great clinical importance.
Exercise has been identified as a behavioural factor that can boost immune function in some settings and therefore potentially serve as an adjuvant for immune responses. Indeed, interest in exercise-induced changes in immune function can be viewed along two lines: chronic exercise or training, or high levels of physical activity over an extended period (month/years), and, separately, acute exercise: the performance of a single bout of exercise (minutes/hours).
Acute exercise is known to have many short-term effects on immune function, but there appear to be contrasting effects of moderate exercise bouts and prolonged/intense exercise bouts. A single bout of exercise is referred to here as ‘acute exercise’, but the intensity and duration continuum may encompass different effects on immune function. Prolonged intense exercise, such as completing a marathon, is thought to result in temporary suppression of immune function, described by the “open window hypothesis” (Nieman and Pedersen, 1999). It has been shown that after prolonged intense exercise, neutrophil phagocytic function, natural killer cell numbers and total lymphocyte counts are reduced during the subsequent 2–24 h (Kakanis et al., 2010), offering a mechanism of reduced cellular immune function increasing susceptibility to infection. A moderate exercise bout, however, is thought to stimulate immune function, described by the “acute-stress induced immune-enhancement hypothesis” (Edwards et al., 2007b). This hypothesis was based on a body of animal evidence which showed exposure to an acute stressor such as restraint stress, inescapable footshock, or exercise at close temporal proximity to antigen administration can enhance primary and secondary antibody responses as well as the cell-mediated response (delayed type hypersensitivity model) (Dhabhar and Viswanathan, 2005, Millan et al., 1996, Silberman et al., 2003). The mechanisms by which acute exercise might influence the immune response are varied and suggest several different sites of action in the development of the response (Edwards and Campbell, 2011). Exercise induction of a pro-inflammatory environment in the muscles (especially in the case of muscle-damaging exercise) (Peake et al., 2005) may result in increased lymphocyte homing to the site of vaccine administration, and/or enhanced antigen uptake and processing, making the initial phase of the immune response more efficient. Indeed, exercise has been shown to preferentially mobilise leuckocytes with tissue-homing potential that may contribute to the pro-inflammatory milieu (Campbell et al. 2009). Relatedly, the well known leukocytosis response to exercise, driven by neuroendocrine mechanisms, includes increased circulation numbers of monocytes and dendritic cells (Ho et al., 2001), the potential antigen presenting cells, increasing likelihood of migration to site of antigen exposure. Finally, lymph drainage is also known to be elevated by muscular contractions (Havas et al., 2000) and thus, exercise may enhanced immune cell transport from the site of antigen administration to draining lymph nodes. See Fig. 1 for summary of hypothesised mechanisms.
Given the significance of vaccine efficacy in prevention of morbidity and mortality due to infectious disease, and the variability in response particularly in vulnerable populations, the suggested role of exercise as a moderator may be important. In the current review we summarise the evidence for effects of exercise in both acute and chronic forms on vaccination responses in human cohorts.
Section snippets
Methods – literature search
To ensure a complete and unbiased review, a systematic search of the published literature was performed. The final search was conducted on May 25th 2013. To ensure a thorough search was conducted and non biassed reporting of studies occurred, six large electronic databases were searched; CINAHL (1981–present), MEDLINE (1950–present), WEB OF SCIENCE (all years), AMED (1985–present), SCOPUS (all years) and SCIENCE DIRECT (all years). Four different groups of keywords were used for each database,
Results
Twenty trials met the inclusion criteria for this review and are described in Table 1, Table 2. Summary results are presented in two parts: (1) acute exercise effects of vaccination response (nine studies, Table 1), and (2) chronic exercise effects on vaccination response (eleven studies, Table 2). The primary findings reported in each paper are summarised in Table 3.
Discussion
The findings from this review suggest that there is a positive association between exercise and the immune response to vaccination, particularly in populations at risk for immune dysfunction, such as older adults. Studies that have investigated the effect of chronic exercise on response to vaccination have found with consistency that moderate exercise training in the older adult population can enhance the immune response. All eight studies involving older adults showed greater responses to
Future directions
Both chronic exercise and acute single-bout exercise are adjuvant possibilities, but little is established regarding the optimal protocols. In chronic exercise the necessary volume, and relative advantages of endurance and/or resistance training has not been investigated. The potential utility of progressive resistance training in older adults is especially interesting given the prevalence of sarcopenia which has been linked to immune dysfunction and increased susceptibility to infection.
Conclusion
In conclusion, this review provides moderately robust evidence that both chronic and acute exercise interventions may improve immune responses to vaccination, particularly in those individuals with sub-optimal responses to vaccination. There are important limitations to the existing literature, with regards to study quality and quantity, as well as many gaps in knowledge about mechanism of effect of exercise as an immune-adjuvant, optimal prescriptive elements, combination of exercise and other
Conflicts of interest
All authors have no conflict of interest.
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