Physical Activity and Vaccine Response

Abstract

Over the past decade, numerous research studies have shown that the immune system’s capacity for creating antibodies after getting vaccinated is better in those who exercise are physically active. Authoritative studies show that exercise is an important ally of the vaccine, amplifying its effectiveness. The immune response to vaccines is usually lower in the elderly population. Several strategies have been used to help overcome this problem. Recently, studies in humans and animals have shown that exercise increases antigen-specific blood antibody levels following vaccination. Exercise has been considered as an effective way to improve vaccine response in the elderly population. In this chapter, we will discuss the effect of exercise on vaccine response. This study summarizes the current understanding of exercise and antibody production. In order to develop intervention strategies, it will be necessary to further elucidate the predisposing factors and mechanisms behind exercise induce antibody response.

1. Introduction

In our daily life, there are harmful viruses, bacteria, and other microorganisms that can invade the human body and cause illness. However, the human body has a mechanism to prevent pathogens from causing disease once they have invaded the body. This mechanism is called “immunity.” Immunity is a powerful defense mechanism that protects us from disease by recognizing pathogens in the body and killing them. Vaccines make use of this mechanism.

Vaccination is one of the most successful public health interventions in preventing infectious diseases and reducing the mortality and morbidity associated with these diseases. The main aim of vaccination is to prevent pathogen-specific infections. The result is to prevent people from becoming seriously ill and dying. On the other hand, aging is the biggest risk factor for impaired immunological health and reduced vaccine efficacy. To enhance the vaccine response, the vaccine itself needs to be modified or behavioral interventions need to be found that alter host factors to enhance the vaccine response.

Exercise improves antibody response to vaccine in human study [1]. Despite the potential beneficial role of exercise on immune responses to vaccination, the underlying mechanisms remain understudied. Based on the studies above, it is generally accepted that prolonged intense exercise is detrimental [2], whilst continuous moderate-intensity exercise is beneficial to immune function [3]. Exercise is a cost-effective behavioral intervention to enhance immune function. Exercise may have a beneficial effect on the immune response to vaccination in elderly population. The two main questions of interest are: (1) how does exercise benefit the effectiveness of vaccination; and (2) what kind of exercise, for how long and at what intensity, would be beneficial in elderly population?

The primary goal of the review presented in this chapter is to provide a better understanding of exercise and vaccine response. This chapter is divided into three parts, with the first section summarizing basic knowledge about vaccines and antibody production. In the second part, we focus on the latest insights into the mechanism of exercise-induced increase in antibody concentration. This section describes the intensity of exercise, the duration of exercise, endogenous opioids, IgG half-life that are modulated by exercise. The third part presents information on our current understanding on immune senescence and effects of exercise on vaccine response in older adult.

2. Vaccination

2.1 What is in a vaccine?

Vaccination is regarded one of the greatest medical discoveries of modern civilization. The eradication of smallpox is one of the most important contribution toward for human and best examples of how vaccination stopped a deadly disease and saved millions of lives [4]. A vaccine is a complex biological product that can be used to safely induce an immune response that confers protection against infection and disease on subsequent exposure to a pathogen.

Vaccine adjuvants usually improve the vaccine response by stimulating the innate immune system, which provides for the rapid first line of defense against infection. Regardless of whether the vaccine is made up of the antigen itself, this weakened version will not cause the disease in the person receiving the vaccine, but it will prompt their immune system to respond much as it would have on its first reaction to the actual pathogen. To achieve this, vaccines are made from pathogenic viruses and bacteria that have been rendered less virulent by reducing their virulence. An essential component of most vaccines is one or more protein antigens that elicit an immune response that provides protection.

2.2 Vaccines induce antibodies

Vaccination response can be understood as a measure of integrated immune function, elicited by antigen exposure and measured by antibody titer and cell-mediated response [4]. The adaptive immune response is mediated by B cells that produce antibodies (humoral immunity) and by T cells (cellular immunity). All vaccines in routine use are thought to mainly confer protection through the induction of antibodies. Immune responses to antigens may be categorized as primary or secondary responses (Figure 1). After vaccination, B-lymphocytes detect the antigens and respond as if a real infectious agent has invaded the body, proliferating to form identical cells that can respond to the vaccine antigens. This response from immune system, generated by the B lymphocytes, is known as the primary response.

Figure 1.

During the primary response, naive B cell differentiation and antibody production occur several days after antigen encounter (initial exposure). In contrast, following secondary antigenic exposure, B cells expand with a shortened lag phase and produce larger quantities of antibodies. The difference between the primary and secondary exposures is the presence of memory B cells and pre-existing antigen-specific antibody. Memory cells differentiate into antibody-secreting plasma cells that output a greater amount of antibody for a longer period of time.

After initial antigen exposure, it takes several days for this adaptive response to become active. After the first exposure to a pathogen, immune activity rises and then levels off and declines. Since the initial immune response is slow, it does not prevent disease. Antibody levels in the circulation wane after primary vaccination, often to a level below that required for protection. During subsequent exposures to the same pathogen, the immune system can respond rapidly, and activity reaches higher levels. The secondary immune responses can usually prevent disease. In encountering a pathogen, the immune system of an individual who has been vaccinated against that specific pathogen is able to mount a protective immune response more rapidly and more robustly. Immune memory is important feature of vaccine-induced protection. Memory of the infection is reinforced, and long-lived antibodies remain in circulation. It takes several days to build to maximum intensity, and the antibody concentration in the blood peaks at about 14 days [5].

Some infections, such as chickenpox, induce a life-long memory of infection [6]. Other infections, such as influenza, vary from season to season to such an extent that even an adult is unable to adapt [7]. Seasonal influenza A and B viruses are constantly evolving in nature, often resulting in antigenic change or “drift” [8]. The composition of influenza vaccines is updated annually to keep pace with antigenic drift [9]. Whether immune memory can protect against a future pathogen encounter depends on the incubation time of the infection, the quality of the memory response and the level of antibodies induced by memory B cells.

3. Exercise and antibody response

3.1 Exercise induces antibody production

The immune response is a complex mechanism, but it is important to understand this in order to consider the possibility that it may be modulated by exercise. Liu and Wang [10] examined exercise-induced blood antibody levels in mice. They examined the plasma antibody levels of mice after infected with Salmonella typhi. The results showed that the antibody titer of the exercising mice was significantly higher (2.76 times higher) than that of the non-exercising group during the experiment. The antibody titer of the exercising mice was 2.76 times higher than that of the control group (Figure 2). Authors observed that after the initial immunization, a primary antibody response occurred. After booster immunization, the antibody levels increased and then remained high in the blood. This result means that maintenance of long-term antibody responses is critical for protective immunity against many pathogens. After this study, effects of exercise on secondary antibody responses have been tested in young mice [12] and rats [13]. Several studies have been conducted on exercise-induced elevation of blood antibody, focusing mainly on the secondary antibody response. Exercise immunologists were intrigued by the dramatic changes in secondary antibody responses in exercising mice.

Figure 2.

Effects of physical training on the murine immunological response. Serum antibody levels in active (exercise) and control (non-exercise) mice (modified from Douglass [11]).

Moderate exercise, such as voluntary wheel running exercise [12] or exercise (8–15 m/minutes) on a treadmill [14], has been shown to have a marked effect on the increase in antibody levels after booster immunization. These findings have proved to be valuable information that prompted exercise immunologists to investigate. Thus, since the early days, the effect of exercise on the increase in blood antibody concentration after booster immunization has been investigated. Moderate exercise may be a powerful adjuvant to vaccination.

The rodent model is known to affect the antibody response after booster immunization. In mice, the primary IgG response to the antigen was not enhanced, but in mice subjected to exercise, the IgG response was enhanced after booster immunization [12]. Subsequent reports also showed that antibody production in exercising mice was enhanced after booster immunization [10, 11, 15]. It is unclear why moderate exercise affects the antibody response after booster immunization, while it does not affect antibody production after initial immunization.

3.2 Effect of moderate intensity physical exercise on antibody response

Both moderate and vigorous-intensity physical activity improve antibody response. Moderate-intensity physical exercises stimulate cellular immunity, while prolonged or high-intensity practices without appropriate rest can trigger decreased cellular immunity, increasing the propensity for infectious diseases [14]. Furthermore, acute and intensive exercise, more common among athletes such as marathon runners, can lead to transient immunodepression [16]. According to the International Society for Exercise and Immunology (ISEI), the immunological decrease occurs after the practice of prolonged physical exercise, that is, after 90 minutes of moderate- to high-intensity physical activity [17].

In contrast, moderate intensity physical activity is responsible for providing an increase in the immune response. As an example, elderly women participating in a moderate intensity physical exercise program aerobic exercises were performed between 60 and 70% of VO₂max, involving at least 30 minutes of exercises in step, jump coordination, and rhythmic movements sometimes dance for at least 12 months (1 hour exercise sessions 4 times a week) produced higher levels of anti-influenza (IgM and IgG) antibodies compared to sedentary women [18]. Another study showed that elderly subjects who performed physical exercised at 65–75% heart rate reserve (HRR), 25–30 minutes, 3 days per week, for 10 months also confirmed that the exercise increased the concentration of antibodies against the influenza vaccine [19].

Moderate-intensity exercise was also effective in increasing the effectiveness of the pneumococcal vaccine. When young adults immunized with pneumococcal vaccine were given 15 minutes of moderate exercise (30 seconds of exercise followed by 30 seconds of rest), they showed higher antibody production than those who did not exercise [20]. Thus, moderate physical exercise helps our body trigger the antigen specific antibody response to effectively.

3.3 Effect of exercise term on secondary antibody response

How long exercise does it take to be effective exercise induce secondary antibody response? Moderate exercise conducted over a 2- to 8-week period enhances secondary antibody response and is mediated. Kapasi et al. compared different duration of moderate exercise training on antibody immune responses in young mice [21]. Female C57BL/6 mice were randomized into 2 to 8-week exercise training or sedentary control group. Mice with 2 weeks of exercise showed a significant increase in antibodies after the additional immunization, comparable to mice with 8 weeks of exercise. Studies on the effect of moderate exercise on increased antibody levels after additional immunization will be reviewed in a later section. A moderate exercise program of 2 weeks may be sufficient to improve secondary antibody production. The author proposed that may be a useful strategy to enhance antibody response to vaccinations in humans.

3.4 Effect of exercise on antigen-specific antibody producing B cell and T cell

Factors responsible for the enhance antibody level after booster immunization have been investigated in detail by Suzuki and Tagami [12]. They examined the effect of exercise on antigen-specific IgG-producing cells in splenic lymphocytes by Enzyme-Linked ImmunoSpot [22]. The antigen-specific IgG-producing cells were significantly higher in the exercising group than in the sedentary group. Authors proposed that effects of voluntary wheel-running exercise on the number of cells which produce tetanus toxoid (TT)-specific IgG producing cells (Figure 3). Voluntary exercise of moderate intensity (60–70% VO₂max) increases the immune response of CD4+ T cells in healthy mice after vaccination [23]. Rogers et al. reported that exercised C57BL/6 mice with OVA intranasally immunization, and significantly increased CD4+ T cells (collected in spleen, mesentery lymph nodes, and Peyer’s patches), TNF-α OVA-specific, and IL-5 were significantly increased. These reports suggest that exercise also effect on B cell and T cell responses.

Figure 3.

Effects of physical training on the murine immunological response. Antigen specific antibody levels in active (exercise) and control (non-exercise) mice (modified from Suzuki and Tagami [12]).

3.5 Effects of exercise on endogenous opioids

Beta-endorphin, an opioid peptide is released into the blood after moderate exercise [24]. However, this phenomenon varies among individuals. Furthermore, endorphin levels in the blood are maintained for 15–60 minutes after exercise [25]. The role of endogenous opioids in exercise-induced increases in secondary antibody concentrations is unknown [12]. It has been suggested that endogenous opioids are involved in the increase in exercise-induced secondary antibody concentrations. Endogenous opioids have been implicated in exercise-induced increases in secondary antibody concentrations. Enkephalins were first observed in the brain and endocrine system. Both endorphins and enkephalins are important regulators of pain. Endorphins have been implicated in immune function [13], pain relief [26], and response to exercise [27, 28, 29]. The role of endogenous opioids in modulating exercise-induced increases in secondary antibody concentrations, especially at the cellular level, needs to be elucidated.

Kapasi et al. [30] initially immunized mice with antigens and administered placebo or an opioid antagonist (naltrexone), while untreated mice received no intervention. The mice were then subjected to exercising for 8 weeks, followed by booster immunization. After the booster immunization, the antibody levels increased in the exercising mice. On the other hand, there was no increase in antibody levels in the mice that received the antagonist. The increase in antibody concentration by endogenous opioids was dose-dependent of intravenous injection [31]. The production of antibodies occurs as a result of the interaction of antigens retained on follicular dendritic cells with B and Th lymphocytes [32, 33].

The mechanism of exercise-induced antibody concentration is activated by the binding of opioids to specific receptors on B cells and T cells [33]. Endogenous opioids also affect the antibody response through receptors on Th (CD4+) cells and by stimulating proliferation [34, 35]. These cascades are the result of induced IL-4 production, and IL-4 increases the viability of splenic B cells [36]. Further research is needed to determine if the effect of exercise is due to increased antibody levels.

3.6 Effects of exercise on IgG half-life

The mechanism that induces exercise-induced increases in blood antibody concentrations is related to the half-life of IgG [12]. The clearance rate of IgG in blood has been found to be highly dependent on its concentration in plasma [37]. The half-life of IgG in blood at physiological concentrations is about 10-fold longer than at IgG higher concentrations [37]. IgG proteins are endocytosed [38]. IgG is induced at the cell surface and released into plasma or interstitial fluid. FcRn regulates IgG epithelial transport and recycling. FcRn binds to IgG in a pH-dependent manner binding to IgG [39, 40]. In an acidic environment, IgG binds strongly to FcRn; the IgG-FcRn complex is transported by lysosomes to the cell surface where it fuses with the cell membrane [41]. At physiological pH, the FcRn receptor has little affinity for IgG. When sorting vesicles fuse to the plasma membrane, IgG dissociates from the receptor and is rapidly released into the extracellular fluid. Clearance of IgG is increased approximately 10-fold, and the efficiency of IgG recycling is over 90% in wild-type animals expressing FcRn [40].

The effect of exercising mice on IgG clearance has been reported [42]. The clearance of IgG with exercise has been reported by Suzuki and Tagami [12]. They investigated for factors that would reduce the clearance of non-specific ¹²⁵I-IgG in the blood after booster immunization (Figure 4). High blood antibody levels may result in low clearance of antibodies. The reason for the low clearance of ¹²⁵I-IgG in the blood of exercising mice has not yet been elucidated; the homeostasis mechanism of IgG depends on the Fc region of IgG [42]. A possible cause of the decreased clearance is the FcRn receptor, which is expressed in the vascular endothelium in mice and has an IgG protective function [43].

Figure 4.

Clearance of radiolabeled IgG from exercise (black circles) and non-exercise (white circles) mice (modified from Suzuki and Tagami [12]).

The FcRn molecule is dependent on dimerization with β2-microglobulin (β2m) [43]. In β2m-deficient mice, a shortening of the half-life of IgG occurs and homeostatic IgG levels are reduced [44]. Suzuki et al. reported on the effects of intraperitoneal immunization of mice with TT to induce primary and secondary antibody responses, protection from IgG catabolism in the liver and β2m expression. The authors reported an exercise-induced increase in blood antibody concentrations and a prolonged half-life of antigen-specific IgG in active mice [45]. Exercising mice had higher levels of radiolabeled IgG in the liver. This phenomenon was also confirmed by immunohistochemical analysis. The expression of the β2m gene was up regulated in the liver of exercised mice. There was a significant correlation between the amount of IgG accumulated in the liver and the concentration of IgG in the blood. There was also a significant correlation between total liver IgG and liver β2m.

4. Exercise and vaccine in older population

4.1 Immune senescence in old adults

Preventive medicine is the most effective and feasible strategy to protect health in old subjects and vaccination against the most common infectious diseases is the most indicated approach. Most currently used vaccines are less immunogenic and effective in the elderly compared to younger adults [46]. This is due to several factors, including immune aging and a different immune response in children and young adults than in older adults with a history of infection. Almost all vaccines are specifically designed for children and young adults. The mechanisms of immune senescence are multiple but seem to be driven largely by changes in T cell-mediated immunity. There are fewer antigen-naïve T cells in the peripheral blood of aged individuals than there are in younger individuals [47].

Aging is a natural process and is described as “immune senescence.” Immune senescence is associated with a decline in the immune system [48]. An important sign of immune senescence is the decline in immune function. Decline in immune function can lead to the development of opportunistic infections [49]. Immune senescence also results in a reduced vaccine response [50], leading to an increased incidence of infectious diseases. Improving immune function is expected to reduce the incidence of infections in the elderly and have beneficial effects in maintaining health. Moderate exercise has been used as an intervention to combat the aging of the immune system.

Aging is associated with declines in humoral and cellular immunity [51], and therefore reduced immune function. The decline in immunity due to aging is more pronounced in acquired immunity than in natural immunity. The capacity of this acquired immunity peaks around the age of 20s and declines to about half of that in the 40s. The main cause of immune senescence thought to be the change in the quality of T cells due to the decline in the function of the thymus gland.

The age-related decline in the function of major cells that take part in the antibody response are reflected by the secondary antibody response [52]. Kapasi et al. focused on age-related changes in immune function and the effects of exercise, and their study clearly showed that older mice exhibited a secondary antibody response similar to that seen in young control mice after exercise [15]. Thus, intense exercise exerts positive effects on the secondary antibody response in older animals. This, exercise-induced attenuation of immune senescence might help to improve immune responses to vaccination. Therefore, the health of the elderly is closely related to the maintenance of immune function. Therefore, the health of the elderly is closely related to the maintenance of the immune system. Thus, exercise has a positive effect on the secondary antibody response in older animals. This suggests that exercise in older animals may contribute to the immune response to vaccination. Hence, the health of the elderly is closely related to the maintenance of immune function.

4.2 Effects of exercise on vaccine response in older adult

Recently, several strategies have been tested to improve the efficacy of a vaccine in older adults. Regular exercise has been associated with enhanced vaccination responses [51, 52]. In contrast, acute exercise had no detrimental effect on vaccination response in healthy older adults [53]. Exercise-induced elevation of antibody concentrations is a tool against infectious diseases. The use of exercise-induced elevation of antibody concentrations to combat infectious diseases in humans has been investigated, and positive results have been observed [19]. Moderate aerobic exercise in the elderly [19] and resistance exercise have been shown to enhance the immune response to influenza vaccination [54, 55]. In addition, several cross-sectional studies have found that physically fit [56] and active older adults [57] have higher antibody responses to booster immunization. Shuler et al. [58] examined antibody titers to influenza vaccination in the elderly. There was no association between physical activity level and the degree of antibody concentration. However, this study did not measure antigen-specific antibodies.

Cross-sectional studies in elderly populations have all reported increased antibody concentrations after booster immunization in participants with high physical fitness [56, 59] or physical activity [57, 58, 60]. This effect of exercise-induced increases in antibody concentrations after vaccination in an elderly population was exemplified by Smith et al. [60]. They compared antibody levels in exercise-induced antibody production by immunizing with keyhole limpet hemocyanin (KLH). The results showed that antibody responses and cell-mediated responses to KLH were stronger in active elderly men than in sedentary elderly men.

Woods et al. demonstrated that 10 months of aerobic exercise (60–70% maximal oxygen uptake, 45–60 minutes, 3 times per week) in previously sedentary elderly subjects resulted in increased blood antibody levels compared to participants who only participated in flexibility training during the same period [61]. Elevated antibody concentrations to antigens have also been observed after chronic exercise; after KLH vaccination, IgG1 and IgM concentrations were higher in participants who completed a 10-month cardiovascular training program than in control participants [62]. Previously reported studies supported the hypothesis that regular exercise improves immune function in the elderly. This is reflected in the increased concentration of antigen-specific antibodies after vaccination, especially in the elderly.

5. Conclusion

In this review, we presented to improve vaccine response through moderate exercise. Currently available evidence shows that moderate exercise impacts upon the secondary antibody response but not the primary response. These effects are mediated by a diverse range of factors, including the functions of antibody producing cells, proliferation of CD4+ T cells, endogenous opioids, and IgG half-life. Over 2-week period enhances secondary antibody response is mediated. Most exercise studies have focused on antibody production, with more work required in this area. Almost all studies have investigated the effects of moderate exercise on immune function. This will provide insight into vaccination that is improved by exercise. The incorporation of molecular biological methods into the field of exercise immunology should improve our understanding of the activation of cells involved in exercise-induced increases in antibody concentrations after booster immunization.

Acknowledgments

I would like to express my heartfelt gratitude to my advisor, Dr. Kazumi Tagami, for her guidance and encouragement throughout my PhD. Dr. Tagami was always happy with me when I succeeded and worked with me to find the cause of my failures. This study was supported in part by grants from the Daiwa Securities Health Foundation and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (No. 16650154 to KT). This paper is a revised and enhanced version of the authors’ recent publication [12, 45].

Abbreviations

CD	cluster of differentiation
TNF	tumor necrosis factor
OVA	ovalbumin
KLH	keyhole limpet