To our knowledge, this is the first evidence that being physically active may enhance immunogenicity of a vaccine against SARS-CoV-2 in a large cohort of patients with ARD. Additionally, a similar benefit was observed in a small cohort of non-ARD individuals. This finding suggests that physical activity may boost vaccine response, which is particularly relevant to immunocompromised individuals who are prone to diminished immunogenicity.
Vaccination is a major strategy in reducing mortality and morbidity rates for several infectious diseases,12 including COVID-19.13 In countries with high capacity of vaccine acquisition and rapid rollouts, both new cases and deaths have been dramatically reduced. However, vaccine efficacy varies between individuals, with particularly low responses found in those with reduced immune function.14,15 mRNA vaccines against SARS-CoV-2 can elicit a reduced humoral response in older individuals and in ARD patients,4–6,16 a finding recently extended to CoronaVac,9 which has been largely used in highly populated countries, and recently approved for emergency use by WHO.17 Indeed, previous data from this trial point out to lower SC (70.4 vs. 95.5%) and titers (12.1 vs. 29.7), frequency of NAb positivity (56.3 vs. 79.3%) and neutralization activity (58.7 vs. 64.5%) in ARD patients vs. controls.9 It becomes clear that the search for adjuvants to enhance vaccine response and improve protection from disease infection is of great clinical importance. Chief amongst these is physical activity, which has been deemed as a behavioral intervention able to boost immune function in different scenarios, thereby potentially serving as an adjuvant to improve vaccine response, including that against SARS-CoV-2. This hypothesis was tested in the present study.
Both observational and interventional studies have shown that habitually physically active individuals, or those receiving exercise interventions, present with higher concentration of IgG and IgM following influenza and keyhole limpet haemocyanin (KLH) vaccination.18–25 Apart from studies involving older individuals, evidence that physical activity may confer better vaccine responses in those with less functional immunity is lacking. In this regard, our data bring novel evidence that, compared to their inactive counterparts, physically active ARD patients may have higher SC rates, GMT and FI-GMT and a trend to higher neutralizing activity, even after controlling for several covariates, including age, sex, BMI and medications. Of relevance, the positive association of physical activity with GMT (+ 32%) was diametrically opposite to those of age (-33%), obesity (-30%) and medications (-27 to -48%), which underscores the potential importance of a physically active lifestyle in counteracting factors known to impair immunogenicity. Furthermore, our exploratory analysis suggests that the benefits of being physically active (i.e., meeting the minimum recommended amount of physical activity) on vaccine immunogenicity tends to wane owing to sedentary behavior (i.e., too much sitting), a finding that has been observed in population-based studies for all-cause mortality,26,27 and that requires confirmation for vaccines responses. We also observed a direct dose-response relationship between physical activity volume and SC, GMT, and FI-GMT. Although current evidence does not yet provide specific information about how intensity, frequency, duration and type of physical activity influence vaccine responses,11 the present findings suggest that engaging in at least 150 min/week of moderate-to-vigorous physical activity while avoiding excessive sitting time may enhance immunogenicity to vaccination against SARS-CoV-2, with higher physical activity amounts (≥ 350 min/week) possibly offering greater benefits.
Hypothetically, young healthy adults might be less responsive to the benefits of physical activity on immunogenicity, since the robust response to most vaccinations in this population may mask more subtle effects of exercise, whereas in those with weaker immune function and higher variability, the immunoenhancement effects may be more noticeable.13 Similar to ARD patients, however, we observed a positive association between physical activity and SC rates and GMT in non-ARD individuals. This suggests the potential applicability of our findings in a more generalized context; nonetheless, these should be validated in a larger cohort of non-immunosuppressed individuals.
The mechanisms by which regular physical activity enhance vaccination responses are not fully understood. However, it is known that moderate-to-vigorous physical activity is able to improve immune function, which is reflected in greater antibody or cell-mediated responses to vaccination.13,28 Even a single bout of exercise can elicit substantial changes in the immune system.29 Described as the ‘‘acute-stress induced immunoenhancement hypothesis’’, the increases in epinephrine, cortisol, heart rate and blood pressure encompass the acute response to exercise.30 Alongside these physiological adjustments is the well-stablished leukocytosis response, the transient increase in muscle-secreted inflammatory cytokines, and the exercise-induced muscle damage leading to leukocyte trafficking to the tissue. These orchestrated adjustments have been postulated to stimulate the activation of immune surveillance in anticipation of antigen entry,28,31 which may be of particular relevance to vaccination.30 Although the clinical benefit of physical activity on vaccines efficacy is commonly inferred from the quantified antibody, neutralization activity or cell-mediated responses, this postulation finds support in a population-based cohort study, in which moderately- and highly-active individuals were less likely to experience an influenza-coded visit to a physician or emergency department.32 Whether SARS-CoV-2 vaccine efficacy may be modulated by physical activity and how it occurs remain to be investigated.
Our data is strengthened by the large prospective cohort of immunocompromised patients with ARD, the assessment of immunogenicity using both SARS-CoV-2 IgG and NAb, and the robust control for numerous covariates. Limitations include the use of questionnaire to assess physical activity, which is prone to recall bias and overreporting; lack of estimates of vaccine effectiveness to bridge to the immunogenicity data; short-term assessment of immunogenicity, precluding any firm conclusions on the persistency of the observed responses; lack of assessment of cell-mediated immune responses; observational nature of the study, hampering causative inferences; and the constraint of the results to the vaccine tested in this study. In this regard, CoronaVac seems to evoke less protective titer compared to others, a response associated with lower protection from SARS-CoV-2 infection.33 This underpins the clinical relevance of the current findings; conversely, it is uncertain whether physical activity may also associate with enhanced responses to other vaccine platforms able to elicit higher protective titer, as a ceiling effect may exist at least for heathy individuals.
Cumulative evidence has shown that physical activity is associated with better outcomes in COVID-19 patients. Consistently active individuals seem less susceptible to COVID-19-related ICU admission and mortality.34 This study brings novel evidence suggesting that a physical active lifestyle may also boost SARS-CoV-2 vaccine immunogenicity, a finding of particular relevance for people with dysfunctional immune system. Collectively, these data reinforce the need for a global call for action to delivery physical activity during the COVID-19 pandemic, with particular emphasis to groups with reduced immune function. Randomized controlled trials are necessary to confirm the efficacy of physical activity in enhancing vaccine responses, and to stablish the optimal dose to elicit the greatest benefits.