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Timing of Vaccination after Training: Immune Response and Side Effects in Athletes

STENGER, TANJA1; LEDO, ALEXANDRA2; ZILLER, CLEMENS1; SCHUB, DAVID2; SCHMIDT, TINA2; ENDERS, MARTIN3; GÄRTNER, BARBARA C.4; SESTER, MARTINA2; MEYER, TIM1

Author Information
Medicine & Science in Sports & Exercise: July 2020 - Volume 52 - Issue 7 - p 1603-1609
doi: 10.1249/MSS.0000000000002278
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Abstract

The prevention of infectious diseases is an important aspect of medical care in athletes. Besides avoiding exposure (1) and other hygienic measures (2), vaccinations provide a powerful means for preventing a number of infectious diseases. In addition to a certain reluctance toward vaccination, which is obvious in the general population, vaccinations in elite athletes are often perceived to have specific problems and disadvantages. Even mild side effects may be of higher relevance for performance in an athlete population. Moreover, finding an acceptable time point for vaccination within tight training and competition schedules is a frequently discussed problem (3,4). Despite some evidence that moderate exercise positively influences the immune response after vaccination, robust knowledge about interactions between timing of vaccination and regular training sessions in elite athletes is still lacking (5).

The incidence of infections may be slightly higher in athletes because of high training loads (6–8), travel (9), and close contact to other athletes and staff members; psychological stress and athlete-specific lifestyle factors (nutritional needs, changing environment, etc) might also contribute. In this context, it has been suggested that this phenomenon may be related to changes in the number and function of lymphocytes in blood after heavy exercise or during competitions, which may increase susceptibility toward infectious agents (“open-window-theory”) (7,8,10), although this view has recently been challenged by the observation that training may rather lead to an enhancement of specific immunity after antigenic challenge (11).

Consequently, the main aims of the present study were to address sport-specific aspects of vaccination and to contribute to developing a more rational basis for vaccination guidelines in competitive athletes (12). We have previously reported that elite athletes show a more pronounced induction of vaccine-specific immunity as compared with nonactive controls (13). Influenza has been chosen as the model vaccine because it is administered on a yearly basis, with the vaccine being specifically adapted to the currently circulating influenza strains. Therefore, many individuals can be considered naïve to the vaccine. Because of seasonality of disease and the availability of the vaccine, in the Northern hemisphere, this vaccination should be administered in the European autumn and therefore cannot easily be postponed to a period without training and competition. Finally, the vaccine is recommended for competitive athletes because influenza is highly contagious and influenza infection may give rise to severe complications (e.g., myocarditis), which compromise training efficacy and performance during competitions (3). In this study, we focused on finding the most favorable time point for a vaccination with regard to the last training session. Based on the aforementioned considerations, we hypothesized that vaccination 26 h after training leads to a more pronounced immune response and less side effects than within only 2 h after training.

METHODS

General design

The study was a randomized prospective intervention study in elite athletes from different disciplines. Two different time points for influenza vaccinations were compared between athletes who were randomly assigned to either a group receiving vaccination within 2 h after an intensive bout of their regular training (“2-h group”) or another group being vaccinated between 24 and 26 h after their last training session (“26-h group”). Results on immunogenicity in relation to nonactive controls were reported elsewhere (13). Recruitment and vaccinations took place from September to December 2016 at the Institute of Sports and Preventive Medicine, Saarbrücken, or directly at the training site. Blood samples were collected immediately before (i.e., relatively shortly after training in the 2-h group) as well as 1, 2, and 26 wk after vaccination. The determination of immunological parameters took place at the Department of Transplant and Infection Immunology, Saarland University, Homburg/Saar, except for the neutralization titers, which were measured at Laboratory Prof. G. Enders and Partners and the Institute of Virology, Infectious Diseases and Epidemiology e.V., Stuttgart, Germany.

Ethical approval

The study was carried out in accordance with the Declaration of Helsinki and approved by the regional ethics committee before commencement (149/16, Ärztekammer des Saarlandes, Saarbrücken, Germany). After being informed in detail about the study and the vaccination, all participants (and their parents in case of minors) gave written informed consent.

Participants

Healthy athletes (age ≥16 yr) who engaged in performance-oriented training on at least 5 d a week were eligible for this study. Exclusion criteria were signs for a current or recent acute infection, allergy to the vaccine, immunosuppression, pregnancy, or rheumatic diseases. The subjects were recruited from the Olympic Training Center Saarbrücken and affiliated clubs mainly via personal communication with the responsible coaches. Before testing, all participants provided structured details on their training history identifying them as eligible for the study.

Forty-six competitive athletes volunteered for this study. One subject (26-h group, wrestling) unexpectedly changed his residence after 1 wk and was excluded from further analysis. Another athlete (2-h group, wrestling) did not have a blood sample drawn after 6 months for personal reasons. An extrapolation of the results was carried out in this case. Therefore, blood samples were fully assessed from 45 athletes (36 male, 9 female; anthropometric data given in Table 1) competing on national or—only in a few cases—on high regional level. We included athletes from 10 different types of sport (wrestling (n = 14), badminton (n = 6), rowing (n = 6), swimming (n = 4), triathlon (n = 4), football (n = 3), hammer throw (n = 3), marathon (n = 2), cycling (n = 2), and basketball (n = 1)). Eighteen of them were members of national teams. Six athletes reported vaccination against influenza within a previous year (two in the 2-h group, four in the 26-h group; P = 0.40). Thirty-five athletes had never been vaccinated against influenza. Four athletes did not know their vaccination status. There were no significant differences between both groups regarding main subject characteristics and their training activities (Table 1).

TABLE 1
TABLE 1:
Subject characteristics (mean ± SD if not otherwise indicated).

Procedure

The vaccine (“Influsplit Tetra” 2016/2017, batch: AFLBA 152AB; GlaxoSmithKline GmbH & Co. KG, Munich, Germany) was administered via intramuscular injection into the deltoid muscle of the nondominant arm in a standardized manner. Side effects or complaints were recorded by the participants themselves using a standardized questionnaire during 2 wk after vaccination (following recommendations of the “Brighton Collaboration” [14]). In addition, the athletes kept a standardized training diary for the 2 d before and the 2 wk after vaccination.

To assess influenza-specific humoral and cellular immune response, venous blood samples (9 mL, lithium–heparin tubes; Sarstedt, Nümbrecht, Germany) were taken from an antecubital vein in a supine position immediately before (i.e., shortly after training in the 2-h group and at least 1 d after the last training session in the 26-h group) and 1, 2, and 26 wk after vaccination. The time of the day was variable and closely related to the time of the training sessions for the first blood sample, of course. It was tried to keep this time constant for all blood samplings; however, this was not possible in 20%–30% of the athletes. Athletes were never fasted and always well hydrated (albeit not formally controlled for). For our target parameters, this moderate degree of standardization was regarded acceptable.

Stimulatory procedures and conditions were described before (13,15). In brief, titrated amounts of the vaccine were used to stimulate influenza-specific T cells in whole blood. Stimulations with Staphylococcus aureus enterotoxin B (SEB) and phosphate-buffered saline served as positive and negative controls, respectively. All stimulations were carried out in the presence of the costimulatory antibodies anti-CD49d and anti-CD28. After 2 h, brefeldin A was added for the intracellular accumulation of cytokines. After a total of 6 h, cells were fixed, permeabilized, and stained for surface and intracellular molecules. Finally, reactive CD4 T cells were flow cytometrically identified by coexpression of the activation marker CD69 and the cytokine interferon-γ. Vaccine-reactive cells were quantified by subtraction of cells obtained after control stimulation.

To analyze the humoral immune response, neutralizing antibodies were quantified using a specific neutralization test for the influenza strains contained in the vaccine (H1N1, H3N2, Brisbane, Phuket) using a procedure and strains as described before (13,16). The neutralizing antibody titer was expressed as the reciprocal of the highest serum dilution that produced a 75% reduction of foci compared with virus control (IC75). Levels of influenza-specific IgG, IgM, and IgA antibodies towards the vaccine strains were quantified as ratios or units per milliliter using a standard enzyme-linked immunosorbent assay according to the manufacturer’s instructions (Anti-Influenza-A/B Pool ELISA; Euroimmun AG, Lübeck, Germany). In addition, a panel of routine blood parameters was assessed before vaccinating each subject to screen for potentially unknown health impairments.

Statistics

Statistics were performed by using GraphPad Prism 5.0 (GraphPad, San Diego, CA) and SPSS statistics (Version 23; IBM Corporation, Armonk, NY). A classic sample size calculation was impossible because of a lack of comparable studies and thus of estimations of the effect size and its expectable variability. Normal distribution was tested using the Shapiro–Wilk test. There was no normal distribution in all assessed parameters except for age, where we used the t-test to test for differences between the groups. In all other cases, nonparametric tests were performed (Mann–Whitney U test for metric variables and Fisher exact test for nominal and categorical variables).

Comparisons between the 2-h group and the 26-h group were conducted to test the hypothesis that immune response as well as number and severity of side effects are different between them. To compare the dynamics of neutralization titers, antibody titers, and CD4 T cells in each individual, the Friedman test was used. Fold increases (ratios of titers before the vaccination and titers to the different time points after vaccination) were compared among the groups using the Mann–Whitney U test. The significance level was set at P < 0.05 for the α error.

RESULTS

Immune response

For the cellular immune response, both groups showed a strong significant increase in vaccine-reactive CD4 T-cell levels, which peaked 1 wk after vaccination (3.7-fold increase (interquartile range [IQR], 3.0–5.4) in the 2-h group and 4.6-fold increase (IQR, 2.8–8.0) in the 26-h group compared with baseline values, P < 0.001). However, the increase in the induction of vaccine-specific CD4 T cells between postvaccination and prevaccination values did not differ between both study groups (P = 0.52, Fig. 1B). In general, polyclonally stimulated, SEB-reactive T-cell levels were stable over time in both groups, which confirmed specific induction of an immunological response to the influenza vaccine (Figs. 1A, B).

FIGURE 1
FIGURE 1:
Vaccine-specific CD4 T cells before and 1 wk, 2 wk, and 6 months after influenza vaccination. A, Levels of vaccine-specific CD4 T cells and polyclonally stimulated SEB-reactive CD4 T cells (median and IQR) of the 2-h group and the 26-h group. B, Comparison of fold changes in reactive CD4 T cells (median and IQR; top: influenza-specific CD4 T cells, bottom: SEB-reactive CD4 T cells). Flu, influenza; pre, before vaccination; w, weeks after vaccination.

As with T-cell levels, influenza-specific antibody levels in both groups showed a significant increase in response to vaccination and peaked after 1 and 2 wk (Fig. 2A). As shown by the magnitude of the increases in antibody levels, induction of influenza-specific IgM levels was far more pronounced (13.1-fold (IQR, 4.4–19.6) in the 2-h group; 17.6-fold (IQR, 7.7–45.3) in the 26-h group) than induction of IgG (1.4-fold (IQR, 1.1–2.1) in the 2-h group; 1.4-fold (IQR, 1.2–2.4) in the 26-h group) and IgA (2.0-fold (IQR, 1.4–2.4) in the 2-h group; 1.6-fold (IQR, 1.2–3.3) in the 26-h group). There were no significant differences between groups for the immune globulin classes (P = 0.24–0.97, Fig. 2B).

FIGURE 2
FIGURE 2:
Influenza-specific antibody levels before and 1 wk, 2 wk, and 6 months after influenza vaccination. A, Levels of influenza-specific IgG (in relative units per milliliter), IgM (ratio), and IgA (ratio; median and IQR) before and after vaccination. B, Comparison of the fold changes (median and IQR) in antibody levels. Ratios for IgA and IgM refer to a semiquantitative value representing the ratio of the extinction of the serum sample divided by the extinction of a calibration serum corresponding to the upper limit of the normal range. Relative units per milliliter refer to a quantitative determination of IgG levels based on a standard curve determined by three calibration sera (negative, upper limit of the normal range, upper limit of measurement range). pre, before vaccination; w, weeks after vaccination.

To assess the functional capacity of the influenza-specific antibodies, titers of neutralizing antibodies against each component of the influenza vaccine were measured using a microneutralization assay. One and 2 wk after vaccination, both study groups showed increased titers of neutralizing antibodies, with the highest ones against H1N1 (medians, 1:5120 in the 2-h group and 1:10,240 in the 26-h group), whereas titers against the influenza B strain Brisbane were lowest (medians, 1:160 and 1:320; Fig. 3A). Regarding the titers of the Brisbane strain, the increase from baseline to 2 wk between both groups (4-fold (IQR, 2–17.8) in the 2-h group; 16-fold (IQR, 4–32.9) in the 26-h group) showed a numerical difference but failed to reach statistical significance (P = 0.06, Fig. 3B). Likewise, all three other strains did not show any between-group differences (P = 0.16–0.72, Fig. 3B).

FIGURE 3
FIGURE 3:
Dynamics of influenza-specific neutralizing antibody titers. A, Influenza-specific neutralizing antibody titers (median) against the influenza strains H1N1, H3N2, Brisbane, and Phuket in both groups. B, Comparison of the fold changes (median and IQR) in neutralizing antibody titers. IC75, inhibitoric concentration; pre, before vaccination; w, weeks after vaccination.

Side effects

Eighty percent (n = 36) of all athletes reported some type of local or systemic side effects some time after vaccination, the most frequent complaint being pain in the arm at the injection site (73% (n = 33)). The occurrence of the different types of side effects in the two groups is summarized in Figure 4. Numerically, the incidence of any type of side effect was slightly lower in the 26-h group (71%) as compared with the 2-h group (88%); however, the difference was not significant (P = 0.27). Among local symptoms, pain in the arm at the injection site was most frequently observed, whereas redness or swelling was rare. However, the incidence of local side effects did not differ between the groups (P = 0.18–0.24). The overall incidence of systemic symptoms (mainly myalgias, fatigue, and headache) was lower compared with local side effects, and again similar between groups (P = 0.37–1.00). We also did not observe any differences between the groups when the intensity or duration of side effects was considered (data not shown). The two most severe systemic effects were fever in one athlete at two consecutive days after vaccination (day 2/3, max. 38.9°C) and swelling of the mamilla in another. All side effects were self-limiting.

FIGURE 4
FIGURE 4:
Local and systemic side effects. Local pain, redness, and swelling at the injection site were quantified in both groups. In addition, information on systemic reactions such as myalgia, nausea, fatigue, and headache was collected.

Training

Complaints during training within the 2 wk after vaccination were reported slightly less frequently in the 26-h group (n = 4 (19%)) as compared with the 2-h group (n = 11 (46%)), but this difference did not reach statistical significance (P = 0.07). Comparing each single day, 1 d after the vaccination, 11 (24%) athletes reported complaints during their training mostly because of pain at the injection site, with no differences between the groups (8 athletes in the 2-h group vs 3 athletes in the 26-h group, P = 0.18). On day 2 after vaccination, there were five (11%) athletes left with such problems (three in the 2-h group and two athletes in the 26-h group). After day 2, four athletes still reported minor complaints (three in the 2-h group and one athlete in the 26-h group). Only one athlete (2-h group) had to switch to a different type of training for one training session (cycling instead of swimming). However, there was no loss in training time after vaccination in any athlete.

None of the results showed any differences between male and female athletes.

DISCUSSION

In this study, elite athletes were vaccinated either within 2 h after the last training session or after a training break of about 1 d. The results indicate that timing of influenza vaccination after sport-specific intense training in elite athletes affects neither the induction of vaccine-specific cellular or humoral immune response nor the number and severity of vaccine-related side effects.

Immune response

Levels of influenza-specific T cells and IgG, IgM, and IgA antibodies as well as titers of influenza-specific neutralizing antibodies were strongly induced and did not differ significantly between the 2-h and the 26-h groups of elite athletes. Thus, the vaccination-induced influenza-specific cellular and humoral immune response was independent from the time elapsed after the last training session. The current findings do not support the assumption of an impaired immune function shortly after acute exercise, as has been put forward in the “open window” theory (17). This theory was based on a higher incidence of minor illnesses such as respiratory tract infections resulting from a loss of circulating lymphocytes, although the clinical significance of these findings is still unclear (18). More recent evidence rather suggests that the previously observed change in lymphocytes does not indicate impaired immune function but may result from mobilization of cells to peripheral tissues, thereby mediating improved immune control (11,19).

Effects of acute exercise on vaccine efficacy in nonathletes

Studies assessing the effect of acute exercise on vaccine responses mainly exist among nonathletes and thus methodologically do not address practical problems in the care of elite athletes. Most of the studies indicate an exercise-induced enhancement of the immune response (20–24). For example, young healthy adults performed eccentric contractions of the upper arm and were vaccinated against influenza 6 h later into the same arm, whereas the control group rested quietly before the vaccination. Cell-mediated responses based on interferon-γ induction and antibody titers were enhanced by exercise (21). Similarly, two other studies reported higher antibody titers after exercise before an influenza vaccination (20,24). In some contrast, the immune response to a meningococcal A vaccination was only found to be stronger in men after an acute exercise stress test compared with a control group, whereas there was no such enhancement in immune response in women (22). Other studies showed no additional effects of exercise before a vaccination (25,26). For example, healthy young adults were vaccinated against influenza at different time points after an eccentric exercise of the shoulder of the nondominant arm. This activity did not alter antibody responses or cell-mediated immunity compared with a control group without prior exercise. The authors speculated that the strong immune responses to the vaccine might have limited further immune improvement by exercise indicating some kind of a ceiling effect (26). It seems that the adjuvant effects of training bouts on the induction of specific immunity are particularly strong in individuals with low preexisting immunity (5). None of the studies, however, compared athletes in whom vaccination was performed at different time delays after training. This is particularly relevant for elite athletes in an ongoing training process; as such, athletes hardly ever have any breaks much longer than 24 h between sessions in their typical training schedules.

Effects of acute exercise on vaccine efficacy in athletes

With regard to well-trained athletes, one study addressed the question if a single intensive bout of exercise could have an effect on vaccination response (27). Triathletes were compared with moderately trained men. The triathletes were split into two groups. One group was vaccinated after performing a half-ironman competition; the others were vaccinated without prior exercise. Similar to our results, antibody titers against diphtheria, tetanus toxoid, and pneumococcal antigens showed no significant differences between the three groups (27). In another study, elite swimmers were able to mount an antibody response to a pneumococcal vaccine comparable to a sedentary control group (28). Overall, the strong induction of specific immunity after vaccination despite training is in accordance with other published results, which found that the induction was even more pronounced in athletes as compared with controls (13). To our knowledge, there are no further studies in elite athletes that assess if the timing of the last training session before vaccination affects immunogenicity after vaccination.

Muscle damage is hypothesized to be associated with higher antibody responses, because it probably induces a proinflammatory environment that may cause an improved antigen uptake and an increased leukocyte homing (29). Various other effects of acute exercise, such as improved lymph drainage by muscular contractions, are described (5). In general, this may explain the fact that the vaccine-induced immune response in our cohort of athletes was more pronounced as compared with nonactive controls (13). Nevertheless, elite athletes on continuous training are generally used to their sport-specific exercises. In our cohort, this could result in a generally lower extent of muscle damage after acute exercise and consequently may explain the lack of difference between the 2-h and the 26-h training group.

Side effects and training

The effect of the time between exercise training and vaccination on the occurrence of side effects has been poorly studied so far (10), although this is a common concern in general sports practice. A higher incidence of pain at the injection site was reported in healthy untrained subjects when the vaccine was administered immediately after an acute bout of eccentric resistance training as compared with an application 6 h after exercise (26). In contrast, timing of vaccination seems to be less relevant in athletes on continuous physical training, as we did not detect significant differences in side effects between athletes vaccinated 2 versus 26 h after exercise. Although there was a slight trend towards less complaints during subsequent training sessions, when the athletes had a training break before the vaccination, this difference did not reach statistical significance. One reason for these different perceptions in healthy untrained subjects and elite athletes might be the consequence of different training modes before vaccination, as the usual training in our athletes did not exclusively include the shoulder muscles. In contrast, the untrained population in the mentioned study had to complete a predefined eccentric exercise of the shoulder, which may have increased the likelihood of pain in the affected arm immediately after vaccination. However, among athletes, the type of sport may also have an influence on the likelihood of side effects; for example, a swimmer might be more prone to feel pain at the deltoid injection site than a runner. In our study, only one athlete (swimmer) had to change his type of training. If training constraints are a concern, other ways of administration, such as intranasal application, may be considered in such disciplines. Because of the limited number of athletes per discipline, it was not possible to address this aspect more explicitly.

Likewise, differences between male and female individuals could not be examined with maximal statistical power because only 20% of our participating athletes were women. A further limitation is our sample size, which was influenced by the restricted recruitability of elite athletes. It does not seem that this has affected our main results very much because effects were shown to be very homogeneous. However, coverage of sport disciplines was not complete, which may impair the generalizability of our findings. Also, the tendency for differences in the antibody response to the Brisbane strain may warrant verification in a larger sample of athletes.

CONCLUSIONS

This study found a strong induction of cellular and humoral immune responses to the influenza vaccination in elite athletes, with no differences in immunogenicity between groups who differed in timing between the last training session and vaccination (2 vs 26 h). The results do not provide any evidence to support an impaired induction of cellular and humoral immunity immediately after an intensive training session. In addition, the incidence of side effects was not significantly different between groups. In summary, influenza vaccination seems to be a safe method of infection prophylaxis in elite athletes, and no constraints need to be applied for timing of vaccinations in relation to their training sessions.

The present study was funded by the German Federal Institute of Sport Science (ZMVI4-072026/16-17).

M. S. is coinventor for a patent application entitled “An in vitro process for the quick determination of the infection status of an infection with an influenza virus type” (European patent application no. 11 181 119.6, Saarland University). No conflict of interest is declared by the other authors. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

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Keywords:

IMMUNE RESPONSE; PERFORMANCE; OPEN WINDOW; TRAINING

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