Effects of Vaccination Day Routine Activities on Influenza Vaccine Efficacy and Vaccination-Induced Adverse Reaction Incidence: A Cohort Study

We aimed to investigate the effect of vaccination day routine activities on the influenza vaccine efficacy and vaccination-induced adverse reaction incidence. Study participants were workers at three hospitals in the Hyogo Prefecture, Japan, who received the influenza vaccine between October and November, 2018 and 2019. Their data were collected using a questionnaire. The main factors, which were examined for vaccination day routine activities, were personal hygiene (bathing), smoking, alcohol consumption, caffeine intake, and exercise. The main outcome markers included influenza incidence during the winter season and vaccination-induced local or systemic adverse reaction incidence. The risk ratio for the main factors of vaccination day routine activities was calculated against the main outcome markers using the modified Poisson regression. Overall, 3780 people received the influenza vaccination, and 2731 submitted the questionnaire. We found that vaccination day routine activities did not affect the influenza vaccine efficacy, and engaging in strenuous exercise on the vaccination day tended to cause systemic adverse reactions. Moreover, lifestyle-related activities had no impact on the incidence of systemic or local adverse reactions. Therefore, it is advisable to only avoid strenuous physical exercise, and no other lifestyle-related restrictions are necessary on the day of influenza vaccination.


Introduction
Influenza is an infectious disease that is most prevalent during winter. Japan's National Institute of Infectious Diseases has reported that out of a population of 126 million, 12 million (9.5%) and 7.28 million (5.7%) people contracted influenza during the winter seasons between 2018 and 2019, and 2019 and 2020, respectively [1]. In 2018, there were 3325 reported deaths due to influenza in Japan [1].
The administration of vaccines against the infection caused by the influenza virus has been a common practice and is the single most effective prevention strategy [2]. Because the majority of the individuals worldwide is expected to remain susceptible to one or more circulating influenza strains at any given time, further understanding of optimal vaccine practices is essential. Inactivated influenza vaccine is prepared by killing influenza viruses and isolating their subvirion or purified surface antigens to create "split" or subunit vaccines [2]. The inactivated influenza vaccine is then introduced into an individual's immune system through injection. This causes rapid distribution of the antigen into the bloodstream and induces a humoral response [2].
Daily exercise [3] lowers the risk of contracting influenza, whereas smoking [4] and alcohol consumption [5] increase the risk. However, these factors do not alter the efficacy of the influenza vaccine [2]. A survey study on US military members reported that there was no significant difference in the efficacy of influenza vaccine with relation to daily routine activities between the groups of smokers and nonsmokers, those with a potential alcohol problem and those without an alcohol problem, and those reporting a high exercise level and those reporting a minimal exercise level [2]. However, another study reported that daily alcohol consumption increases the risk of developing adverse reactions after influenza vaccination [6].
In Japan, where the use of public bathhouses is part of the culture, people are usually advised to avoid taking a bath or engaging in exercise after receiving a vaccine, including the influenza vaccine. This is because of the risk of localized infection via the injection site while in the bath or the difference in temperature between the changing and bathing rooms, which may cause people to get sick [7]. At public bathhouses, the bathtubs may be used multiple times by many individuals consecutively. Therefore, hygiene of the hot water in the bath may not be as good as in a private home. In fact, vaccination guidelines before 1994 instructed people to avoid bathing and urged people to rest on the vaccination day [7].
In Japan, healthcare professionals often document some details of the vaccinated individuals, including routine activities performed on the day of vaccination, such as personal hygiene (bathing), smoking, alcohol consumption, or exercising, to assess the efficacy and adverse reactions of the influenza vaccine. However, to the best of our knowledge, no reports exist regarding the influence of routine activities performed on the day of vaccination, such as personal hygiene (bathing), smoking, alcohol consumption, or exercising, on the efficacy and adverse reactions of the influenza vaccine. These results could affect lifestyle-related activities on the vaccination day.
Therefore, we aimed to investigate the effect of the abovementioned routine activities performed on the vaccination day on vaccine efficacy and adverse reaction incidence after vaccination.

Study Design
This cohort study was conducted with the approval of the Ethics Committee of Hyogo Prefectural Tamba Medical Center (Approval No. Tan-I No. 1166). Participants provided their written informed consent for study participation and result publication.

Participants
The study participants were all vaccinated employees at three hospitals in Hyogo Prefecture (Hyogo Prefectural Tamba Medical Center, Toyooka Public Hospital, and Shiso Municipal Hospital) who received the influenza vaccine between October and November 2018 or 2019. Mass vaccination had been performed for all employees during this period. In Japan, a mass influenza vaccination program for healthcare professionals is conducted in hospitals every year during the influenza season. All healthcare professionals in the three hospitals who took the influenza vaccine were eligible to participate in our study.

Setting
Each participant was provided with a vaccine screening healthcare questionnaire prior to vaccine administration. This is a standard procedure in Japan, and the standardized questionnaire was analyzed in this study. The questions included participant characteristics, their routine activities on the vaccination day, and the incidence of adverse reactions after vaccination. The questionnaire was collected 10 days after the participants were vaccinated with reference to a previous study [8].

Details of the Questionnaire
Participant characteristics included the following: age, sex, pregnancy status (women only), underlying conditions, body temperature at the time of vaccination, poor physical condition at the time of vaccination, influenza vaccination history, and food/drug allergy history.
Routine activities on the vaccination day included the following: personal hygiene (bath, shower only, washed using a towel or not washed), smoking (nonsmoker, previous smoker, smoker but did not smoke on vaccination day, smoker and smoked on vaccination day), alcohol consumption (consumed alcohol or did not consume alcohol on vaccination day), caffeine intake (consumed caffeine or did not consume caffeine on vaccination day), and exercise with perspiration (exercised or did not exercise on vaccination day).
The incidence of the following local adverse reactions on injection site was determined: redness, swelling, induration, pain, heat sensation, pruritus, and heaviness/lassitude. The incidence of the following systemic adverse reactions was determined: fever, chills, headache, fatigue, nasal discharge, cough, nausea, diarrhea, difficulty moving the upper limbs, and numbness.

Incidence of Influenza
Influenza was diagnosed using rapid influenza diagnostic tests, which are immunoassays that can identify the presence of influenza A and B viral nucleoprotein antigens. The questionnaires provided prior to vaccine administration, including those analyzed in this study, were sequentially numbered before distribution and managed by the Infection Control Office of each hospital, independent of the study organizer. Each Infection Control Office confirmed the identity of the participants who contracted influenza during the 2018-2019 and 2019-2020 winter seasons among those vaccinated in 2018 and 2019, respectively. Individuals affected by influenza were matched to the numbers on the questionnaires to confirm the incidence of influenza during each season.
Using the abovementioned method, participant characteristics, presence or absence of adverse reactions, and incidence of influenza were blinded from researchers to protect the participants' privacy.

Definition of Underlying Conditions
Underlying conditions were defined and classified as the presence or absence of the following conditions: cancer, immunological disease/diseases caused by steroid use, renal disease, diabetes, hypertension, hepatic disease, and pulmonary disease.

Data Analysis of Participants' Background Characteristics
Means of continuous variables and percentiles of categorical variables were calculated to characterize participants.

Main Factors
Routine activities on vaccination day are listed below.

Statistical Analysis
The risk ratio and 95% confidence interval for the main factors from the routine activities on vaccination day were calculated against the main outcome markers using modified Poisson regression. Analysis was performed based on the following three models.
Model 1 Rough analysis. Model 2 Adjustment for sex, age, and underlying conditions. Model 3 Model 2 + adjustment for routine activities (personal hygiene, smoking, alcohol consumption, caffeine intake, and exercise).
Data were analyzed using Stata MP version 15 (StataCorp, College Station, TX, USA).

Results
The fractions of the numbers of questionnaires received and people who were vaccinated at Hyogo Prefectural Tamba Table 1 (missing values were excluded from calculations).   The mean age ± standard deviation was 42.7 ± 12.7 years, and women accounted for 76.18% of the participants. The majority of participants had no underlying conditions.
Regarding routine activities on vaccination day, 70.57% of the participants took a bath, 11.02% were previous smokers, 0.41% were smokers but did not smoke, 6.34% were smokers and smoked on that day, 16.97% drank alcohol, 49.83% consumed caffeine, and 4.95% exercised.
Of the vaccinated participants, 81.67% and 19.99% experienced local and systemic adverse reactions, respectively; 82.66% experienced either a local or systemic adverse reaction. Table 2 shows the effects of vaccination day routine activities on influenza incidence. From the risk ratio, none of the activities significantly affected the incidence of influenza. Table 3 shows the effect of vaccination day routine activities on the incidence of adverse reactions.  Table 4 shows the effect of vaccination day routine activities on the incidence of local adverse reactions. From the risk ratio, none of the activities significantly affected the adverse reactions. Table 5 shows the effect of vaccination day routine activities on the incidence of systemic adverse reactions.

Discussion
In the present study, we found that vaccination day routine activities, such as personal hygiene (bathing), smoking, alcohol consumption, caffeine intake, and exercise, did not affect the efficacy of the influenza vaccine. Furthermore, we found that engaging in strenuous exercise on the vaccination day tended to cause systemic adverse reactions. Moreover, apart from exercise, lifestyle-related activities had no impact on the incidence of systemic and local adverse reactions.
According to previous study findings, daily exercise lowers the risk of contracting influenza [2]. This result is possibly attributed to improved viral clearance [9], increased antibody titer levels [10], or the effect of neuroendocrine factors [11]. Conversely, the risk of contracting influenza has been reported to increase with smoking [3] and alcohol consumption [4]. Tobacco components have been suggested to block antiviral pathways and increase susceptibility to influenza through oxidative stress-associated mechanisms [12]. Moreover, smoking decreases the host defense properties of the respiratory mucosa [13]. Furthermore, chronic alcohol consumption may cause an inflammatory environment and alter CD8T cell response, thereby increasing susceptibility to influenza viruses [4]. Moreover, previous studies have reported that daily habitual smoking, alcohol consumption, and regular exercise have no effect on influenza vaccine efficacy [5]. We found that lifestyle factors, such as personal hygiene (bathing), smoking, alcohol consumption, caffeine intake, and exercise, had no effect on the influenza vaccine efficacy. Before 1994, people were advised to avoid bathing and were encouraged to rest on the vaccination day [7]. However, the basis of such instructions hitherto, remains unclear. Our study findings showed, for the first time, that such restrictions were unnecessary prior to receiving the influenza vaccine and that people should continue to perform their normal daily activities on the vaccination day. On the vaccination day, only strenuous exercise that could cause sweating and heavy alcohol consumption should be avoided, as noted in the vaccination guidelines [7], and no other lifestyle-related restrictions are unnecessary.
Although daily alcohol consumption has been reported to increase the risk of developing adverse reactions [6], no special consideration has been given to the mechanism of alcohol consumption. Systemic adverse reactions that were frequently observed included fatigue (8.67%), difficulty moving the upper limbs (7.14%), and headache (4.89%), which may be caused by an increased immune response associated with exercise. It has been reported that an increase in the serum levels of macrophage migration inhibitory factor is involved in systemic adverse reactions after vaccination [14]. We believe that the increase in macrophage migration inhibitory factor due to exercise is associated with the increase in the incidence of systemic adverse reactions [15].
In this study, the incidences of influenza among participants were 6.46% and 4.71% during the 2018-2019 and 2019-2020 winter seasons, respectively. We believe that the findings of our study are important because the national influenza incidence rates for Japan were 9.5% and 5.7% [1] during the 2018-2019 and 2019-2020 winter seasons, respectively, and all participants were healthcare professionals who have sufficient knowledge regarding infection control measures. A study conducted in Australia and the Philippines with healthy adults reported that approximately 50% of participants had some types of adverse reactions after influenza vaccination [16]. Another study conducted in Japan among healthcare professionals reported that 73.9% and 15.8% of the professionals had local and systemic reactions, respectively [8]. In the present study, 81.67% and 19.99% of participants had local and systemic adverse reactions, respectively, which corroborated with previous study findings. Therefore, we believe that the incidence of influenza and adverse reaction incidence used as outcome markers in our study were reasonable.

Limitations
Adverse reactions were self-reported and not objectively monitored. Although the study participants were all healthcare professionals with a certain level of reliability, the participants' subjectivity may still be observed. In addition, because it is easy to track a large number of people, this group was targeted. The collection rate of 72.24% in this study was high; in contrast, the collection rate for Japanese questionnaire survey has been reported to be 14-18% [17].
It has been reported that, in the Japanese population, >30% of men and 10% of women smoke [18], 19-29% of men and 2-11% of women drink alcohol [19], and 10-30% of people exercise regularly [20]. In the present study, 6.34%, 16.97%, and 4.95% of participants smoked, consumed alcohol, and exercised, respectively. There was a possibility of selection bias as the participants were medical professionals. Hence, care should be taken when generalizing the results of this study. If the general public is included in the target population, the proportion of individuals smoking and/or consuming alcohol on the day of vaccination will increase, and the proportion of individuals exercising on the day will decrease. There are reports that daily smoking, alcohol consumption, and exercise do not affect the efficacy of influenza vaccines [2]. If the general public is included in the target population, the degree of impact of lifestyle on the day of vaccination is unknown, but it may not change much.
Other factors, such as using analgesics or other medications, might have influenced the adverse reaction and risk of contracting influenza; however, they were not explored in the current study.

Conclusions
Routine activities on the vaccination day, such as personal hygiene (bathing), smoking, alcohol consumption, caffeine intake, and exercise, did not influence the efficacy of the influenza vaccine. Among the influenza vaccine adverse reactions, only strenuous exercise affected the incidence of systemic adverse reactions. On vaccination day, no other lifestylerelated restrictions are necessary, barring strenuous physical exercise. Informed Consent Statement: Participants provided their written informed consent for study participation and result publication.

Data Availability Statement:
The data sets used and/or analyzed during the present study are available from the first author on reasonable request.