| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ORIGINAL ARTICLES |
From the School of Sport and Exercise Sciences (V.E.B., D.C., C.R., L.K.H.) and Department of Immunology, School of Medicine (M.D.), University of Birmingham, Birmingham, England.
Address correspondence to: Professor Douglas Carroll, School of Sport and Exercise Sciences, University of Birmingham, Birmingham, B15 2TT, England. Email: carrolld{at}bham.ac.uk
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
METHODS: Two hundred sixty medical school undergraduates, who had received the three-dose hepatitis B vaccine before recruitment to this study, completed questionnaires measuring exposure to stressful life events during the past year, customary coping strategies, and health behaviors. Antibodies against hepatitis B surface antigen were determined; levels <100 mIU/ml were deemed inadequate.
RESULTS: Two participant cohorts were identified: those vaccinated within the last year and those vaccinated earlier. In the early vaccination cohort, participants with greater-than-average stress exposures had a more than two-fold increased risk of having an inadequate antibody titer. Coping by accepting the reality of stressful situations proved protective, whereas coping by substance use increased the risk of having an inadequate antibody count in this cohort. These associations remained significant after adjustment for possible mediators. Furthermore, the effects of stress and coping were largely independent of one another. Neither stress nor coping was significantly associated with antibody status in the recently vaccinated cohort.
CONCLUSIONS: The present study confirms that the immune system is sensitive to variations in psychological factors. Stressful life events and coping strategy seem to have a continuing impact on hepatitis B antibody status.
Key Words: psychological stress, • coping, • hepatitis B vaccination, • immune function.
Abbreviations: anti-HBs = antibodies against hepatitis B surface antigen; BMI = body mass index; CI = confidence interval; LESS = Life Events Scale for Students; OR = odds ratio
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
Exposure to stressful circumstances, such as university examinations, marital disruption, and unemployment, would seem to have a deleterious effect on a variety of cellular enumerative (6–8) and in vitro functional (8–11) immune measures. There are difficulties of interpretation, however, with both of these general approaches to studying immune function. Changes in cell number, for example, do not necessarily reflect changes in functional efficiency (12). In vitro assessment of the functional immune response to a specific antigen might be considered a stronger methodology (13), but caution should always be exercised when generalizing in vitro to in vivo effects (12).
What are required are direct studies of psychological influences on in vivo immune function. One approach here is to study the influence of psychological exposures on vaccination outcome (14). There is now evidence that chronic stress is related to inadequate antibody response to the influenza vaccine in older adults (15, 16). Compared with control subjects, elderly spousal caregivers displayed poorer cellular and humoral immune responses to influenza vaccination (15). Similarly, those caring for spouses with dementia registered higher levels of emotional distress than control subjects and also showed a lower antibody response to vaccination (16). The results of research involving the hepatitis B vaccination are less consistent. In a study in which the three hepatitis B injections were scheduled to coincide with university examination periods, those students who were already antibody-positive before the second injection reported being less anxious and having lower levels of perceived stress than those students who had not, by that time, seroconverted (17). Similarly, individuals with high levels of stress during the 2 months after the first hepatitis B injection were found to have lower levels of antibody at the conclusion of a low-dose (2-µg) vaccination protocol (18), although when this study was repeated using the standard dose (10-µg) of vaccine, no relationship between stress and antibody count was found (19). Finally, there is one contrary result: Higher levels of perceived stress among medical students have been reported to be associated with higher peak antibody titers (20). Differences in protocols and outcome measures make it difficult to directly compare studies and undoubtedly account for some of the discrepancies in results. Further investigation of the effects of stress on antibody status after hepatitis B vaccination would seem warranted.
Another shortcoming of existing hepatitis B vaccine studies is that they have not always adequately controlled for variations in unhealthy behavior, a common correlate of stress exposure (21, 22). Because alcohol consumption (23) and smoking (24) can influence the immune status after vaccination, it is important that studies test whether associations between stress and antibody status are mediated by variations in unhealthy behaviors. Furthermore, virtually no attention has been paid to the possible effects of coping strategies on the immune response to vaccination. Nevertheless, there is a growing body of evidence that the coping strategies used by both healthy participants (25) and immunocompromised patients (26, 27) are associated with various measures of cellular immune function. Variations in coping styles are also linked to length of survival among patients with cancer (28), AIDS (29), and those who undergo bone marrow transplantation (30). The only hepatitis B vaccination study that considered the link between coping and antibody response reported no significant associations (18). Successful coping, however, was inferred from the absence of psychoneurotic and psychosomatic symptoms, and specific coping strategies were not assessed.
The present study examined the association between levels of exposure to stressful life events and variations in the use of different coping strategies and antibody status after hepatitis B vaccination in a young, healthy population. In addition, the effects of unhealthy behaviors were explored as potential mediators of any association between stress, coping, and antibody count.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
Procedure
All participants had completed the standard three-dose recombinant hepatitis B vaccine program before the study. University regulations require that all first-year medical school students attend the Occupational Health Department to have a single postvaccine blood sample taken so that their hepatitis B antibody levels can be determined. At this time, participants were asked when they received each of the three vaccinations and were administered a series of questionnaires measuring life events, customary coping strategies, and health behaviors. These were automatically scored using a scanning system (Scanning Systems SR-360). All participants provided informed consent, allowing access to their hepatitis B antibody titer results. The study was approved by the appropriate ethics committees.
Questionnaires
Psychological stress.
Participants completed Linden’s (31) LESS. This student-specific life events inventory required participants to select those life events that they had experienced in the past 12 months from a list of 36 chosen as likely to be pertinent to a university student population. Each stressful event has a prescribed weighted score appropriate to the severity and potential impact of the event. The most stressful event in the list, death of a parent, attracts a weighting of 100, and other events are scaled accordingly. The weighted scores of all the events checked by the participant were totaled to give an overall life events score. Following on from Linden (31), participants were characterized as having high and low life events exposures, using a median split of LESS scores.
Coping styles.
The Brief COPE (32) was administered to assess customary (ie, traitlike) coping styles. The Brief COPE is based on the original COPE inventory (33), has 28 items, and measures 14 conceptually differentiable coping styles: active coping, planning, positive reframing, acceptance, humor, religion, using emotional support, using instrumental support, self-distraction, denial, venting, substance use, behavioral disengagement, and self-blame. Despite the fact that each coping strategy is measured by only two items, internal consistency is acceptable, with Cronbach’s 
for the different coping strategies ranging from 0.50 to 0.90. Response options for each item varied from 0 ("I don’t do this at all") to 3 ("I do this a lot").
Health behaviors.
Health behaviors over the 6 weeks before testing were assessed using a questionnaire adapted from the Whitehall II study (34). Participants were asked, on average, how many cigarettes they smoked per day (0, 1–5, 6–10, 11–20, 21+), how many units of alcohol1 they drank per week (0, 1–5, 6–0, 11–20, 21–40, 40+), and how many hours they slept per night (0–3, 4–5, 6–7, 8–9, 10–11, 12+). A simple categorical scoring system was used in all cases. For example, participants who indicated that they slept for 8 to 9 hours per night were allocated a score of 3. Participants also reported the average number of hours spent per week (0, 1–2, 3–5, 6–8, 9–10, 11+) engaged in exercise of different intensities. Using a weighting of 1, 2, or 3 for light, moderate, or vigorous intensity activity, respectively, a composite exercise score was derived bysumming the number of hours at each intensity multiplied by the appropriate weighting.
Vaccinations and Measurement of Antibody Levels
All participants had completed a vaccination program with Engerix B (Smith-Kline Beecham Pharmaceuticals, Uxbridge, UK) or HB-VAX II (Pasteur Merieux MSD Ltd, Maidenhead, UK) by the standard schedule of three doses at 0, 1, and 6 months. Mean and median times taken to complete the program of vaccination were 6.26 months (SD = 2.25) and 6.00 months (IQR = 2.00), respectively. Vaccines had been administered by the university Occupational Health Department or by the participants’ own general practitioner. Serum was assayed for levels of antibodies against hepatitis B surface antigen (anti-HBs) at the Public Health Laboratory Service, Heartlands Hospital, Birmingham. Serum antibody levels were determined quantitatively using an anti-HBs enzyme-linked immunoassay kit (DiaSorin, Saluggia, Italy) according to the manufacturer’s instructions. Anti-HBs concentrations were capped at 1000 mIU/ml because the assays were undertaken for clinical reasons. Given this, it was inappropriate to represent these data as a continuous variable. In the United Kingdom, evidence of antibody titers of 
100 mIU/ml is required before medical school students are allowed access to patients. Students with anti-HBs concentrations of <10 mIU/ml have to repeat the full vaccination program, and those with anti-HBs between 10 and 99 mIU/ml are required to a receive a single booster vaccination. Accordingly, in the present study, antibody titers <100 mIU/ml were considered inadequate, and those 100 mIU/ml were deemed adequate. There is precedence for dichotomizing at this point (35, 36).
Statistical Analysis
Data were analyzed using SPSS for Windows (version 10.0). The dichotomous characterization of antibody status (adequate vs. inadequate) was the dependent variable throughout. Logistic regression analyses examined whether antibody status could be predicted from differences in timing of vaccination, stressful life events, the use of coping strategies, demographic data, or health behaviors. Because antibody titer data were unavailable for one participant, the effective sample size was 259. Furthermore, occasional questionnaire data were missing, but this never amounted to the loss of more than four participants per analysis, although 10 participants did not provide information on the timing of vaccinations. p values 
.05 were considered statistically significant.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
100 mIU/ml); the remaining 62 (24%) had an inadequate count (<100 mIU/ml) necessitating booster immunization. The median antibody count for this latter group was 31.81 mIU/ml (IQR = 42.97), whereas the median antibody count for the former group was 657.15 mIU/ml (IQR = 569.96). Preliminary logistic regression analysis indicated that timing of vaccination, treated as a continuous variable in months since initial vaccination, had an effect on antibody status (OR = 1.11, 95% CI = 1.01–1.22, p < .001); the longer the time elapsed since initial vaccination, the greater the likelihood of participants having inadequate antibody levels. Timing of vaccination also showed a pronounced bimodal distribution; participants tended either to have completed their hepatitis B vaccination course before starting university or to have undergone vaccination as part of the university’s program for medical students, which began in the autumn term of their first year.2 Accordingly, in all subsequent analyses participants were treated as two distinct cohorts: a recently vaccinated cohort of 102 (41%) participants who had begun the 6-month vaccination program within the previous 12 months (mean = 9.25, SD = 3.18) and a cohort of 147 (59%) who had begun the vaccination program earlier (mean = 19.43, SD = 4.42 months). Of this latter cohort, 91% had started their vaccination program 13 to 24 months before assessment.
Predictors of Antibody Status in the Recently Vaccinated Cohort
In this cohort, the median antibody count was 595.00 mIU/ml (IQR = 456.06); 94 (92%) were judged to have an adequate antibody count, whereas only 8 (8%) had an inadequate count. The mean age of participants in this cohort was 19.04 years (SD = 0.93), and their mean BMI was 22.82 kg/m2 (SD = 3.25). The majority were women (64%) and white (68%). The median weighted score on the LESS was 213.00 (IQR = 203.25). Neither life events (OR = 1.89, 95% CI = 0.42–8.41, p = .40) nor coping strategy was associated with antibody status. In addition, none of the demographic or health behavior variables were predictive.
Predictors of Antibody Status in the Earlier Vaccination Cohort
Within the cohort that started the vaccination program more than 1 year before assessment, variations in the timing of vaccination did not influence antibody status (OR = 0.99, 95% CI = 0.89–1.07, p = .64). Their median antibody count was 273.04 mIU/ml (IQR = 721.32); a Mann-Whitney U test revealed that the antibody counts of this cohort were significantly lower than those recorded for the recently vaccinated participants (U = 4728.50, p < .001). The numbers with adequate and inadequate antibody counts in this earlier vaccination cohort were 98 (67%) and 48 (33%), respectively. Their mean age was 19.10 years (SD = 0.83), mean BMI was 22.88 kg/m2 (SD = 3.58), and again the majority were women (69%) and white (64%).
The median weighted score on the LESS was 225.00 (IQR = 172.00). For those below the median (N = 74), the mean weighted LESS score was 149.78 (SD = 48.98), whereas for those above the median (N = 73), it was 344.85 (SD = 94.99). Participants with life events scores above the median were at significantly increased risk of having an inadequate antibody titer (OR = 2.54, 95% CI = 1.24–5.18, p = .01); 31 (43%) of those with high weighted LESS scores had an inadequate antibody count, compared with 17 (23%) of those with low LESS scores. Of the demographic variables analyzed, there were no significant associations between adequacy of the antibody count and age (OR = 1.11, 95% CI = 0.74–1.68, p = .61), sex (OR = 0.97, 95% CI = 0.46–2.05, p = .94), and BMI (OR = 0.99, 95% CI = 0.90–1.10, p = .91). However, whites were more likely to have inadequate titers than nonwhites (OR = 4.15, 95% CI = 1.76–9.79, p = .001). Nevertheless, in a multiple logistic regression model with ethnicity entered (OR = 3.62, 95% CI = 1.51–8.67, p = .004), high life events exposure was still associated with a two-fold increase in risk of having an inadequate antibody titer (OR = 2.15, 95% CI = 1.02–4.53, p = .04).
Given that the association between life events exposure and adequacy of antibody titer could be behaviorally mediated, the association between unhealthy behaviors and antibody count was explored. Smoking (OR = 1.63, 95% CI = 0.86–3.09, p = .14), sleep duration (OR = 0.91, 95% CI = 0.56– 1.50, p = .71), and exercise (OR = 1.00, 95% CI = 0.93–1.07, p = .92) were not significantly related to the adequacy of the hepatitis B antibody titer. In contrast, higher alcohol consumption was associated with increased risk (OR = 1.41, 95% CI = 1.09–1.81, p = .009). In a multiple logistic regression model in which alcohol consumption was entered (OR = 1.33, 95% CI = 1.02–1.73, p = .03), life events remained a significant predictor of the adequacy of the antibody count (OR = 2.10, 95% CI = 1.00–4.39, p = .05). There was a substantial relationship between ethnicity and alcohol consumption (
2(5) = 60.61, coefficient of contingency = 0.54, p < .001); whites drank significantly more alcohol than nonwhites. In a logistic regression model including both ethnicity and alcohol consumption, only ethnicity emerged as a predictor of antibody status (OR = 3.08, 95% CI = 1.21–7.81, p = .02); the analogous statistics for alcohol consumption were OR = 1.23, 95% CI = 0.92 to 1.65, and p = .16. It is clear that ethnicity and alcohol consumption were highly confounded; consequently, we did not adjust for both ethnicity and alcohol consumption in the same regression models reported below.
Of the coping strategies studied, only coping by substance use (OR = 1.46, 95% CI = 1.21–1.89, p = .005) and acceptance coping (OR = 0.78, 95% CI = 0.61–0.99, p = .04) were significantly associated with immune function. Whereas the use of acceptance coping was protective, coping by substance use increased the risk of having an inadequate hepatitis B antibody count. In addition, coping by self-blame tended to be detrimental to antibody status (OR = 1.20, 95% CI = 0.98–1.47, p = .07). After adjustment for ethnicity, the association with antibody status remained significant for coping by substance use (OR = 1.44, 95% CI = 1.11–1.88, p = .006), but it became marginal for acceptance coping (OR = 0.78, 95% CI = 0.60–1.01, p = .06).
Both coping by substance use (OR = 1.37, 95% CI = 1.05–1.79, p = .02) and acceptance coping (OR = 0.73, 95% CI = 0.56–0.95, p = .02) remained significant predictors of antibody status after adjustment for alcohol consumption. Furthermore, coping by self-blame became a significant predictor of adequacy of antibody titer in separate models that adjusted for ethnicity (OR = 1.26, 95% CI = 1.02–1.56, p = .03) and alcohol consumption (OR = 1.25, 95% CI = 1.01–1.54, p = .04). In a model entering all three coping strategies, coping by substance use (OR = 1.45, 95% CI = 1.12–1.89, p = .006) and acceptance coping (OR = 0.77, 95% CI = 0.59–0.99, p = .05), but not self-blame (OR = 1.17, 95% CI = 0.95–1.45, p = .15), emerged as significant predictors of antibody status.
To test the proposition that the association between exposure to stressful life events and antibody status might be mediated by coping strategy, multiple logistic regression was undertaken, in which, in addition to life events, coping by substance use and acceptance coping were entered. The outcome of this analysis indicated that, after adjustment for variations in coping strategy, the association between LESS scores and antibody status remained significant (OR = 2.20, 95% CI = 1.02–4,72, p = .04). The magnitude of this association, however, was smaller than that found in the bivariate analysis (see earlier), suggesting that the association between stress and antibody count may be moderated, to an extent, by coping strategy. In this model, both coping by substance use (OR = 1.38, 95% CI = 1.06–1.80, p = .02) and acceptance coping (OR = 0.76, 95% CI = 0.58–0.99, p = .04) also emerged as predictors of adequacy of antibody status.3
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
In the earlier vaccination cohort, exposure to stressful life events was significantly associated with the adequacy of antibody status after hepatitis B vaccination. Those with life events scores above the median had a more than two-fold increased risk of having an antibody titer sufficiently low to require additional vaccination. This association would not seem to be mediated by variations in demographics and unhealthy behavior, even though whites and those who drank more alcohol had poorer antibody counts.
To our knowledge, this is the first demonstration that variations in the use of specific coping strategies relate to antibody count after vaccination. Again, however, the effects of coping were manifest only in the earlier vaccination cohort. Their use of acceptance coping was protective, whereas coping by substance use increased the risk of having an inadequate antibody titer. Acceptance coping was signified by agreement with two questionnaire statements: "I accept the reality of the fact that it has happened" and "I learn to live with it." As such, acceptance coping can be regarded as the opposite of denial and is considered a functional coping response, in that a person who accepts the reality of a stressful situation is likely to be engaged in the attempt to deal with it (33). Coping by substance use was measured by the items "I use alcohol or other drugs to make myself feel better" and "I use alcohol or other drugs to help me get through it." In contrast to acceptance, coping by substance use is regarded as dysfunctional because it involves disengagement and the failure to deal directly with a stressful situation (33). One parsimonious possibility here is that coping by substance use is merely a proxy for variations in alcohol consumption. However, in multivariate analysis, the association between coping by substance use and adequacy of antibody count withstood correction for reported alcohol intake. This suggests either that coping by substance use embraces drugs other than alcohol or that it is a manifestation of a more general tendency to disengage in the face of stress. Overall, it would seem that not only stress is important for the integrity of the immune system but also the manner in which individuals cope. In this regard, our results extend those of previous studies showing that coping strategies are associated with measures of cellular immune function (25–27). Considered together, they suggest a mechanism for the relationship between customary coping styles and the course of disease (28–30). It is important to note that the relationship between stress and adequacy of immune function in the present study remained significant after adjustment for acceptance coping and coping by substance use. Accordingly, the relationship between stress and antibody status is not mediated by variations in coping strategy, although it may be moderated to an extent.
Neither stress nor coping strategy was associated with antibody status in the recently vaccinated cohort. However, only eight (8%) participants who began their vaccination program within the last year had inadequate titers. Not only does this mean that there is low power to detect early, clinically significant, stress effects, it also suggests that the efficacy of the standard three-dose hepatitis B vaccination program is such that it may largely override the potential effects of any psychological factors at this stage. This sort of explanation has been used by one research group to explain why they observed stress effects with a low-dose hepatitis B vaccination program but not with the standard program (19). The only study, using the standard dose, that has reported a negative association between stress and the antibody response to hepatitis B vaccination measured perceived stress rather than life events and focused on seroconversion after the first vaccination instead of final antibody status (17). As such, comparison with the current study is difficult.
The present study provides further evidence, in the context of an in vivo model, that immune function is sensitive to psychological factors. Those with greater-than-average stress exposures had a more than two-fold increased risk of having an inadequate hepatitis B antibody titer. In addition, the study provides the first clear indication that the extents to which people opt for particular coping strategies also influence antibody status after vaccination. The associations observed between psychological factors and immune function seem to be independent of demographic and behavioral influences. However, significant relationships appear only for those participants in the early vaccination cohort. In a recent study, elderly spousal caregivers showed lower pneumococcal-specific antibody titers than control subjects, but only at later assessments, 3 to 6 months after vaccination (37). Their data suggest that the major influence of stress on response to pneumococcal vaccination derives from effects on the rate of deterioration of antibody protection rather than the magnitude of the initial antibody response. This provides a possible explanation for the pattern of results obtained in the present study. Future research should track the associations between stress, coping, and hepatitis B antibody status longitudinally to determine whether psychological factors affect initial seroconversion, final antibody status after completion of the vaccination program, and the subsequent rate of decay of antibody count.
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
|
NOTES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
2Some medical schools in the United Kingdom, but not Birmingham, require students to have completed the hepatitis B vaccination program before entry.
3Epidemiological research frequently takes a simple arithmetic approach to stressful life events rather than one that takes into account event severity. When these analyses were repeated with high and low life events exposure based on a simple count of the number of life events checked, outcomes similar to those above emerged. For example, those who scored above the median in the number of life events were more than twice as likely to have an inadequate antibody titer (OR = 2.76, 95% CI = 1.36–5.61, p = .005).
Received for publication February 23, 2001.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. Kern and T. Ziemssen Review: Brain immune communication psychoneuroimmunology of multiple sclerosis Multiple Sclerosis, January 1, 2008; 14(1): 6 - 21. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Hamer, D. Wolvers, and R. Albers Using Stress Models to Evaluate Immuno-Modulating Effects of Nutritional Intervention in Healthy Individuals J. Am. Coll. Nutr., December 1, 2004; 23(6): 637 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. E. Burns, M. Drayson, C. Ring, and D. Carroll Perceived Stress and Psychological Well-Being Are Associated With Antibody Status After Meningitis C Conjugate Vaccination Psychosom Med, November 1, 2002; 64(6): 963 - 970. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
