The time course of the inflammatory response to the Salmonella typhi vaccination

https://doi.org/10.1016/j.bbi.2013.01.004Get rights and content

Abstract

The Salmonella typhi vaccination induces transient increases in inflammatory-responsive cytokines and molecules. For instance, it causes small, mild increases in interleukin-6 (IL-6) within a few hours and C-reactive protein (CRP) within 24 h. No study has charted either the time course of the inflammatory response to this vaccine or any associated changes in mood, physical symptoms, and cardiac function. In a blinded crossover experimental design, eight participants received the S. typhi vaccine (vaccination condition) and a saline (control condition) injection on two separate days, at least one week apart. Blood samples and mood ratings were collected at 0, 4, 5, 6, 7, 8 and 24 h post-injection, physical symptoms and pain were assessed at 4–8 and 24 h post-injection, and cardiovascular function was recorded until 8 h post-injection. Repeated measures analyses of variance and polynomial trend analyses compared the timecourse of the response patterns between the two conditions. Whereas there were no temporal changes in the control condition, the vaccination increased granulocytes, IL-6, TNF-α, and CRP (all p’s < .05). Specifically, the granulocytes, IL-6 and TNF-α peaked after 6–8 h while CRP peaked after 24 h. This vaccine-induced mild inflammatory response was not accompanied by any changes in mood or cardiovascular activity. We also found that participants tended to report more pain in the injected limb in the vaccination condition (p < .07). In sum, our study charted the timecourse of key inflammatory-responsive markers following S. typhi vaccination and identified the timing of their modest peaks. It is worth noting that changes in these markers were not accompanied by any notable changes in mood or cardiovascular activity, and thus the S. typhi vaccination is a suitable method to induce increases in inflammatory-responsive markers, without altering mood or cardiovascular parameters.

Highlight

► The study characterized the inflammatory response to S typhi vaccination over 24 h, revealing changes in inflammation but not mood or cardiac measures.

Introduction

Inflammation is an adaptive response of the immune system to infection and tissue damage (Medzhitov, 2008). Two characteristic features of this response are rapid tissue infiltration by leukocytes and the release of inflammatory-responsive cytokines (Medzhitov, 2008). Acute inflammation is deemed functional and protective whereas a chronic inflammatory response is generally considered dysregulated and harmful (Medzhitov, 2008, Stevens et al., 2005). Indeed, chronic inflammation has been implicated in the aetiology of a range of diseases, such as cardiovascular disease and its complications (Hansson, 2005, Levy et al., 2008, Libby, 2006, Ridker et al., 2000). In addition, inflammation is also suspected to play an aetiological role in cognitive dysfunction and psychopathology. For example, patients exhibiting elevated inflammatory activity, such as acute coronary syndromes (Lesperance et al., 2004) and auto-immune diseases like rheumatoid arthritis (Zautra et al., 2004), show increases in dysphoric mood and posses a substantially elevated risk for the development of clinical depression and anxiety. While this is often used to suggest a role of inflammation in mood disorders, interpretation of such patient data is confounded by other biological (e.g., medications) and psychological risk factors (Cleland et al., 2000, Vita et al., 2004). Therefore, experimental approaches have been explored whereby the effects of inflammatory activity can be studied in healthy participants.

Two experimental manipulations frequently used to induce transient systemic inflammation involve the administration of low dose Escherichia coli endotoxin and vaccination against Salmonella typhi. The latter pathogen is the cause of typhoid fever and one of the main sources of food poisoning. The benefits of using the S. typhi vaccination is that it is approved by regulatory bodies (e.g., US Food and Drug Agency) and does not typically induce fever or feelings of malaise (Hingorani et al., 2000, Strike et al., 2004, Wright et al., 2005), which is in contrast to endotoxin (Reichenberg, 2001). However, mild unpleasant side effects, like aching joints, headache and nausea, to typhoid vaccination have been noted in some (Wright et al., 2005) but not other (Brydon et al., 2009) studies.

Typhoid vaccination reliably induces a mild systemic inflammatory response: increases in IL-6 have been documented within 2 h (Brydon et al., 2009) and are sustained up to 12 h (Antoniades et al., 2011) post vaccination. There is less consistent evidence for TNF-α, with some studies reporting increases at 4 h post vaccination (Kharbanda et al., 2002), and others not finding any changes (Hingorani et al., 2000, Wright et al., 2005). Increases in the acute phase protein CRP are consistently seen at 24 h post vaccination (Antoniades et al., 2011, Padfield et al., 2010). However, no prior study has charted the time course of these responses, and it is therefore unknown when the peak responses are reached and how long they remain elevated. Finally, physical symptoms accompanying vaccine-induced inflammation have typically been assessed only at one or two time points, and, therefore, the time course of physical symptomatology is also unknown.

A similar story can be told about the effects of typhoid vaccination on mood, which has yet to be fully characterized. Studies that administered endotoxin found transient increases in negative mood states, such as anxiety and depression (Eisenberger et al., 2009, Eisenberger et al., 2010, Reichenberg, 2001), whereas studies that injected S. typhi vaccination reported more equivocal effects. One study reported an increase in negative mood following vaccination, but this effect only became apparent after the ratings were contrasted with a placebo control condition that was associated with an elevated positive mood; hence, these data indicated the absence of positive mood induction rather than the presence of negative mood (Strike et al., 2004). Another study observed positive correlations between changes in IL-6 and negative mood at 3 h post-vaccination, such that greater IL-6 responses were associated with more negatively-valenced feelings (Wright et al., 2005). In contrast, there was no increase in negative mood within 2 h after vaccination (Brydon et al., 2009). Therefore, it is likely that changes in mood occur only when the inflammatory response has had more than a couple of hours to develop. A time course study is required to resolve this issue. Although one study has examined the time course of mood in response to vaccination, it did not provide data on the inflammatory response and its links with mood and physical symptoms (Strike et al., 2004).

Based on the putative role of inflammation in cardiovascular pathology, typhoid vaccination has been utilized in studies of the inflammation–cardiovascular function relationship. Studies have yet to demonstrate any effects of vaccination on blood pressure, heart rate, cardiac output, and total peripheral resistance (Chia et al., 2003, Padfield et al., 2010, Strike et al., 2004, Vlachopoulos et al., 2005). However, using lipopolysaccharide as a stimulus, one study observed reductions in heart rate variability (Kox et al., 2011), which is consistent with the literature on the bi-directional regulation between the inflammatory system and the vagal nerve (Andersson and Tracey, 2012). It is therefore surprising that no studies have examined the influence of vaccine-induced inflammation on cardiovascular indices of vagal, or for that matter sympathetic drive, particularly given preliminary evidence that decreased heart rate variability may be a potential mechanism linking depression with elevated cardiac mortality in patients who have suffered a myocardial infarction (Carney and Freedland, 2009, Taylor, 2010).

Grounded on the literature reviewed above, the present study was designed to characterize the inflammatory response to S. typhi vaccination over a 24 h period. No study to date has reported the time course of inflammatory, psychological (mood, symptoms) and physiological (cardiovascular) responses to vaccination, and, therefore, our findings should improve our understanding of the effects of vaccination in humans. It was anticipated that the vaccine would induce systemic inflammation (as reflected by increases in circulating leukocytes, TNF-α, IL-6, and CRP), increases in negative mood, and reduced heart rate variability. The effects on self reported physical symptoms were also explored, however, due to lack of prior evidence, no specific predictions were made.

Section snippets

Participants

Eight (N = 8) male participants (mean age ± SD = 26.63 ± 8.07 years, mean body mass index ± SD = 23.21 ± 1.80 kg/m2) were recruited. At the time of testing, none were suffering from an acute illness or infection, reported a history of inflammatory, cardiovascular or auto-immune disorders, or had taken any medication in the last 4 weeks. None had vaccine-related allergies or had received a typhoid vaccination in the last 12 months. Participants reported to the laboratory having refrained from vigorous exercise

Inflammatory response to vaccination

Fig. 1 illustrates the inflammatory response to vaccination in terms of changes in the numbers of lymphocytes, monocytes and granulocytes as well as the concentrations of IL-6, TNF-α and CRP. The 2 Condition × 7 Time ANOVAs yielded overall condition by time interaction effects for granulocytes (F(1, 6) = 12.07, p = .002, ε = .50, η2 = .50) and IL-6 (F(1, 7) = 11.24, p = .042, ε = .51, η2 = .32), with a trend for monocytes (F(1, 6) = 1.09, p = .098, ε = .42, η2 = .30). To characterize the time course of the inflammatory

Discussion

The present study aimed to characterize the time course of the inflammatory, physical, mood and cardiovascular responses to a typhoid vaccination. This study was the first, to our knowledge, to compare the time course of the inflammatory response to a vaccination and saline injection over a 24 h period. In support of our predictions, the administration of a 0.5 ml dose of the S. typhi vaccine increased the concentrations of two cytokines, IL-6 and TNF-α, as well as the numbers of other immune

Conclusion

To our knowledge, this is the first time course study to examine the inflammatory effects of S. typhi vaccination, and its impact on mood, symptoms, and cardiovascular activity. It appears that the S. typhi vaccination induces a relatively mild inflammatory response, as evidenced by the doubling of IL-6 and TNF-α, which peaked at 6–8 h post vaccination. Elevations in the numbers of granulocytes were also demonstrated in the vaccination condition. CRP also increased following vaccination, with

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