Investigating the Effects of Typhoid Vaccine on Sleep in Healthy Volunteers

Research studies have found a relationship between the immune system (how the body reacts to an infection) and the development of depression. As it is still unclear how they might be linked the investigators will use a typhoid vaccination to activate the body's immune system and will measure the response by looking at changes in sleep patterns.

Elevated levels of pro-inflammatory cytokines are implicated in the pathogenesis of major depression. Both clinical and animal studies have shown that pro-inflammatory cytokines can induce a behavioural repertoire of symptoms collectively referred to as 'sickness behaviours,' which include cognitive and mood symptoms, such as depression, anxiety, memory impairment, fatigue, anhedonia and sleep disturbance. Raised circulating pro-inflammatory cytokines exhibited during chronic medical illness, such as rheumatoid arthritis, are frequently associated with higher rates of co-morbid depression compared to the general population. Medically healthy individuals with major depression have also been shown to have raised pro-inflammatory cytokine levels. Moreover, administration of interferon-α (IFN-α), a recombinant form of inflammatory cytokine that is commonly used as a therapy for hepatitis C virus (HCV) and certain cancers, is well documented to precipitate depression and cognitive impairment in 30-50% of patients. In a previous study in this Department the investigators showed, using magnetic resonance spectroscopy (MRS), that IFN- α increased markers of glutamate activity. This is of particular interest because of the postulated role of glutamate in mood regulation and cognition. Converging evidence of the link between inflammation and depression has therefore led to the hypothesis that chronic low-grade inflammation could lead to more persistent alterations in neuropsychological function that might be instrumental in the pathogenesis of major depression. However, the mechanisms for this potential modulation of mood and cognitive function remain unclear. In order to examine the relationship between inflammation and depression, experimental models of inflammation have been developed that involve exogenous administration of cytokines or cytokine-inducers, for example salmonella typhi (typhoid) vaccination. This study will utilise typhoid vaccination as a model of acute inflammatory challenge in healthy volunteers, which has previously been shown to stimulate a mild, non-sickness inducing inflammatory response that significantly increases levels of the pro-inflammatory cytokine, interleukin (IL)-6, in a safe manner without increasing symptoms of illness, body temperature and blood pressure. This model has been shown to elicit a transient depression-like syndrome in healthy volunteers, including a range of behavioural changes such as cognitive dysfunction, fatigue and modulation of subjective ratings of mood. The investigators believe this will serve as a good model to investigate effects of immune activation on sleep. Sleep electroencephalogram (EEG) recordings will explore the effects of immune activation on sleep, as sleep changes are observed in clinical depression. Healthy volunteers will be recruited for this study, so that the investigators can investigate the effects of inflammatory challenge in participants that do not currently have an inflammatory condition. The present exploratory study therefore aims to enhance the investigators understanding of the intriguing link between inflammation and emotional dysfunction by examining the effects of inflammatory challenge using typhoid vaccine on sleep using a detailed psychiatric assessment and sleep EEG recordings.

A single 0.5mL injection of 0.9% sodium chloride saline solution into the non-dominant deltoid muscle in the arm

Acute (night 1) differences in sleep architecture, measured using polysomnography, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Changes in Interleukin-6 (IL-6) levels following typhoid vaccine compared to placebo (saline) injection

Change in PANAS subjective mood rating scores, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Change in VAS Bond and Lader subjective mood rating scores, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Change in adverse effects scores, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Change in LSEQ subjective rating scores, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Randomisation guess, following afternoon administration of the typhoid vaccine compared to placebo (saline) injection

Inclusion Criteria: Participant is willing and able to give informed consent for participation in the study. Healthy adults, Male or Female, aged 18 to 40 years. Not currently taking any medications (except the contraceptive pill). Good sleeper determined by self-report and sleep screening interview Exclusion Criteria: The participant may not enter the study if ANY of the following apply: Any current or previous Axis 1 psychiatric disorder on DSM-5 Diagnosis of current sleep disorder Any significant current medical condition likely to interfere with the conduct of the study or analysis of data Typhoid vaccination within the last 3 years Any vaccination within the last 6 months History of allergies to drugs or vaccines or any component of the typhoid vaccine Congenital or acquired immune deficiency (including participants receiving immunosuppressive or antimitotic drugs) Bleeding disorder, e.g. haemophilia or thrombocytopenia Current or recent physical illness or infection within previous 2 weeks Steroidal or non-steroidal anti-inflammatory medication within preceding 2 weeks, including aspirin and ibuprofen Current substance misuse Child bearing age and not using reliable form of contraception Has taken part in a psychological or medical experiment involving taking any kinds of drugs within the last 6 weeks Pregnant or breast feeding

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