International Journal of Clinical Medicine, 2012, 3, 544-551
http://dx.doi.org/10.4236/ijcm.2012.36098 Published Online November 2012 (http://www.SciRP.org/journal/ijcm)

The Effects of Influenza Vaccination on Immune Functionin Patients with Chronic Fatigue Syndrome/Myalgic
Encephalomyelitis
Ekua Weba Brenu1,2*, Mieke van Driel1,3, Donald R. Staines1,4, Sanne Kreijkamp-Kaspers1,2,
Sharni Lee Hardcastle1,2, Sonya Maree Marshall-Gradisnik1,2
1School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, Australia; 2The National
Center for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, Australia; 3Discipline of General Practice,
School of Medicine, University of Queensland, Brisbane, Australia; 4Queensland Health, Gold Coast Public Health Unit, Gold Coast,
Australia.
Email: *e.brenu@griffith.edu.au
Received August 13th, 2012; revised September 14th, 2012; accepted October 10th, 2012

ABSTRACT
Immune dysfunction is a hallmark of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The purposeof this pilot study was to identify the effects of influenza vaccination on immune function in patients with CFS/ME. We
included 7 patients meeting the Centre for Disease Control and Prevention criteria (CDC 1994) for ME/CFS and 8 control subjects. Bloods were collected from all participants prior to vaccination with Influvac, a trivalent inactivated influenza vaccine (TIV), 14 and 28 days following vaccination. The immune parameters examined include Natural Killer(NK) phenotypes, NK cytotoxic activity, FOXP3 and Th1/Th2/Th17 related cytokines. Flow cytometric protocols were
employed. There was no significant difference in NK phenotypes and Tregs numbers between CFS/ME patients andhealthy controls. However, NK activity was significantly decreased at baseline and at 28 days, while at 14 days it significantly increased in the CFS/ME patients compared to the healthy controls. Th1 pro-inflammatory cytokines increased considerably in the CFS/ME patients at 28 days compared to the non-fatigued controls. Only one Th2 cytokine,
IL-4, increased in the CFS/ME participants. FOXP3 expressing Tregs only increased significantly at day 28 post vaccination in the CFS/ME patients compared to the healthy controls. Self-rated wellbeing was lower for patients at day 28
while at baseline and day 14 no differences were observed. In this pilot study immunization with influenza vaccine isaccompanied by a degree of immune dysregulation in CFS/ME patients compared with controls. While vaccination may
protect CFS/ME patients against influenza, it has the ability to increase cytotoxic activity and pro-inflammatory reactions post vaccination. The role of Tregs in promoting a toxic effect at 28 days post-vaccination in our patient groupcannot be ruled out. The benefits of influenza vaccine still likely outweigh the risks CFS/ME patients experience following vaccination.
Keywords: Chronic Fatigue Syndrome; Influenza; Vaccination; Natural Killer Cells; Cytokines

1. Introduction
The influenza virus is genetically variable thus new vaccines are developed annually to ensure effective protecttion against new strains of the virus. Variation in the virus mainly occurs in the main viral glycoproteins, haemaglutinin (H) and neuraminidase (N) [1]. The immune
system is important in eliminating and clearing viral infections. Usually, during an influenza infection, recognition of an infected cell occurs via the retinoic acid inducible gene I (RIG-I) while influenza genomic RNA isdetected by the Toll-like receptor 7 (TLR-7) [2-4].
*

Corresponding author.

Copyright © 2012 SciRes.

This stimulates the generation and production of soluble
proteins belonging to the type I interferon (IFNs) family,
which in turn suppress viral reproduction [5]. Both theinnate and adaptive immune systems are required tocombat viral infections. In the innate immune system,
macrophages secrete IL-1β and IL-18 [6] while adaptive immune system cells such as CD4+ T and CD8+ T
cells generate influenza specific memory cells. These cells
are equipped to recognize conserved sequences within
the virus that serve as a protective mechanism for thevirus by making them undetectable for the vaccine [7,8].
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a disease with unknown aetiology
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Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

characterized by severe fatigue and flu-like symptoms[9,10]. CFS/ME affects a substantial number or people
worldwide and has been associated with a number ofviruses [11-15]. Although the exact cause of CFS/ME is
unknown, serological studies have shown high rates ofviral titres in CFS/ME patients [15-18]. This may indicate an inability to effectively clear infections as immune
function has been shown to be decreased in CFS/ME
patients when compared to non-CFS/ME individuals[19-22]. A number of factors such as mental, physical,
psychological stresses and viral infections may exacerbate symptoms of CFS/ME [23].
Administration of TIV to CFS/ME patients in general,
is a controversial issue [1,24-29]. This is mainly related
to the view that vaccines may affect the immune system
in CFS/ME patients resulting in a worsening of symptoms and consequently physical health. Incidentally, asurvey of CFS/ME patients revealed that 31% of patients
who had not received influenza vaccination were of theview that immunization was hazardous to their health.
However, among patients who had been vaccinated anddeveloped complications 28% were optimistic and 26%
agreed that vaccines were not detrimental to their health[29]. The degree of support for the influenza vaccine washigher among CFS/ME patients who had experienced
positive outcomes from previous vaccinations; 45% rated
vaccinations as favourable, while 55% agreed it was advantageous [29]. A recent study investigated the effect ofinfluenza vaccination on immune response and noted thatin some cases, administration of whole virus influenza
vaccine was observed to raise antibody titres, with nosignificant side effects in the CFS/ME group in comparison to the non-CFS/ME group [27]. Additionally,
there was no significant difference in the symptoms of
CFS/ME patients with or without the influenza vaccine 6
weeks after vaccination [27]. The results of this firststudy suggest there is no demonstrable impact on theability to generate antibodies. However, the effect on
cellular immunity, which is known to be affected in
CFS/ME patients, has not been studied before. Wholevirus influenza vaccines are also inactivated however due
to the adverse events of whole virus influenza vaccines,
only split virus influenza vaccines have been available in
the US since 2001.
The purpose of this study is to explore the effects ofinfluenza vaccination on immune function in CFS/ME
patients, by examining and comparing NK activity, NK
phenotypes, cytokine secretion pre, 14 and 28 days post
vaccination.

2. Materials and Methods
2.1. Participants Selection
A total of 15 participants were selected from a database
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of patients living in the South East Queensland region ofAustralia [30]. Seven patients were classified as having
CFS/ME using the Centre of Disease Prevention andControl (CDC) 1994 case definition [31]. The nonCFS/ME controls comprised of 8 participants from thesame region. Written consent was obtained from all participants prior to blood sampling. A volume of 40 mL of
non-fasting morning blood samples were collected fromthe antecubital vein into lithium heparin and EDTA tubes.
Full blood count measurements were obtained prior to
immunological assessments.

2.2. Vaccine Intervention
Prior to vaccination contraindications for vaccination
were checked as per the Australian immunisation handbook [32]. In the absence of contraindications the vaccine was administered by intramuscular injection in the
deltoid muscle by a doctor. The patient was observed forat least 15 minutes post vaccination to monitor any immediate adverse effects. The type of influenza vaccine
used was Influvac (Solvay Pharmaceuticals) an inactivated influenza vaccine. Each 0.5 mL pre-filled syringe
contains 15 μg haemagglutinin of each of the three recommended strains produced for the 2011 flu season(2011) A/California/, 7/2009 (H1N1)—like strain, A/Perth/,
16/2009 (H3N2)—like strain and B/, Brisbane/60/2008—
like strain). The vaccine batch number was documented
on the day of administration. At follow up patients wereasked to report any adverse effects following vaccination.
At every blood collection participants self-rated theirgeneral wellbeing, cold and flu symptoms and mood on avisual analogue scale (VAS), with the best imaginable orno symptoms rated as 0 and the worst imaginable as 10.

2.3. NK Cytotoxic Activity
A flow cytometric based cytotoxic protocol was used tomeasure NK cytotoxic activity [19,30,33]. This involved
isolating peripheral blood mononuclear cells (PBMCs)
from whole blood samples using density gradient centrifugation. Subsequently cells were labeled with 0.4%
PKH-26 (Sigma, St. Louis, MO). PBMCs were then incubated with K562 cells, for 4 hours at 37˚C in 95% air,
5% CO2 using a ratio of 25 (NK cells):1 (K562). Apoptosis of K562 cells were analyzed [19,30] via FACSCalibur flow cytometry (BD Bioscience, San Jose, CA),
after labeling cells with Annexin V-FITC and 7-AAD
reagent (BD Pharmingen, San Diego, CA).

2.4. NK Phenotypes Quantitation
NK cell subsets distribution, i.e. CD56brightCD16− NKcells and CD56dimCD16+ NK cells was determined aspreviously described [19,30]. Preferential isolation of
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The Effects of Influenza Vaccination on Immune Function in Patients with
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

NK cells was performed using a negative selection system, RosetteSep Human Natural Killer Cell Enrichment
Cocktail (StemCell Technologies, Vancouver, BC) fromwhole blood. NK cells were labelled with monoclonal
antibodies for CD56 (FITC) and CD16 (PE) (BD Pharmingen, San Jose, CA).

2.5. Cytokine Secretion Following Mitogenic
Stimulation
Cytokines were measured following mitogenic stimulation of cultured PBMCs. In brief PBMCs were isolated
from whole blood using ficoll-hypaque density gradientcentrifugation. PBMCs were placed in cell culture media
with or without 1 µg of phytohemagluttinin for 72 hours
at a concentration of 1 × 106 cells/mL in RPMI culture
media at 37˚C in 95% air with 5% CO2. Cell supernatants
were collected immediately and stored at −80˚C for later
assessment. Th1, Th2 and Th17 cytokine profiles were
determined using the cytometric bead array kit (BDPharmingen, San Jose, CA) [30,34]. The concentrationsof the following cytokines IL-2, IL-4, IL-6, IL-10, tumor
necrosis factor (TNF)-α, interferon (INF)-γ and IL-17A
were measured.

2.6. Examination of Regulatory T Cells in
CFS/ME Patients.
Assessment of Tregs was performed as previously described [30]. PBMCs isolated from 10 ml of whole blood
were washed and stained with monoclonal antibodies
FITC-CD4 and APC-CD25 (BD Pharmingen, San Diego,
CA). Cells were then permeablised and fixed with buffers containing diethylene glycol and formaldehyde. Subsequently, cells were stained with PE-FOXP3 and evaluated on the flow cytometer. FOXP3 was determined on
CD4+ CD25+ T cells.

3. Results
3.1. Participants Information
The study population consisted of 7 CFS/ME patientswith an average age of 48 years old and 8 controls all
females with an average age of 38 years old. All patients
fulfilled the CDC criteria for CFS. At baseline there wereno statistically significant differences between the twogroups but at day 14 and particularly day 28 post vaccinetion, the CFS/ME patients recorded a significantly lower
general wellbeing compared to the controls (Figure 1).

3.2. Assessment of NK Cytotoxic Activity
NK cytotoxic activity was significantly decreased (p <0.05) in CFS/ME patients compared to the control groupprior to vaccination and at 28 days following vaccination.
However, there was no significant decrease in the twogroups at 14 days post vaccination (Figure 2).

3.3. Distribution of NK Cells
NK phenotypes were classified as CD56dimCD16+ andCD56brightCD16− NK cells. CD56dimCD16+ andCD56brightCD16− NK cells numbers were not significantly different at any time point in CFS/ME patientscompared to non-fatigued controls.

3.4. Cytokine Secretion Pre and Post Vaccination
Cytokine secretion following mitogenic stimulation did
not differ before and 14 days after vaccination in the
CFS/ME and control groups. At 28 days post vaccination,
significant increases in IL-4, IL-17A, IFN-γ and TNF-α
were observed in the CFS/ME patient compared to the

2.7. Statistical Analysis
Statistical analysis was performed using SPSS software
version 18.0. All data are reported as means plus/minus
standard error of the mean (±SEM). Analysis of variancetest (ANOVA) and repeated measures was used to compare continuous data. As the different variables were
examined at three different time points, time was considered as the within-subjects factor while group was the
between-subject factor. Changes in data between time
points were further assessed using Bonferroni post-hoc
analysis. To assess within subject stability Pearson andSpearman’s rank correlations were determined between
the three time points. Significance was set at p-values
less than or equal to 0.05.
Approval for this study was obtained from the Bond
University Human Research Ethics Committee.
Copyright © 2012 SciRes.

Figure 1. Self rated wellbeing in the CFS/ME and non-fatigued controls. The graph represents wellbeing of the participants (CFS/ME and non-fatigued controls) throughout
the study that is at baseline, day 14 and day 28. The ■ represent control data while ● depicts the CFS/ME data. Data
are presented as means ± SEM. *Represents a statisticalsignificant result in relation to controls, p < 0.05 vs nonfatigued control.
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controls (Figures 3(a)-(d). There was no significant difference in FOXP3 pre and 14 days post vaccination.
However, an increase in FOXP3 was observed 28 days
post vaccination in the CFS/ME group compared to thecontrols (Figure 4).

4. Discussion

Figure 2. NK cytotoxic activity pre and post vaccination.
NK cytotoxic activity is presented as the % of K562 cells
lysed by NK cells pre (baseline) and post vaccination (day
14 and day 28) in the non-fatigue control group (white bars)
while and the CFS/ME group (black bars). *Represents astatistical significant result in relation to controls. Data arepresented as means ± SEM.

Our pilot study suggests that vaccination with seasonal
Influenza vaccine, Influvac may affect cellular immune
function in CFS/ME patients, such as increase of NK
function and differential changes in the expression of
release of certain proteins by lymphocytes. However, thephenotypes of immune cells such as NK phenotypes may
not necessarily be affected by influenza vaccines as thesecells remained unchanged post vaccination. An increasein T cell related proteins occurred post vaccination.
Overall wellbeing of CFS/ME patients was also significantly lower on the last day of the study. The idea
behind the seasonal administration of the influenza vaccine relates to its ability to protect against the effects of

(a)

(b)

(c)

(d)

Figure 3. Levels of different cytokines pre and post vaccination. The graph (a) represents the secretion of IL-4; (b) TNF-α; (c)IFN-γ and (d) IL-17A pre (baseline) and post vaccination (day 14 and day 28). The white bars depict data from thenon-fatigued controls and the black bars are representative of the CFS/ME patients. Data are presented as means ± SEM.
*
Represents a statistical significant result in relation to controls, p < 0.05.
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The Effects of Influenza Vaccination on Immune Function in Patients with
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Figure 4. Intracellular FOXP3 expression pre and post vaccination. The graph represents the FOXP3 production fromintracellular staining of Treg cells pre (baseline) and post(day 14 and day 28) vaccination. The white bars depict datafrom the non-fatigued controls and the black bars are representative of the CFS/ME patients. Data are presented asmeans ± SEM. *Represents a statistical significant result in
relation to controls, p < 0.05.

different strains of the influenza virus. Previous studies
have confirmed the protective effects of certain vaccines
on the immune system in CFS/ME patients [1,26,28]. To
our knowledge this is the first study to report the impact
of influenza vaccination on the cellular immune system
in CFS/ME patients.
Immune cell function, in particular, NK cytotoxic activity was decreased prior to vaccination and 28 days
post vaccination, and increased at day 14 in the CFS/ME
group compared to the non-fatigued controls. This suggests that TIV affected responses in the immune system
14 days after vaccination, however, this immune response returned to its initial status at 28 days following
vaccination as NK cytotoxic activity decreased at bothbaseline and day 28. The cause of the increase in NK
activity in the CFS/ME patients following vaccination is
not explicitly known, however, administration of TIV
and LAIV influenza vaccines have the potential to induce
cytotoxic activity in NK cells. Importantly, these vaccines are known to generate memory cytotoxic cells incytotoxic CD8+ T cells that are important for preventing
influenza [35,36].
The mechanism of cytotoxic activity involves the activation of granule dependent pathways, which facilitate
the release of cytolytic proteins, perforin and granzymes,
into the cytoplasm of the viral or tumor cell. Influenza
virus decreases the expression of these molecules, specially perforin [37]. Administration of TIV increases theexpression of perforin in CD8+ T cells and this likely
occurs in NK cells, thereby enhancing cytotoxic activity
Copyright © 2012 SciRes.

in some cells [38]. In adults, reduced levels of granzyme
B increase the threat of influenza. However, higher levelsof granzyme B and NK activity have been observed inolder compared to younger individuals following influenza vaccination [39, 40]. This presupposes that the influenza vaccine may enhance cytotoxic activity by prolonging the cytotoxic process and increasing the presenceof lytic proteins in cytotoxic cells. Accordingly, the typeof influenza vaccine used may have an impact on theactivity of NK cells. For example, NK cell activity is
prolonged in the presence of TIV [41]. Hence, this may
be a contributory factor to the elevated cytotoxic activity
following influenza vaccination with the TIV used in ourpatients. These findings may support the rationale that
influenza vaccines are protective rather than harmful inmost individuals. Additionally, the significant decreasein cytotoxic activity may be correlated with the low levels of wellbeing 28 days after vaccination. This is consistent with the literature that reduced well-being with
low immune function, particularly decreases in NK cell
cytotoxic activity [42]. However, the rise in inflammatory cytokines at this time point, together with potentiallypathogenic regulatory T cell activity may suggest enhanced toxicity contributing to a lowered sense of wellbeing.
The majority of the cytokines that were significantly
increased in the CFS/ME patients were Th1 cytokines
including IFN-γ and TNF-α, IL-17 was also increased.
IL-4 was the only Th2 cytokine that was increased in the
CFS/ME patients compared to the non-fatigued controls.
Hence, it can be deduced that influenza vaccines may
increase the production of both pro- and anti-inflammatory cytokines in the CFS/ME patients. This is consistent
with the observation that CFS/ME patients have somebackground dysregulation of their immune system andcorrelates with the clinically reported worsening ofsymptoms. However Influenza vaccines can cause headaches, arthralgia, fever, nausea and malaise [43], whichcoincidentally are symptoms of CFS/ME.
The effect of the influenza vaccine on the immune
system, in terms of cytokine response is not immediateand seems to occur at a later stage. In the adaptive immune system, vaccines such as the TIV effectively
prompt Th1 related immune response which is characterized by the presence of IL-2 [44]. Similarly, an increase in IL-17 was observed after vaccination of micewith TIV. Although these studies were done in mice,
they may provide a snapshot of the actual effects of inactivated influenza vaccines on the human immune system.
Cytokine effects were only observed 28 days post vaccination and prior to this, no significant changes in cytokines were observed. A predominant Th1 immune response suggests that an increase or exacerbation in
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Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

pro-inflammatory activity possibly occurs in CFS/ME
patients. However, in a previous study, we reported thatcytokines tend to fluctuate in CFS/ME patients and thismay persist following vaccination, although, the samples
size was too small to draw further conclusions. Similarly,
in vitro examination of different types of influenza vaccines shows the ability to stimulate a Th1 immune typeresponse in PBMCs, which again was more prevalent in
the older compared to the younger participants [45,46].
This is suggestive of an improvement in immune response as a consequence of the administration of vaccines.
This pilot study demonstrates the potential effects of
TIV on immune function in CFS/ME patients compared
to non-fatigued individuals. The cause of the heightened
cytotoxic activity is not clear, however, this increase incytotoxic function is subsequently followed by an increasein pro-inflammatory cytokines. Whether this substantial
increase in cytokines is related to the influenza vaccine is
not entirely known, as cytokines have the tendency tooscillate; however, no oscillations were observed prevaccination and at day 14. Interestingly, altered Treg
function at 28 days may also influence lowered wellbeing in this patient group. More investigations are required to see if the Treg subset may be pathogenic. The
influenza vaccine may play a role in modifying the pattern of immune expression observed in our CFS/ME patients.
Our study has limitations. A relatively small sample
size of patients and controls was used and this may havebiased the changes observed in the parameters measured.
Additionally, immune measurements were not taken
within the first few days post vaccination. These measurements may be important in determining the rate ofchange in cytotoxic activity and cytokines immediately
after administering the vaccine. In addition, only one
type of vaccine, i.e. the TIV, was investigated. Perhaps
future studies on the effects of other vaccines on the immune system may be important in disseminating the typeof vaccines to recommend to CFS/ME individuals.

5. Conclusion
In conclusion, the challenge of determining the most effective intervention against influenza in individuals withcomplex disorders such as CFS/ME remains to be determined. Influenza vaccines such as TIV may be important
in increasing immunity against pathogens by increasing
cytotoxic mechanisms and pro-inflammatory cytokines.
However, as the effectiveness of influenza vaccines is
not 100% in all individuals, it is possible that in somecases vaccination against influenza may be protective as
it has the ability to increase cytotoxic activity and proinflammatory reactions post vaccination, while adverse
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effects may ensue in others. These vaccines should be
administered with caution in patients with complex disorders where immune function is severely compromised.
The advantage of influenza vaccine however, may likely
offset the risks associated with CFS/ME.

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