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Vaccine 28 (2010) 7273–7278
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/vaccine
Candidate hepatitis C vaccine trials and people who inject drugs: Challenges and
Lisa Mahera,∗, Bethany Whitea, Margaret Hellardb, Annie Maddenc, Maria Prinsd,
Thomas Kerre, Kimberly Pagef
aViral Hepatitis Epidemiology and Prevention Program, National Centre in HIV Epidemiology and Clinical Research and School of Public Health and Community Medicine, University
of New South Wales, Centre for Immunology, Corner Boundary and West Streets, Darlinghurst, NSW 2010, Australia
bCentre for Population Health, The Macfarlane Burnet Institute for Medical Research, 85 Commercial Road, Melbourne, Victoria 3004, Australia
cAustralian Intravenous and Injecting League (AIVL), Sydney Building, Level 1/112-116 Alinga Street, Canberra, ACT 2600, Australia
dAcademic Medical Centre, University of Amsterdam and Infectious Disease Cluster, GGD Amsterdam Public Health Service, Department of Research, Amsterdam 1000 CE,
eUrban Health Research Elective, British Columbia Centre for Excellence in HIV/AIDS, St Paul’s Hospital, 806-1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
fDepartment of Epidemiology and Biostatistics, University of California San Francisco, 50 Beale Street, Suite 1200, San Francisco, CA 94105, USA
a r t i c l ei n f o
Received 19 May 2010
Received in revised form 17 August 2010
Accepted 24 August 2010
Available online 9 September 2010
Hepatitis C virus
People who inject drugs
a b s t r a c t
interventions and low uptake of treatment in this group highlight the need for increased investment in
biomedical interventions, notably safe and efficacious vaccines. While several candidates are currently
in development, field trials in PWID present challenges, including ethical issues associated with trial
literacy, informed consent and standards of care. Significant biological and social factors and differences
between HIV and HCV suggest that HCV warrants targeted vaccine preparedness research to lay the
groundwork for successful implementation of future trials.
© 2010 Elsevier Ltd. All rights reserved.
Chronic hepatitis C virus (HCV) infection is a major cause of
morbidity and mortality globally and a key factor driving increases
in rates of liver cancer and demand for liver transplantation in
high- and middle-income countries . In comparison to hepati-
tis B virus, for which there is a safe and efficacious vaccine, and
for which therapeutic agents for the treatment of chronic infec-
tion are available and reasonably well tolerated, there is no vaccine
for HCV and current antiviral treatments are complex, costly, toxic,
and of limited efficacy in the relatively small proportion able to
access them . The burden of HCV-related disease is associated
with significant costs to the health system resulting from the need
to manage chronic illness and the demand on services for treat-
ment of advanced liver disease. As the incidence of advanced liver
disease increases these costs will continue to escalate [3,4], high-
lighting the need for increased investment in effective prevention
interventions, notably safe and efficacious vaccines .
∗Corresponding author. Tel.: +61 293850936; fax: +61 293850920.
E-mail address: LMaher@nchecr.unsw.edu.au (L. Maher).
diversity, HCV, like HIV, presents challenges for vaccine develop-
ment [6,7]. However, HCV transmission events, acute infection,
viral dynamics and infection outcomes are distinct from those that
occur with HIV. HCV is significantly more infectious than HIV and
almost 3% of the world’s population [1,10], unlike HIV, many peo-
ple are not aware of their status. In the U.S., it is estimated that
75% of the estimated 2.7–3.9 million Americans living with chronic
HCV infection are unaware that they are infected . Despite this,
international efforts to develop an effective HCV vaccine lag well
behind HIV vaccine development.
People who inject drugs (PWID) are at high risk of HCV infec-
tion and are the key affected community globally. HCV prevalence
and incidence of up to 95% and 45/100 person-years, respectively,
have been reported in PWID [12–18]. Evidence of the effective-
ness of stand-alone interventions to prevent HCV infection in
this group is limited. Studies of the effects of exposure to pre-
ventive interventions, including drug treatment , needle and
syringe distribution (reviewed in ), harm reduction and edu-
cation programs , and bleach disinfection , have failed
to provide conclusive evidence of efficacy. While a recent Dutch
0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
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L. Maher et al. / Vaccine 28 (2010) 7273–7278
reduction (needle and syringe distribution and methadone treat-
RCT found reductions in risk behavior but no difference in HCV
incidence (18.4/100 person-years) between the intervention and
control groups . These data suggest that further decreases in
tive biomedical interventions, notably preventive vaccines .
Despite improvements in, and the relative cost effectiveness of,
antiviral treatments for HCV [3,26–28], barriers to screening and
diagnosis  mean that treatment is unlikely to impact transmis-
sion in the short to medium-term. Low uptake among PWID ,
the likelihood of re-infection [17,31,32] and the prohibitive cost
of medications suggest that treatment is implausible as a global
ies have shown that HCV vaccine strategies targeting PWID can be
both cost effective  and the most efficient approach to control-
ling the epidemic . Canadian researchers showed that targeted
immunization with an 80% effective HCV vaccine and 51% compli-
a universal approach and reduce HCV-related deaths and overall
Research in non-human primates suggests that the design of at
least a partially effective vaccine against HCV is feasible [7,34,35].
First, the immunological responses associated with spontaneous
eradication of the virus  are becoming more clearly understood
and many researchers propose that duplication of such immune
events through immunization is a realistic option . Studies in
effective immunological protective mechanisms [17,31,38–41].
However, results on protective immunity in drug users are incon-
sistent, which might be partially explained by differences in study
design [17,31,32,42,43]. While some chimpanzee studies indicate
that it is possible to impede the progression to chronic infection
after both homologous and heterologous challenges, other stud-
ies have not been as successful in preventing infection or chronic
persistent infection (reviewed in ).
HCV infection in uninfected people, reduce viral persistence in
infected individuals, or sustain virological response in individu-
als with chronic infection, are currently in preclinical development
or early stage clinical trials (reviewed in [6,7,34]). The majority
of reported trials are on therapeutic HCV vaccines, where results
have been mixed. Wedemeyer et al.  examined the effect of
the HCV peptide vaccine IC41 on HCV-specific T-cell responses and
virological relapse rates in 60 patients with chronic HCV geno-
type 1 infection when added to pegylated interferon plus ribavirin
standard therapy. In that trial, HCV-specific T-cell responses were
HCV-RNA relapse [44,45]. In a recent Phase 1 trial of dendritic cell
immunotherapy in HCV infected individuals who had failed con-
ventional therapy, durable immune responses were not observed,
nor effects on HCV viral load, antibody response or levels of cir-
culating cytokines . A third therapeutic candidate, the HCV
Core ISCOMATRIXTMvaccine, was recently evaluated in 30 healthy
volunteers . Antibody responses were detected in all but one
participant and there was no indication of a dose response, sug-
gesting it would be worth pursuing further work in HCV infected
patients. Only one recent trial of a prophylactic vaccine has been
reported on: a Phase 1 trial of a prophylactic vaccine (HCV E1E2)
in healthy adults . The vaccine was found to be safe, generally,
well tolerated at the different dosage levels, and with measurable
induced antibody and lymphoproliferative responses. All of these
Phase 1 trials were conducted in healthy volunteers, and with one
exception , explicitly excluded participants with a history of
drug use in the past year.
subjects of candidate prophylactic HCV vaccines in PWID, includ-
ing ethical issues associated with trial literacy, informed consent,
standards of care, recruitment and retention, and the need for high
incidence of infection. While our review suggests that the chal-
lenges of ensuring the interest and participation of this population
in candidate HCV vaccine trials should not be under-estimated, we
also identify a number of opportunities, including the potential
for formative research to better understand the social and cultural
drivers of vaccination demand in this group and the possibility of
with vulnerable populations.
Clinical trials of candidate HCV vaccines raise significant biolog-
ical, methodological and ethical challenges.
Important concerns include expectations regarding efficacy,
viral heterogeneity, and immunology. HCV is an RNA-based virus
with a variable genome and the capacity to evolve over time to
evade drug and immunologic pressure . The seven major geno-
types share less than 80% sequence homology with each other, in
excess of 50 subtypes have been identified [50,51], and both the
duration and success rate of current treatments for HCV are geno-
type dependent, presenting challenges for both vaccine and drug
First-generation HCV vaccines are expected to be of moderate
efficacy (≤60%), a key issue encountered in HIV vaccine trial prepa-
ration (reviewed in ). A principal HCV candidate developed by
Okairos and currently in Phase I trials, is based on novel repli-
cation defective Adenovirus vectors with low/no seroprevalence
in humans: the chimpanzee Adenovirus AdCh3, and the human
Adenovirus Ad6, encoding the HCV non-structural antigens, with
genetically inactivated RNA-dependent RNA polymerase (NSmut)
. In various animal models, strong induction of HCV T- and
B-cell responses have been shown. In chimpanzees, the vaccine
induces potent, broad and long-lasting T-cell responses capable
of protecting against acute and chronic infection after challenge
with highly heterologous virus . The NSmut sequence is from
HCV genotype 1, subtype b, BK strain, which is conserved among
for infection with type 1 virus, protection against other subtypes
HIV vaccine trial acceptability  and may be important determi-
which found a moderate level of HIV vaccine acceptability (65.6 on
a 100-point scale) across 20 studies involving 7,576 participants
found significantly lower acceptability (40.4 vs. 73.8) for moderate
unteers, and not in PWID who may have various comorbidities and
may demonstrate poorer immunological responses to viral infec-
vaccine . Other concerns include side effects, durability of pro-
tection, and the potential for detectable vaccine-induced antibody
seroconversion. Detection of antibody was an important issue for
both participants and researchers in HIV vaccine trials , raising
the potential for unblinding/unmasking. However, it is unknown
how this factor will play out with HCV vaccines currently in devel-
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L. Maher et al. / Vaccine 28 (2010) 7273–7278
opment which are anticipated to prevent persistent, rather than
Trial design issues include trial literacy, standard of care,
trial size and duration, protocol adherence and cohort reten-
tion. A recent study of trial-experienced and trial-naive PWID
found low acceptability (55–60%) of key clinical trial concepts
such as equipoise, placebo and double-blinding. Participants who
demonstrated understanding of placebo and double-blinding were
. Challenges associated with the standard of care for PWID in
prevention trials are not limited to low- and middle-income coun-
try settings. Despite the fact that sharing of contaminated syringes
has been identified as a major risk factor for HCV infection, cover-
age of sterile injecting equipment is often suboptimal and gaps in
coverage continue to sustain the epidemic . Globally, only 8%
of injectors have access to needle and syringe programs and less
than half the countries with known injecting drug use populations
provide access to opioid substitution treatment . Moreover,
in many settings, prevention interventions for PWID remain con-
troversial, unsupported or banned , potentially making the
provision of standard of care difficult, if not impossible.
Evidence is also mounting that treatment of acute HCV is highly
efficacious [38,65]. Incorporating treatment for incident cases into
vaccine trials will be challenging. In 2006 Chiron and NIDA began
discussions and planning regarding the design and implementa-
tion of trial to test a prophylactic vaccine (E1/E2) vaccine. The
scope of the planning was wide and included input from groups
discussing the parameters of future trials and when and whether
treatment for acute HCV infection could be offered. While this took
place at the same time that Novartis was taking over Chiron, the
trial idea was subsequently dropped and Dr. Frank Vocci, formerly
with NIDA, noted that this decision was principally in association
with the perceived challenges and costs associated with providing
treatment for acute HCV infection (personal communication with
KP, January 2008).
incidence are necessary in order to determine appropriate stan-
dards of care in future vaccine trials . In addition to concerns in
attrition, suboptimal adherence and lack of community engage-
ment have been identified as factors contributing to the premature
termination of recent late-stage HIV prevention trials [66,67]. Effi-
cacy trials are lengthy and expensive and the capacity to conduct
them is limited. Effective evaluation of candidate HCV vaccines in
Phase II/III studies will require the ability to recruit and follow-
up HCV uninfected individuals in settings of relatively high HCV
incidence. While several studies provide estimates of incidence,
Lower-than-expected rates of enrolment and higher than expected
rates of loss-to-follow-up can also result in underpowered trials
that fail to reveal effective interventions, or delay the public health
impact of a positive trial.
While little work has been conducted on the feasibility of con-
ducting HCV vaccine trials with PWID, rates of willingness to
participate in HIV vaccine trials between 41 and 86% have been
reported in this group . Significantly, the AIDSVAX B/E effi-
enrolled and retained in a preventive vaccine trial  and while
is feasible [13–17,19], long-term commitments to study partici-
pation and multi-dose vaccine schedules are required in proof of
concept and efficacy trials. Retention is critical because loss-to-
follow-up reduces study power and biases results. PWID can be
a challenging population to track and retain in intervention studies
due to factors including mobility, unstable living conditions and
high rates of arrest and incarceration . Higher risk individu-
als, particularly those not connected to mainstream public health
programs, may be even more difficult to recruit and follow-up.
Several studies have also shown that incidence is highest among
new injectors who are often less engaged with the health system
and may be hardest to reach [14,16,18,71]. Community engage-
ment and ethnographic fieldwork provide mechanisms to increase
recruitment and retention by identifying potential sites and pop-
ulations and assessing community interest in future vaccine trials
PWID are often socially vulnerable due to factors including
poverty, stigma, racism and gender inequality. These powerful
social and cultural forces must be addressed when conducting
HCV research or implementing prevention programs. Communi-
edge and participation are affected by poverty, culture and stigma
in order to minimize potential ethical concerns . In addition,
where law enforcement and incarceration remain the dominant
policy responses to injecting drug use, this can undermine public
health programming and intervention studies by increasing risky
gender or ethnic affiliation . Community groups are likely to be
vigilant regarding ethical issues, especially perceived exploitation
of vulnerable populations. Our experience over two decades sug-
gests that partnership approaches, combined with the provision
of support and referral services, may increase trust and improve
A frequent concern in prevention trials in high risk groups is
the potential for risk inhibition or compensation following receipt
of vaccine. Mathematical models have predicted that the potential
benefits of an HIV vaccine may be completely lost if continued or
increased risk behavior occurs following immunization . How-
ever, behavioral disinhibition has not been observed in studies of
HIV post-exposure prophylaxis and actual vaccine interventions
impact factors such as the provision of clean injecting equipment.
As Baral et al.  have observed, “A consistent and disturbing
finding in reviewing the published work on vaccination in PWID
is that they are at high risk for vaccine-preventable infections, but
generally have among the lowest immunization coverage rates”
(p. 672). Hepatitis B virus (HBV) vaccination programs that target
behavioral risk groups have been successful in some settings. In
the Netherlands, estimated HBV vaccine coverage following imple-
mentation of a targeted vaccination program via Public Health
among PWID is high when convenience is maximized and remu-
neration offered [86–88], accelerated schedules have also been
recommended for PWID in response to poor completion [59,89].
Little is known about the social and cultural dimensions of vac-
cine demand in PWID. Formative research can support vaccine trial
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L. Maher et al. / Vaccine 28 (2010) 7273–7278
tudes of target groups, identifying barriers to trial participation
and intervention uptake, and improving ethical informed consent
. A recent study designed to inform preparedness for candidate
HCV vaccine trials identified the benefits of early and extended
community engagement in informing site selection, identifying
into the development of research protocols .
Better understanding of PWID attitudes and decision making
cine trial readiness and trial operations . Planning for clinical
trials also needs to recognise the concerns of participants and to
the development of HCV vaccines progresses, methods need to be
developed to maximize informed and committed involvement by
it speaks to the capacity to provide informed consent, investing
time and resources in developing effective and sustained commu-
nity engagement is also necessary to build the capacity of PWID to
participate in clinical trials .
Many PWID face the possibility of HCV infection with a complex
sense of inevitability, fostered by structural barriers to effective
prevention . This ‘sense of inevitability’, potentially a major
barrier to effective behavioral interventions, may represent a con-
structive opportunity with respect to vaccine trials, as vaccines
represent a ‘new’ way of engaging with one’s sense of personal risk
and ability to respond. For some at least, vaccines may represent an
‘easy’ way of bypassing or rendering irrelevant the structural bar-
riers to avoiding infection. Finally, HCV vaccine trials can benefit
from lessons learned from HIV prevention trials . In contrast
to HIV prevention trials, which are often conducted ‘on’ vulnera-
ble populations in resource poor settings, high HCV incidence in
PWID in resource-rich settings provides opportunities to develop
models of best practice for conducting prevention trials ‘with’ the
communities most likely to benefit.
Throughout this commentary we have drawn analogies
between HCV and HIV vaccine research. While there is much to
be learned from HIV vaccine research, we suggest that HCV also
poses unique challenges and requires targeted efforts specific to
this infection. Firstly, HCV is not HIV. Transmission events, acute
infection, viral dynamics and infection outcomes are different from
those that occur with HIV. People at risk for HCV and participat-
ing in HCV research, including vaccine-related research, must be
interpretations, as well as risk, transmission and infectivity pat-
terns. HCV is significantly more infectious than HIV and sharing
of injecting equipment is a highly efficacious route of transmis-
sion [8,95]. HCV infection is spontaneously cleared by 20–40% of
evaluation of immune responses, there are important differences
in other areas, including differences in the effect of the vaccine
on infection outcome. These issues have been reviewed by Strick-
land et al. . In brief, a successful prophylactic HCV vaccine will
shown limited promise in eliciting the immune responses that will
prevent infection and research has shifted to include candidates
designed to modify disease progression by altering viral set-point,
an outcome that is more challenging to assess [7,96]. Efforts to
develop and test HIV vaccines have also received a great deal more
resources and effort than HCV vaccine research [7,34,96,97].
Secondly, PWID are a difficult to reach population and HCV vac-
cine trials with this group will present particular challenges. PWID
at high risk of HCV are younger and may be newer to injecting than
those at risk of HIV . While the HIV vaccine trial conducted
in Thailand involved participants recruited from methadone clin-
ics in Bangkok, it is possible that this population may be more
stable than injectors at risk of HCV . Moreover, in developed
country settings, populations in drug treatment, particularly those
engaged in opioid substitution treatment, are not likely to be can-
didates for vaccine trials as a high proportion are anti-HCV positive
[98,99]. There is a need for high quality data on the factors asso-
ciated with recruitment and retention of out-of-treatment PWID,
both in cohort studies and clinical trials. Thirdly, prevention trials
must also provide standard of care prevention for participants. As
noted previously, there remains considerable uncertainty around
HCV, as well as ongoing controversy around their implementation
and scale up. Based on the evidence reviewed here, a minimum
prevention package for PWID enrolled in candidate HCV vaccine
trials includes access to risk reduction counseling, sterile injecting
equipment, drug dependency treatment, and other medical care
and treatment evaluation as needed.
ally . PWID are the population at greatest risk of HCV infection
[12–18] and stand to benefit greatly from a vaccine. While current
prevention approaches have been successful at reducing risk and
is unlikely to be contained without at least a partially effective
vaccine. A safe and efficacious vaccine could significantly reduce
HCV transmission among PWID, averting considerable morbidity
that lessons learned from HIV, while helpful, will not completely
inform HCV trial preparation or implementation. The challenges of
ensuring interest and participation among PWID in field trials of
candidate HCV vaccines should not be under-estimated. In addi-
tion to distinct biological challenges in relation to HCV such as
viral heterogeneity, and trial design issues including standards of
care, PWID are often socially and economically marginalized, vul-
nerable to high rates of arrest and incarceration and may suspect
and/or distrust the medical community. Little is known about atti-
tudes towards immunization, barriers to uptake, and willingness
to participate in vaccine trials in this group. However, in contrast
to HIV and other infectious diseases such as tuberculosis, high HCV
incidence in high- and middle-income settings provides opportu-
nities to develop models of best practice for conducting prevention
trials with this population. The significant biological and social fac-
tors and differences between HIV and HCV reviewed here suggest
that hepatitis C warrants targeted vaccine preparedness research
in order to lay the groundwork for successful implementation of
future trials with PWID.
This research was supported by the award of a National Health
and Medical Research Council (NHMRC) Project Grant (Applica-
tion 630483: Hepatitis C Vaccine Preparedness Study). Bethany
White is supported by an NHMRC Dora Lush postgraduate research
scholarship and Lisa Maher and Margaret Hellard are supported by
NHMRC Senior Research Fellowships. Thomas Kerr is supported by
the Michael Smith Foundation for Health Research and the Cana-
dian Institutes for Health Research and Kimberly Page is supported
by U.S. National Institutes for Health (NIH) 2 R01 DA016017-03A1
and 5 U19 AI40034-13. The National Centre in HIV Epidemiology
and Clinical Research is affiliated with the Faculty of Medicine,
Author's personal copy
L. Maher et al. / Vaccine 28 (2010) 7273–7278
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