First trial of the HIV-1 vaccine in Africa: Ugandan experience

Abstract

Problems in setting up the first trial of an HIV-1 vaccine in Uganda are described here by Mugerwa and colleagues. The authors explain how they solved these problems and give suggestions to help researchers who are starting future trials of HIV vaccines.

Full text

First trial of the HIV-1 vaccine in Africa: Ugandan
experience
Roy D Mugerwa, Pontiano Kaleebu, Peter Mugyenyi, Edward Katongole-Mbidde, David L Hom,
Rose Byaruhanga, Robert A Salata, Jerrold J Ellner and the HIV-1 Vaccine Trial Group
Problems in setting up the first trial of an HIV-1 vaccine in Uganda are described here by Mugerwa
and colleagues. The authors explain how they solved these problems and give suggestions to help
researchers who are starting future trials of HIV vaccines
Trials of the HIV-1 vaccine have been conducted in
Europe, North America, Brazil, China, and Thailand.1
The first trial of a candidate vaccine in Africa was
recently completed in Uganda. It involved a ran-
domised, placebo controlled trial of a vaccine in
healthy volunteers at low risk of HIV infection.23The
vaccine, called “ALVAC-HIV,” uses a live recombinant
canarypox vector to express envelope and core genes
of HIV-1.
Many commentators predicted that it would be dif-
ficult to conduct trials of HIV vaccines in developing
countries because of scientific, sociobehavioural,
ethical, and logistical barriers.4–8 Before we started the
trial in Uganda, we gathered data to help us overcome
these potential barriers. We collected epidemiological9
and sociobehavioural10 data about people who had
participated in studies that looked at preparing for
trials of the HIV vaccine. These data showed the preva-
lence and incidence of HIV, behaviours placing people
at risk of becoming infected with HIV, and the social
acceptability of a vaccine against HIV.9–11 The people
received detailed education and counselling about
infection with HIV and about HIV vaccines, and we
recruited some for our trial.11 We organised three open
workshops at the HIV candidate vaccine trial
workshop in Kampala in 1996 to gain consensus from
scientists, policy makers, community representatives,
and the media about how to undertake research into
HIV vaccines.
Despite these initiatives to solve problems before
the trial began, we still encountered many barriers. In
this article, we discuss these barriers and the strategies
that we developed to overcome them.
Social, behavioural, and ethical issues
Public misconceptions and media misinformation
Despite elaborate preparations for the Ugandan trial
of the HIV vaccine, misconceptions arose about the
trial’s purpose among the general public and potential
volunteers. Between 20 and 30 people infected with
HIV, who mistakenly thought that the vaccine was
therapeutic, asked to be enrolled in the study. Three
themes recurred during weekly meetings of focus
groups held for the benefit of potential volunteers:
belief that the vaccine would protect against unsafe sex,
fear that volunteers were to be injected with HIV, and
fear that volunteers would be exposed deliberately to
people infected with HIV.
Most of the confusion was due to widespread
rumours and conflicting media reports about the
vaccine. Many media writers, reporters, and editors
seemed not to understand concepts such as the differ-
ence between drugs and candidate vaccines. One
report in a Ugandan newspaper (New Vision 22
September 1996) referred to ALVAC-HIV as a “candi-
date drug”; some journalists confused the vaccine with
the newly introduced combination of anti-HIV drugs.
The latter error led to false hopes of treatment and to
demands that ALVAC-HIV be given to as many people
as possible. Meanwhile, an ongoing campaign by the
Ministry of Health to increase vaccination of children
against polio was disrupted by allegations that the
polio vaccine was contaminated with HIV.
Political issues and intrigue
Such public stigmatisation of the trial meant that the
matter had to be openly debated in parliament and
approved by a ministerial cabinet before being
sanctioned by the president of Uganda. Many public
figures tried to make political gains from the situation,
by expressing concerns about Ugandans serving as
guinea pigs for experiments that could not be done in
Europe or the United States. On the day of the first
vaccination, a controversial but influential member of
the Ugandan parliament organised a rally, which was
broadcast live on a local radio station. “This vaccine
should be tried on animals in the National Parks. Presi-
dent Museveni has sanctioned its use on Ugandans in
exchange for money to finance his war in the Congo,”
he declared, amid wild applause.
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Summary points
During Africa’s first trial of a candidate HIV
vaccine, we encountered social, political, legal, and
ethical barriers to completing the trial
Widespread public and media fear existed about
the risks of participating in the trial, including the
risks of becoming infected and being
experimented on
The lack of adequate ethical guidelines and a
regulatory control mechanism for biomedical
research led to delays in approval of the study
protocol
Doctors planning trials of HIV vaccines need to
interact closely with representatives from the
communities involved, the media, volunteers, and
other stakeholders
Education and debate
See also Clinical
review p211
Department of
Medicine, Makerere
University Medical
School, Kampala,
Uganda
Roy D Mugerwa
professor
Medical Research
Council, Uganda
Virus Research
Institute, Entebbe,
Uganda
Pontiano Kaleebu
scientific research
officer
Joint Clinical
Research Center,
Kampala, Uganda
Peter Mugyenyi
director
Rose Byaruhanga
chief counsellor
Uganda Cancer
Institute, Kampala,
Uganda
Edward
Katongole-Mbidde
head
Clinical Research
Group of the New
Jersey Medical
School, University
of Medicine and
Dentistry of New
Jersey, Newark, New
Jersey 07107-3000,
USA
David L Hom
assistant professor
Department of
Medicine, Division
of Infectious
Diseases, Case
Western Reserve
University,
University Hospitals
of Cleveland,
Cleveland, Ohio
44106-5083, USA
Robert A Salata
professor
continued over
BMJ 2002;324:226–9
226 BMJ VOLUME 324 26 JANUARY 2002 bmj.com

Ethical concerns
Before the study began, the Uganda network on law,
ethics, and HIV raised concerns about the informed
consent process, possible coercion of volunteers, reim-
bursement, and volunteers’ confidentiality. The net-
work wondered how we would ensure that volunteers
fully understood the risks inherent in participation
during the process of obtaining informed consent. To
resolve this potential problem, we translated the
consent form into the participants’ language and gave
them two weeks to read it and ask questions. We also
tested their understanding of the trial
—
volunteers who
failed to score at least 70% in these tests were referred
for further education at focus group discussions. We
felt that certain scientific terminology would be difficult
for the general public to understand, so we simplified
some research terms by using culturally and socially
familiar analogies
—
“air supply” was used for placebo,
“wrapping” for blinding, and “lottery” for random-
isation.
To avoid the possibility of coercion, all staff involved
in the study were civilian rather than from a military
background. The only incentives for participants were
treatments for simple conditions such as malaria, free
condoms, counselling, lunch, $10 (£7) for the time
spent in the trial, and reimbursement of transport
costs. With respect to confidentiality, we did not discuss
volunteers’ participation with their spouses, family
members, or friends
—
this decision was left to the
volunteers themselves.
Safety of the trial participants
The safety of participants in the trial became a lively
public issue. The annual expenditure on health in
Uganda is only $6 per person. Families already
overburdened with sick members would have neither
the motivation nor the resources to look after relatives
falling ill as a result of their participation in the vaccine
trial. A woman living with AIDS was reported in a local
newspaper as saying, “Researchers should take full
responsibility for any consequences of the trial. If
volunteers fall ill, let the scientists look after them.”
The vaccine manufacturer had arranged insurance
for volunteers experiencing injuries related to the vac-
cine. Volunteers who tested positive for antibodies to
HIV because of the vaccine were to be offered special
participation cards to protect from being discriminated
against for immigration, insurance, and employment
purposes. Some potential volunteers declined to
participate because of fears about being ineligible for
future vaccine trials and the prospect of inadequate
compensation for their families if they died.
The high prevalence of infection with HIV in some
poor countries, combined with such countries’
inadequate resources for purchasing antiretroviral
medications, makes them ideal testing sites for
candidate vaccines. Ugandans were concerned about
reports in the foreign media that manufacturers might
choose to trial vaccines in poor countries to reduce
product liability in case of injury or to exploit weaker
legal, ethical, or regulatory mechanisms for conducting
biomedical research.
A newspaper report (New Vision 1 March 1997)
asked whether the trial was an example of “hit and run
research” by scientists from rich countries, in which a
poor country was chosen as the setting because the
study would be cheaper and fewer questions would be
asked about safety and ethics. A bishop of the Church
of Uganda warned that the church would resist trials of
HIV vaccines if safety measures for volunteers were not
guaranteed. “People made in the image of God are not
to be used as objects to be disposed of when
experiments fail,” he commented during a church
sermon.
Scientific issues
The risks to volunteers
We believe that some objections raised in the research
community and among medical professionals were of
importance; others were due to jealousy on the part of
professionals not involved in the trial. For example,
three prominent Ugandan scientists
—
a geneticist, a
virologist, and an immunologist
—
raised fears that the
vaccine might undergo dangerous mutations that
could lead people to develop strange abnormalities.
They further argued that the virus might replicate in
vaccinated individuals, causing disseminated disease,
and that the individuals would then infect their
partners through sexual transmission, since the
vaccine uses a live vector.To these doctors, the trial was
comparable to the infamous Tuskegee experiment, in
which American researchers investigating the course
of syphilis denied treatment to African-American
patients deliberately and without the patients’ knowl-
edge. The three scientists claimed that the motive of
our trial was to spread HIV and other viruses among
uninfected Ugandans and eventually to wipe out the
African race, even though a major safety feature of
canarypox is its inability to replicate in mammals.12
The disagreements between scientists created
apprehension among the public. Attempts to clear up
the misunderstandings and allay the anxiety delayed
the start of the trial. The delay caused further specula-
tion about the worthiness of the vaccine, as the public
wondered why the trial was taking so long to start. On
11 September 1996, New Vision quoted experts as say-
ing that the candidate vaccine was safe; this seemed to
contradict an earlier report in the same paper, which
stated that the main aim of the trial was to evaluate
safety in local conditions. The public became
Election posters for President Museveni of Uganda, who was accused of sanctioning the use
of a trial HIV vaccine on Ugandans in exchange for money to finance war in the Congo
GIDEON MENDEL/NETWORK
Education and debate
New Jersey Medical
School, Newark,
New Jersey
07103-2714, USA
Jerrold J Ellner
professor
Correspondence to:
R D Mugerwa
profrdm@imul.com
227BMJ VOLUME 324 26 JANUARY 2002 bmj.com

distrustful, with some asking why, if the vaccine was
safe, were trials being conducted in Uganda. The pub-
lic could not understand that, although no adverse
effects had been found when the HIV vaccine was
tested elsewhere, its safety for the indigenous peoples
of Africa could not be assumed.
Recommendations based on the
Ugandan experience
Many countries lack regulatory mechanisms and a
legal framework for conducting biomedical research.
This, together with absent or inadequate ethical guide-
lines, poses problems that hinder reviews and approv-
als of research. Any country wishing to undertake
research into HIV vaccines needs to have a national
plan that clearly addresses these issues. The recently
formulated ethical guidelines by the joint United
Nations programme on HIV and AIDS (UNAIDS) can
be used as a basis for developing local guidelines.13
National regulatory agencies must be set up early
enough to assess the quality, safety, and potential
efficacy of new vaccines against HIV.
A related issue is the need to have at least two com-
mittees with appropriate representation to review ethi-
cal and scientific aspects of study protocols.In Uganda,
the protocol for the trial had to be approved by six dif-
ferent local committees
—
ethics, science, technology,
biosafety, drug authority, and social services
—
because
there was no national regulatory and control
mechanism for conducting research into HIV vaccines.
This meant that no single committee was considered
competent enough to handle this new and sensitive
subject. The time taken to form the committees
delayed the date that the first participant was enrolled
by one year.
The local population has confidence in trials when
national scientists are seen to participate actively in the
process of developing vaccines. These national
scientists should be involved, therefore, in all scientific
discussions, including those about the choice of
vaccine construct and study design and about
implementation of the study. Early negotiations with
funding and collaborating institutions should include
delicate issues such as patent rights, intellectual
property, compensation for injuries induced by the
vaccine, appropriate treatment for volunteers who
become infected with HIV naturally, and, where
relevant, availability of the vaccine for the participating
country once it is licensed.
Lack of information leads to misinformation.
Politicians and other community leaders should be
given information to encourage public support for
trials of vaccines and to reassure potential study volun-
teers. An information strategy for the public,
volunteers, and the media
—
who should be given regu-
lar progress reports on various aspects of the trial
—
is
essential. An information desk to issue periodic
bulletins and correct misinformation appearing in the
electronic or printed media can help avert crises. An
advisory board including representatives of the local
community may provide a critical link between
researchers and the public. Focus group discussions
provide an opportunity for trial volunteers to air their
concerns and for researchers to understand volun-
teers’ problems and provide information about the
ongoing study as well as about trials in other countries.
Conclusion
Before researchers start any trials of HIV vaccines, they
need to gain support from politicians, the media, and
the general public. Respected local scientists must be
involved in the planning and implementation of stud-
ies to enhance their credibility and to identify cultural
or logistical issues that might hinder recruitment. All
stakeholders must be involved in discussions about
important scientific, social, legal, ethical, and other
concerns before the study begins. The success of future
trials of HIV vaccines in poor countries depends
on adequate mechanisms of regulatory control as
well as a clearly defined approval process for research
protocols.
We thank the study volunteers for their patience, understanding,
and enthusiasm about being involved in this landmark trial. We
thank the laboratory and clinical staff of the Joint Clinical
Research Center and the Uganda Virus Research Institute. We
acknowledge the support of the Ugandan Ministry of Health
and UNAIDS. We thank Dr Harriet Mayanja for her advice and
contribution to the drafting of this paper.
Funding: Funding was provided by the US National Institute
of Allergy and Infectious Diseases (AI-35173 and AI-36219) and
Fogarty International Center (TW-00011), Bethesda, Maryland,
with support from the Government of Uganda and UNAIDS,
Geneva, Switzerland. The vaccine was provided by Aventis-
Pasteur (formerly Pasteur Merieux Connaught), Lyons, France.
Competing interests: None declared.
Number of people
Men
(15-49 years)
Women
(15-49 years)
Children
(10-14 years)
0
100 000
200 000
300 000
400 000
500 000
Estimated number of people living with HIV and AIDS in Uganda at
the end of 1999. Data from UNAIDS/WHO epidemiological fact sheet
on HIV/AIDS and sexually transmitted infections. Uganda. 2000
update
Number of people
Rural Urban Rural
Intercourse of risk Non-regular partner
Urban
0
20
40
60
80
100
Men
Women
Proportion of people reporting use of condom during most recent
“intercourse of risk” (left) and proportion of sexually active people
having at least one sexual partner other than their regular partner in
the past 12 months (right) in rural and urban areas of Uganda in
1995. Data from UNAIDS/WHO epidemiological fact sheet on
HIV/AIDS and sexually transmitted infections. Uganda. 2000 update
Education and debate
228 BMJ VOLUME 324 26 JANUARY 2002 bmj.com

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(Accepted 22 November 2001)
How can HIV be prevented in South Africa? A social
perspective
Catherine Campbell, Yodwa Mzaidume
South Africa’s lack of government leadership in the fight against HIV and AIDS has resulted in
disunity in local HIV/AIDS circles. Catherine Campbell and Yodwa Mzaidume suggest that peer
education
—
with local people taking control of HIV prevention efforts
—
can be successful but depends
on collaboration between many stakeholder groups at local, national, and international level
HIV and AIDS prevention programmes often have
little impact because such programmes have tradition-
ally had a biomedical focus and an emphasis on
individual behaviour. Yet social and community level
factors influence the rate and method of HIV
transmission and can affect the success or failure of
prevention programmes.
In this paper we discuss the importance of these
factors with reference to a South African prevention
programme. We argue that HIV prevention efforts are
affected by the participation of a wide range of groups
and processes at local, national,and international level.
The scope of research, interventions, and policies must
be widened to take this into account.
Community participation
Among marginalised groups in poor countries,
providing information about health risks changes the
behaviour of, at most, one in four people
—
generally
those who are more affluent and better educated.1This
is because health related behaviours (such as condom
use) are determined not only by individual choice but
also by the extent to which social conditions enable
such behaviours. Health promoters need to develop
policies and interventions that promote “health
enabling” social conditions (conditions that enable and
support health enhancing behaviour).23
Concepts such as community participation and
stakeholder partnerships are increasingly included as
articles of faith in HIV prevention policies and
interventions worldwide. Community led peer educa-
tion and participation by local stakeholders are widely
used strategies.4Our understanding of the processes
through which participation might bring health
benefits, however, is still limited.5
We explored community participation through our
involvement in the evaluation and implementation of
the Carletonville project. This project is a community
led HIV intervention programme in a South African
Summary points
The participation of local community members is
a key element in HIV prevention worldwide
Despite the proliferation of community based
approaches to HIV prevention, few studies have
examined the role of social factors in a
programme’s success
In particular, little is known about why
community participation affects sexual health
Community led peer education involves training
local people to take control of HIV prevention
efforts
This type of peer education in marginalised
groups can create trusting and cooperative
relationships in homogeneous local peer groups
The success of peer education also depends,
however, on collaboration among diverse
stakeholder groups at local, national, and
international level
Education and debate
London School of
Economics, London
WC2A 2AE
Catherine
Campbell
reader in social
psychology
Mothusimpilo
Project, c/o
Carletonville
Hospital, Private
Bag X2023,
Carletonville, 2500,
South Africa
Yodwa Mzaidume
outreach coordinator
Correspondence to:
C Campbell
c.campbell@lse.ac.uk
BMJ 2002;324:229–32
229BMJ VOLUME 324 26 JANUARY 2002 bmj.com