What is the Merck/HVTN proof-of-concept trial or the Step Trial?The Merck/HVTN proof-of-concept trial is the name of a clinical trial to test an investigational HIV
vaccine. The trial will be run by Merck & Co., Inc., which developed the investigational vaccine, and
by the HIV Vaccine Trials Network (HVTN). The investigational vaccine is described in Section 5
below.
The main purposes of this trial are to obtain more information about the safety of the study vaccine in
humans and to learn if the study vaccine can prevent HIV infection. For vaccine recipients who
become HIV-infected through high-risk behavior, the trial will test whether the study vaccine lowers
the level of HIV in the blood.
The products in this trial are not produced from live virus or from HIV-infected human cells. There is
no possibility that they contain live (or killed) HIV virus. The investigational vaccine in this trial
cannot cause HIV infection.
What is a vaccine trial?
A vaccine is given to prevent infection or fight disease. Currently there is no vaccine against HIV.
Part of the process of finding an HIV vaccine that works is testing investigational vaccines that seem
most likely to help the body fight HIV. A vaccine trial is a standard way to test a specific
investigational vaccine so that researchers can prove that the investigational vaccine is safe, and can
find out more about whether it might work to prevent or fight disease. The people who participate in
HIV vaccine trials play an important part in the scientific research that may lead to an HIV vaccine.
Who are the people who participate in HIV vaccine trials?
Many types of people participate in HIV vaccine trials. In this trial, all participants must be generally
healthy and HIV-negative (free of HIV infection). People have many reasons for joining HIV vaccine
trials, including altruism (a desire to help others) and to advance scientific knowledge. Before
deciding to enter the trial, potential participants are provided with information about HIV and AIDS,
about the reasons for the trial, about possible risks and benefits of participation, and about trial
procedures.
Can a study vaccine cause HIV infection?
It is impossible to get HIV infection or develop AIDS from experimental vaccines. They not made
from live HIV, killed HIV, or HIV-infected cells.
The investigational vaccine in this trial cannot cause HIV infection.
What kind of vaccine is being tested?
The investigational vaccine is called MRKAd5 HIV-1 gag/pol/nef. It is composed of an adenovirus vector and an HIV gene insert.
A vector, such as a weakened non-HIV virus, is used to carry a few non-reproducing HIV genes into
the body to create an immune response. In this investigational vaccine, the vector is made from
adenovirus type 5 (Ad5), a virus that causes the common cold and sore throats, but the vector has
been crippled so that it cannot grow or spread in the body or to other people.
A synthetic insert consists of some extra genes added into the vector. In this case, the genes added are HIV genes (gag, pol, and nef).
Neither the virus vector nor the HIV genes can cause HIV or AIDS.
Why is this trial being done?
Based on the research that has been conducted to date, the investigational vaccine has shown
promising characteristics. After testing the investigational vaccine in the laboratory, in animals, and
in some people (to see if it is safe and if it provokes an immune response), researchers are interested
in obtaining more information about the safety of the investigational vaccine and learning if the
vaccine can prevent HIV infection completely, or at least lower the level of HIV in the blood if infection is not completely prevented.
How could this investigational vaccine help prevent HIV/AIDS?
The investigational vaccine transports synthetically produced HIV genes into the cells. The delivery
of these genes could stimulate the body to generate a cellular immune response to HIV, producing an
army of killer cells (called T-cells) that are programmed to recognize and kill HIV-1 infected cells.
The idea is to train the immune system to eliminate cells that show signs of HIV infection, thus
potentially reducing the damage that HIV can do to the body. If a person later becomes infected with
HIV, hopefully the immune system would be prepared to respond.
If the investigational vaccine is effective, will it be licensed after this trial is completed?
This is a “proof of concept” trial. It will not generate sufficient data to support a vaccine licensing
application. If the data show that the investigational vaccine affords some protection against HIV, or
that it reduces the viral load in those participants who become infected with HIV, this information will guide future research efforts.
What does the study vaccine contain?
The investigational vaccine contains the following:
A weakened form of adenovirus type 5,
the HIV genes gag, pol, and nef, and
saline (salt) solution.
Has this vaccine been studied before?
The investigational vaccine has been tested in more than 250 people. More than 60 people were given
the investigational vaccine at the same dose or higher than the dose used in this trial. Two similar
HIV investigational vaccines have been tested in more than 450 people.
Before being given to people, the investigational vaccine was tested in mice, rabbits and monkeys.
Who is eligible to participate in this trial?
Participants must be must be HIV-negative (not HIV infected) adults between 18 and 45 years of age,
and considered to be at high risk of HIV infection (due to behavior, mainly sexual, that puts them at
risk). Special efforts will be made to enroll high-risk women into the trial.
All participants must meet certain medical and non-medical criteria for eligibility, and volunteers are
carefully screened to make sure they meet the eligibility requirements. One of the main medical
criteria is a low level of pre-existing antibodies against adenovirus type 5, the vector component of
the study vaccine. These antibodies may exist even in very healthy people; if a volunteer is ineligible
for the trial because of adenovirus antibodies, this does not indicate a health problem.
How can people find out if they are qualified to join this trial?
Each potential participant is asked for a medical history and given a physical examination. Blood is
taken for analysis. The participant is asked to answer a series of personal questions about sexual
activity and drug use.
A woman who wants to join the trial will be given a urine pregnancy test. A woman who is pregnant
or breastfeeding is not allowed to participate in the trial, and all female participants must agree to
avoid pregnancy for the duration of the trial.
All volunteers are tested to ensure they are HIV-negative (not HIV infected). A volunteer who is
HIV-positive at screening cannot enroll in the trial.
Information about participants will be kept confidential and will be used only for trial purposes.
When and where is this trial being conducted?
The Merck/HVTN proof-of-concept trial is an international trial, and there will be research sites in a
number of countries. The trial is expected to begin enrolling participants around the end of 2004. It
will be conducted at 16 study sites in 13 US cities: Boston, MA; Chicago, IL; Atlanta, GA; Denver,
CO; Houston, TX; Los Angeles, CA; Miami, FL; New York, NY; Philadelphia, PA; St. Louis, MO;
San Francisco, CA; San Juan, PR; and Seattle, WA. It will also be conducted in Santo Domingo,
Dominican Republic; Port-au-Prince, Haiti; Iquitos, Peru; Lima, Peru; Toronto, Canada; and Sydney,
Australia.
What is the design of this trial?
The trial will enroll about 1500 people. Over the course of six months, half of these people will be
given three doses of the investigational vaccine, and the other half will be given three doses of a
placebo (an injection without any active vaccine) consisting of a saline (salt) solution.
For the rest of their time in the trial (about four more years), participants will be tested for HIV
infection every six months. All trial participants will be given state-of-the-art counseling to reduce
risk behavior. Because the trial enrolls people whose behavior puts them at high risk for HIV
infection, it is expected that some people will become infected. Some of these people will have
received placebo, but others may have received the investigational vaccine. These people will be
tested to see if the investigational vaccine lowers the level of HIV in the blood.
The Merck/HVTN proof-of-concept trial is a multicenter, randomized, placebo-controlled, doubleblind
trial. ‘Multicenter’ means that people in more than one place volunteer for the study.
‘Randomized’ means that participants are randomly assigned to get study vaccine or placebo.
‘Placebo-controlled’ means that some people are given placebo, so the researchers can tell if the
investigational vaccine makes a difference. ‘Double-blind’ means that neither the participants nor the
scientists know who is getting the investigational vaccine and who is getting the placebo.
How will the safety and rights of participants be protected?
This trial adheres to international standards for the ethical conduct of research as established by the
Helsinki Declaration of the World Medical Assembly and Council for International Organizations of
Medical Sciences (CIOMS) guidelines.
Trial participants play a very important role in the search for an HIV vaccine, and the safety and
rights of participants are given the highest priority. Still, it is important for participants to realize that
any new, investigational vaccine may have both medical and non-medical risks.
Before they join the trial, volunteers are provided with information about HIV and AIDS, about the
reasons for the trial, about possible risks and benefits, and about trial procedures. Clinic staff allow
ample time to talk with volunteers and answer their questions, and information is also provided in
writing.
After the trial has been fully explained, volunteers are asked to sign an informed consent form before
enrolling. This form will help ensure that participants have been given all the information they need.
Volunteers will be given plenty of time to consider whether or not they want to join the trial. They
may decide not to enroll as participants. If they do enroll, they may still leave the trial at any time
without losing the benefits of their standard medical care.
During the trial, clinic staff will monitor participants to make sure the investigational vaccine is not
causing problems. Throughout the trial, any pertinent information researchers learn about the safety
of the trial will be provided to participants. Participants will be able to decide whether or not to stay
in the study based on any new information they learn.
Participants are reminded frequently that being part of a vaccine trial does not mean they are
protected from HIV infection. They are counseled at each clinic visit on ways to avoid HIV infection
(including, for example, correct and consistent condom use).
Is this investigational vaccine safe?
Based on the data from animal studies and earlier trials in people, scientists believe that the
investigational vaccine is safe enough to use in this trial. One purpose of this trial is to get more
information about the safety of the investigational vaccine.
Previous studies have tested the investigational vaccine in more than 250 people, more than 60 of
whom were given the investigational vaccine at the same dose or higher than the dose used in this
trial. Two similar HIV vaccines have been tested in more than 450 people.
Before being given to people, the investigational vaccine was tested in mice, rabbits, and monkeys.
While scientists believe that there are no serious safety risks with the investigational vaccine, there is
always the possibility that there could be problems that no one expected. This is why this
investigational vaccine, like any new drug or vaccine, needs to be tested in participants in a controlled
clinical setting. Participants’ health and safety will be closely monitored throughout the trial.
Because the investigational vaccine does not contain live HIV virus, there is no way for the study
vaccine to cause HIV infection.
How is the safety of the investigational vaccine monitored?
Several groups monitor this trial for safety and to make certain the study is being conducted
according to appropriate scientific and ethical standards. These groups include the US Food and Drug
Administration (FDA), the US National Institutes of Health (NIH), the HVTN, and Merck & Co., Inc.
Physicians on the team that designed the Merck/HVTN proof-of-concept trial will monitor the safety
of the trial. This team carefully considered all of the available information to decide that the
investigational vaccine was safe enough to study in this trial.
In addition, there will be an independent Data and Safety Monitoring Board (DSMB); a group of
experts not affiliated with Merck and Co., Inc., the HVTN, or the clinical trial investigators, who will
carefully monitor the safety of the trial participants. If there are safety concerns, the DSMB can
recommend that the trial be modified or stopped.
Are there non-medical (social) risks?
Participants are asked to carefully consider all risks before joining a trial. Some risks are medical
(related to health), but there are also non-medical, or social, risks. Trial participation takes time and
commitment. It can also lead to complications with others who do not agree with the participant’s
choice to join the trial, or who do not have enough information about HIV vaccines. For example,
some people have reported that being in a trial has upset their spouse, friends or family members.
Participating in a trial may also restrict the volunteer’s behavior. For instance, participants are asked
not to donate blood, and women should avoid pregnancy during the trial.
Others have experienced discrimination when they told people they were participating in clinical
research for an HIV vaccine. In the case of discrimination, study staff can (at a participant’s request
and with their permission) talk to insurance companies, employers, and others to explain a
participant’s involvement in a trial.
The investigational vaccine could cause a false positive result on a standard HIV test (see Section 19),
and such a result may lead to being treated unfairly by others.
It is important to remember that being given the investigational vaccine does not mean the participant
is protected from HIV infection that is due to sexual contact, sharing of injection drug equipment, or
any other transfer of blood or bodily fluids. Trial participants will also not know whether they have
received the investigational vaccine or the placebo, which is an inactive substance (saline solution)
with no protective properties. Participants are therefore counseled to avoid behavior that will put them
at risk of HIV infection.
To help avoid problems that could come from participating in a trial, participants will be offered an
identification card that shows that they have joined an HIV vaccine study. A number will be listed on
the card that may be called for information or for help in resolving problems.
Could the investigational vaccine cause a “false positive” result on an HIV antibody test?
Some investigational vaccines may cause a trial participant to have an HIV test that appears HIV
positive. Standard HIV tests look for antibodies (a part of the immune system) that recognize HIV.
This investigational vaccine could cause the body to produce these antibodies. In this case, the
standard HIV test could show a positive result. If the investigational vaccine causes this result, it does
not necessarily mean the study participant is infected with HIV. A false positive means that some
tests make a person appear infected; other, more specific tests can prove that there is actually no
infection.
Participants are counseled to get HIV testing done only at their trial site, because the site has access to
specific tests that can differentiate between false positives and true HIV infection. These tests will be
available even after the study ends.
No medical side effects or health problems are associated with a false positive HIV test result. But
such a result may lead to being treated unfairly by others. People with a positive HIV test, even a
false positive, are not allowed to donate blood. They may also have difficulties with getting
insurance, medical/dental care, traveling to other countries, employment, service in the military or
Peace Corps, or relationships with friends and family. Clinic staff members are available to help with
any difficulty, and services exist to help any study participant with a false positive HIV result.
What will be done with a participant’s trial records?
Information about trial participants will be used for HIV vaccine or vaccine trial-related research
only. Any information collected about participants will be kept as private as possible. Most records
have only a participant ID number, not a name. Samples used for tests are identified by number only,
not by name. Any test results are confidential, and will not be made part of a participant’s medical
records.
We cannot guarantee absolute privacy. For example, certain information about trial participants may
be released if required by law. In addition, most groups that review the safety of and conduct the trials
will be able to review the records—but all the members of these groups are obligated to keep all
information confidential.
A Certificate of Confidentiality from the US Food and Drug Administration (FDA) helps protect
participant confidentiality. This certificate means that researchers and clinicians cannot be forced to
give identifiable information to anyone not connected to the study, even in court proceedings. There
are some exceptions to the Certificate of Confidentiality, such as in the case of government audit.
These exceptions will be explained to volunteers at the trial sites.
What will happen to participants if they become HIV-infected from their behavior during this
trial?
While the investigational vaccine cannot cause HIV infection there is no guarantee that the
investigational vaccine will prevent HIV infection. All participants must be HIV negative when they
enroll in the trial.
The investigational vaccine cannot cause infection with HIV. It’s important to note that participants
can still get infected with HIV through sexual contact, sharing of injection drug equipment, or any
other exchange of blood or bodily fluids, even if they are receiving the study vaccine.
Participants are counseled to avoid behavior that would put them at risk of HIV infection. Those who
become infected during the trial will stop receiving injections, but clinic staff will ask to continue
monitoring their health for the rest of their scheduled time in the trial, and the researchers will test to
see how the body controls HIV infection.
There are many drugs that can be used to treat HIV infection, but none of these drugs can cure HIV
infection. These drugs are not provided as part of this trial. Participants who become infected during
the trial will be referred to an appropriate doctor or medical agency for medical care, including antiretroviral
therapy, and counseling.
How long will it take to find out if the study vaccine works?
Depending on the results of this trial and other trials, this investigational vaccine might be tested
further in a larger trial. Such a trial would test safety in more people, and give a better idea of whether the immune system responds to a vaccine. If results remain promising, more trials would be planned
to see if the investigational vaccine helps prevent HIV infection. Participants in this trial may not be
eligible for future HIV vaccine trials.
Who is sponsoring this trial?
This trial is sponsored by Merck & Co., Inc. in collaboration with the HIV Vaccine Trials Network
(HVTN) HVTN.
Who is conducting this trial?
The trial will be run by Merck & Co., Inc., and by the HIV Vaccine Trials Network (HVTN).
Merck & Co., Inc. is a global research-driven pharmaceutical products company. Merck discovers,
develops, manufactures and markets a broad range of products to improve human and animal health,
directly and through its joint ventures. Merck, which has a long history of addressing major public
health needs through the development of vaccines, has been conducting research to develop an HIV
vaccine for more than 15 years.
The HVTN is a global partnership of researchers, governments, pharmaceutical companies, academic
institutions, and community members. The HVTN is dedicated to conducting international clinical
HIV vaccine trials in the safest, most efficient way possible. The HVTN is funded and supported by
the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health
(NIH), an agency of the US Department of Health and Human Services (DHHS).
Who reviewed and approved this trial?
The study vaccine is considered investigational, meaning that the FDA allows its use only in research.
It has been manufactured according to FDA guidelines and was reviewed by the FDA. The protocol
team (the people from Merck and Co., Inc, the HVTN and DAIDS) who designed the trial) also
carefully reviewed the information about the investigational vaccine before deciding to begin the trial.
The trial has also been reviewed by the World Health Organization (WHO), the Joint United Nations
Programme on HIV/AIDS (UNAIDS).
The safety and rights of participants in the Merck/HVTN proof-of-concept trial are monitored by
Institutional Biosafety Committees (IBC) and Institutional Review Boards (IRB) at to each research
center. Community members are involved throughout the trial to ensure that the rights and needs of
participants are being met.
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