1. WHAT IS THE AVEG 202/HIVNET 014 HIV VACCINE TRIAL?
This trial combines two experimental HIV vaccines--vCP205 and rgp120 to try to safely stimulate an immune response against HIV. Each vaccine preferentially stimulates a different arm of the immune system.
It is called a prime-boost vaccine strategy because in earlier trials, the two vaccines were given sequentially, over a period of months. The booster vaccine, rgp120, was intended to increase the immune response generated by the primer vaccine, vCP205.
In this trial, the vaccines will be given simultaneously. The intent, however, remains the same: use one vaccine to augment the immune response generated by the other.
Although vCP205 and rgp120 have each been tested in humans before, both alone and in combination, this is the largest clinical study ever to use the two vaccines together. Because of its size, this trial will provide enough data to determine if the vaccine combination warrants further testing to determine its efficacy in preventing HIV infection.
2. HOW MANY OTHER VACCINES HAVE BEEN TESTED?
Worldwide, more than 40 HIV preventive vaccine trials have been initiated to collect safety data on the candidate vaccines and to obtain preliminary information on their ability to stimulate immune responses. Since 1987, NIAID's AIDS Vaccine Evaluation Group (AVEG) has enrolled more than 2100 men and women in 27 Phase I and Phase II preventive vaccine trials involving at least 17 experimental vaccines. This is only the second Phase II HIV vaccine trial sponsored by NIAID.
3. WHY IS THE STUDY BEING CONDUCTED?
This prime-boost vaccine approach appears to show the mostpromise among HIV vaccine strategies tested to date for inducing neutralizing antibodies, proteins that can block the virus from infecting cells, and for eliciting cytotoxic T-lymphocyte (CTL)responses directed against HIV. CTLs, also known as "killer T cells," are white blood cells that can potentially kill cells infected with HIV. This Phase II trial is being conducted so that additional data can be obtained about the safety and immunogenicity of this combined vaccine strategy. Depending on the results of this Phase II study, this vaccine strategy might be considered for evaluation in a large-scale efficacy field trial.
4. WHO IS SPONSORING THE STUDY?
The study is being conducted by AVEG and the HIV Network for Prevention Trials (HIVNET), both of which are supported by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health. The vaccines are being provided by their manufacturers Pasteur Merieux/Connaught (vCP205) of Lyon, France, and Chiron Vaccines (rgp120) of Emeryville, Calif.
5. WHEN AND WHERE IS THE STUDY BEING CONDUCTED?
The study will begin enrolling patients this spring. It will be conducted at the six AIDS Vaccine Evaluation Units and the eight domestic sites in the HIVNET, located in 12 cities across the country. The cities are St. Louis, Baltimore, Birmingham, Rochester (N.Y), Seattle (two sites), Nashville, New York City (two sites), San Francisco, Denver, Boston, Chicago, and Philadelphia. For further information and contact numbers, call the AIDS Clinical Trials Information Service at 1-800-TRIALS-A, or visit their website at http://www.actis.org.
6. WHO IS ELIGIBLE TO PARTICIPATE IN THE STUDY?
The study will enroll a total of 420 healthy, HIV-uninfected men and women between 18 and 60 years of age. Study participants will include individuals with a lower risk for acquiring HIV infection (60 individuals) as well as those with a higher risk of infection due to injection drug use or unsafe vaginal or anal sex (360 individuals).
7. WHY ARE BOTH HIGHER RISK AND LOWER RISK VOLUNTEERS BEING RECRUITED?
The investigators want to assess the vaccines in populations for whom HIV vaccines are intended. Hypothetically, prior exposure to HIV, which might be expected among the higher risk population, could alter the safety of or change the immune responses to the test vaccines. The lower risk participants will provide a control group for comparison.
8. WHAT IS THE DESIGN OF THE STUDY?
Participants will be randomly assigned to one of three study groups. The first group will simultaneously receive both vaccines; the second group will simultaneously receive vCP205 and the placebo for rgp120; and the third group will simultaneously receive the placebos for both vaccines.
The two vaccines are given simultaneously, in separate injection sites, rather than sequentially because prior studies found that simultaneous administration induces antibody responses more rapidly and does not appear to inhibit CTL responses.
All participants will receive four immunizations at 0, 1, 3, and 6 months. Every three months for two years, their blood will tested for HIV infection and their immune responses will be checked. There will be two additional annual follow-up visits.
Volunteers will receive a high dose (106.3 TCID50) of vCP205, suitable for potential larger scale trials, and 50 micrograms of rgp120. Placebo recipients will receive saline injections.
9. HOW DOES THIS VACCINE STRATEGY WORK?
The two vaccines are given in combination to try to stimulate different parts of the immune system. vCP205 is given primarily to stimulate the body's production of CTLs (which may kill HIV-infected cells), while rgp120 is given to stimulate the production of HIV antibodies (which may kill free virus that is outside the cells).
10. WHAT HAVE PREVIOUS STUDIES OF THESE VACCINES FOUND?
In trials of low and high doses of vCP205 with rgp120 boost, more than 90 percent of the participants developed antibodies that neutralized the same strain of virus as that used in the vaccine, and about 50 percent of volunteers developed CTL responses. However, these studies were only done in people at lower risk.
11. WHAT IS THE vCP205 VACCINE MADE OF?
vCP205 is made from the canarypox virus, which can cause disease in canaries but cannot cause disease in humans. In making the vaccine, the canarypox virus was attenuated, or weakened. It is now so weak it no longer can cause disease in canaries. vCP205 uses the weakened canarypox virus to carry copies of parts of several HIV genes. These genes code for the following proteins: the envelope protein gp120 (MN strain); the protein the anchors gp120 in the envelope, gp41 (LAI strain); gag, a gene that codes for p55, the core protein (LAI); and pol, a gene that codes for the HIV enzymes (LAI).
12. WHY WAS THE CANARYPOX VIRUS CHOSEN TO MAKE THIS VACCINE?
Scientists chose canarypox to make vCP205 because: (1) research has shown that the virus appears to be safe to use in humans, (2) it carries the vaccine genes into the body's cells, (3) it can accommodate large amounts of foreign DNA in its genome, and (4) it is relatively easy for researchers to work with.
When injected into the body, the canarypox virus can enter some human cells, but it will NOT replicate. However, it will make the HIV proteins encoded in the genes that are inside the canarypox virus. These proteins trick the immune system into thinking that the host is infected with HIV. The immune system of the host may then make CTLs in response to these proteins, as if it were fighting an actual HIV infection.
13. IS vCP205 SAFE? CAN THE HIV GENES IN vCP205 VACCINE TURN INTO HIV?
vCP205 lacks some very important genes that are absolutely necessary to make HIV. Volunteers cannot become infected with HIV from vCP205, nor can they pass the canarypox or the genes it carries onto anyone else.
More than 400 volunteers in France and the United States have received canarypox-based HIV vaccines, and no serious side effects have been reported.
14. WHAT IS THE rgp120 VACCINE?
The recombinant glycoprotein 120 (rgp120) vaccine is a genetically engineered copy of an HIV surface protein. Because most neutralizing antibodies in HIV-infected people are directed against rgp120, vaccines involving rgp120 were among the first developed and are the most well-studied. In nearly everyone who has received rgp120, the vaccine has stimulated their immune systems to make antibodies against this HIV surface protein.
The vaccine is made from SF-2, a laboratory-adapted HIV strain representative of most viruses in the United States. It is formulated with MF59, an adjuvant that enhances the immune response.
15. IS rgp120 SAFE?
Because it is NOT made directly from HIV, rgp120 cannot cause HIV infection. Over the last six years, rgp120 has been given to more than 800 adults, children, and newborns in Phase I (small) and Phase II (larger) studies. The vaccine is very safe and is generally well-tolerated.
16. WHAT ARE THE POTENTIAL SIDE EFFECTS OF THESE VACCINES?
vCP205 and rgp120 have been tested in more than 300 people. So far, the combination has not caused serious medical problems in anyone. However, more information about its safety in larger numbers of people is needed. The vaccine injections may cause a sore arm, headache, or a slight fever in some people for a few days. These symptoms have also been seen in placebo recipients.
17. IS THERE ANY POSSIBILITY THAT THE VACCINE COULD BE HARMFUL?
For any experimental vaccine, this question cannot be answered completely in advance, before it is tested in people. Scientists have wondered, for example, about the possibility that the vaccines may cause someone exposed to HIV to become infected with HIV more easily or cause the HIV infection to be worse. However, so far this has not been seen in any animals or people who have received the vaccines.
18. WILL STUDY PARTICIPANTS TEST POSITIVE ON HIV TESTS?
The vCP205/rgp120 vaccine combination may cause some people to transiently test positive on a standard HIV antibody test (ELISA). Study participants will be tested with both a standard antibody test as well as a new ELISA. The standard ELISA will determine if the study participants are making antibodies in response to the vaccines, while the new ELISA, which detects antibodies for HIV proteins not included in the vaccines, can help determine if they test HIV positive from an actual infection. If the new ELISA test is positive, the participant will be given a polymerase chain reaction (PCR) test, which detects minute amounts of HIV genetic material, to determine if HIV infection is actually present.
All volunteers will be offered an identification card indicating that they may test positive for HIV as a result of their participation in the trial. The card will list an 800 number to call through which the medical staff can be reached to help resolve any problems regarding insurance, discrimination, or other issues related to HIV testing.
19. HOW WILL YOU KNOW IF THIS VACCINE STRATEGY IS EFFECTIVE?
This Phase II study will expand our knowledge of the safety and immunogenicity of this prime-boost vaccine approach. However, a larger vaccine efficacy trial in people at higher risk of HIV infection will still be needed to fully determine the effectiveness of the use of vCP205 and rgp120 in combination. AVEG 202/HIVNET 014 will be using the vCP205 vaccine at a dose suitable for such potential large-scale trials.
20. WHERE CAN I GET MORE INFORMATION ABOUT THIS TRIAL?
Further information about this trial is available from the AIDS Clinical Trials Information Service, 1-800-TRIALS-A (1-800-874-2572), or through their website at http://www.actis.org.