Investigation of the Safety of an HIV-1 Vaccine Given Intra-muscularly and Intra-nasally to Healthy Female Subjects

The current treatment of HIV is aimed at delaying the disease process after the body has been infected with the virus. HIV treatment does not prevent the spreading of the virus to uninfected people. Prevention of HIV infection could be realized by a vaccine. An effective vaccine could slow down the world wide epidemic. None of the potential vaccines investigated in the past 20 years could provide protection to HIV. All these vaccines were aimed at stimulating an immune reaction in the blood. A new theory has been raised that protection against HIV should take place at the site where the virus in most cases enters the body after sexual contacts, in the vagina and rectum. Mymetics Corporation, sponsor of this clinical trial, has developed a new vaccine, based on the so-called virosome technique. This vaccine should be able to induce a local immune reaction in the mucosa of vagina and rectum. Investigations in laboratory animals showed that the newly developed vaccine was safe and well tolerated and a local immune reaction in the mucosa could be established. The next step is to investigate if the concept of mucosal immunity does also apply in the human being. Therefore this trial is being designed to investigate if the newly developed vaccine is also safe and well tolerated in healthy subjects. In addition, it will be investigated if the vaccine can induce an immune response in the mucosa of vagina and rectum. The vaccine will be investigated for the first time in man. The vaccine consists of a very small part of the HIV 1 virus, coupled to a carrier, the virosome. The vaccine also contains two proteins of the influenza virus. These are needed for stability of the vaccine and activation of the immune system in general. There will be two groups of 12 healthy female subjects. In total 24 subjects will participate in this study. The first group will be vaccinated with a low dose of the vaccine (10 microgram of peptide). If the vaccine is assessed as safe during the safety reviews, the second group will be vaccinated with a high dose of vaccine (50 microgram of peptide). Safety and tolerability of the high dose will also be assessed during two safety reviews. Each subject will be vaccinated on four occasions, separated by eight weeks. The first two vaccinations will be given in the muscles and the third and fourth vaccination will be given in the nose in order to enhance the immune response in the mucosa. In both groups, eight subjects will be vaccinated with the real vaccine and four subjects will be vaccinated with the carrier only (placebo). Nor the investigator neither the subject will know which vaccination they receive. It will be a so-called double-blinded study. Safety and tolerability will be assessed by the local and systemic adverse reactions. In addition, blood and urine will be investigated and subjects will have a physical examination including vital signs measurements. At home, subjects will complete a diary card for the registration of local and systemic adverse events. The immune response in blood will be measured. For the investigation of the mucosal immune response, a smear from the mucosa of vagina and rectum will be taken and investigated at four visits. This will be performed with special sponges and it is a painless procedure. Total duration of the study for each subject will be 32-34 weeks. HIV infection due to this vaccination is not possible.

Inclusion criteria

• Female, aged between 18 and 45 years, extremes included
• Having regular menstrual cycles (24 to 30 days). Women that got sterilized by bilateral tubal ligation are allowed, as long as they have regular cycles
• Non-smoking or smoking (no more than 10 cigarettes or 2 cigars or 2 pipes per day, for at least 3 months prior to selection)
• Body Mass Index (BMI) of 18.0 to 30.0 kg/m2, extremes included. BMI is calculated as the weight (in kg) divided by the square of height (in m)
• Informed Consent Form (ICF) signed voluntarily before first trial-related activity
• Able to comply with all protocol requirements
• Healthy on the basis of a medical evaluation that reveals the absence of any clinically relevant abnormality and includes a physical examination, a gynecological examination, medical history, electrocardiogram, vital signs and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening
• If the subject is of childbearing potential, agrees to use adequate contraception (oral contraceptives or double barrier method, as described in section 5.2.4, point 7 of the protocol) and not become pregnant for the duration of the study.

Exclusion criteria

• Male
• Female subject without regular menstrual cycle (24-30 days)
• History of total hysterectomy
• Female subject of childbearing potential without use of effective birth control method(s), or not willing to continue practicing these birth control method(s) for the duration of the trial
• Spermicides or other chemicals as used in contraceptive barrier methods (i.e., a male or female condom, diaphragm, cervical cap or intra-uterine device);
• A positive pregnancy test or breast feeding at screening
• A positive HIV-1 or HIV-2 test at trial screening
• Having vaginitis as observed by local inspection and vaginal swab
• Recurrent vaginal infections or sexually transmitted diseases within one year prior to vaccination
• A positive test for Hepatitis A (confirmed by hepatitis A antibody IgM), hepatitis B (confirmed by hepatitis B surface antigen), or hepatitis C (confirmed by hepatitis C virus antibody) infection at trial screening
• History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drugs which in the investigator's opinion would compromise subject safety or compliance with trial procedures
• Currently active or underlying diabetes, gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, auto-immune disease(s), inheritable immune deficiency(s), infectious disease(s), nasal disorders (i.e. rhinitis, chronic nose bleeds, chronic sinusitis, polyps, chronic cold sores), dental or mouth infections, or rectal problems (fistals, hemorrhoids)
• History of allergic disease (i.e. egg, milk, dairy products) or reaction likely to be exacerbated by any component of the vaccine to be administered in this trial, and severe allergic disease(s)
• Contraindication to i.m. injections, history of bleeding disorder or use of anticoagulant therapy within 4 weeks prior to the first study vaccination
• Having received any of the following substances:

• Nasal or inhalation corticosteroids within 2 weeks prior to first vaccination
• Vaginal and/or rectal treatment within 3 days prior to first mucosal sampling
• HIV vaccine in a prior clinical trial
• Immunosuppressive medications within 6 months prior to first vaccination
• Blood products within 120 days prior to the first vaccination
• Immunoglobulin within 60 days prior to the first vaccination
• Any investigational or non-registered drug or vaccine within 30 days preceding the first vaccination
• Any planned vaccination during the study period and safety follow-up
• Allergy treatment with antigen injections, within 14 days prior to the first study vaccination
• Current anti-tuberculosis preventive therapy or treatment
• Serious adverse reactions to vaccines such as, but not limited to, anaphylaxis, urticaria (hives), respiratory difficulty, angioedema, or abdominal pain or a history of anaphylactic reactions
• Donation of blood or plasma within the 30 days preceding the first vaccination
• Acute disease at the time of enrollment.