Gallo Vaccine Discovery Consortium
OVERVIEW:
A vaccine that protects against HIV-1 must be capable of stimulating a strong immune response that can inactivate, or neutralize, a broad range of HIV-1 strains. To do this, a vaccine must contain antibody-stimulating agents, or antigens, that are common to multiple strains. One such antigen region forms when the gp120 viral envelop protein binds to the CD4 receptor during viral invasion of a cell. A vaccine based on this stabilized gp120-CD4 transition state could elicit antibodies that can neutralize subsequent infections. This gp120-CD4 intermediate, or CD4i, epitope is highly conserved across diverse HIV-1 strains.
The Gallo-led VDC has developed vaccine candidates that spur antibody responses to CD4i epitopes. The researchers are testing these candidates to see if they can prevent infection in a laboratory model using a monkey-human HIV-like hybrid virus known as SHIV. The investigators are also exploring whether the candidate vaccine can prevent mucosal infection by stimulating antibodies against CD4i epitopes. The CD4i epitopes may be highly prevalent in the mucosa where viruses are establishing acute infection. Blocking acute infection has the potential to stop HIV-1 from replicating and establishing latent infection.
Previous work by the Gallo team has shown that parenteral immunization of rhesus macaques with a CD4i immunogen called Rhesus Full Length Single Chain (rhFLSC), followed by challenge with SHIV, resulted in significantly accelerated clearance of plasma viremia and an absence of long-term tissue viremia.
RESEARCH OBJECTIVES:
1. Systemic Immunity and Sterilizing Protection: To determine whether optimal parenteral immunization with rhFLSC can elicit sterilizing immunity against a mucosal challenge with SHIV162P3.
2. Mucosal Immunity and Sterilizing Protection: To determine whether optimal mucosal immunization with rhFLSC can elicit sterilizing immunity against a mucosal challenge with SHIV162P3.
3. Passive Humoral Immunity and Sterilizing Protection: To determine whether sterilizing immunity against a mucosal challenge with a SHIV162P3 is afforded by passive immunization with monoclonal antibodies specific for CD4i epitopes.
PROGRESS:
A study in rhesus macaques is underway that will optimize systemic immunization protocols to enhance immune responses to levels predicted to be required for sterilizing protection. These studies have led to the identification of an immunogen/adjuvant combination that will be optimized prior to carrying out a mucosal challenge study with SHIV162P3.
A study in rhesus macaques is underway to optimize mucosal immunization protocols to enhance immune responses to levels predicted to be required for sterilizing protection.
Passive immunization with monoclonal antibodies specific for novel gp120-CD4 epitopes (CD4i epitopes) is being explored to determine whether sterilizing immunity is possible for CD4i epitopes. A new algorithm was developed to isolate and characterize monoclonal antibodies from memory B cell subsets. A large panel of new CD4i monoclonals has been developed and is under characterization for neutralization breadth, potency, and for Fc-mediated effector functions. In addition, a number of new monoclonal antibodies have been isolated for other epitopes such as those associated with the CD4 binding domain. These antibodies are also under characterization.