Gallo: Systemic, Mucosal & Passive Immunity
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 research consortium 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.
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 (mAbs) specific for CD4i epitopes.
A study in rhesus macaques is underway using an optimized parenteral immunization protocol that enhances antibody responses to a level predicted to be required for sterilizing protection against a repeat low-dose rectal challenge with SHIV162p3. This protocol is designed to also prolong the circulating antibody response during the challenge period of the study.
A second study in rhesus macaques is underway to determine whether mucosal immunization can elicit sterilizing protection against a low-dose rectal challenge with SHIV162p3. This protocol uses rhFLSC stably expressed by vesicular stomatitis virus (VSV) as the mucosal immunogen.
A third study, again in rhesus macaques employs passive immunization to determine whether CD4i monoclonal antibodies afford sterilizing protection against a rectal challenge with SHIV162p4. A large number of mAbs have been isolated and characterized for neutralization specificity as well as Fc-mediated effector function. Candidate mAbs will be evaluated in both wild-type and attenuated forms in which neutralization is preserved but Fc-mediated effector function is abrogated by mutations in the Fc region. In addition to a CD4i mAb protection will also be evaluated for a new broadly neutralizing mAb that recognizes a new epitope that involves elements of the V1/V2 region, V3 region, and co-receptor binding domain. This mAb will also be evaluated in a wild-type and attenuated form lacking the ability to mediate Fc-effector function.