Lehner Vaccine Discovery Consortium
When a virus enters the body, immune system cells respond by engulfing viral particles and displaying parts of them on their surfaces. These antigen-presenting cells, or APCs, display viral antigens in the context of molecules called human leukocyte antigens (HLAs) or major histocompatibility complexes (MHCs).
Several lines of evidence suggest that a vaccine that raises an immune response to HLA molecules could protect against HIV-1. A large study of maternal to child HIV-1 transmission found that transmission was more likely when mother and infant shared the same HLA class I alleles. The envelope of the HIV-1 virus contains HLA class I and II proteins as well as other cell surface molecules acquired when the virus particle buds through the cellular membrane of the infected human cell in which it was made. Furthermore, HLA class I alleles (B57 and B27) are significantly correlated with slow progression in HIV-1 infected humans (elite controllers).
In the Lehner-led VDC, immunizations against HLA alloantigens in combinat The goal of this project is to establish the proof of concept that allo-immunization prevents SIV/HIV infection in rhesus macaques.
1. Harness allogeneic, innate and adaptive immunity by xeno- or allo-immunization of macaques with HLA or MHC (Mamu) class 1 and class 2 antigens. Heat shock protein (HSP70) will be used as a co-adjuvant, which elicits innate and anti-HIV/SIV immune responses and Titermax as a major systemic adjuvant. In another arm of immunization, trimeric HIV gp140 and SIV p27 will be added to the MHC antigens, HSP70 and Titermax, as these complement non-cognate with SIV/HIV-specific immunity.
2. Target mucosal as well as systemic immunity by parallel intramuscular and vaginal vaccination of macaques, using the above vaccine components.
3. The challenge virus (SHIV SF162P) will share one HLA or Mamu class 1 and class 2 allele with those of the vaccine when grown in human or macaque T cells, respectively.
4. Induce protective immunity based on multifunctional, complementary immune responses and harnessing the most potent allo-immune responses.
5. Determine correlates of protection against the SHIV infection by evaluating innate, non-cognate, and adaptive mucosal mechanism of immunity.
The two vaccine candidates have been prepared and administered; a xenogeneic vaccine and an allogeneic vaccine for testing in rhesus macaques.
The xenogeneic vaccine consists of HLA-class I and HLA-class II (human antigens), HIVgp140, SIVp27, and HSP70 formulated with dextran into Dextramers. Intramuscular or subcutaneous immunization of the vaccine with a co-adjuvant was carried out at 0, 4, 8 and 16 weeks.
The macaques were challenged IV with SHIVSF162.P4, 4 weeks after the last immunization and the viral load was monitored. The results showed significant decrease in peak and cumulative viral load or total prevention of infection against the heterologous SHIVSF162.P4 in one group of macaques compared with the unimmunized control group over the post-challenge period of 10 weeks. Importantly, the protected group of macaques were immunized with HLA-class I + II and HIVgp140 + SIVp27 linked to HSP70 and mixed with the Titermax adjuvant. High levels of antibodies were induced to the immunizing HLA-class I (A2, A2, A3 and A11) and HLA-class II (DR4) antigens, demonstrating that the recombinant HLA antigens are potent immunogens.
A significant inverse correlation was found between the viral load and the HLA-I antibodies and this appeared to be specific to the protected group of macaques at all periods examined. Significant complement dependent neutralizing activity was also found in this group of macaques and an inverse correlation with the viral load. Among the innate anti-viral factors APOBEC3G mRNA was investigated and found to be significantly increased in the immunized groups, again with an inverse correlation with the cumulative viral load. These promising results have now been followed by rectal mucosal HLA or Mamu immunization in addition to HIVgp140, SIVp27, HSP70 all linked to dextran and mixed with CPG. Low dose rectal challenge of SHIVSF162.P4 has been administered and the results will be shortly evaluated.