One of the many questions facing HIV vaccine developers is: which parts of the virus should the vaccine induce immune responses against? A new study just published in the Journal of Immunology by Genoveffa Franchini's group at the National Cancer Institute suggests that inducing responses against a broad array of HIV proteins may enhance the efficacy of vaccination. The researchers employed a prime-boost vaccine approach (DNA followed by a pox virus vector called NYVAC) in macaque monkeys that were subsequently challenged with the highly pathogenic SIVmac251 (a close simian relation to HIV). Control animals received sham (placebo) vaccines while three groups of eight macaques each were given vaccines containing:
A. A combination of genes encoding modified forms of the HIV proteins Nef, Tat and Rev (dubbed retanef by the researchers)
B. The retanef combination plus gag, pol and env genes
C. The gag, pol and env genes
Six months after the final booster immunization, all animals were challenged intrarectally with SIVmac251. The researchers report that macaques in group B experienced a statistically significant 3-7 day delay in the emergence of viral replication after challenge compared to controls and groups A & C. The animals in group B also showed a significantly lower peak of viral replication during acute infection compared to the other groups. In the chronic phase of infection, group B macaques had lower viral loads than controls but the difference between animals in groups B and C did not reach statistical significance.
In terms of SIV-specific immune responses, the group B macaques possessed CD4 T cell responses to Gag and Env of a lesser magnitude than those seen in group C animals and a similar finding is reported for CD8 T cell responses to Gag. However these differences were only significant at the time of the peak of the immune response shortly after vaccination. The researchers state that “these results suggest that the breadth of the immune response is probably more important than high frequency responses to a limited number of epitopes.” The results also suggest that if vaccines containing fewer genes (such as the Merck Ad5 vaccine) show some hint of efficacy in humans, it’s possible that these results could be improved upon by including a broader array of HIV genes.
The Journal of Immunology, 2006, 176: 85-96.
Improved Vaccine Protection from Simian AIDS by the Addition of Nonstructural Simian Immunodeficiency Virus Genes
Zden k Hel*, , Wen-Po Tsai*, Elzbieta Tryniszewska*, , Janos Nacsa*, Phillip D. Markham , Mark G. Lewis, George N. Pavlakis||, Barbara K. Felber#, Jim Tartaglia** and Genoveffa Franchini2,*
* Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD 20892; Department of Pathology, Center for AIDS Research, University of Alabama, Birmingham, AL 35249; Third Department of Pediatrics, Medical University of Bialystok, Waszyngtona, Poland; Advanced BioScience Laboratories, Kensington, MD 20895; Bioqual, Rockville, MD 20850; || Human Retrovirus Section and # Human Retrovirus Pathogenesis Section, National Cancer Institute, Frederick, MD 21702; and ** Sanofi-Pasteur, Toronto, Canada
An HIV-1 vaccine able to induce broad CD4+ and CD8+ T cell responses may provide long-term control of viral replication. In this study we directly assess the relative benefit of immunization with vaccines expressing three structural Ags (Gag, Pol, and Env), three early regulatory proteins (Rev, Tat, and Nef), or a complex vaccine expressing all six Ags. The simultaneous administration of all six Ags during vaccination resulted in Ag competition manifested by a relative reduction of CD8+ T cell and lymphoproliferative responses to individual Ags. Despite the Ag competition, vaccination with all six Ags resulted in a delay in the onset and a decrease in the extent of acute viremia after mucosal challenge exposure to highly pathogenic SIVmac251. Reduced levels of acute viremia correlated with lower post-set point viremia and long-term control of infection. In immunized animals, virus-specific CD4+ T cell and lymphoproliferative responses were preserved during acute viremia, and the maintenance of these responses predicted the long-term virological outcome. Taken together, these results suggest that the breadth of the immune response is probably more important than high frequency responses to a limited number of epitopes. These data provide the first clear evidence of the importance of nonstructural HIV Ags as components of an HIV-1 vaccine.