The HIV-1 epidemic has presented a global health challenge for the past 40+ years. To combat this pathogen researchers have developed effective drugs to suppress the virus and limit disease. However, the development of a vaccine to prevent HIV-1 infection has been less successful due to the enormous genetic diversity of HIV-1 and its global prevalence. Despite being limited in their success, some vaccine trials have provided useful insights into what type of immune response can reduce infection risk and limit virus abundance in the blood. These responses include non-neutralizing antibodies, polyfunctional CD4+ T cells that express two or more cytokines, and CD8+ T cells that recognize a variety of HIV-1 immunogens. To address the challenges of extensive HIV-I genetic variation and limited success with current vaccine approaches, mosaic and consensus immunogens were designed to increase the breadth of antigen recognition and enhance immune response activation following vaccination. Both mosaic and consensus HIV-1 immunogen vaccines were tested in a clinical trial led by a team of researchers including Drs. Kristen Cohen, Andrew Fiore-Gartland, Peter Gilbert and M. Juliana McElrath from the Fred Hutchinson Cancer Center Vaccine and Infectious Disease Division. Their findings were published recently in the Journal of Clinical Investigation.
“To counter global HIV-1 diversity, the ideal vaccine would elicit T cell responses against multiple distinct epitopes (i.e., breadth) with the ability to cross-react with diverse variants within targeted epitope regions (i.e., depth),” state the researchers. To achieve these vaccine characteristics, immunogens were designed using either a mosaic or consensus method. The mosaic approach creates a synthetic protein that includes bits of common circulating HIV-1 proteins that could be recognized by T cells. The consensus immunogen is generated by aligning amino acid sequences of HIV-1 proteins and selecting the most common amino acid at each site in the coding sequence. The researchers state that “by presenting the most common forms of circulating epitopes, mosaic and consensus immunogen approaches could elicit responses that enhance the cross-reactive potential of vaccine-elicited responses against diverse circulating viruses, enabling better control of viremia and limiting in vivo evolution of variant “escape” viruses.”
Proof-of-principle studies in monkeys have shown that mosaic HIV immunogens can increase the breadth and depth of immune responses as compared to consensus or native immunogens. For the clinical trial in humans, the researchers compared the mosaic version to the consensus and native HIV-1 envelope immunogens. Each vaccine was given in three doses followed by two additional doses of the same MVA-CMDR HIV-1 vaccine while another group received placebo vaccines. The researchers analyzed humoral antibody responses and T cell responses. They observed a peak in these responses two weeks after the final vaccine dose. However, each immunogen (mosaic, consensus and native) elicited similar levels of total antibody titers and CD8+ T cell levels. Of note, a slight increase in CD4+ T cell response was observed for the mosaic immunogen vaccination group as compared to the other immunogen groups. To determine the breadth of the T cell responses, the researchers mapped the T cell epitopes to the HIV-1 envelope immunogen. The mosaic immunogen produced CD4+ T cells capable of recognizing an average of 2.5 epitopes. In contrast, the consensus and native immunogen responsive CD4+ T cells recognized an average of 1.6 and 1.1 epitopes, respectively. These results demonstrate an increase in the breadth of the T cell response to the mosaic immunogen as compared to the other immunogens. The researchers also conducted a COMPASS analysis to determine the polyfunctionality of the CD4+ T cell response and found increased polyfunctionality for both mosaic and consensus immunogen vaccines as compared to the native immunogen group after the third vaccination. Lastly, the researchers evaluated the “depth” of T cell responses to recognize multiple epitope variants. The mosaic immunogen design again provided a marginal increase in the depth of CD4+ T cell responses as compared to the consensus and native groups. “Overall T cell breadth was largely due to Env-specific CD4+ T cell responses. Priming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants,” summarize the researchers.
These findings highlight important lessons from these alternative immunogen designs. The mosaic and consensus immunogen approaches did not enhance humoral antibody responses over what was achieved with the native immunogen, yet both designs generate more polyfunctional CD4+ T cells as compared to the native sequence. Importantly, the mosaic immunogen increases breadth of the T cell immune responses. However, none of these vaccine strategies provide adequate cross-reactivity of variant epitopes. While the mosaic immunogen design strategy is the leading approach tested in this clinical trial, the researchers stress that additional optimization of prime-boost regimens should be completed to enhance the cross-reactivity of elicited immune responses to variant epitopes.
The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the Bill & Melinda Gates Foundation.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Peter Gilbert and M Juliana McElrath contributed to this work.
Cohen KW, Fiore-Gartland A, Walsh SR, Yusim K, Frahm N, Elizaga ML, Maenza J, Scott H, Mayer KH, Goepfert PA, Edupuganti S, Pantaleo G, Hutter J, Morris DE, De Rosa SC, Geraghty DE, Robb ML, Michael NL, Fischer W, Giorgi EE, Malhi H, Pensiero MN, Ferrari G, Tomaras GD, Montefiori DC, Gilbert PB, McElrath MJ, Haynes BF, Korber BT, Baden LR; NIAID HVTN 106 Study Group. 2023. Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults. J Clin Invest. 133(4):e163338.