Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (10), p.3050-3055
• Main Authors: Akondy, Rama S., Johnson, Philip L. F., Nakaya, Helder I., Edupuganti, Srilatha, Mulligan, Mark J., Lawson, Benton, Miller, Joseph D., Pulendran, Bali, Antia, Rustom, Ahmed, Rafi
• Format: Article
• Language: English
• Subjects: Biological Sciences; CD8-Positive T-Lymphocytes - immunology; Cohort Studies; Fever; Gene Expression Profiling; Humans; Immune response; Immunization; Pathogens; Peak load; T cell receptors; Tumors; Vaccines; Vector-borne diseases; Viral Load; Viruses; Yellow Fever Vaccine - immunology; Yellow fever virus - genetics; Yellow fever virus - immunology; Yellow fever virus - isolation & purification
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1500475112

Significance Current vaccine development against persistent infections such as HIV and tuberculosis focuses on eliciting CD8 T cell immunity through the use of replication-incompetent or single-cycle vectors. Although inherently safe, these vectors deliver limited amounts of antigen. We investigate how antigen load affects the CD8 response by analyzing the viral load and the magnitude of the specific CD8 response after immunization with the live attenuated yellow fever vaccine (YFV-17D). Our results show that the magnitude of the CD8 response is proportional to the amount of antigen when virus load is below a threshold value and saturates above. This finding highlights the requirement that T cell-based vaccines deliver sufficient antigen to elicit a large CD8 response that may be needed for protection. CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load ( R ² ∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell–based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell–based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.