Prolonged Evolution of Virus-Specific Memory T Cell Immunity after Severe Avian Influenza A (H7N9) Virus Infection

Abstract

Since 2013, influenza A H7N9 virus has emerged as the most common avian influenza virus subtype causing human infection, and it is associated with a high fatality risk. However, the characteristics of immune memory in patients who have recovered from H7N9 infection are not well understood. We assembled a cohort of 45 H7N9 survivors followed for up to 15 months after infection. Humoral and cellular immune responses were analyzed in sequential samples obtained at 1.5 to 4 months, 6 to 8 months, and 12 to 15 months postinfection. H7N9-specific antibody concentrations declined over time, and protective antibodies persisted longer in severely ill patients admitted to the intensive care unit (ICU) and patients presenting with acute respiratory distress syndrome (ARDS) than in patients with mild disease. Frequencies of virus-specific gamma interferon (IFN-γ)-secreting T cells were lower in critically ill patients requiring ventilation than in patients without ventilation within 4 months after infection. The percentages of H7N9-specific IFN-γ-secreting T cells tended to increase over time in patients ≥60 years or in critically ill patients requiring ventilation. Elevated levels of antigen-specific CD8 T cells expressing the lung-homing marker CD49a were observed at 6 to 8 months after H7N9 infection compared to those in samples obtained at 1.5 to 4 months. Our findings indicate the prolonged reconstruction and evolution of virus-specific T cell immunity in older or critically ill patients and have implications for T cell-directed immunization strategies. Avian influenza A H7N9 virus remains a major threat to public health. However, no previous studies have determined the characteristics and dynamics of virus-specific T cell immune memory in patients who have recovered from H7N9 infection. Our findings showed that establishment of H7N9-specific T cell memory after H7N9 infection was prolonged in older and severely affected patients. Severely ill patients mounted lower T cell responses in the first 4 months after infection, while T cell responses tended to increase over time in older and severely ill patients. Higher levels of antigen-specific CD8 T cells expressing the lung-homing marker CD49a were detected at 6 to 8 months after infection. Our results indicated a long-term impact of H7N9 infection on virus-specific memory T cells. These findings advance our understanding of the dynamics of virus-specific memory T cell immunity after H7N9 infection, which is relevant to the development of T cell-based universal influenza vaccines.

Divergent Peptide Presentations of HLA-A*30 Alleles Revealed by Structures With Pathogen Peptides

“…Screening of immunogenic peptides which are presented by specific MHC I molecules is crucial for the development of vaccines for infection diseases or cancer immunotherapy and for T-cell immune response evaluation (45)(46)(47)(48)(49)(50)(51). Recently, several pre-clinical and clinical studies have shown that vaccines targeting predicted personal tumor neoantigens are feasibility, safety, and immunogenicity (45,50,(52)(53)(54)(55).…”

Persistence of H7N9 virus antibody response 2 years after infection

“…To our knowledge, measurement of antibody response to H7N9 virus in 14 patients of our previous cohort 2 years after infection is the longest longitudinal study of H7N9 patients ever reported. Previous longitudinal studies have reported antibody response of H7N9 patients, but only a few had complete dataset (2‐9 patients) and shorter follow‐up periods (102‐375 days) . In our previous cohort study, 22 patients who were laboratory‐confirmed H7N9 virus infection were prospectively evaluated the dynamic changes in their antibody response at the acute phase, 100, 200, and 300 days after symptom onset.…”

“…Previous longitudinal studies have reported antibody response of H7N9 patients, but only a few had complete dataset (2-9 patients) and shorter follow-up periods (102-375 days). 14,15 In our previous cohort study, 7 22 patients who were laboratory-confirmed H7N9 virus infection were prospectively evaluated the dynamic changes in their antibody response at the acute phase, 100, 200, and 300 days after symptom onset. In this study, 14 of these 22 patients were followed up.…”

“…Among 22 patients who participated in the last follow-up visit (about 1 year after infection),7 14 consented to this new follow-up testing, with a median follow-up of 850 days (interquartile range 841-865) after symptom onset. Participants ranged from 41 to 77 years of age (median 60.5 years), and 6 (42.9%) were female (Table 1).…”

Specificity, kinetics and longevity of antibody responses to avian influenza A(H7N9) virus infection in humans

“…Among these serum samples, fifty-five specimens collected after hospital discharge of patients from the 2013 and 2013-2014 epidemics were tested and reported in a previous study investigating the virus-specific antibody responses and T cell memory in A(H7N9) survivors within the year following illness onset. 23 The study protocol was reviewed and approved by the ethics committee of School of Public Health, Fudan University and the ethics committee of Chinese Center for Disease Control and Prevention. Written informed consent was obtained from all participants.…”