Cellular immune correlates of protection against symptomatic pandemic influenza

Abstract

The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)(+) interleukin-2 (IL-2)(-) CD8(+) T cells (r = -0.6, P = 0.004). Within this functional CD8(+)IFN-γ(+)IL-2(-) population, cells with the CD45RA(+) chemokine (C-C) receptor 7 (CCR7)(-) phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8(+) T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development.

Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge

“…These data, highlight and confirm that T cells confer a degree of protection against the clinical symptoms of influenza A virus infection. Most commercially available influenza vaccines primarily induce strain-specific antibodies, however it has been demonstrated that heterosubtypic T cells can confer broad-spectrum protection (32)(33)(34). A correlation between IAV-directed T cells and reduced viral shedding with less severe illness in humans has been demonstrated in a number of clinical studies (32,33,35).…”

“…Most commercially available influenza vaccines primarily induce strain-specific antibodies, however it has been demonstrated that heterosubtypic T cells can confer broad-spectrum protection (32)(33)(34). A correlation between IAV-directed T cells and reduced viral shedding with less severe illness in humans has been demonstrated in a number of clinical studies (32,33,35). It has also been demonstrated that protective levels of NP-specific T cell responses are found in 43% of the adult population (36).…”

Urgent challenges in implementing live attenuated influenza vaccine

“…This cross-reactive immunity may be what protects many adults from severe illness during a pandemic. 43 Between 2008 and 2014, uptake of LAIV in US 2-8 year olds increased from 20.1% to 38%. 44 One suggestion is that VE observations in the US are a result of recurrent exposure to LAIV over a prolonged time.…”

Cell culture-based influenza vaccines: A necessary and indispensable investment for the future

“…8,9 As far as T lymphocyte responses are concerned, several studies have shown that human CD4 C and CD8 C T cell responses typically cross-react to multiple influenza strains and subtypes, and mainly target internal components of the virus, [10][11][12] and that both CD4 C and CD8 C T cells may independently protect humans from infection or disease. 13,14 Evidence from elderly subjects, in whom the antibody response is quantitatively poor compared to adults, 15 suggests that CD4 C and CD8 C T cell responses may correlate better with protection. [16][17][18] Studies focusing on identifying early predictors of correlates of protection following infection or vaccination have identified an array of other molecular signatures.…”