Natural influenza infection produces a greater diversity of humoral responses than vaccination in immunosuppressed transplant recipients

Hirzel, Cédric; Chruscinski, Andrzej; Ferreira, Victor H; L'Huillier, Arnaud G; Natori, Yoichiro; Han, Sang Hoon; Cordero, Elisa; Humar, Atul; Kumar, Deepali

doi:10.1111/ajt.16503

“…Current subunit vaccine strategies to optimize T cell responses to influenza challenge are mostly directed towards the most mutable proteins such as Haemagglutinin and Neuraminidase. There is evidence to suggest that HLA-I restricted T cell responses are more directed towards the more highly conserved internal viral proteins, whereas humoral responses are dominated by envelope proteins [ 43 ]. Despite the proteome of influenza comprising of only a dozen proteins, this yields many thousands of potential T cell epitopes.…”

Section: Discussionmentioning

confidence: 99%

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

Nicholas

¹

,

Bailey²,

Staples³

et al. 2022

View full text Add to dashboard Cite

CD8+ and CD4+ T cells provide cell-mediated cross-protection against multiple influenza strains by recognising epitopes bound as peptides to human leukocyte antigen (HLA) class I and -II molecules respectively. Two challenges in identifying the immunodominant epitopes needed to generate a universal T cell influenza vaccine are: A lack of cell models susceptible to influenza infection which present population-prevalent HLA allotypes, and an absence of a reliable in-vitro method of identifying class II HLA peptides. Here we present a mass spectrometry-based proteomics strategy for identifying viral peptides derived from the A/H3N2/X31 and A/H3N2/Wisconsin/67/2005 strains of influenza. We compared the HLA-I and -II immunopeptidomes presented by ex-vivo influenza challenged human lung tissues. We then compared these with directly infected immortalised macrophage-like cell line (THP1) and primary dendritic cells fed apoptotic influenza-infected respiratory epithelial cells. In each of the three experimental conditions we identified novel influenza class I and II HLA peptides with motifs specific for the host allotype. Ex-vivo infected lung tissues yielded few class-II HLA peptides despite significant numbers of alveolar macrophages, including directly infected ones, present within the tissues. THP1 cells presented HLA-I viral peptides derived predominantly from internal proteins. Primary dendritic cells presented predominantly viral envelope-derived HLA class II peptides following phagocytosis of apoptotic infected cells. The most frequent viral source protein for HLA-I and -II was matrix 1 protein (M1). This work confirms that internal influenza proteins, particularly M1, are a rich source of CD4+ and CD8+ T cell epitopes. Moreover, we demonstrate the utility of two ex-vivo fully human infection models which enable direct HLA-I and -II immunopeptide identification without significant viral tropism limitations. Application of this epitope discovery strategy in a clinical setting will provide more certainty in rational vaccine design against influenza and other emergent viruses.

show abstract

“…Natural infection with influenza virus in patients with transplants resulted in stronger Ab responses with a greater variety than vaccination with a split virus vaccine [ 248 ]. It has also been shown that booster vaccinations provide additional immunogenic protection in recipients of solid organ transplants [ 249 ].…”

Section: Immunocompromised Individualsmentioning

confidence: 99%

“…Although studies have shown beneficial effects from high doses and booster vaccinations, at the current moment the main recommendation for immunocompromised populations is to receive the annual inactivated influenza vaccine at the standard single dose [ 240 ]. There are different methods that are being researched to improve vaccine immunogenicity in immunocompromised individuals by addition of adjuvants, such as MF59 or increasing vaccine dosages [ 248 , 260 ].…”

Section: Immunocompromised Individualsmentioning

confidence: 99%

Review of Influenza Virus Vaccines: The Qualitative Nature of Immune Responses to Infection and Vaccination Is a Critical Consideration

Chan

¹

,

Alizadeh

²

,

Alizadeh

³

et al. 2021

View full text Add to dashboard Cite

Influenza viruses have affected the world for over a century, causing multiple pandemics. Throughout the years, many prophylactic vaccines have been developed for influenza; however, these viruses are still a global issue and take many lives. In this paper, we review influenza viruses, associated immunological mechanisms, current influenza vaccine platforms, and influenza infection, in the context of immunocompromised populations. This review focuses on the qualitative nature of immune responses against influenza viruses, with an emphasis on trained immunity and an assessment of the characteristics of the host–pathogen that compromise the effectiveness of immunization. We also highlight innovative immunological concepts that are important considerations for the development of the next generation of vaccines against influenza viruses.

show abstract

“…There is evidence to suggest that HLA-I restricted T cell responses are more directed towards the more highly conserved internal viral proteins, whereas humoral responses are dominated by envelope proteins [39]. Despite the proteome of influenza comprising of only a dozen proteins, this yields many thousands of potential T cell epitopes.…”

Section: Discussionmentioning

confidence: 99%

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

Nicholas

¹

,

Bailey

²

,

Staples

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

CD8+ and CD4+ T cells provide cell-mediated cross-protection against multiple influenza strains by recognising epitopes bound as peptides to human leukocyte antigen (HLA) class I and -II molecules respectively. Two challenges in identifying the immunodominant epitopes needed to generate a universal T cell influenza vaccine are: A lack of cell models susceptible to influenza infection which present population-prevalent HLA allotypes, and an absence of a reliable in-vitro method of identifying class II HLA peptides. Here we present a mass spectrometry-based proteomics strategy for identifying viral peptides derived from the A/H3N2/X31 and A/H3N2/Wisconsin/67/2005 strains of influenza. We compared the HLA-I and -II immunopeptidomes presented by ex-vivo influenza challenged human lung tissues. We then compared these with directly infected immortalised macrophage-like cell line (THP1) and primary dendritic cells fed apoptotic influenza-infected respiratory epithelial cells. In each of the three experimental conditions we identified novel influenza class I and II HLA peptides with motifs specific for the host allotype. Ex-vivo infected lung tissues yielded few class-II HLA peptides despite significant numbers of alveolar macrophages, including directly infected ones, present within the tissues. THP1 cells presented HLA-I viral peptides derived predominantly from internal proteins. Primary dendritic cells presented predominantly viral envelope-derived HLA class II peptides following phagocytosis of apoptotic infected cells. The most frequent viral source protein for HLA-I and -II was matrix 1 protein (M1). This work confirms that internal influenza proteins, particularly M1, are a rich source of CD4+ and CD8+ T cell epitopes. Moreover, we demonstrate the utility of two ex-vivo fully human infection models which enable direct HLA-I and -II immunopeptide identification without significant viral tropism limitations. Application of this epitope discovery strategy in a clinical setting will provide more certainty in rational vaccine design against influenza and other emergent viruses.

show abstract

Natural influenza infection produces a greater diversity of humoral responses than vaccination in immunosuppressed transplant recipients

Cited by 7 publications

References 44 publications

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

Review of Influenza Virus Vaccines: The Qualitative Nature of Immune Responses to Infection and Vaccination Is a Critical Consideration

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

Contact Info

Product

Resources

About