scholarly journals Universally Immune: How Infection Permissive Next Generation Influenza Vaccines May Affect Population Immunity and Viral Spread

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1779
Author(s):  
Maireid B. Bull ◽  
Carolyn A. Cohen ◽  
Nancy H.L. Leung ◽  
Sophie A. Valkenburg
Keyword(s):  
T Cell ◽  
Immune Escape ◽  
Viral Vector ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Unintended Effects ◽  
T Cell Epitopes ◽  
Next Generation ◽  
Viral Spread

Next generation influenza vaccines that target conserved epitopes are becoming a clinical reality but still have challenges to overcome. Universal next generation vaccines are considered a vital tool to combat future pandemic viruses and have the potential to vastly improve long-term protection against seasonal influenza viruses. Key vaccine strategies include HA-stem and T cell activating vaccines; however, they could have unintended effects for virus adaptation as they recognise the virus after cell entry and do not directly block infection. This may lead to immune pressure on residual viruses. The potential for immune escape is already evident, for both the HA stem and T cell epitopes, and mosaic approaches for pre-emptive immune priming may be needed to circumvent key variants. Live attenuated influenza vaccines have not been immunogenic enough to boost T cells in adults with established prior immunity. Therefore, viral vectors or peptide approaches are key to harnessing T cell responses. A plethora of viral vector vaccines and routes of administration may be needed for next generation vaccine strategies that require repeated long-term administration to overcome vector immunity and increase our arsenal against diverse influenza viruses.

scholarly journals Positive Selection in CD8+T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

2015 ◽  
Vol 89 (22) ◽  
pp. 11275-11283 ◽  
Author(s):  
Heather M. Machkovech ◽  
Trevor Bedford ◽  
Marc A. Suchard ◽  
Jesse D. Bloom
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Positive Selection ◽  
Swine Influenza ◽  
Selective Advantage ◽  
Influenza Viruses ◽  
T Cell Epitopes ◽  
Human Influenza ◽  
Human Influenza Virus

ABSTRACTNumerous experimental studies have demonstrated that CD8+T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+T cells. Here we use a novel computational approach to test for selection in CD8+T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.IMPORTANCEThere is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8+T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal models and are associated with decreased symptoms in humans, no studies have proven with statistical significance that influenza virus evolves under positive selection to escape T cells. Here we use comparisons of human and swine influenza viruses to rigorously demonstrate that human influenza virus evolves under pressure to fix mutations in the nucleoprotein that promote escape from T cells. We further show that viruses with these mutations have a selective advantage since they are preferentially located on the “trunk” of the phylogenetic tree. Overall, our results show that CD8+T cells targeting nucleoprotein play an important role in shaping influenza virus evolution.

scholarly journals Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

2018 ◽  
Author(s):  
Zheng-Rong Tiger Li ◽  
Veronika I. Zarnitsyna ◽  
Anice C. Lowen ◽  
Daniel Weissman ◽  
Katia Koelle ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cd8 T Cell ◽  
Influenza Vaccines ◽  
T Cell Epitopes ◽  
Word Count ◽  
Mhc I ◽  
Escape Variant ◽  
Replicative Fitness

AbstractThe high-degree conservation of CD8 T cell epitopes of influenza A virus (IAV) may allow T cell-inducing vaccines effective across different strains and subtypes. This conservation is not fully explained by functional constraint, since additional mutation(s) can compensate the replicative fitness loss of IAV escape-variant. Here, we propose three additional mechanisms that contribute to the conservation of CD8 T cell epitopes of IAV. First, influenza-specific CD8 T cells may protect predominantly against severe pathology rather than infection and may only have a modest effect on transmission. Second, polymorphism of human MHC-I gene restricts the advantage of an escape-variant to only a small fraction of human population, who carry the relevant MHC-I alleles. Finally, infection with CD8 T cell-escapevariants may result in compensatory increase in the responses to other epitopes of IAV. A combination of population genetics and epidemiological models is used to examine how the interplay between these mechanisms affects the rate of invasion of IAV escape-variants. We conclude that the invasion of an escape-variant will be very slow with a timescale of decades or longer, even if the escape-variant does not have a replicative fitness loss. Our results suggest T cell-inducing vaccines may not engender the rapid evolution of IAV and serve as a foundation for future modeling works on the long-term effectiveness and impacts of T cell-inducing influenza vaccines. (Word count: 221)ImportanceUniversal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear to which extent the T cell-inducing vaccines will select for viruses that escape the T cell responses. Our mathematical models suggest how the nature of CD8 T cell protection contributes to the conservation of the CD8 T cell epitopes of influenza A virus. Also, it points out the essential biological parameters and questions that need addressing by future experimental works. (Word count: 91)

scholarly journals Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

2019 ◽  
Vol 94 (7) ◽  
Author(s):  
Monique T. A. de Beijer ◽  
Diahann T. S. L. Jansen ◽  
Yingying Dou ◽  
Wim J. E. van Esch ◽  
Juk Yee Mok ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Viral Replication ◽  
Immune Escape ◽  
The Novel ◽  
T Cell Epitopes ◽  
Infected Population ◽  
B Virus ◽  
Hla Binding

ABSTRACT Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA supertypes prevalent in HBV-infected patients. Potential epitopes expected to be the least prone to immune escape were subjected to a state-of-the-art in vitro assay to validate their HLA-binding capacity. Using this method, a total of 13 HLA binders derived from HBx and 33 binders from Pol were identified across HLA types. Subsequently, we demonstrated interferon gamma (IFN-γ) production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively, these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design. IMPORTANCE Multiple HBV-derived T cell epitopes have been reported, which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets that are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for the development of globally effective HBV antigen-specific immunotherapies.

scholarly journals Long-Term Specific Immune Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine: Characterization of CD8+-T-Cell Epitopes Recognized

2003 ◽  
Vol 77 (20) ◽  
pp. 11220-11231 ◽  
Author(s):  
Hanne Gahéry-Ségard ◽  
Gilles Pialoux ◽  
Suzanne Figueiredo ◽  
Céline Igéa ◽  
Mathieu Surenaud ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We studied the effect of booster injections and the long-term immune response after injections of an anti-human immunodeficiency virus type 1 (HIV-1) lipopeptide vaccine. This vaccine was injected alone or with QS21 adjuvant to 28 HIV-uninfected volunteers. One month later, after a fourth injection of the vaccine, B- and T-cell anti-HIV responses were detected in >85% of the vaccinated volunteers. One year after this injection, a long-term immune response was observed in >50% of the volunteers. At this point, a positive QS21 effect was observed only in the sustained B-cell and CD4+-T-cell responses. To better characterize the CD8+-T-cell response, we used a gamma interferon enzyme-linked immunospot method and a bank of 59 HIV-1 epitopes. For the six most common HLA molecules (HLA-A2, -A3, -A11, -A24, -B7 superfamily, and -B8), an average of 10 (range, 3 to 15) HIV-1 epitopes were tested. CD8+-T-cell responses were evaluated according to the HLA class I molecules of the volunteers. Each assessment was based on 18 HIV-1 epitopes in average. We showed that 31 HIV-1 epitopes elicited specific CD8+-T-cell responses after vaccination. The most frequently recognized peptides were Nef 68-76 (-B7), Nef 71-79 (-B7), Nef 84-92 (-A11), Nef 135-143 (-B7), Nef 136-145 (-A2), Nef 137-145 (-A2), Gag 259-267 (-B8), Gag 260-268 (-A2), Gag 267-274 (-A2), Gag 267-277 (-B7), and Gag 276-283 (A24). We found that CD8+-T-cell epitopes were induced at a higher number after a fourth injection (P < 0.05 compared to three injections), which indicates an increase in the breadth of HIV CD8+-T-cell epitope recognition after the boost.

scholarly journals Immunogenicity of a Recombinant Influenza Virus Bearing Both the CD4+ and CD8+ T Cell Epitopes of Ovalbumin

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Bruno Garulli ◽  
Giuseppina Di Mario ◽  
Ester Sciaraffia ◽  
Yoshihiro Kawaoka ◽  
Maria R. Castrucci
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Influenza Viruses ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Additional Tool

Recombinant influenza viruses that bear the single immunodominant CD8+ T cell epitopeOVA257−264or the CD4+ T cell epitopeOVA323−339of the model antigen ovalbumin (OVA) have been useful tools in immunology. Here, we generated a recombinant influenza virus,WSN-OVAI/II, that bears both OVA-specific CD8+ and CD4+ epitopes on its hemagglutinin molecule. Live and heat-inactivatedWSN-OVAI/IIviruses were efficiently presented by dendritic cellsin vitroto OT-I TCR transgenic CD8+ T cells and OT-II TCR transgenic CD4+ T cells.In vivo,WSN-OVAI/IIvirus was attenuated in virulence, highly immunogenic, and protected mice from B16-OVA tumor challenge in a prophylactic model of vaccination. Thus,WSN-OVAI/IIvirus represents an additional tool, along with OVA TCR transgenic mice, for further studies on T cell responses and may be of value in vaccine design.

scholarly journals Frequency of Interferon-Resistance Conferring Substitutions in Amino Acid Positions 70 and 91 of Core Protein of the Russian HCV 1b Isolates Analyzed in the T-Cell Epitopic Context

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
V. S. Kichatova ◽  
K. K. Kyuregyan ◽  
N. V. Soboleva ◽  
A. A. Karlsen ◽  
O. V. Isaeva ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Immune Escape ◽  
Core Protein ◽  
Significant Proportion ◽  
In Silico Analysis ◽  
Hla Class I ◽  
T Cell Epitopes ◽  
Hla Class I Molecules ◽  
Negative Effect

Amino acid substitutions R70Q/H and L91M in HCV subtype 1b core protein can affect the response to interferon and are associated with the development of hepatocellular carcinoma. We found that the rate of R70Q/H in HCV 1b from Russia was 31.2%, similar to that in HCV strains from Asia (34.0%), higher than that in the European (18.0%, p=0.0010), but lower than that in the US HCV 1b strains (62.8%, p<0.0001). Substitution L91M was found in 80.4% of the Russian HCV 1b isolates, higher than in Asian isolates (43.8%, p<0.0001). Thus, a significant proportion of Russian HCV 1b isolates carry the unfavorable R70Q/H and/or L91M substitution. In silico analysis of the epitopic structure of the regions of substitutions revealed that both harbor clusters of T-cell epitopes. Peptides encompassing these regions were predicted to bind to a panel of HLA class I molecules, with substitutions impairing peptide recognition by HLA I molecules of the alleles prevalent in Russia. This indicates that HCV 1b with R70Q/H and L91M substitutions may have evolved as the immune escape variants. Impairment of T-cell recognition may play a part in the negative effect of these substitutions on the response to IFN treatment.

scholarly journals Sequential Immune Escape and Shifting of T Cell Responses in a Long-Term Survivor of Melanoma

2005 ◽  
Vol 174 (11) ◽  
pp. 6863-6871 ◽  
Author(s):  
Galina V. Yamshchikov ◽  
David W. Mullins ◽  
Chien-Chung Chang ◽  
Takeshi Ogino ◽  
Lee Thompson ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Escape ◽  
T Cell Responses ◽  
Cell Responses ◽  
Term Survivor

scholarly journals Dry-Coated Live Viral Vector Vaccines Delivered by Nanopatch Microprojections Retain Long-Term Thermostability and Induce Transgene-Specific T Cell Responses in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e67888 ◽  
Author(s):  
Frances E. Pearson ◽  
Celia L. McNeilly ◽  
Michael L. Crichton ◽  
Clare A. Primiero ◽  
Sally R. Yukiko ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Vector ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals Increased Protein Degradation Improves Influenza Virus Nucleoprotein-Specific CD8+T Cell ActivationIn Vitrobut Not in C57BL/6 Mice

2016 ◽  
Vol 90 (22) ◽  
pp. 10209-10219 ◽  
Author(s):  
Arwen F. Altenburg ◽  
Carolien E. van de Sandt ◽  
Stella E. van Trierum ◽  
Heidi L. M. De Gruyter ◽  
Peter R. W. A. van Run ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Influenza A ◽  
T Cell Responses ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara

ABSTRACTDue to antigenic drift of influenza viruses, seasonal influenza vaccines need to be updated annually. These vaccines are based on predictions of strains likely to circulate in the next season. However, vaccine efficacy is greatly reduced in the case of a mismatch between circulating and vaccine strains. Furthermore, novel antigenically distinct influenza viruses are introduced into the human population from animal reservoirs occasionally and may cause pandemic outbreaks. To dampen the impact of seasonal and pandemic influenza, vaccines that induce broadly protective and long-lasting immunity are preferred. Because influenza virus-specific CD8+T cells are directed mainly against relatively conserved internal proteins, like nucleoprotein (NP), they are highly cross-reactive and afford protection against infection with antigenically distinct influenza virus strains, so-called heterosubtypic immunity. Here, we used modified vaccinia virus Ankara (MVA) as a vaccine vector for the induction of influenza virus NP-specific CD8+T cells. To optimize the induction of CD8+T cell responses, we made several modifications to NP, aiming at retaining the protein in the cytosol or targeting it to the proteasome. We hypothesized that these strategies would increase antigen processing and presentation and thus improve the induction of CD8+T cell responses. We showed that NP with increased degradation rates improved CD8+T cell activationin vitroif the amount of antigen was limited or if CD8+T cells were of low functional avidity. However, after immunization of C57BL/6 mice, no differences were detected between modified NP and wild-type NP (NPwt), since NPwt already induced optimal CD8+T cell responses.IMPORTANCEDue to the continuous antigenic drift of seasonal influenza viruses and the threat of a novel pandemic, there is a great need for the development of novel influenza vaccines that offer broadly protective immunity against multiple subtypes. CD8+T cells can provide immunity against multiple subtypes of influenza viruses by the recognition of relatively conserved internal antigens. In this study, we aimed at optimizing the CD8+T cell response to influenza A virus by making modifications to influenza A virus nucleoprotein (NP) expressed from the modified vaccinia virus Ankara (MVA) vaccine vector. These modifications resulted in increased antigen degradation, thereby producing elevated levels of peptides that can be presented on major histocompatibility complex (MHC) class I molecules to CD8+T cells. Although we were unable to increase the NP-specific immune response in the mouse strain used, this approach may have benefits for vaccine development using less-immunogenic proteins.

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