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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 59230

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Special Issue Editors

Dr. Marios Koutsakos

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Guest Editor

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia
Interests: influenza viruses; viral vaccines; adaptive immunity to viruses

Dr. Sophie Valkenburg

E-Mail Website1 Website2
Guest Editor

Division of Public Health Laboratory Sciences, HKU Pasteur Research Pole, Hong Kong, China
Interests: influenza; T cells; antibody; COVID19

Special Issue Information

Dear Colleagues,

Influenza viruses remain a constant global threat with a significant health and socioeconomic impact every year, and have the potential to cause devastating pandemics. Despite this, current vaccines against influenza viruses are only modestly effective, require annual reformulation, and may not provide protection against emerging influenza viruses from animal reservoirs. Therefore, new vaccines are needed to combat influenza viruses.

The design of such vaccines requires a thorough understanding of the immune response to influenza viruses, and of the host–pathogen interactions that determine immune disease versus immune protection. Therefore, the aim of this Special Issue on “Immunity to Influenza Viruses” is to explore the immune response to influenza A and B viruses from humans and animals. Original research and comprehensive review articles presenting recent progress, challenges, and future perspectives in influenza immunity and vaccines are invited. These may cover influenza virus–host interactions, innate immunity to influenza viruses, antiviral restriction, immune evasion mechanisms, antibody and B-cell responses to influenza viruses, T-cell-mediated immune responses to influenza viruses and vaccines against influenza viruses, as well as immune responses and vaccines in high-risk groups.

Dr. Marios Koutsakos
Dr. Sophie Valkenburg
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

influenza viruses
innate immunity
adaptive immunity
vaccines
virus–host interaction

Published Papers (13 papers)

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Editorial

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2 pages, 161 KiB

Open AccessEditorial

Special Issue—Immunity to Influenza Viruses

by Marios Koutsakos and Sophie A. Valkenburg

Viruses 2022, 14(2), 319; https://doi.org/10.3390/v14020319 - 3 Feb 2022

Viewed by 1663

Abstract

Influenza viruses remain a constant global threat with significant health and socioeconomic impact every year and have the potential to cause devastating pandemics [...] Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

Research

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18 pages, 3959 KiB

Open AccessArticle

Protective Efficacy of Recombinant Influenza Hemagglutinin Ectodomain Fusions

by Nidhi Mittal, Nayanika Sengupta, Sameer Kumar Malladi, Poorvi Reddy, Madhuraj Bhat, Raju S. Rajmani, Koen Sedeyn, Xavier Saelens, Somnath Dutta and Raghavan Varadarajan

Viruses 2021, 13(9), 1710; https://doi.org/10.3390/v13091710 - 27 Aug 2021

Cited by 2 | Viewed by 4446

Abstract

In current seasonal influenza vaccines, neutralizing antibody titers directed against the hemagglutinin surface protein are the primary correlate of protection. These vaccines are, therefore, quantitated in terms of their hemagglutinin content. Adding other influenza surface proteins, such as neuraminidase and M2e, to current quadrivalent influenza vaccines would likely enhance vaccine efficacy. However, this would come with increased manufacturing complexity and cost. To address this issue, as a proof of principle, we have designed genetic fusions of hemagglutinin ectodomains from H3 and H1 influenza A subtypes. These recombinant H1-H3 hemagglutinin ectodomain fusions could be transiently expressed at high yield in mammalian cell culture using Expi293F suspension cells. Fusions were trimeric, and as stable in solution as their individual trimeric counterparts. Furthermore, the H1-H3 fusion constructs were antigenically intact based on their reactivity with a set of conformation-specific monoclonal antibodies. H1-H3 hemagglutinin ectodomain fusion immunogens, when formulated with the MF59 equivalent adjuvant squalene-in-water emulsion (SWE), induced H1 and H3-specific humoral immune responses equivalent to those induced with an equimolar mixture of individually expressed H1 and H3 ectodomains. Mice immunized with these ectodomain fusions were protected against challenge with heterologous H1N1 (Bel/09) and H3N2 (X-31) mouse-adapted viruses with higher neutralizing antibody titers against the H1N1 virus. Use of such ectodomain-fused immunogens would reduce the number of components in a vaccine formulation and allow for the inclusion of other protective antigens to increase influenza vaccine efficacy. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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18 pages, 2858 KiB

Open AccessArticle

Influenza Antigens NP and M2 Confer Cross Protection to BALB/c Mice against Lethal Challenge with H1N1, Pandemic H1N1 or H5N1 Influenza A Viruses

by Nutan Mytle, Sonja Leyrer, Jon R. Inglefield, Andrea M. Harris, Thomas E. Hickey, Jacob Minang, Hang Lu, Zhidong Ma, Hanné Andersen, Nathan D. Grubaugh, Tina Guina, Mario H. Skiadopoulos and Michael J. Lacy

Viruses 2021, 13(9), 1708; https://doi.org/10.3390/v13091708 - 27 Aug 2021

Cited by 9 | Viewed by 3047

Abstract

Influenza hemagglutinin (HA) is considered a major protective antigen of seasonal influenza vaccine but antigenic drift of HA necessitates annual immunizations using new circulating HA versions. Low variation found within conserved non-HA influenza virus (INFV) antigens may maintain protection with less frequent immunizations. Conserved antigens of influenza A virus (INFV A) that can generate cross protection against multiple INFV strains were evaluated in BALB/c mice using modified Vaccinia virus Ankara (MVA)-vectored vaccines that expressed INFV A antigens hemagglutinin (HA), matrix protein 1 (M1), nucleoprotein (NP), matrix protein 2 (M2), repeats of the external portion of M2 (M2e) or as tandem repeats (METR), and M2e with transmembrane region and cytoplasmic loop (M2eTML). Protection by combinations of non-HA antigens was equivalent to that of subtype-matched HA. Combinations of NP and forms of M2e generated serum antibody responses and protected mice against lethal INFV A challenge using PR8, pandemic H1N1 A/Mexico/4108/2009 (pH1N1) or H5N1 A/Vietnam/1203/2004 (H5N1) viruses, as demonstrated by reduced lung viral burden and protection against weight loss. The highest levels of protection were obtained with NP and M2e antigens delivered as MVA inserts, resulting in broadly protective immunity in mice and enhancement of previous natural immunity to INFV A. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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9 pages, 656 KiB

Open AccessArticle

Changes in Cell-Mediated Immunity (IFN-γ and Granzyme B) Following Influenza Vaccination

by Naruhito Otani, Kazuhiko Nakajima, Kaori Ishikawa, Kaoru Ichiki, Takashi Ueda, Yoshio Takesue, Takuma Yamamoto, Susumu Tanimura, Masayuki Shima and Toshiomi Okuno

Viruses 2021, 13(6), 1137; https://doi.org/10.3390/v13061137 - 13 Jun 2021

Cited by 11 | Viewed by 2602

Abstract

Interferon gamma (IFN-γ) is considered a key moderator of cell-mediated immunity. However, little is known about its association with granzyme B, which plays an important role in the effector function of cytotoxic T lymphocytes (CTLs). In the present study, we collected blood samples from 32 healthy adults before and after vaccination with inactivated influenza vaccine in 2017/18 to measure the levels of IFN-γ and granzyme B, which play roles in cell-mediated immunity, and hemagglutination inhibition (HAI) antibody, which plays a role in humoral immunity. The levels of IFN-γ and granzyme B were significantly correlated both before and after vaccination. Furthermore, the post-vaccine fold increases in the IFN-γ and granzyme B levels were significantly correlated. The levels of IFN-γ and granzyme B decreased five months after vaccination in more than half of the subjects who exhibited an increase in IFN-γ and granzyme B at two weeks post-vaccination. This is the first study to investigate the correlation between IFN-γ and granzyme B levels following influenza vaccination. Our study suggests that both IFN-γ and granzyme B can be used as markers of cell-mediated immunity. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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16 pages, 4654 KiB

Open AccessArticle

Establishing a Multicolor Flow Cytometry to Characterize Cellular Immune Response in Chickens Following H7N9 Avian Influenza Virus Infection

by Xiaoli Hao, Shuai Li, Lina Chen, Maoli Dong, Jiongjiong Wang, Jiao Hu, Min Gu, Xiaoquan Wang, Shunlin Hu, Daxin Peng, Xiufan Liu and Shaobin Shang

Viruses 2020, 12(12), 1396; https://doi.org/10.3390/v12121396 - 6 Dec 2020

Cited by 17 | Viewed by 3662

Abstract

Avian influenza virus (AIV) emerged and has continued to re-emerge, continuously posing great threats to animal and human health. The detection of hemagglutination inhibition (HI) or virus neutralization antibodies (NA) is essential for assessing immune protection against AIV. However, the HI/NA-independent immune protection is constantly observed in vaccines’ development against H7N9 subtype AIV and other subtypes in chickens and mammals, necessitating the analysis of the cellular immune response. Here, we established a multi-parameter flow cytometry to examine the innate and adaptive cellular immune responses in chickens after intranasal infection with low pathogenicity H7N9 AIV. This assay allowed us to comprehensively define chicken macrophages, dendritic cells, and their MHC-II expression, NK cells, γδ T cells, B cells, and distinct T cell subsets in steady state and during infection. We found that NK cells and KUL01⁺ cells significantly increased after H7N9 infection, especially in the lung, and the KUL01⁺ cells upregulated MHC-II and CD11c expression. Additionally, the percentages and numbers of γδ T cells and CD8 T cells significantly increased and exhibited an activated phenotype with significant upregulation of CD25 expression in the lung but not in the spleen and blood. Furthermore, B cells showed increased in the lung but decreased in the blood and spleen in terms of the percentages or/and numbers, suggesting these cells may be recruited from the periphery after H7N9 infection. Our study firstly disclosed that H7N9 infection induced local and systemic cellular immune responses in chickens, the natural host of AIV, and that the flow cytometric assay developed in this study is useful for analyzing the cellular immune responses to AIVs and other avian infectious diseases and defining the correlates of immune protection. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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Review

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13 pages, 874 KiB

Open AccessReview

Innate Immune Responses to Influenza Virus Infections in the Upper Respiratory Tract

by Edin J. Mifsud, Miku Kuba and Ian G. Barr

Viruses 2021, 13(10), 2090; https://doi.org/10.3390/v13102090 - 17 Oct 2021

Cited by 31 | Viewed by 9377

Abstract

The innate immune system is the host’s first line of immune defence against any invading pathogen. To establish an infection in a human host the influenza virus must replicate in epithelial cells of the upper respiratory tract. However, there are several innate immune mechanisms in place to stop the virus from reaching epithelial cells. In addition to limiting viral replication and dissemination, the innate immune system also activates the adaptive immune system leading to viral clearance, enabling the respiratory system to return to normal homeostasis. However, an overzealous innate immune system or adaptive immune response can be associated with immunopathology and aid secondary bacterial infections of the lower respiratory tract leading to pneumonia. In this review, we discuss the mechanisms utilised by the innate immune system to limit influenza virus replication and the damage caused by influenza viruses on the respiratory tissues and how these very same protective immune responses can cause immunopathology. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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18 pages, 826 KiB

Open AccessReview

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

by Maireid B. Bull, Carolyn A. Cohen, Nancy H.L. Leung and Sophie A. Valkenburg

Viruses 2021, 13(9), 1779; https://doi.org/10.3390/v13091779 - 6 Sep 2021

Cited by 5 | Viewed by 3766

Abstract

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. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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25 pages, 867 KiB

Open AccessReview

Antibody Responsiveness to Influenza: What Drives It?

by Xia Lin, Fangmei Lin, Tingting Liang, Mariette F. Ducatez, Mark Zanin and Sook-San Wong

Viruses 2021, 13(7), 1400; https://doi.org/10.3390/v13071400 - 19 Jul 2021

Cited by 5 | Viewed by 2974

Abstract

The induction of a specific antibody response has long been accepted as a serological hallmark of recent infection or antigen exposure. Much of our understanding of the influenza antibody response has been derived from studying antibodies that target the hemagglutinin (HA) protein. However, growing evidence points to limitations associated with this approach. In this review, we aim to highlight the issue of antibody non-responsiveness after influenza virus infection and vaccination. We will then provide an overview of the major factors known to influence antibody responsiveness to influenza after infection and vaccination. We discuss the biological factors such as age, sex, influence of prior immunity, genetics, and some chronic infections that may affect the induction of influenza antibody responses. We also discuss the technical factors, such as assay choices, strain variations, and viral properties that may influence the sensitivity of the assays used to measure influenza antibodies. Understanding these factors will hopefully provide a more comprehensive picture of what influenza immunogenicity and protection means, which will be important in our effort to improve influenza vaccines. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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16 pages, 271 KiB

Open AccessReview

Selecting and Using the Appropriate Influenza Vaccine for Each Individual

by Toshiki Sekiya, Marumi Ohno, Naoki Nomura, Chimuka Handabile, Masashi Shingai, David C. Jackson, Lorena E. Brown and Hiroshi Kida

Viruses 2021, 13(6), 971; https://doi.org/10.3390/v13060971 - 24 May 2021

Cited by 15 | Viewed by 4292

Abstract

Despite seasonal influenza vaccines having been routinely used for many decades, influenza A virus continues to pose a global threat to humans, causing high morbidity and mortality each year. The effectiveness of the vaccine is largely dependent on how well matched the vaccine strains are with the circulating influenza virus strains. Furthermore, low vaccine efficacy in naïve populations such as young children, or in the elderly, who possess weakened immune systems, indicates that influenza vaccines need to be more personalized to provide broader community protection. Advances in both vaccine technologies and our understanding of influenza virus infection and immunity have led to the design of a variety of alternate vaccine strategies to extend population protection against influenza, some of which are now in use. In this review, we summarize the progress in the field of influenza vaccines, including the advantages and disadvantages of different strategies, and discuss future prospects. We also highlight some of the challenges to be faced in the ongoing effort to control influenza through vaccination. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

24 pages, 3852 KiB

Open AccessReview

B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat

by Jenna J. Guthmiller, Henry A. Utset and Patrick C. Wilson

Viruses 2021, 13(6), 965; https://doi.org/10.3390/v13060965 - 22 May 2021

Cited by 28 | Viewed by 5649

Abstract

Antibodies are critical for providing protection against influenza virus infections. However, protective humoral immunity against influenza viruses is limited by the antigenic drift and shift of the major surface glycoproteins, hemagglutinin and neuraminidase. Importantly, people are exposed to influenza viruses throughout their life and tend to reuse memory B cells from prior exposure to generate antibodies against new variants. Despite this, people tend to recall memory B cells against constantly evolving variable epitopes or non-protective antigens, as opposed to recalling them against broadly neutralizing epitopes of hemagglutinin. In this review, we discuss the factors that impact the generation and recall of memory B cells against distinct viral antigens, as well as the immunological limitations preventing broadly neutralizing antibody responses. Lastly, we discuss how next-generation vaccine platforms can potentially overcome these obstacles to generate robust and long-lived protection against influenza A viruses. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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9 pages, 209 KiB

Open AccessReview

Systems Immunology: Revealing Influenza Immunological Imprint

by Adriana Tomic, Andrew J. Pollard and Mark M. Davis

Viruses 2021, 13(5), 948; https://doi.org/10.3390/v13050948 - 20 May 2021

Cited by 7 | Viewed by 4075

Abstract

Understanding protective influenza immunity and identifying immune correlates of protection poses a major challenge and requires an appreciation of the immune system in all of its complexity. While adaptive immune responses such as neutralizing antibodies and influenza-specific T lymphocytes are contributing to the control of influenza virus, key factors of long-term protection are not well defined. Using systems immunology, an approach that combines experimental and computational methods, we can capture the systems-level state of protective immunity and reveal the essential pathways that are involved. New approaches and technological developments in systems immunology offer an opportunity to examine roles and interrelationships of clinical, biological, and genetic factors in the control of influenza infection and have the potential to lead to novel discoveries about influenza immunity that are essential for the development of more effective vaccines to prevent future pandemics. Here, we review recent developments in systems immunology that help to reveal key factors mediating protective immunity. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

19 pages, 380 KiB

Open AccessReview

T Cell Immunity against Influenza: The Long Way from Animal Models Towards a Real-Life Universal Flu Vaccine

by Anna Schmidt and Dennis Lapuente

Viruses 2021, 13(2), 199; https://doi.org/10.3390/v13020199 - 28 Jan 2021

Cited by 20 | Viewed by 5248

Abstract

Current flu vaccines rely on the induction of strain-specific neutralizing antibodies, which leaves the population vulnerable to drifted seasonal or newly emerged pandemic strains. Therefore, universal flu vaccine approaches that induce broad immunity against conserved parts of influenza have top priority in research. Cross-reactive T cell responses, especially tissue-resident memory T cells in the respiratory tract, provide efficient heterologous immunity, and must therefore be a key component of universal flu vaccines. Here, we review recent findings about T cell-based flu immunity, with an emphasis on tissue-resident memory T cells in the respiratory tract of humans and different animal models. Furthermore, we provide an update on preclinical and clinical studies evaluating T cell-evoking flu vaccines, and discuss the implementation of T cell immunity in real-life vaccine policies. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

20 pages, 1065 KiB

Open AccessReview

Emerging Role of Mucosal Vaccine in Preventing Infection with Avian Influenza A Viruses

by Tong Wang, Fanhua Wei and Jinhua Liu

Viruses 2020, 12(8), 862; https://doi.org/10.3390/v12080862 - 7 Aug 2020

Cited by 21 | Viewed by 6397

Abstract

Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans. Full article

(This article belongs to the Special Issue Immunity to Influenza Viruses)

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