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Vaccines
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Immune Responses to Influenza Virus Antigens
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Immune Responses to Influenza Virus Antigens

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Influenza Virus Vaccines".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 65680

Special Issue Editor

Dr. Lynda Coughlan

E-Mail Website
Guest Editor
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Interests: influenza vaccines; adenoviral vectors; vaccines; respiratory pathogens; extracellular vesicles

Special Issue Information

Dear Colleagues,

The successful development of a universal influenza virus vaccine, which provides broad and durable protection, is a long-standing goal in the field. In addition to selecting optimized immunogens, achieving this will require in-depth understanding of the mechanisms which determine long-lived immunity. The identification of vaccine platforms capable of eliciting cross-reactive and protective immune responses, as well detailed knowledge of the relative contribution of both cellular and humoral immune responses, will be required.

The sub-optimal performance of traditional influenza vaccines has paved the way for the development of next-generation universal influenza virus vaccines using structurally stabilized or chimeric antigens, in the form of recombinant protein, viral vectors or nanoparticle-based platforms. In addition to this, the use of adjuvants has been employed in an effort to increase the breadth or durability of cross-reactive immunity.

In this special issue, we encourage the submission of articles which present advances in our understanding of human immune responses to natural infection or immunization, studies which evaluate the immunogenicity and efficacy of novel universal influenza vaccines in animals or in clinical trials, as well as efforts to increase our understanding of the longevity of immunity directed towards cross-reactive epitopes.

Dr. Lynda Coughlan
Guest Editor

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. Vaccines 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 2700 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
  • virus
  • vaccine
  • universal vaccine
  • immunogenicity
  • immune response

Published Papers (15 papers)

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Research

Jump to: Review

19 pages, 3939 KiB  
Article
Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection
by Ying Huang, Monique S. França, James D. Allen, Hua Shi and Ted M. Ross
Vaccines 2021, 9(7), 793; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070793 - 16 Jul 2021
Cited by 21 | Viewed by 3247
Abstract
Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally [...] Read more.
Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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26 pages, 3442 KiB  
Article
Exploiting Pan Influenza A and Pan Influenza B Pseudotype Libraries for Efficient Vaccine Antigen Selection
by Joanne Marie M. Del Rosario, Kelly A. S. da Costa, Benedikt Asbach, Francesca Ferrara, Matteo Ferrari, David A. Wells, Gurdip Singh Mann, Veronica O. Ameh, Claude T. Sabeta, Ashley C. Banyard, Rebecca Kinsley, Simon D. Scott, Ralf Wagner, Jonathan L. Heeney, George W. Carnell and Nigel J. Temperton
Vaccines 2021, 9(7), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070741 - 05 Jul 2021
Cited by 6 | Viewed by 4653
Abstract
We developed an influenza hemagglutinin (HA) pseudotype library encompassing Influenza A subtypes HA1-18 and Influenza B subtypes (both lineages) to be employed in influenza pseudotype microneutralization (pMN) assays. The pMN is highly sensitive and specific for detecting virus-specific neutralizing antibodies against influenza viruses [...] Read more.
We developed an influenza hemagglutinin (HA) pseudotype library encompassing Influenza A subtypes HA1-18 and Influenza B subtypes (both lineages) to be employed in influenza pseudotype microneutralization (pMN) assays. The pMN is highly sensitive and specific for detecting virus-specific neutralizing antibodies against influenza viruses and can be used to assess antibody functionality in vitro. Here we show the production of these viral HA pseudotypes and their employment as substitutes for wildtype viruses in influenza neutralization assays. We demonstrate their utility in detecting serum responses to vaccination with the ability to evaluate cross-subtype neutralizing responses elicited by specific vaccinating antigens. Our findings may inform further preclinical studies involving immunization dosing regimens in mice and may help in the creation and selection of better antigens for vaccine design. These HA pseudotypes can be harnessed to meet strategic objectives that contribute to the strengthening of global influenza surveillance, expansion of seasonal influenza prevention and control policies, and strengthening pandemic preparedness and response. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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16 pages, 1535 KiB  
Article
Influenza A Virus Hemagglutinin Trimer, Head and Stem Proteins Identify and Quantify Different Hemagglutinin-Specific B Cell Subsets in Humans
by Aafke Aartse, Dirk Eggink, Mathieu Claireaux, Sarah van Leeuwen, Petra Mooij, Willy M. Bogers, Rogier W. Sanders, Gerrit Koopman and Marit J. van Gils
Vaccines 2021, 9(7), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070717 - 02 Jul 2021
Cited by 10 | Viewed by 3336
Abstract
Antibody responses against the influenza A virus hemagglutinin (HA)-protein are studied intensively because they can protect against (re)infection. Previous studies have focused on antibodies targeting the head or stem domains, while other possible specificities are often not taken into account. To study such [...] Read more.
Antibody responses against the influenza A virus hemagglutinin (HA)-protein are studied intensively because they can protect against (re)infection. Previous studies have focused on antibodies targeting the head or stem domains, while other possible specificities are often not taken into account. To study such specificities, we developed a diverse set of HA-domain proteins based on an H1N1pdm2009-like influenza virus strain, including monomeric head and trimeric stem domain, as well as the full HA-trimer. These proteins were used to study the B cell and antibody responses in six healthy human donors. A large proportion of HA-trimer B cells bound exclusively to HA-trimer probe (54–77%), while only 8–18% and 9–23% were able to recognize the stem or head probe, respectively. Monoclonal antibodies (mAbs) were isolated and three of these mAbs, targeting the different domains, were characterized in-depth to confirm the binding profile observed in flow cytometry. The head-directed mAb, targeting an epitope distinct from known head-specific mAbs, showed relatively broad H1N1 neutralization and the stem-directed mAb was able to broadly neutralize diverse H1N1 viruses. Moreover, we identified a trimer-directed mAb that did not compete with known head or stem domain specific mAbs, suggesting that it targets an unknown epitope or conformation of influenza virus’ HA. These observations indicate that the described method can characterize the diverse antibody response to HA and might be able to identify HA-specific B cells and antibodies with previously unknown specificities that could be relevant for vaccine design. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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10 pages, 5352 KiB  
Article
Development of a Macrophage-Based ADCC Assay
by Melissa B. Uccellini, Sadaf Aslam, Sean T. H. Liu, Fahmida Alam and Adolfo García-Sastre
Vaccines 2021, 9(6), 660; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060660 - 17 Jun 2021
Cited by 7 | Viewed by 3661
Abstract
Fc-dependent effector functions are an important determinant of the in vivo potency of therapeutic antibodies. Effector function is determined by the combination of FcRs bound by the antibody and the cell expressing the relevant FcRs, leading to antibody-dependent cellular cytotoxicity (ADCC). A number [...] Read more.
Fc-dependent effector functions are an important determinant of the in vivo potency of therapeutic antibodies. Effector function is determined by the combination of FcRs bound by the antibody and the cell expressing the relevant FcRs, leading to antibody-dependent cellular cytotoxicity (ADCC). A number of ADCC assays have been developed; however, they suffer from limitations in terms of throughput, reproducibility, and in vivo relevance. Existing assays measure NK cell-mediated ADCC activity; however, studies suggest that macrophages mediate the effector function of many antibodies in vivo. Here, we report the development of a macrophage-based ADCC assay that relies on luciferase expression in target cells as a measure of live cell number. In the presence of primary mouse macrophages and specific antibodies, loss of luciferase signal serves as a surrogate for ADCC-dependent killing. We show that the assay functions for a variety of mouse and human isotypes with a model antigen/antibody complex in agreement with the known effector function of the isotypes. We also use this assay to measure the activity of a number of influenza-specific antibodies and show that the assay correlates well with the known in vivo effector functions of these antibodies. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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13 pages, 3722 KiB  
Article
Introduction of Cysteines in the Stalk Domain of Recombinant Influenza Virus N1 Neuraminidase Enhances Protein Stability and Immunogenicity in Mice
by Shirin Strohmeier, Juan Manuel Carreño, Ruhi Nichalle Brito and Florian Krammer
Vaccines 2021, 9(4), 404; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9040404 - 19 Apr 2021
Cited by 10 | Viewed by 3424
Abstract
Influenza virus surface glycoproteins represent the main targets of the immune system during infection and vaccination. Current influenza virus vaccines rely mostly on the hemagglutinin, requiring a close match between the vaccine and circulating strains. Recently, the neuraminidase (NA) has become an attractive [...] Read more.
Influenza virus surface glycoproteins represent the main targets of the immune system during infection and vaccination. Current influenza virus vaccines rely mostly on the hemagglutinin, requiring a close match between the vaccine and circulating strains. Recently, the neuraminidase (NA) has become an attractive target; however low immunogenicity and stability in vaccine preparations remain an obstacles. Here, we took advantage of the hypervariable stalk domain of the NA to introduce cysteines at different positions and to produce more stable multimeric forms of the protein. We generated 11 N1 constructs and characterized the proteins by performing sodium dodecyl sulfate polyacrylamide gel electrophoresis and by testing their enzymatic activity and representation of antigenic epitopes. Moreover, we evaluated their potential to induce a protective immune response in vivo and characterized the polyclonal antibody responses of immunized mice. We observed that the introduction of cysteines at certain positions led to the formation of stable N1 dimers, which are capable of inducing a strong antibody response characterized by neuraminidase inhibiting activity and protection of mice from high dose viral challenge. Overall, our results provide evidence for the feasibility of introducing stalk modifications to enhance the stability and immunogenicity of NA-based recombinant antigens. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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15 pages, 3252 KiB  
Article
Comparison of Immunogenicity and Safety between a Single Dose and One Booster Trivalent Inactivated Influenza Vaccination in Patients with Chronic Kidney Disease: A 20-Week, Open-Label Trial
by Yu-Tzu Chang, Tsai-Chieh Ling, Ya-Yun Cheng, Chien-Yao Sun, Jia-Ling Wu, Ching Hui Tai, Jen-Ren Wang and Junne-Ming Sung
Vaccines 2021, 9(3), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9030192 - 25 Feb 2021
Cited by 5 | Viewed by 3062
Abstract
Background: Non-dialysis-dependent chronic kidney disease (CKD-ND) patients are recommended to receive a one-dose influenza vaccination annually. However, studies investigating vaccine efficacy in the CKD-ND population are still lacking. In this study, we aimed to evaluate vaccine efficacy between the one-dose and two-dose regimen [...] Read more.
Background: Non-dialysis-dependent chronic kidney disease (CKD-ND) patients are recommended to receive a one-dose influenza vaccination annually. However, studies investigating vaccine efficacy in the CKD-ND population are still lacking. In this study, we aimed to evaluate vaccine efficacy between the one-dose and two-dose regimen and among patients with different stages of CKD throughout a 20-week follow-up period. Methods: We conducted a single-center, non-randomized, open-label, controlled trial among patients with all stages of CKD-ND. Subjects were classified as unvaccinated, one-dose, and two-dose groups (4 weeks apart) after enrollment. Serial changes in immunological parameters (0, 4, 8, and 20 weeks after enrollment), including seroprotection, geometric mean titer (GMT), GMT fold-increase, seroconversion, and seroresponse, were applied to evaluate vaccine efficacy. Results: There were 43, 84, and 71 patients in the unvaccinated, one-dose, and two-dose vaccination groups, respectively. At 4–8 weeks after vaccination, seroprotection rates in the one- and two-dose group for H1N1, H3N2, and B ranged from 82.6–95.8%, 97.4–100%, and 73.9–100%, respectively. The concomitant seroconversion and GMT fold-increases nearly met the suggested criteria for vaccine efficacy for the elderly population. Although the seroprotection rates for all of the groups were adequate, the seroconversion and GMT fold-increase at 20 weeks after vaccination did not meet the criteria for vaccine efficacy. The two-dose regimen had a higher probability of achieving seroprotection for B strains (Odds ratio: 3.5, 95% confidence interval (1.30–9.40)). No significant differences in vaccine efficacy were found between early (stage 1–3) and late (stage 4–5) stage CKD. Conclusions: The standard one-dose vaccination can elicit sufficient protective antibodies. The two-dose regimen induced a better immune response when the baseline serum antibody titer was low. Monitoring change in antibody titers for a longer duration is warranted to further determine the current vaccine strategy in CKD-ND population. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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18 pages, 3964 KiB  
Article
Development and Assessment of a Pooled Serum as Candidate Standard to Measure Influenza A Virus Group 1 Hemagglutinin Stalk-Reactive Antibodies
by Juan Manuel Carreño, Jacqueline U. McDonald, Tara Hurst, Peter Rigsby, Eleanor Atkinson, Lethia Charles, Raffael Nachbagauer, Mohammad Amin Behzadi, Shirin Strohmeier, Lynda Coughlan, Teresa Aydillo, Boerries Brandenburg, Adolfo García-Sastre, Krisztian Kaszas, Min Z. Levine, Alessandro Manenti, Adrian B. McDermott, Emanuele Montomoli, Leacky Muchene, Sandeep R. Narpala, Ranawaka A. P. M. Perera, Nadine C. Salisch, Sophie A. Valkenburg, Fan Zhou, Othmar G. Engelhardt and Florian Krammeradd Show full author list remove Hide full author list
Vaccines 2020, 8(4), 666; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines8040666 - 09 Nov 2020
Cited by 5 | Viewed by 6180
Abstract
The stalk domain of the hemagglutinin has been identified as a target for induction of protective antibody responses due to its high degree of conservation among numerous influenza subtypes and strains. However, current assays to measure stalk-based immunity are not standardized. Hence, harmonization [...] Read more.
The stalk domain of the hemagglutinin has been identified as a target for induction of protective antibody responses due to its high degree of conservation among numerous influenza subtypes and strains. However, current assays to measure stalk-based immunity are not standardized. Hence, harmonization of assay readouts would help to compare experiments conducted in different laboratories and increase confidence in results. Here, serum samples from healthy individuals (n = 110) were screened using a chimeric cH6/1 hemagglutinin enzyme-linked immunosorbent assay (ELISA) that measures stalk-reactive antibodies. We identified samples with moderate to high IgG anti-stalk antibody levels. Likewise, screening of the samples using the mini-hemagglutinin (HA) headless construct #4900 and analysis of the correlation between the two assays confirmed the presence and specificity of anti-stalk antibodies. Additionally, samples were characterized by a cH6/1N5 virus-based neutralization assay, an antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and competition ELISAs, using the stalk-reactive monoclonal antibodies KB2 (mouse) and CR9114 (human). A “pooled serum” (PS) consisting of a mixture of selected serum samples was generated. The PS exhibited high levels of stalk-reactive antibodies, had a cH6/1N5-based neutralization titer of 320, and contained high levels of stalk-specific antibodies with ADCC activity. The PS, along with blinded samples of varying anti-stalk antibody titers, was distributed to multiple collaborators worldwide in a pilot collaborative study. The samples were subjected to different assays available in the different laboratories, to measure either binding or functional properties of the stalk-reactive antibodies contained in the serum. Results from binding and neutralization assays were analyzed to determine whether use of the PS as a standard could lead to better agreement between laboratories. The work presented here points the way towards the development of a serum standard for antibodies to the HA stalk domain of phylogenetic group 1. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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11 pages, 1791 KiB  
Article
Serologically-Based Evaluation of Cross-Protection Antibody Responses among Different A(H1N1) Influenza Strains
by Serena Marchi, Ilaria Manini, Otfried Kistner, Pietro Piu, Edmond J. Remarque, Alessandro Manenti, Fabrizio Biuso, Tommaso Carli, Giacomo Lazzeri, Emanuele Montomoli and Claudia Maria Trombetta
Vaccines 2020, 8(4), 656; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines8040656 - 05 Nov 2020
Cited by 4 | Viewed by 1841
Abstract
After the influenza H1N1 pandemic of 2009, the seasonal A/Brisbane/59/2007 strain was replaced by the A/California/07/2009 strain for the influenza virus vaccine composition. After several seasons with no indications on the occurrence of antigenic drift, A/Michigan/45/2015 was chosen as the H1N1 vaccine strain [...] Read more.
After the influenza H1N1 pandemic of 2009, the seasonal A/Brisbane/59/2007 strain was replaced by the A/California/07/2009 strain for the influenza virus vaccine composition. After several seasons with no indications on the occurrence of antigenic drift, A/Michigan/45/2015 was chosen as the H1N1 vaccine strain for the 2017/2018 season. Since the immune response to influenza is shaped by the history of exposure to antigenically similar strains, the potential cross-protection between seasonal human influenza vaccine strains and the emerging pandemic strains was investigated. Human serum samples were tested by hemagglutination inhibition and single radial hemolysis assays against A/Brisbane/59/2007, A/California/07/2009, and A/Michigan/45/2015 strains. Strong cross-reactions between A/California/07/2009 and A/Michigan/45/2015 strains were observed in 2009/2010, most likely induced by the start of the 2009 pandemic, and the subsequent post-pandemic seasons from 2010/2011 onward when A/California/07/2009 became the predominant strain. In the 2014/2015 season, population immunity against A/California/07/2009 and A/Michigan/45/2015 strains increased again, associated with strong cross-reactions. Whereas hemagglutination inhibition assay has a higher sensitivity for detection of new seasonal drift, the single radial hemolysis assay is an excellent tool for determining the presence of pre-existing immunity, allowing a potential prediction on the booster potential of influenza vaccines against newly emerging drifted strains. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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16 pages, 2557 KiB  
Article
Immunogenicity and Safety of the Quadrivalent Adjuvant Subunit Influenza Vaccine in Seropositive and Seronegative Healthy People and Patients with Common Variable Immunodeficiency
by Mikhail P. Kostinov, Elena A. Latysheva, Aristitsa M. Kostinova, Nelly K. Akhmatova, Tatyana V. Latysheva, Anna E. Vlasenko, Yulia A. Dagil, Ekaterina A. Khromova and Valentina B. Polichshuk
Vaccines 2020, 8(4), 640; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines8040640 - 02 Nov 2020
Cited by 4 | Viewed by 2916
Abstract
Background. Influenza prophylaxis with the use of quadrivalent vaccines (QIV) is increasingly being introduced into healthcare practice. Methods. In total, 32 healthy adults and 6 patients with common variable immunodeficiency (CVID) received adjuvant QIV during 2018–2019 influenza season. Depending on initial antibody titers, [...] Read more.
Background. Influenza prophylaxis with the use of quadrivalent vaccines (QIV) is increasingly being introduced into healthcare practice. Methods. In total, 32 healthy adults and 6 patients with common variable immunodeficiency (CVID) received adjuvant QIV during 2018–2019 influenza season. Depending on initial antibody titers, healthy volunteers were divided into seronegative (≤1:20) and seropositive (≥1:40). To evaluate immunogenicity hemagglutination inhibition assay was used. Results. All participants completed the study without developing serious post-vaccination reactions. Analysis of antibody titer 3 weeks after immunization in healthy participants showed that seroprotection, seroconversion levels, GMR and GMT for strains A/H1N1, A/H3N2 and B/Colorado, B/Phuket among initially seronegative and seropositive participants meet the criterion of CHMP effectiveness. CVID patients showed increase in post-vaccination antibody titer without reaching conditionally protective antibody levels. Conclusion. Adjuvant QIV promotes formation of specific immunity to vaccine strains, regardless of antibodies’ presence or absence before. In CVID patients search of new regimens should be continued. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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Review

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21 pages, 1872 KiB  
Review
Cross-Reactivity Conferred by Homologous and Heterologous Prime-Boost A/H5 Influenza Vaccination Strategies in Humans: A Literature Review
by Adinda Kok, Ron A. M. Fouchier and Mathilde Richard
Vaccines 2021, 9(12), 1465; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9121465 - 10 Dec 2021
Cited by 4 | Viewed by 2819
Abstract
Avian influenza viruses from the A/H5 A/goose/Guangdong/1/1996 (GsGd) lineage pose a continuing threat to animal and human health. Since their emergence in 1997, these viruses have spread across multiple continents and have become enzootic in poultry. Additionally, over 800 cases of human infection [...] Read more.
Avian influenza viruses from the A/H5 A/goose/Guangdong/1/1996 (GsGd) lineage pose a continuing threat to animal and human health. Since their emergence in 1997, these viruses have spread across multiple continents and have become enzootic in poultry. Additionally, over 800 cases of human infection with A/H5 GsGd viruses have been reported to date, which raises concerns about the potential for a new influenza virus pandemic. The continuous circulation of A/H5 GsGd viruses for over 20 years has resulted in the genetic and antigenic diversification of their hemagglutinin (HA) surface glycoprotein, which poses a serious challenge to pandemic preparedness and vaccine design. In the present article, clinical studies on A/H5 influenza vaccination strategies were reviewed to evaluate the breadth of antibody responses induced upon homologous and heterologous prime-boost vaccination strategies. Clinical data on immunological endpoints were extracted from studies and compiled into a dataset, which was used for the visualization and analysis of the height and breadth of humoral immune responses. Several aspects leading to high immunogenicity and/or cross-reactivity were identified, although the analysis was limited by the heterogeneity in study design and vaccine type used in the included studies. Consequently, crucial questions remain to be addressed in future studies on A/H5 GsGd vaccination strategies. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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17 pages, 1124 KiB  
Review
The Human Antibody Response to the Influenza Virus Neuraminidase Following Infection or Vaccination
by Madhusudan Rajendran, Florian Krammer and Meagan McMahon
Vaccines 2021, 9(8), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080846 - 02 Aug 2021
Cited by 11 | Viewed by 5101
Abstract
The influenza virus neuraminidase (NA) is primarily involved in the release of progeny viruses from infected cells—a critical role for virus replication. Compared to the immuno-dominant hemagglutinin, there are fewer NA subtypes, and NA experiences a slower rate of antigenic drift and reduced [...] Read more.
The influenza virus neuraminidase (NA) is primarily involved in the release of progeny viruses from infected cells—a critical role for virus replication. Compared to the immuno-dominant hemagglutinin, there are fewer NA subtypes, and NA experiences a slower rate of antigenic drift and reduced immune selection pressure. Furthermore, NA inhibiting antibodies prevent viral egress, thus preventing viral spread. Anti-NA immunity can lessen disease severity, reduce viral shedding, and decrease viral lung titers in humans and various animal models. As a result, there has been a concerted effort to investigate the possibilities of incorporating immunogenic forms of NA as a vaccine antigen in future vaccine formulations. In this review, we discuss NA-based immunity and describe several human NA-specific monoclonal antibodies (mAbs) that have a broad range of protection. We also review vaccine platforms that are investigating NA antigens in pre-clinical models and their potential use for next-generation influenza virus vaccines. The evidence presented here supports the inclusion of immunogenic NA in future influenza virus vaccines. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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26 pages, 1060 KiB  
Review
Animal Models Utilized for the Development of Influenza Virus Vaccines
by Ericka Kirkpatrick Roubidoux and Stacey Schultz-Cherry
Vaccines 2021, 9(7), 787; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070787 - 14 Jul 2021
Cited by 15 | Viewed by 7725
Abstract
Animal models have been an important tool for the development of influenza virus vaccines since the 1940s. Over the past 80 years, influenza virus vaccines have evolved into more complex formulations, including trivalent and quadrivalent inactivated vaccines, live-attenuated vaccines, and subunit vaccines. However, [...] Read more.
Animal models have been an important tool for the development of influenza virus vaccines since the 1940s. Over the past 80 years, influenza virus vaccines have evolved into more complex formulations, including trivalent and quadrivalent inactivated vaccines, live-attenuated vaccines, and subunit vaccines. However, annual effectiveness data shows that current vaccines have varying levels of protection that range between 40–60% and must be reformulated every few years to combat antigenic drift. To address these issues, novel influenza virus vaccines are currently in development. These vaccines rely heavily on animal models to determine efficacy and immunogenicity. In this review, we describe seasonal and novel influenza virus vaccines and highlight important animal models used to develop them. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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12 pages, 4768 KiB  
Review
Bridging the B Cell Gap: Novel Technologies to Study Antigen-Specific Human B Cell Responses
by Henry A. Utset, Jenna J. Guthmiller and Patrick C. Wilson
Vaccines 2021, 9(7), 711; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070711 - 01 Jul 2021
Cited by 4 | Viewed by 4253
Abstract
The generation of high affinity antibodies is a crucial aspect of immunity induced by vaccination or infection. Investigation into the B cells that produce these antibodies grants key insights into the effectiveness of novel immunogens to induce a lasting protective response against endemic [...] Read more.
The generation of high affinity antibodies is a crucial aspect of immunity induced by vaccination or infection. Investigation into the B cells that produce these antibodies grants key insights into the effectiveness of novel immunogens to induce a lasting protective response against endemic or pandemic pathogens, such as influenza viruses, human immunodeficiency virus, or severe acute respiratory syndrome coronavirus-2. However, humoral immunity has largely been studied at the serological level, limiting our knowledge on the specificity and function of B cells recruited to respond to pathogens. In this review, we cover a number of recent innovations in the field that have increased our ability to connect B cell function to the B cell repertoire and antigen specificity. Moreover, we will highlight recent advances in the development of both ex vivo and in vivo models to study human B cell responses. Together, the technologies highlighted in this review can be used to help design and validate new vaccine designs and platforms. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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16 pages, 1127 KiB  
Review
An Antigenic Thrift-Based Approach to Influenza Vaccine Design
by Jai S. Bolton, Hannah Klim, Judith Wellens, Matthew Edmans, Uri Obolski and Craig P. Thompson
Vaccines 2021, 9(6), 657; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060657 - 16 Jun 2021
Cited by 4 | Viewed by 4728
Abstract
The antigenic drift theory states that influenza evolves via the gradual accumulation of mutations, decreasing a host’s immune protection against previous strains. Influenza vaccines are designed accordingly, under the premise of antigenic drift. However, a paradox exists at the centre of influenza research. [...] Read more.
The antigenic drift theory states that influenza evolves via the gradual accumulation of mutations, decreasing a host’s immune protection against previous strains. Influenza vaccines are designed accordingly, under the premise of antigenic drift. However, a paradox exists at the centre of influenza research. If influenza evolved primarily through mutation in multiple epitopes, multiple influenza strains should co-circulate. Such a multitude of strains would render influenza vaccines quickly inefficacious. Instead, a single or limited number of strains dominate circulation each influenza season. Unless additional constraints are placed on the evolution of influenza, antigenic drift does not adequately explain these observations. Here, we explore the constraints placed on antigenic drift and a competing theory of influenza evolution – antigenic thrift. In contrast to antigenic drift, antigenic thrift states that immune selection targets epitopes of limited variability, which constrain the variability of the virus. We explain the implications of antigenic drift and antigenic thrift and explore their current and potential uses in the context of influenza vaccine design. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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19 pages, 9319 KiB  
Review
Neutrophils and Influenza: A Thin Line between Helpful and Harmful
by Sneha T. George, Jonathan Lai, Julia Ma, Hannah D. Stacey, Matthew S. Miller and Caitlin E. Mullarkey
Vaccines 2021, 9(6), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060597 - 04 Jun 2021
Cited by 18 | Viewed by 7380
Abstract
Influenza viruses are one of the most prevalent respiratory pathogens known to humans and pose a significant threat to global public health each year. Annual influenza epidemics are responsible for 3–5 million infections worldwide and approximately 500,000 deaths. Presently, yearly vaccinations represent the [...] Read more.
Influenza viruses are one of the most prevalent respiratory pathogens known to humans and pose a significant threat to global public health each year. Annual influenza epidemics are responsible for 3–5 million infections worldwide and approximately 500,000 deaths. Presently, yearly vaccinations represent the most effective means of combating these viruses. In humans, influenza viruses infect respiratory epithelial cells and typically cause localized infections of mild to moderate severity. Neutrophils are the first innate cells to be recruited to the site of the infection and possess a wide range of effector functions to eliminate viruses. Some well-described effector functions include phagocytosis, degranulation, the production of reactive oxygen species (ROS), and the formation of neutrophil extracellular traps (NETs). However, while these mechanisms can promote infection resolution, they can also contribute to the pathology of severe disease. Thus, the role of neutrophils in influenza viral infection is nuanced, and the threshold at which protective functions give way to immunopathology is not well understood. Moreover, notable differences between human and murine neutrophils underscore the need to exercise caution when applying murine findings to human physiology. This review aims to provide an overview of neutrophil characteristics, their classic effector functions, as well as more recently described antibody-mediated effector functions. Finally, we discuss the controversial role these cells play in the context of influenza virus infections and how our knowledge of this cell type can be leveraged in the design of universal influenza virus vaccines. Full article
(This article belongs to the Special Issue Immune Responses to Influenza Virus Antigens)
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