Influenza Virus Vaccines

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 (4 December 2020) | Viewed by 32973

Special Issue Editor


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Guest Editor
Department of Microbiology, Harvard Medical School; Ragon Institute of MGH, MIT and Harvard.
Interests: protein engineering; immunogen design; antibody discovery; viral entry

Special Issue Information

Dear Colleagues,

Current influenza vaccines fail to deliver reliable or long-lasting protection, so improved influenza vaccines are needed. Developing these vaccines will require new approaches, new technologies, and the integration of diverse fields of study. This Special Issue seeks all types of manuscripts (e.g., research articles, short communications, and reviews) to explore the current state of the field and the developments at its horizon. The development of a universal influenza vaccine is the goal of current influenza research. The definition of “universal” should include a vaccine that can induce broad immunity (1) within currently circulating H1N1 and H3N2 viruses, (2) across subtypes (heterosubtypic), and (3) potentially pre-pandemic viruses (e.g., H5Nx, H7Nx, and H9Nx). The broad protection afforded by a universal influenza vaccine will likely come from immunogens that elicit immunity targeting conserved epitopes on viral glycoproteins such as the influenza hemagglutinin (HA); these epitopes include the receptor binding site (RBS), stem, and newly defined interface. Although HA has historically been the focus, encouraging data support NA as a component. We solicit manuscripts that describe new approaches to immunogen design, the role of immune imprinting and pre-exisiting immunity on vaccine development, as well as characterization of anti-influenza humoral responses. Whereas the role of antibodies is emphasized, we also encourage manuscripts that highlight potential T-cell-based vaccines. We expect this Special Issue will yield new insights that will directly contribute to influenza vaccine development and extend to other rapidly-evolving pathogens.

Dr. Aaron G. Schmidt
Guest Editor

Manuscript Submission Information

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Keywords

  • influenza
  • viral vaccines
  • immunogen design
  • adaptive immunity
  • therapeutic antibodies
  • antibody discovery
  • virus-host co-evolution
  • immune imprinting

Published Papers (9 papers)

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Research

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13 pages, 1922 KiB  
Article
NIgPred: Class-Specific Antibody Prediction for Linear B-Cell Epitopes Based on Heterogeneous Features and Machine-Learning Approaches
by Chi-Hua Tung, Yi-Sheng Chang, Kai-Po Chang and Yen-Wei Chu
Viruses 2021, 13(8), 1531; https://doi.org/10.3390/v13081531 - 3 Aug 2021
Cited by 4 | Viewed by 2549
Abstract
Upon invasion by foreign pathogens, specific antibodies can identify specific foreign antigens and disable them. As a result of this ability, antibodies can help with vaccine production and food allergen detection in patients. Many studies have focused on predicting linear B-cell epitopes, but [...] Read more.
Upon invasion by foreign pathogens, specific antibodies can identify specific foreign antigens and disable them. As a result of this ability, antibodies can help with vaccine production and food allergen detection in patients. Many studies have focused on predicting linear B-cell epitopes, but only two prediction tools are currently available to predict the sub-type of an epitope. NIgPred was developed as a prediction tool for IgA, IgE, and IgG. NIgPred integrates various heterologous features with machine-learning approaches. Differently from previous studies, our study considered peptide-characteristic correlation and autocorrelation features. Sixty kinds of classifier were applied to construct the best prediction model. Furthermore, the genetic algorithm and hill-climbing algorithm were used to select the most suitable features for improving the accuracy and reducing the time complexity of the training model. NIgPred was found to be superior to the currently available tools for predicting IgE epitopes and IgG epitopes on independent test sets. Moreover, NIgPred achieved a prediction accuracy of 100% for the IgG epitopes of a coronavirus data set. NIgPred is publicly available at our website. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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10 pages, 1253 KiB  
Article
Autoreactivity of Broadly Neutralizing Influenza Human Antibodies to Human Tissues and Human Proteins
by Surender Khurana, Megan Hahn, Laura Klenow and Hana Golding
Viruses 2020, 12(10), 1140; https://doi.org/10.3390/v12101140 - 8 Oct 2020
Cited by 11 | Viewed by 2713
Abstract
Broadly neutralizing monoclonal antibodies (bNAbs) against conserved domains in the influenza hemagglutinin are in clinical trials. Several next generation influenza vaccines designed to elicit such bNAbs are also in clinical development. One of the common features of the isolated bNAbs is the use [...] Read more.
Broadly neutralizing monoclonal antibodies (bNAbs) against conserved domains in the influenza hemagglutinin are in clinical trials. Several next generation influenza vaccines designed to elicit such bNAbs are also in clinical development. One of the common features of the isolated bNAbs is the use of restricted IgVH repertoire. More than 80% of stem-targeting bNAbs express IgVH1-69, which may indicate genetic constraints on the evolution of such antibodies. In the current study, we evaluated a panel of influenza virus bNAbs in comparison with HIV-1 MAb 4E10 and anti-RSV MAb Palivizumab (approved for human use) for autoreactivity using 30 normal human tissues microarray and human protein (>9000) arrays. We found that several human bNAbs (CR6261, CR9114, and F2603) reacted with human tissues, especially with pituitary gland tissue. Importantly, protein array analysis identified high-affinity interaction of CR6261 with the autoantigen “Enhancer of mRNA decapping 3 homolog” (EDC3), which was not previously described. Moreover, EDC3 competed with hemagglutinin for binding to bNAb CR6261. These autoreactivity findings underscores the need for careful evaluation of such bNAbs for therapeutics and stem-based vaccines against influenza virus. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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11 pages, 2286 KiB  
Article
Highly Immunogenic Nanoparticles Based on a Fusion Protein Comprising the M2e of Influenza A Virus and a Lipopeptide
by Anna A. Zykova, Elena A. Blokhina, Roman Y. Kotlyarov, Liudmila A. Stepanova, Liudmila M. Tsybalova, Victor V. Kuprianov and Nikolai V. Ravin
Viruses 2020, 12(10), 1133; https://doi.org/10.3390/v12101133 - 6 Oct 2020
Cited by 5 | Viewed by 2369
Abstract
The highly conserved extracellular domain of the transmembrane protein M2 (M2e) of the influenza A virus is a promising target for the development of broad-spectrum vaccines. However, M2e is a poor immunogen by itself and must be linked to an appropriate carrier to [...] Read more.
The highly conserved extracellular domain of the transmembrane protein M2 (M2e) of the influenza A virus is a promising target for the development of broad-spectrum vaccines. However, M2e is a poor immunogen by itself and must be linked to an appropriate carrier to induce an efficient immune response. In this study, we obtained recombinant mosaic proteins containing tandem copies of M2e fused to a lipopeptide from Neisseria meningitidis surface lipoprotein Ag473 and alpha-helical linkers and analyzed their immunogenicity. Six fusion proteins, comprising four or eight tandem copies of M2e flanked by alpha-helical linkers, lipopeptides, or a combination of both of these elements, were produced in Escherichia coli. The proteins, containing both alpha-helical linkers and lipopeptides at each side of M2e repeats, formed nanosized particles, but no particulate structures were observed in the absence of lipopeptides. Animal study results showed that proteins with lipopeptides induced strong M2e-specific antibody responses in the absence of external adjuvants compared to similar proteins without lipopeptides. Thus, the recombinant M2e-based proteins containing alpha-helical linkers and N. meningitidis lipopeptide sequences at the N- and C-termini of four or eight tandem copies of M2e peptide are promising vaccine candidates. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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21 pages, 1997 KiB  
Article
Efficacy of Heterologous Prime-Boost Vaccination with H3N2 Influenza Viruses in Pre-Immune Individuals: Studies in the Pig Model
by Sharon Chepkwony, Anna Parys, Elien Vandoorn, Koen Chiers and Kristien Van Reeth
Viruses 2020, 12(9), 968; https://doi.org/10.3390/v12090968 - 1 Sep 2020
Cited by 10 | Viewed by 2545
Abstract
In a previous study in influenza-naïve pigs, heterologous prime-boost vaccination with monovalent, adjuvanted whole inactivated vaccines (WIV) based on the European swine influenza A virus (SwIAV) strain, A/swine/Gent/172/2008 (G08), followed by the US SwIAV strain, A/swine/Pennsylvania/A01076777/2010 (PA10), was shown to induce broadly cross-reactive [...] Read more.
In a previous study in influenza-naïve pigs, heterologous prime-boost vaccination with monovalent, adjuvanted whole inactivated vaccines (WIV) based on the European swine influenza A virus (SwIAV) strain, A/swine/Gent/172/2008 (G08), followed by the US SwIAV strain, A/swine/Pennsylvania/A01076777/2010 (PA10), was shown to induce broadly cross-reactive hemagglutination inhibition (HI) antibodies against 12 out of 15 antigenically distinct H3N2 influenza strains. Here, we used the pig model to examine the efficacy of that particular heterologous prime-boost vaccination regimen, in individuals with pre-existing infection-immunity. Pigs were first inoculated intranasally with the human H3N2 strain, A/Nanchang/933/1995. Seven weeks later, they were vaccinated intramuscularly with G08 followed by PA10 or vice versa. We examined serum antibody responses against the hemagglutinin and neuraminidase, and antibody-secreting cell (ASC) responses in peripheral blood, draining lymph nodes, and nasal mucosa (NMC), in ELISPOT assays. Vaccination induced up to 10-fold higher HI antibody titers than in naïve pigs, with broader cross-reactivity, and protection against challenge with an antigenically distant H3N2 strain. It also boosted ASC responses in lymph nodes and NMC. Our results show that intramuscular administration of WIV can lead to enhanced antibody responses and cross-reactivity in pre-immune subjects, and recall of ASC responses in lymph nodes and NMC. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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15 pages, 3536 KiB  
Article
Comparative Analyses of the Antiviral Activities of IgG and IgA Antibodies to Influenza A Virus M2 Protein
by Kosuke Okuya, Nao Eguchi, Rashid Manzoor, Reiko Yoshida, Shinji Saito, Tadaki Suzuki, Michihito Sasaki, Takeshi Saito, Yurie Kida, Akina Mori-Kajihara, Hiroko Miyamoto, Osamu Ichii, Masahiro Kajihara, Hideaki Higashi and Ayato Takada
Viruses 2020, 12(7), 780; https://doi.org/10.3390/v12070780 - 20 Jul 2020
Cited by 4 | Viewed by 3317
Abstract
The influenza A virus (IAV) matrix-2 (M2) protein is an antigenically conserved viral envelope protein that plays an important role in virus budding together with another envelope protein, hemagglutinin (HA). An M2-specific mouse monoclonal IgG antibody, rM2ss23, which binds to the ectodomain of [...] Read more.
The influenza A virus (IAV) matrix-2 (M2) protein is an antigenically conserved viral envelope protein that plays an important role in virus budding together with another envelope protein, hemagglutinin (HA). An M2-specific mouse monoclonal IgG antibody, rM2ss23, which binds to the ectodomain of the M2 protein, has been shown to be a non-neutralizing antibody, but inhibits plaque formation of IAV strains. In this study, we generated chimeric rM2ss23 (ch-rM2ss23) IgG and IgA antibodies with the same variable region and compared their antiviral activities. Using gel chromatography, ch-rM2ss23 IgA were divided into three antibody subsets: monomeric IgA (m-IgA), dimeric IgA (d-IgA), and trimeric and tetrameric IgA (t/q-IgA). We found that t/q-IgA had a significantly higher capacity to reduce the plaque size of IAVs than IgG and m-IgA, most likely due to the decreased number of progeny virus particles produced from infected cells. Interestingly, HA-M2 colocalization was remarkably reduced on the infected cell surface in the presence of ch-rM2ss23 antibodies. These results indicate that anti-M2 polymeric IgA restricts IAV budding more efficiently than IgG and suggest a role of anti-M2 IgA in cross-protective immunity to IAVs. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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Review

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10 pages, 983 KiB  
Review
Influenza Vaccines toward Universality through Nanoplatforms and Given by Microneedle Patches
by Sijia Tang, Wandi Zhu and Bao-Zhong Wang
Viruses 2020, 12(11), 1212; https://doi.org/10.3390/v12111212 - 24 Oct 2020
Cited by 4 | Viewed by 3554
Abstract
Influenza is one of the top threats to public health. The best strategy to prevent influenza is vaccination. Because of the antigenic changes in the major surface antigens of influenza viruses, current seasonal influenza vaccines need to be updated every year to match [...] Read more.
Influenza is one of the top threats to public health. The best strategy to prevent influenza is vaccination. Because of the antigenic changes in the major surface antigens of influenza viruses, current seasonal influenza vaccines need to be updated every year to match the circulating strains and are suboptimal for protection. Furthermore, seasonal vaccines do not protect against potential influenza pandemics. A universal influenza vaccine will eliminate the threat of both influenza epidemics and pandemics. Due to the massive challenge in realizing influenza vaccine universality, a single vaccine strategy cannot meet the need. A comprehensive approach that integrates advances in immunogen designs, vaccine and adjuvant nanoplatforms, and vaccine delivery and controlled release has the potential to achieve an effective universal influenza vaccine. This review will summarize the advances in the research and development of an affordable universal influenza vaccine. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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22 pages, 2371 KiB  
Review
A Decade in Review: A Systematic Review of Universal Influenza Vaccines in Clinical Trials during the 2010 Decade
by Brigette N. Corder, Brianna L. Bullard, Gregory A. Poland and Eric A. Weaver
Viruses 2020, 12(10), 1186; https://doi.org/10.3390/v12101186 - 20 Oct 2020
Cited by 24 | Viewed by 4681
Abstract
On average, there are 3–5 million severe cases of influenza virus infections globally each year. Seasonal influenza vaccines provide limited protection against divergent influenza strains. Therefore, the development of a universal influenza vaccine is a top priority for the NIH. Here, we report [...] Read more.
On average, there are 3–5 million severe cases of influenza virus infections globally each year. Seasonal influenza vaccines provide limited protection against divergent influenza strains. Therefore, the development of a universal influenza vaccine is a top priority for the NIH. Here, we report a comprehensive summary of all universal influenza vaccines that were tested in clinical trials during the 2010–2019 decade. Of the 1597 studies found, 69 eligible clinical trials, which investigated 27 vaccines, were included in this review. Information from each trial was compiled for vaccine target, vaccine platform, adjuvant inclusion, clinical trial phase, and results. As we look forward, there are currently three vaccines in phase III clinical trials which could provide significant improvement over seasonal influenza vaccines. This systematic review of universal influenza vaccine clinical trials during the 2010–2019 decade provides an update on the progress towards an improved influenza vaccine. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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19 pages, 5398 KiB  
Review
Progress in the Development of Universal Influenza Vaccines
by Wenqiang Sun, Tingrong Luo, Wenjun Liu and Jing Li
Viruses 2020, 12(9), 1033; https://doi.org/10.3390/v12091033 - 17 Sep 2020
Cited by 28 | Viewed by 4914
Abstract
Influenza viruses pose a significant threat to human health. They are responsible for a large number of deaths annually and have a serious impact on the global economy. There are numerous influenza virus subtypes, antigenic variations occur continuously, and epidemic trends are difficult [...] Read more.
Influenza viruses pose a significant threat to human health. They are responsible for a large number of deaths annually and have a serious impact on the global economy. There are numerous influenza virus subtypes, antigenic variations occur continuously, and epidemic trends are difficult to predict—all of which lead to poor outcomes of routine vaccination against targeted strain subtypes. Therefore, the development of universal influenza vaccines still constitutes the ideal strategy for controlling influenza. This article reviews the progress in development of universal vaccines directed against the conserved regions of hemagglutinin (HA), neuraminidase (NA), and other structural proteins of influenza viruses using new technologies and strategies with the goals of enhancing our understanding of universal influenza vaccines and providing a reference for research into the exploitation of natural immunity against influenza viruses. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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20 pages, 1515 KiB  
Review
Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function
by Rongyuan Gao, Zizhang Sheng, Chithra C. Sreenivasan, Dan Wang and Feng Li
Viruses 2020, 12(3), 276; https://doi.org/10.3390/v12030276 - 1 Mar 2020
Cited by 23 | Viewed by 5540
Abstract
Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) [...] Read more.
Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms. Full article
(This article belongs to the Special Issue Influenza Virus Vaccines)
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