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Viruses
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Advances in Universal Influenza Vaccines and Therapies
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Advances in Universal Influenza Vaccines and Therapies

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 (1 September 2022) | Viewed by 28429

Special Issue Editors

Dr. Charles J. Russell

E-Mail Website
Guest Editor
1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA
2. Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163, USA
Interests: negative-strand RNA viruses; influenza virus antivirals; respiratory virus vaccines; virus entry; viral envelope glycoprotein structure and function; emerging respiratory viruses; animal models
Special Issues, Collections and Topics in MDPI journals
Dr. Julia L. Hurwitz

E-Mail Website
Guest Editor
1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA
2. Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163, USA
Interests: vaccine development; immune responses at the mucosal surface; parvovirus vaccine development; how vitamins influence the immune response; how sex influences the immune response; asthma and the immune response; stem cell/organ transplants and the immune response
Dr. Jarrod J. Mousa

E-Mail Website
Guest Editor
Center for Vaccines and Immunology, Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, 501 DW Brooks Drive, Athens, GA 30602, USA
Interests: human metapneumovirus; influenza virus; streptococcus pneumoniae; pneumocystis; host-pathogen interactions; antibodies

Special Issue Information

Dear Colleagues,

Seasonal and emerging influenza viruses have major implications for public health. Seasonal influenza A and B viruses are associated with high rates of illness and hospitalization each year, and vaccine strategies vary in efficacy year to year. Additionally, influenza viruses can lead to (and, in fact, have led to) pandemics, and the development of new, innovative strategies to improve protection against both seasonal and pandemic influenza viruses remains a high priority. The production of universal influenza vaccines and therapies is multifaceted, with numerous involved components under investigation, such as several vaccine candidates, adjuvants, vaccine platforms, small-molecule drugs, protein inhibitors, broadly reactive monoclonal antibodies, and influenza-specific immune responses.

This Special Issue aims to describe recent strategies that target influenza with vaccines and to understand and predict the corresponding immunological responses. Subtopics of interest include, but are not limited to:

  • Influenza A and B virus vaccines;
  • Full-length and engineered forms of viral antigens;
  • General and high-risk host populations;
  • Universal influenza vaccine design;
  • Conventional and novel antigens;
  • Conventional and novel platforms for vaccine development;
  • Conventional and novel adjuvants/ formulations/ routes and technologies for delivery;
  • Immune effectors/mechanisms and correlates of protection.

Dr. Charles J. Russell
Dr. Julia L. Hurwitz
Dr. Jarrod J. Mousa
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 virus
  • seasonal virus
  • pandemic virus
  • hemagglutinin
  • neuraminidase
  • live-attenuated
  • subunit vaccine
  • mRNA and DNA vaccines
  • vaccine
  • antiviral
  • antibody
  • B-cell
  • T-cell
  • Innate cell
  • effector function
  • structure
  • adjuvant
  • vulnerable hosts

Published Papers (12 papers)

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Research

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14 pages, 2174 KiB  
Article
R-DOTAP Cationic Lipid Nanoparticles Outperform Squalene-Based Adjuvant Systems in Elicitation of CD4 T Cells after Recombinant Influenza Hemagglutinin Vaccination
by Thomas R. Henson, Katherine A. Richards, Siva K. Gandhapudi, Jerold G. Woodward and Andrea J. Sant
Viruses 2023, 15(2), 538; https://doi.org/10.3390/v15020538 - 15 Feb 2023
Cited by 1 | Viewed by 3092
Abstract
It is clear that new approaches are needed to promote broadly protective immunity to viral pathogens, particularly those that are prone to mutation and escape from antibody-mediated immunity. Prototypic pathogens of this type are influenza and SARS-CoV-2, where the receptor-binding protein exhibits extremely [...] Read more.
It is clear that new approaches are needed to promote broadly protective immunity to viral pathogens, particularly those that are prone to mutation and escape from antibody-mediated immunity. Prototypic pathogens of this type are influenza and SARS-CoV-2, where the receptor-binding protein exhibits extremely high variability in its receptor-binding regions. T cells, known to target many viral proteins, and within these, highly conserved peptide epitopes, can contribute greatly to protective immunity through multiple mechanisms but are often poorly recruited by current vaccine strategies. Here, we have studied a promising novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP), which was previously recognized for its ability to generate anti-tumor immunity through the induction of potent cytotoxic CD8 T cells. Using a preclinical mouse model, we have assessed an R-DOTAP nanoparticle adjuvant system for its ability to promote CD4 T cell responses to vaccination with recombinant influenza protein. Our studies revealed that R-DOTAP consistently outperformed a squalene-based adjuvant emulsion, even when it was introduced with a potent TLR agonist CpG, in the ability to elicit peptide epitope-specific CD4 T cells when quantified by IFN-γ and IL-2 ELISpot assays. Clinical testing of R-DOTAP containing vaccines in earlier work by others has demonstrated an acceptable safety profile. Hence, R-DOTAP can offer exciting opportunities as an immune stimulant for next-generation prophylactic recombinant protein-based vaccines. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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19 pages, 2516 KiB  
Article
How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans
by Sherri L. Surman, Bart G. Jones, Rhiannon R. Penkert, Robert E. Sealy, Tony Marion, Paul G. Thomas, Geoffrey Neale, Beisi Xu and Julia L. Hurwitz
Viruses 2023, 15(2), 482; https://doi.org/10.3390/v15020482 - 09 Feb 2023
Cited by 5 | Viewed by 1917
Abstract
Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype [...] Read more.
Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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21 pages, 2617 KiB  
Article
Recombinant Protein Vaccines Formulated with Enantio-Specific Cationic Lipid R-DOTAP Induce Protective Cellular and Antibody-Mediated Immune Responses in Mice
by Siva K. Gandhapudi, Hua Shi, Martin R. Ward, John Peyton Bush, Margarita Avdiushko, Karuna Sundarapandiyan, Lauren V. Wood, Mania Dorrani, Afsheen Fatima, Joe Dervan, Frank Bedu-Addo, Greg Conn, Ted M. Ross and Jerold G. Woodward
Viruses 2023, 15(2), 432; https://doi.org/10.3390/v15020432 - 04 Feb 2023
Cited by 2 | Viewed by 2268
Abstract
Adjuvants are essential components of subunit vaccines added to enhance immune responses to antigens through immunomodulation. Very few adjuvants have been approved for human use by regulatory agencies due to safety concerns. Current subunit vaccine adjuvants approved for human use are very effective [...] Read more.
Adjuvants are essential components of subunit vaccines added to enhance immune responses to antigens through immunomodulation. Very few adjuvants have been approved for human use by regulatory agencies due to safety concerns. Current subunit vaccine adjuvants approved for human use are very effective in promoting humoral immune responses but are less effective at promoting T-cell immunity. In this study, we evaluated a novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP) as an immunomodulator for subunit vaccines capable of inducing both humoral- and cellular-mediated immunity. Using recombinant protein antigens derived from SARS-CoV2 spike or novel computationally optimized broadly reactive influenza antigen (COBRA) proteins, we demonstrated that R-DOTAP nanoparticles promoted strong cellular- and antibody-mediated immune responses in both monovalent and bivalent vaccines. R-DOTAP-based vaccines induced antigen-specific and polyfunctional CD8+ and CD4+ effector T cells and memory T cells, respectively. Antibody responses induced by R-DOTAP showed a balanced Th1/Th2 type immunity, neutralizing activity and protection of mice from challenge with live SARS-CoV2 or influenza viruses. R-DOTAP also facilitated significant dose sparing of the vaccine antigens. These studies demonstrate that R-DOTAP is an excellent immune stimulator for the production of next-generation subunit vaccines containing multiple recombinant proteins. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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15 pages, 1582 KiB  
Article
Adjuvant-Mediated Differences in Antibody Responses to Computationally Optimized Hemagglutinin and Neuraminidase Vaccines
by Kaito Nagashima, Nada Abbadi, Ved Vyas, Abigail Roegner, Ted M. Ross and Jarrod J. Mousa
Viruses 2023, 15(2), 347; https://doi.org/10.3390/v15020347 - 25 Jan 2023
Cited by 2 | Viewed by 1950
Abstract
Computationally optimized broadly reactive antigens (COBRAs) are a next-generation universal influenza vaccine candidate. However, how these COBRAs induce antibody responses when combined with different adjuvants has not previously been well-characterized. Therefore, we performed in vivo studies with an HA-based H1 COBRA, Y2, and [...] Read more.
Computationally optimized broadly reactive antigens (COBRAs) are a next-generation universal influenza vaccine candidate. However, how these COBRAs induce antibody responses when combined with different adjuvants has not previously been well-characterized. Therefore, we performed in vivo studies with an HA-based H1 COBRA, Y2, and an NA-based N1 COBRA, N1-I, to assess this effect for the H1N1 subtype. We tested the adjuvants AddaVax, AddaS03, CpG, and Alhydrogel. AddaS03 performed the best, eliciting high IgG titers and hemagglutination inhibition (HAI) activity for Y2 immunizations. Interestingly, serum antibody epitopes were relatively similar across adjuvant groups. Moreover, following N1-I immunization with these adjuvants, AddaS03 also elicited the highest IgG and neuraminidase inhibition (NAI) titers against the 2009 pandemic virus, A/California/07/2009 (A/CA/09). These results inform adjuvant selection efforts for H1 and N1 COBRA HA and NA antigens in a mouse model. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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19 pages, 10056 KiB  
Article
Urine Metabolome Dynamics Discriminate Influenza Vaccination Response
by Tori C. Rodrick, Yik Siu, Michael A. Carlock, Ted M. Ross and Drew R. Jones
Viruses 2023, 15(1), 242; https://doi.org/10.3390/v15010242 - 14 Jan 2023
Cited by 1 | Viewed by 2535
Abstract
Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single [...] Read more.
Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as “High”, “Low”, or “None” based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p < 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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15 pages, 2220 KiB  
Article
Evaluation of Pre-Pandemic Trivalent COBRA HA Vaccine in Mice Pre-Immune to Historical H1N1 and H3N2 Influenza Viruses
by Pan Ge and Ted M. Ross
Viruses 2023, 15(1), 203; https://doi.org/10.3390/v15010203 - 11 Jan 2023
Cited by 1 | Viewed by 2188
Abstract
Initial exposure to influenza virus(es) during early childhood produces protective antibodies that may be recalled following future exposure to subsequent viral infections or vaccinations. Most influenza vaccine research studies use immunologically naïve animal models to assess vaccine effectiveness. However, most people have an [...] Read more.
Initial exposure to influenza virus(es) during early childhood produces protective antibodies that may be recalled following future exposure to subsequent viral infections or vaccinations. Most influenza vaccine research studies use immunologically naïve animal models to assess vaccine effectiveness. However, most people have an extensive influenza immune history, with memory cells produced by viruses or vaccines representing multiple influenza viruses. In this study, we explored the effect influenza seasonal virus-induced immunity has on pre-pandemic influenza virus vaccination. The mice that were pre-immune to historical H1N1 and H3N2 seasonal influenza viruses were vaccinated with adjuvanted pre-pandemic (H2, H5, and H7) HA-based computationally optimized broadly reactive antigen (COBRA) vaccines, and were fully protected from lethal challenge, whereas the mock-vaccinated mice, with or without pre-immunity, were not protected from morbidity or mortality. Detectable antibody titers were present in the pre-immune mice vaccinated with a single dose of vaccine, but not in the immunologically naïve mice. The mice vaccinated twice with the trivalent COBRA HA vaccine had similar antibody titers regardless of their pre-immune status. Overall, seasonal pre-immunity did not interfere with the immune responses elicited by pre-pandemic COBRA HA vaccines or the protection against pre-pandemic viruses. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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21 pages, 4124 KiB  
Article
Multi-Influenza HA Subtype Protection of Ferrets Vaccinated with an N1 COBRA-Based Neuraminidase
by Amanda L. Skarlupka, Xiaojian Zhang, Uriel Blas-Machado, Spencer F. Sumner and Ted M. Ross
Viruses 2023, 15(1), 184; https://doi.org/10.3390/v15010184 - 09 Jan 2023
Cited by 2 | Viewed by 2133
Abstract
The influenza neuraminidase (NA) is a promising target for next-generation vaccines. Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 (A/California/07/2009, CA/09) or H5N1 [...] Read more.
The influenza neuraminidase (NA) is a promising target for next-generation vaccines. Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 (A/California/07/2009, CA/09) or H5N1 (A/Vietnam/1203/2004, Viet/04) influenza challenges. The N1-I COBRA NA vaccine elicited antibodies with neutralizing ELLA activity against both seasonal and pandemic H1N1 influenza, as well as the H5N1 influenza virus. In both models, N1-I COBRA NA-vaccinated ferrets that were challenged with CA/09 virus had similar morbidity (weight loss and clinical symptoms) as ferrets vaccinated with the CA/09 HA control vaccine. There were significantly reduced viral titers compared to the mock-vaccinated control animals. Ferrets vaccinated with N1-I COBRA NA or Viet/04 NA vaccines were protected against the H5N1 virus infection with minimal clinical symptoms and negligible weight loss. In contrast, ferrets vaccinated with the CA/09 NA vaccine lost ~10% of their original body weight with 25% mortality. Vaccination with either HA or NA vaccines did not inhibit contact transmission of CA/09 virus to naïve cage mates. Overall, the N1-I COBRA vaccine elicited protective immune responses against both H1N1 and H5N1 infections and partially mitigated disease in contact-transmission receiving ferrets. These results indicate that the N1-I COBRA NA performed similarly to the CA/09 HA and NA positive controls. Therefore, the N1-I COBRA NA alone induces protection against viruses from both H5N1 and H1N1 subtypes, indicating its value as a vaccine component in broadly protective influenza vaccines. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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16 pages, 882 KiB  
Article
T Cell Transcriptional Signatures of Influenza A/H3N2 Antibody Response to High Dose Influenza and Adjuvanted Influenza Vaccine in Older Adults
by Iana H. Haralambieva, Huy Quang Quach, Inna G. Ovsyannikova, Krista M. Goergen, Diane E. Grill, Gregory A. Poland and Richard B. Kennedy
Viruses 2022, 14(12), 2763; https://doi.org/10.3390/v14122763 - 11 Dec 2022
Cited by 4 | Viewed by 2446
Abstract
Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional [...] Read more.
Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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13 pages, 2742 KiB  
Article
Proteomic Signatures of the Serological Response to Influenza Vaccination in a Large Human Cohort Study
by Shaohuan Wu, Smruti Pushalkar, Shuvadeep Maity, Matthew Pressler, Justin Rendleman, Burcu Vitrinel, Michael Carlock, Ted Ross, Hyungwon Choi and Christine Vogel
Viruses 2022, 14(11), 2479; https://doi.org/10.3390/v14112479 - 09 Nov 2022
Viewed by 1447
Abstract
The serological response to the influenza virus vaccine is highly heterogeneous for reasons that are not entirely clear. While the impact of demographic factors such as age, body mass index (BMI), sex, prior vaccination and titer levels are known to impact seroconversion, they [...] Read more.
The serological response to the influenza virus vaccine is highly heterogeneous for reasons that are not entirely clear. While the impact of demographic factors such as age, body mass index (BMI), sex, prior vaccination and titer levels are known to impact seroconversion, they only explain a fraction of the response. To identify signatures of the vaccine response, we analyzed 273 protein levels from 138 serum samples of influenza vaccine recipients (2019–2020 season). We found that levels of proteins functioning in cholesterol transport were positively associated with seroconversion, likely linking to the known impact of BMI. When adjusting seroconversion for the demographic factors, we identified additional, unexpected signatures: proteins regulating actin cytoskeleton dynamics were significantly elevated in participants with high adjusted seroconversion. Viral strain specific analysis showed that this trend was largely driven by the H3N2 strain. Further, we identified complex associations between adjusted seroconversion and other factors: levels of proteins of the complement system associated positively with adjusted seroconversion in younger participants, while they were associated negatively in the older population. We observed the opposite trends for proteins of high density lipoprotein remodeling, transcription, and hemostasis. In sum, careful integrative modeling can extract new signatures of seroconversion from highly variable data that suggest links between the humoral response as well as immune cell communication and migration. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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22 pages, 3884 KiB  
Article
Vaccination History, Body Mass Index, Age, and Baseline Gene Expression Predict Influenza Vaccination Outcomes
by Christian V. Forst, Matthew Chung, Megan Hockman, Lauren Lashua, Emily Adney, Angela Hickey, Michael Carlock, Ted Ross, Elodie Ghedin and David Gresham
Viruses 2022, 14(11), 2446; https://doi.org/10.3390/v14112446 - 04 Nov 2022
Cited by 4 | Viewed by 1798
Abstract
Seasonal influenza is a primary public health burden in the USA and globally. Annual vaccination programs are designed on the basis of circulating influenza viral strains. However, the effectiveness of the seasonal influenza vaccine is highly variable between seasons and among individuals. A [...] Read more.
Seasonal influenza is a primary public health burden in the USA and globally. Annual vaccination programs are designed on the basis of circulating influenza viral strains. However, the effectiveness of the seasonal influenza vaccine is highly variable between seasons and among individuals. A number of factors are known to influence vaccination effectiveness including age, sex, and comorbidities. Here, we sought to determine whether whole blood gene expression profiling prior to vaccination is informative about pre-existing immunological status and the immunological response to vaccine. We performed whole transcriptome analysis using RNA sequencing (RNAseq) of whole blood samples obtained prior to vaccination from 275 participants enrolled in an annual influenza vaccine trial. Serological status prior to vaccination and 28 days following vaccination was assessed using the hemagglutination inhibition assay (HAI) to define baseline immune status and the response to vaccination. We find evidence that genes with immunological functions are increased in expression in individuals with higher pre-existing immunity and in those individuals who mount a greater response to vaccination. Using a random forest model, we find that this set of genes can be used to predict vaccine response with a performance similar to a model that incorporates physiological and prior vaccination status alone. A model using both gene expression and physiological factors has the greatest predictive power demonstrating the potential utility of molecular profiling for enhancing prediction of vaccine response. Moreover, expression of genes that are associated with enhanced vaccination response may point to additional biological pathways that contribute to mounting a robust immunological response to the seasonal influenza vaccine. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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Review

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13 pages, 2326 KiB  
Review
Enhancing Immunogenicity of Influenza Vaccine in the Elderly through Intradermal Vaccination: A Literature Analysis
by Huy Quang Quach and Richard B. Kennedy
Viruses 2022, 14(11), 2438; https://doi.org/10.3390/v14112438 - 03 Nov 2022
Cited by 8 | Viewed by 1786
Abstract
Background: Aging and immunosenescence lead to a gradual decline in immune responses in the elderly and the immunogenicity of influenza vaccines in this age group is sub-optimal. Several approaches have been explored to enhance the immunogenicity of influenza vaccines in the elderly, including [...] Read more.
Background: Aging and immunosenescence lead to a gradual decline in immune responses in the elderly and the immunogenicity of influenza vaccines in this age group is sub-optimal. Several approaches have been explored to enhance the immunogenicity of influenza vaccines in the elderly, including incorporating vaccine adjuvant, increasing antigen dosage, and changing the route of vaccine administration. Method: We systematically compared the immunogenicity and safety of influenza vaccines administered by intradermal (ID) route and either intramuscular (IM) or subcutaneous (SC) routes in older adults aged ≥ 65. Results: Of 17 studies included in this analysis, 3 studies compared the immunogenicity of ID vaccination to that of SC vaccination and 14 studies compared ID and IM vaccinations. ID vaccination was typically more immunogenic than both IM and SC routes at the same dosage. Importantly, a minimum of 3 µg of hemagglutinin antigen could be formulated in an ID influenza vaccine without a significant loss of immunogenicity. ID administration of standard-dose, unadjuvanted influenza vaccine was as immunogenic as IM injection of adjuvanted influenza vaccine. Waning of influenza-specific immunity was significant after 6 months, but there was no difference in waning immunity between vaccinations in ID, IM, or SC routes. While ID vaccination elicited local adverse reactions more frequently than other routes, these reactions were mild and lasted for no more than 3 days. Conclusions: We conclude that ID vaccination is superior to IM or SC routes and may be a suitable approach to compensate for the reduced immunogenicity observed in elderly adults. We also conclude that the main benefit of ID influenza vaccine lies in its dose-sparing effect. Additional research is still needed to further develop a more immunogenic ID influenza vaccine. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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Other

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11 pages, 1264 KiB  
Perspective
Broadly Protective Neuraminidase-Based Influenza Vaccines and Monoclonal Antibodies: Target Epitopes and Mechanisms of Action
by Nada Abbadi and Jarrod J. Mousa
Viruses 2023, 15(1), 200; https://doi.org/10.3390/v15010200 - 10 Jan 2023
Cited by 1 | Viewed by 3712
Abstract
Neuraminidase (NA) is an important surface protein on influenza virions, playing an essential role in the viral life cycle and being a key target of the immune system. Despite the importance of NA-based immunity, current vaccines are focused on the hemagglutinin (HA) protein [...] Read more.
Neuraminidase (NA) is an important surface protein on influenza virions, playing an essential role in the viral life cycle and being a key target of the immune system. Despite the importance of NA-based immunity, current vaccines are focused on the hemagglutinin (HA) protein as the target for protective antibodies, and the amount of NA is not standardized in virion-based vaccines. Antibodies targeting NA are predominantly protective, reducing infection severity and viral shedding. Recently, NA-specific monoclonal antibodies have been characterized, and their target epitopes have been identified. This review summarizes the characteristics of NA, NA-specific antibodies, the mechanism of NA inhibition, and the recent efforts towards developing NA-based and NA-incorporating influenza vaccines. Full article
(This article belongs to the Special Issue Advances in Universal Influenza Vaccines and Therapies)
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