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The Recent Development of Influenza Vaccine: 2nd Edition

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

Deadline for manuscript submissions: 31 March 2025 | Viewed by 5401

Special Issue Editor


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Guest Editor
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
Interests: influenza; older population; adjuvants; universal vaccine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the increased importance of influenza vaccination in the elderly due to increased morbidity and mortality, vaccine efficacy is only 17-53% versus 70-90% in young adults. The development of vaccines for an ever-increasing aging population has been an arduous challenge due to immunosenescence. Some approaches to improve vaccine efficacy in the elderly include high-dose vaccines and the use of better adjuvants. Currently, high-dose influenza vaccines and adjuvanted vaccines are approved in the US for people aged 65 years and older. These influenza vaccines induce elevated hemagglutination inhibition (HAI) titers by enhancing the immunogenicity of vaccines. The efficacy of controlling lung viral replication by vaccination with adjuvants that induce antibody, CD4, and CD8 T cell responses is desirable. Recent advances in developing universal vaccines that generate immunity against stalk proteins might provide better protection against various strains of influenza virus. We welcome articles that provide the latest developments in vaccines and novel adjuvants and mechanisms of long-term efficacy studies or review articles in this area for this Special Issue.

Dr. Ramireddy Bommireddy
Guest Editor

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Keywords

  • influenza
  • older population
  • adjuvants
  • universal vaccine

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Published Papers (5 papers)

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Research

16 pages, 3076 KiB  
Article
Neuraminidase Antibody Response to Homologous and Drifted Influenza A Viruses After Immunization with Seasonal Influenza Vaccines
by Yulia Desheva, Maria Sergeeva, Polina Kudar, Andrey Rekstin, Ekaterina Romanovskaya-Romanko, Vera Krivitskaya, Kira Kudria, Ekaterina Bazhenova, Ekaterina Stepanova, Evelina Krylova, Maria Kurpiaeva, Dmitry Lioznov, Marina Stukova and Irina Kiseleva
Vaccines 2024, 12(12), 1334; https://doi.org/10.3390/vaccines12121334 - 27 Nov 2024
Viewed by 520
Abstract
Background/Objectives: Humoral immunity directed against neuraminidase (NA) of the influenza virus may soften the severity of infection caused by new antigenic variants of the influenza viruses. Evaluation of NA-inhibiting (NI) antibodies in combination with antibodies to hemagglutinin (HA) may enhance research on the [...] Read more.
Background/Objectives: Humoral immunity directed against neuraminidase (NA) of the influenza virus may soften the severity of infection caused by new antigenic variants of the influenza viruses. Evaluation of NA-inhibiting (NI) antibodies in combination with antibodies to hemagglutinin (HA) may enhance research on the antibody response to influenza vaccines. Methods: The study examined 64 pairs of serum samples from patients vaccinated with seasonal inactivated trivalent influenza vaccines (IIVs) in 2018 according to the formula recommended by the World Health Organization (WHO) for the 2018–2019 flu season. Antibodies against drift influenza viruses A/Guangdong-Maonan/SWL1536/2019(H1N1)pdm09 and A/Brisbane/34/2018(H3N2) were studied before vaccination and 21 days after vaccination. To assess NI antibodies, we used an enzyme-linked lectin assay (ELLA) with pairs of reassortant viruses A/H6N1 and A/H6N2. Anti-HA antibodies were detected using a hemagglutination inhibition (HI) test. The microneutralization (MN) test was performed in the MDCK cell line using viruses A/H6N1 and A/H6N2. Results: Seasonal IIVs induce a significant immune response of NI antibodies against influenza A/H1N1pdm09 and A/H3N2 viruses. A significantly reduced ‘herd’ immunity to drift influenza A/H1N1pdm09 and A/H3N2 viruses was shown, compared with previously circulating strains. This reduction was most pronounced in strains possessing neuraminidase N2. Seasonal IIVs caused an increase in antibodies against homologous and drifted viruses; however, an increase in antibodies to drifting viruses was observed more often among older patients. The level of NI antibodies for later A/H1N1pdm09 virus in response to IIVs was statistically significantly lower among younger people. After IIV vaccination, the percentage of individuals with HI antibody levels ≥ 1:40 and NI antibody levels ≥ 1:20 was 32.8% for drift A/H1N1pdm09 virus and 17.2% for drift A/H3N2 virus. Antisera containing HI and NI antibodies exhibited neutralizing properties in vitro against viruses with unrelated HA of the H6 subtype. Conclusions: Drift A/H1N1pdm09 and A/H3N2 viruses demonstrated significantly lower reactivity to HI and NI antibodies against early influenza viruses. In response to seasonal IIVs, the level of seroprotection has increased, including against drift influenza A viruses, but protective antibody levels against A/H1N1pdm09 have risen to a greater extent. A reduced immune response to the N1 protein of the A/H1N1pdm09 drift virus was obtained in individuals under 60 years of age. Based on our findings, it is hypothesized that in the cases of a HA mismatch, vaccination against N1-containing influenza viruses may be necessary for individuals under 60, while broader population-level vaccination against N2-containing viruses may be required. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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Figure 1

Figure 1
<p>Molecular analysis and enzymatic activity of NA from A/H1N1pdm09 and A/H3N2 viruses. (<b>A</b>) A cartoon-style molecular model of NA from the A/Guangdong-Maonan/SWL1536/2019(H1N1)pdm09 virus, from amino acid 82 to 469 (numbering as in the case of the H1N1 2009 pandemic virus) with major amino acid substitutions in the structure indicated. (<b>B</b>) A molecular model of NA A/Brisbane/34/2018 (H3N2), from amino acid 82 to 469 (classical H3N2 strain numbering). (<b>C</b>) Enzymatic activity of NA of viruses A/H6N1 and A/H6N2 was studied in the desialyzation reaction of the high-molecular substrate (fetuin), sorbed on a polymeric carrier using peroxidase-labeled lectin. The OD450 was measured depending on the hemagglutinating activity of the viruses.</p>
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<p>Antibodies to A/H1N1pdm09 and A/H3N2 viruses in sera of patients vaccinated with inactivated influenza vaccines (IIVs) corresponded to the WHO recommendations for the Northern Hemisphere during the 2018–2019 flu season. The total number of participants was 64: 30 people were 60 years old and older and 34 were under 60 years old. (<b>A</b>) Antibody levels to HA and NA of influenza viruses A/South Africa/3626/13 (H1N1)pdm09, A/Hong Kong/4801/2014 (H3N2), A/Guangdong-Maonan/SWL 1536/2019(H1N1)pdm09 and A/Brisbane/34/2018(H3N2) pre- and post-vaccination. (<b>B</b>) The HI and NI antibody levels to the vaccine and drifting viruses A/H1N1pdm09 and A/H3N2 in sera collected before vaccination. Each point represents an individual patient serum, here and below: *—<span class="html-italic">p</span> &lt; 0.05, ***—<span class="html-italic">p</span> &lt; 0.001, ****—<span class="html-italic">p</span> &lt; 0.0001. (<b>C</b>) Combined seroconversions to the vaccine and drifted influenza viruses on day 21 following vaccination with IIVs regardless of the vaccine type, presented by Venn’s diagrams. Numbers in circles present the absolute number of responders to each virus. The total number of subjects was 64, with 30 people 60 years old or older and 34 under 60. The number of nonresponders to both antigens is not shown on Venn’s diagram. Seroconversion to influenza A virus antigens was defined as a fourfold increase in HI antibody titers and a twofold increase in NI antibody titers.</p>
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<p>Antibody titers to HA and NA of influenza viruses in paired blood sera of patients vaccinated with seasonal IIVs 2018–2019 years of formulation (<span class="html-italic">n</span> = 64). S1—pre-vaccination antibody titers, S2—antibody titers 21 days after vaccination. The population in the analysis included all participants, regardless of age or vaccine type. Each dot represents an individual serum. (<b>A</b>) HI antibodies to A/Michigan/45/2015(H1N1)pdm09 and A/Guangdong-Maonan/SWL1536/2019(H1N1)pdm09 viruses. (<b>B</b>) NI antibodies to H6N1/13 and H6N1/19 influenza viruses. (<b>C</b>) HI antibodies to A/Singapore/INFIMH-16-0019/2016(H3N2) and A/Brisbane/34/2018(H3N2) virus. (<b>D</b>) NI antibodies to H6N2/14 and H6N2/18 influenza virus. ***—<span class="html-italic">p</span> &lt; 0.001, ****—<span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Proportions of individuals with antibody titers ≥ 1:40 for HI antibodies and ≥ 1:20 for NI antibodies to HA and NA of influenza viruses A/H1N1pdm09 and A/H3N2 post-vaccination with seasonal IIVs (<span class="html-italic">n</span> = 64). The population in the analysis included all participants, regardless of age or vaccine type. (<b>A</b>) The HI and NI antibodies to A/South Africa/3626/13 (H1N1)pdm09 and A/Hong Kong/4801/2014 (H3N2). (<b>B</b>) The HI and NI antibodies to A/Guangdong-Maonan/SWL 1536/2019(H1N1)pdm09 and A/Brisbane/34/2018 (H3N2).</p>
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<p>Seroprotection levels to HA and NA of influenza viruses A/H1N1pdm09 and A/H3N2 pre- and post-vaccination with seasonal IIVs in patients of different age groups. For HI antibodies, the seroprotection level was determined as 1:40, and for NI antibodies—as 1:20. *—<span class="html-italic">p</span> &lt; 0.05, Fisher’s exact test.</p>
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<p>Results of the study of neutralizing antibodies using the MN test in MDCK cell line. S1—pre-vaccination antibody titers, S2—antibody titers 21 days after vaccination. ***—<span class="html-italic">p</span> &lt; 0.001. (<b>A</b>) The NI antibodies to the H6N1/19 virus. The population in the analyses included all participants, regardless of age or vaccine type. (<b>B</b>) Correlation analysis of neutralizing antibodies and antibodies to HA and NA of the A/Guangdong-Maonan/SWL1536/2019(H1N1)pdm09 virus before and after vaccination. (<b>C</b>) The NI antibodies to the H6N2/18 virus. (<b>D</b>) Correlation analysis of neutralizing antibodies and antibodies to HA and NA of the A/Brisbane/34/2018(H3N2) virus before and after vaccination.</p>
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<p>Antibody titers against drifted A/H1N1pdm09 and A/H3N2 HA and NA in patients vaccinated with split influenza vaccines (<span class="html-italic">n</span> = 29) and subunit influenza vaccines (<span class="html-italic">n</span> = 35). Each dot represents an individual serum. (<b>A</b>) HI antibodies to the A/Guangdong-Maonan/SWL1536/2019(H1N1)pdm09 virus. (<b>B</b>) NI antibodies to H6N1/19 influenza virus. (<b>C</b>) HI antibodies to A/Brisbane/34/2018(H3N2) virus. (<b>D</b>) NI antibodies to H6N2/18 influenza virus. *—<span class="html-italic">p</span> &lt; 0.05, ***—<span class="html-italic">p</span> &lt; 0.001.</p>
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13 pages, 991 KiB  
Article
The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy
by Michelle Clarke, Suja M. Mathew, Lynne C. Giles, Ian G. Barr, Peter C. Richmond and Helen S. Marshall
Vaccines 2024, 12(12), 1307; https://doi.org/10.3390/vaccines12121307 - 22 Nov 2024
Viewed by 632
Abstract
Background/Objectives: Influenza vaccination is recommended for pregnant women, offering the dual benefit of protecting pregnant women and their newborn infants against influenza. This study aimed to investigate the impact of body mass index (BMI) on influenza vaccine responses in pregnant women and their [...] Read more.
Background/Objectives: Influenza vaccination is recommended for pregnant women, offering the dual benefit of protecting pregnant women and their newborn infants against influenza. This study aimed to investigate the impact of body mass index (BMI) on influenza vaccine responses in pregnant women and their newborns. Methods: Participants included pregnant women attending the Women’s and Children’s Hospital in South Australia between 2018 and 2021. Maternal blood samples were collected prior to and at 1 and 6 months post-influenza vaccination to measure antibody responses by hemagglutination inhibition (HI) assay. Cord blood samples were also collected. The percentages of participants achieving HI titre ≥40 were compared between obese and non-obese groups. Results: A total of 73 women were enrolled and received quadrivalent influenza vaccination at a mean age of 32 years (range 21–44 y) and median gestation of 24 weeks (range 11–37 weeks). BMI at vaccination was ≥30 kg/m2 for 21/73 women (29%). Most pregnant women demonstrated antibody titres ≥ 40 to all four influenza vaccine strains at 1 month post-vaccination regardless of BMI category (BMI ≥ 30 kg/m2: 19/20; 95% vs. BMI < 30 kg/m2: 47/49; 96%). At 6 months post-vaccination, 12/17 (71%) obese women compared to 36/43 (84%) non-obese women (p = 0.25) maintained HI titres ≥ 40. Cord blood serology showed HI titres ≥ 40 for 11/17 (65%) infants born to mothers with BMI ≥ 30 compared to 30/35 (86%) infants delivered by mothers with BMI < 30 kg/m2. Conclusions: A high BMI did not impair influenza vaccine antibody responses in pregnant women at 1 month post-vaccination. However, at 6 months post-vaccination, and in the cord blood samples, the percentages maintaining HI titre ≥ 40 were lower for obese women than for non-obese pregnant women. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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Figure 1
<p>Participant flow chart.</p>
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<p>Pre- and post-vaccination HI titres by BMI category for (<b>a</b>) A/H3N2; (<b>b</b>) A/H1N1; (<b>c</b>) B/Victoria; and (<b>d</b>) B/Yamagata.</p>
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27 pages, 6621 KiB  
Article
Safety, Immunogenicity and Protective Activity of a Modified Trivalent Live Attenuated Influenza Vaccine for Combined Protection Against Seasonal Influenza and COVID-19 in Golden Syrian Hamsters
by Ekaterina Stepanova, Victoria Matyushenko, Daria Mezhenskaya, Ekaterina Bazhenova, Tatiana Kotomina, Alexandra Rak, Svetlana Donina, Anna Chistiakova, Arina Kostromitina, Vlada Novitskaya, Polina Prokopenko, Kristina Rodionova, Konstantin Sivak, Kirill Kryshen, Valery Makarov, Larisa Rudenko and Irina Isakova-Sivak
Vaccines 2024, 12(12), 1300; https://doi.org/10.3390/vaccines12121300 - 21 Nov 2024
Viewed by 603
Abstract
Background/Objectives: Influenza viruses and SARS-CoV-2 are currently cocirculating with similar seasonality, and both pathogens are characterized by a high mutational rate which results in reduced vaccine effectiveness and thus requires regular updating of vaccine compositions. Vaccine formulations combining seasonal influenza and SARS-CoV-2 strains [...] Read more.
Background/Objectives: Influenza viruses and SARS-CoV-2 are currently cocirculating with similar seasonality, and both pathogens are characterized by a high mutational rate which results in reduced vaccine effectiveness and thus requires regular updating of vaccine compositions. Vaccine formulations combining seasonal influenza and SARS-CoV-2 strains can be considered promising and cost-effective tools for protection against both infections. Methods: We used a licensed seasonal trivalent live attenuated influenza vaccine (3×LAIV) as a basis for the development of a modified 3×LAIV/CoV-2 vaccine, where H1N1 and H3N2 LAIV strains encoded an immunogenic cassette enriched with conserved T-cell epitopes of SARS-CoV-2, whereas a B/Victoria lineage LAIV strain was unmodified. The trivalent LAIV/CoV-2 composition was compared to the classical 3×LAIV in the golden Syrian hamster model. Animals were intranasally immunized with the mixtures of the vaccine viruses, twice, with a 3-week interval. Immunogenicity was assessed on day 42 of the study, and the protective effect was established by infecting vaccinated hamsters with either influenza H1N1, H3N2 or B viruses or with SARS-CoV-2 strains of the Wuhan, Delta and Omicron lineages. Results: Both the classical 3×LAIV and 3×LAIV/CoV-2 vaccine compositions induced similar levels of serum antibodies specific to all three influenza strains, which resulted in comparable levels of protection against challenge from either influenza strain. Protection against SARS-CoV-2 challenge was more pronounced in the 3×LAIV/CoV-2-immunized hamsters compared to the classical 3×LAIV group. These data were accompanied by the higher magnitude of virus-specific cellular responses detected by ELISPOT in the modified trivalent LAIV group. Conclusions: The modified trivalent live attenuated influenza vaccine encoding the T-cell epitopes of SARS-CoV-2 can be considered a promising tool for combined protection against seasonal influenza and COVID-19. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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Figure 1

Figure 1
<p>A list of LAIV viruses used in this study. (<b>A</b>) Schematic representation of LAIV reassortant viruses either used as monovalent preparations (<b>upper panel</b>) or in trivalent compositions (<b>lower panel</b>). The dose of each vaccine strain is shown above the virus figure. (<b>B</b>) Scheme of the modified influenza A NA gene, where the SARS-CoV-2 T-cell cassette is inserted into the NA open reading frame via the P2A self-cleavage site, which facilitates independent intracellular processing of the influenza NA protein and the inserted cassette [<a href="#B9-vaccines-12-01300" class="html-bibr">9</a>].</p>
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<p>The scheme of the experiment for assessment of the safety, immunogenicity and protective potential of the studied monovalent and trivalent LAIV candidates in Syrian hamsters. Doses of vaccine viruses administered alone or in trivalent compositions are shown on <a href="#vaccines-12-01300-f001" class="html-fig">Figure 1</a>A. D—days of the experiment. Red circles denote the extracted nasal turbinate tissues.</p>
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<p>Safety assessment of the modified trivalent 3×LAIV/CoV2 vaccine in Syrian hamsters. Animals were immunized twice with the indicated vaccine variant on days 0 and 21, and body weight was evaluated during the immunization phase, until day 42 of the experiment.</p>
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<p>Serum IgG antibody responses to influenza viruses in immunized hamsters (ELISA with whole sucrose gradient-purified virus antigens). OD<sub>450</sub> values (<b>left panel</b>) and endpoint serum IgG titers (<b>right panel</b>) in reaction with H1N1 antigens (<b>A</b>), H3N2 antigens (<b>B</b>) and B/Victoria antigens (<b>C</b>). Antibody levels were measured at day 42 of the study, after two doses of the vaccines. (****) <span class="html-italic">p</span> &lt; 0.0001, (***) <span class="html-italic">p</span> &lt; 0.001, (**) <span class="html-italic">p</span> &lt; 0.01, (*) <span class="html-italic">p</span> &lt; 0.05 (ANOVA with post hoc Tukey test).</p>
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<p>Protective efficacy of a modified trivalent LAIV and control monovalent and trivalent LAIVs against three seasonal influenza viruses in the Syrian hamster model. Titers of influenza A/H1N1 (<b>top panel</b>), A/H3N2 (<b>middle panel</b>) and type B viruses (<b>bottom panel</b>) in the lungs and nasal turbinates are shown. Animals in the placebo group received PBS. (****) <span class="html-italic">p</span> &lt; 0.0001, (**) <span class="html-italic">p</span> &lt; 0.01, (*) <span class="html-italic">p</span> &lt; 0.05 (ANOVA with post hoc Tukey test).</p>
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<p>Protective efficacy of a modified trivalent LAIV and control monovalent and trivalent LAIVs against SARS-CoV-2 of three different antigenic lineages. Viral titers in nasal turbinates (NTs) and lung tissues on day 6 post-challenge are shown: (<b>A</b>) Wuhan strain; (<b>B</b>) Delta variant; (<b>C</b>) Omicron variant. (<b>D</b>) Sum of clinical symptom scores within 6 days of infection. (****) <span class="html-italic">p</span> &lt; 0.0001, (***) <span class="html-italic">p</span> &lt; 0.001, (**) <span class="html-italic">p</span> &lt; 0.01, (*) <span class="html-italic">p</span> &lt; 0.05 (ANOVA with post hoc Tukey test).</p>
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<p>Histopathological assessment of protective effect of 3×LAIV/CoV2 against Wuhan challenge in a hamster model. Representative micrographs of hematoxylin–eosin-stained lung sections of animals on day 6 after challenge are shown using 50× (<b>upper panel</b>, scale bar: 500 µm), 200× (<b>middle panel</b>, scale bar: 100 µm) and 400× magnifications (<b>lower panel</b>, scale bar: 100 µm).</p>
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<p>Semi-quantitative analyses of the airway, lung/alveolar and vascular damage to the lungs of immunized and control hamsters on day 6 after challenge with Wuhan (<b>upper panel</b>), Delta (<b>middle panel</b>) and Omicron (<b>lower panel</b>) SARS-CoV-2 variants. Data were analyzed by one-way ANOVA with Tukey’s post hoc multiple-analyses test. (*) <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>Levels of IFNγ-secreting cells in splenocytes of immunized Syrian hamsters on day 6 after infection with hCoV-19/Russia/StPetersburg-3524/2020 (line B.1, Wuhan). Isolated splenocytes were stimulated in vitro with influenza viruses (<b>upper panel</b>) and live SARS-CoV-2 or PepTivator (<b>lower panel</b>), followed by quantification of IFNγ-secreting cells using the Hamster IFN-γ ELISpot Plus kit.</p>
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16 pages, 1793 KiB  
Article
A Polysaccharide-Based Oral-Vaccine Delivery System and Adjuvant for the Influenza Virus Vaccine
by Chaitanya K. Valiveti, Mrigendra Rajput, Neelu Thakur, Tooba Momin, Malabika Bhowmik and Hemachand Tummala
Vaccines 2024, 12(10), 1121; https://doi.org/10.3390/vaccines12101121 - 29 Sep 2024
Viewed by 1665
Abstract
Influenza virus enters the host body through the mucosal surface of the respiratory tract. An efficient immune response at the mucosal site can interfere with virus entry and prevent infection. However, formulating oral vaccines and eliciting an effective mucosal immune response including at [...] Read more.
Influenza virus enters the host body through the mucosal surface of the respiratory tract. An efficient immune response at the mucosal site can interfere with virus entry and prevent infection. However, formulating oral vaccines and eliciting an effective mucosal immune response including at respiratory mucosa presents numerous challenges including the potential degradation of antigens by acidic gastric fluids and the risk of antigen dilution and dispersion over a large surface area of the gut, resulting in minimal antigen uptake by the immune cells. Additionally, oral mucosal vaccines have to overcome immune tolerance in the gut. To address the above challenges, in the current study, we evaluated inulin acetate (InAc) nanoparticles (NPs) as a vaccine adjuvant and antigen delivery system for oral influenza vaccines. InAc was developed as the first polysaccharide polymer-based TLR4 agonist; when tailored as a nanoparticulate vaccine delivery system, it enhanced antigen delivery to dendritic cells and induced a strong cellular and humoral immune response. This study compared the efficacy of InAc-NPs as a delivery system for oral vaccines with Poly (lactic-co-glycolic acid) (PLGA) NPs, utilizing influenza A nucleoprotein (Inf-A) as an antigen. InAc-NPs effectively protected the encapsulated antigen in both simulated gastric (pH 1.1) and intestinal fluids (pH 6.8). Moreover, InAc-NPs facilitated enhanced antigen delivery to macrophages, compared to PLGA-NPs. Oral vaccination studies in Balb/c mice revealed that InAc-Inf-A NPs significantly boosted the levels of Influenza virus-specific IgG and IgA in serum, as well as total and virus-specific IgA in the intestines and lungs. Furthermore, mice vaccinated with InAc-Inf-A-NPs exhibited notably higher hemagglutination inhibition (HI) titers at mucosal sites compared to those receiving the antigen alone. Overall, our study underscores the efficacy of InAc-NPs in safeguarding vaccine antigens post-oral administration, enhancing antigen delivery to antigen-presenting cells, and eliciting higher virus-neutralizing antibodies at mucosal sites following vaccination. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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<p>Characterization of InAc-Inf-A-NPs: (<b>A</b>) the mean particle size distribution was measured using DLS; (<b>B</b>) Zeta potential shows the surface charge of InAc-Inf-A-NPs a slightly negative or neutral (−0.9 ± 0.2 mV); (<b>C</b>) the morphology of InAc-Inf-A-NPs were spherical particles with a diameter of ~500 nm as shown by scanning electron microscopy (SEM).</p>
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<p>Efficacy of InAc-NPs in preventing premature release of the encapsulated antigen. InAc-NPs containing Fluoresceine Sodium dye as the encapsulated antigen were dispersed in DI Water, Simulated Gastric Fluid (SGF), or Simulated Intestinal Fluid (SIF). Suspension was incubated in an orbital shaker at a speed of 100 rpm at 37 °C for 24 h. Fluorescein concentration in the supernatant solution at different time points was measured by fluorimeter and % cumulated release was calculated by comparing its fluorescent intensity with 100% release of Fluoresceine Sodium from NPs dissolved in 100% acetone or DMF.</p>
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<p>InAc-FITC-Ova-NPs uptake by murine macrophages. The InAc-FITC-Ova-NPs or PLGA-FITC-Ova-NPs each with 25 µg equivalent to FITC-Ova were incubated with wild-type macrophages. After 1 h incubation, the cells were analyzed by flow cytometry for the number of cells having the antigen (FITC-Ova, green fluorescence) and the relative amount of antigen per cell by mean fluorescent intensity (MFI).</p>
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<p>Fold change in Inf-A specific IgG (panel (<b>A</b>)) and IgA (panel (<b>B</b>)) in the serum following oral vaccination. BALB/c mice were vaccinated by oral administration of saline, Influenza A peptide alone in saline, or Influenza A peptide encapsulated in InAc-NPs (InAc-Inf-A-NPs). Two doses were given at one-week intervals. Blood was collected on day 0, day 7, and day 35 post-first vaccination. Panel (<b>A</b>) shows fold change in Inf-A-specific IgG tier at day 0, day 7-, and 35 days post-first vaccination while Panel (<b>B</b>) shows fold change in Inf-A-specific IgA tiers in serum at 35 days post-first vaccination. * Shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>The concentration of total IgA (panel (<b>A</b>)) and Inf-A specific IgA (panel (<b>B</b>)) in the tissues following oral vaccination. BALB/c mice were orally vaccinated with two doses of saline, Influenza A peptide alone in saline, or InAc-Inf-A-NPs one week apart. Following five weeks of the first vaccination, the mice were sacrificed, and the tissues such as ileum (small intestine), lungs, and spleen were collected. Collected tissue samples were homogenized in protease inhibitor and normalized for equal protein concentration followed by measuring the concentration of total IgA (panel (<b>A</b>)) and influenza virus A specific IgA (panel (<b>B</b>)) by sandwich ELISA. * shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>Hemagglutination inhibition (HI) titer following oral vaccination. BALB/c mice were orally vaccinated with two doses of saline, Influenza A peptide alone in saline, or InAc-Inf-A-NPs one week apart. After five weeks of the first vaccination, mice were sacrificed, and tissues were collected. The tissue samples were homogenized in protease inhibitor and supernatants of these homogenates were analyzed for the functionality of Influenza A virus-specific antibodies using HI assays. * shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05 in HI titer in tissue homogenates.</p>
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20 pages, 6998 KiB  
Article
Immunity and Protective Efficacy of a Plant-Based Tobacco Mosaic Virus-like Nanoparticle Vaccine against Influenza a Virus in Mice
by Adthakorn Madapong, Erika M. Petro-Turnquist, Richard J. Webby, Alison A. McCormick and Eric A. Weaver
Vaccines 2024, 12(10), 1100; https://doi.org/10.3390/vaccines12101100 - 26 Sep 2024
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Abstract
Background: The rapid production of influenza vaccines is crucial to meet increasing pandemic response demands. Here, we developed plant-made vaccines comprising centralized consensus influenza hemagglutinin (HA-con) proteins (H1 and H3 subtypes) conjugated to a modified plant virus, tobacco mosaic virus (TMV) nanoparticle (TMV-HA-con). [...] Read more.
Background: The rapid production of influenza vaccines is crucial to meet increasing pandemic response demands. Here, we developed plant-made vaccines comprising centralized consensus influenza hemagglutinin (HA-con) proteins (H1 and H3 subtypes) conjugated to a modified plant virus, tobacco mosaic virus (TMV) nanoparticle (TMV-HA-con). Methods: We compared immune responses and protective efficacy against historical H1 or H3 influenza A virus infections among TMV-HA-con, HA-con protein combined with AddaVax™ adjuvant, and whole-inactivated virus vaccine (Fluzone®). Results: Immunogenicity studies demonstrated robust IgG, IgM, and IgA responses in the TMV-HA-con and HA-con protein vaccinated groups, with relatively low induction of interferon (IFN)-γ+ T-cell responses across all vaccinated groups. The TMV-HA-con and HA-con protein groups displayed partial protection (100% and 80% survival) with minimal weight loss following challenge with two H1N1 strains. The HA-con protein group exhibited 80% and 100% survival against two H3 strains, whereas the TMV-HA-con groups showed reduced protection (20% survival). The Fluzone® group conferred 20–100% survival against two H1N1 strains and one H3N1 strain, but did not protect against H3N2 infection. Conclusions: Our findings indicate that TMV-HA and HA-con protein vaccines with adjuvant induce protective immune responses against influenza A virus infections. Furthermore, our results underscore the potential of plant-based production using TMV-like nanoparticles for developing influenza A virus candidate vaccines. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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Figure 1
<p>Immune correlates of the TMV-HA-con vaccines. BALB/c mice were divided into two experiments: H1-HA and H3-HA groups. All vaccinated groups were intramuscularly (IM) prime/boost immunized with different vaccines at 0- and 21-days post-vaccination (DPV). Following vaccination, five mice from each group were sacrificed at 21 and 35 DPV for collections of blood, spleens, and lungs. Blood was collected and sera were separated and used for hemagglutination inhibition (HI), microneutralization assays, and ELISA. Splenocytes were isolated for use in ELISpot assays. Lungs were homogenized, and lung supernatants were collected and used in HA-specific ELISA.</p>
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<p>Protection against lethal challenge with historical influenza A viruses. BALB/c mice were divided into two experimental groups: H1-HA and H3-HA groups. All groups were intramuscularly (IM) prime/boost immunized with different vaccines at 0- and 21-days post-vaccination (DPV), as previously mentioned. At 35 DPV, mice were intranasally challenged with 20 µL of 10 MLD<sub>50</sub> of mouse-adapted influenza A viruses including A/Puerto Rico/8/1934 (H1N1), A/Fort Monmouth/1/1947 (H1N1), A/Texas/1/1977 (H3N1), and A/Aichi/2/1968 (H3N2). Mice were monitored daily for weight loss for 14 days and euthanized when they lost 25% of their starting weight.</p>
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<p>Sequence identity and Antigenic Site Characterization. All of the HA sequences used in the studies were aligned and analyzed for sequence identity and similarity scores and shown using a Gonnet similarity matrix. The H1-HA amino acid sequences were aligned using ClustalW, and the variable head domains and antigenic sites are indicated by the boxes (<b>A</b>). The H3-HA amino acid sequences were aligned using ClustalW, and the variable head domains and antigenic sites are indicated by the boxes (<b>B</b>). The similarity matrices and alignments were performed using MacVector (version 18.6.4). The (Sa, Sb, Ca, and Cb) of the H1 and (A, B, C, D, and E) antigenic sites of the H3 HA proteins are indicated by the boxed regions.</p>
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<p>IgG responses in sera against panels of human H1-HA or H3-HA proteins after vaccination as measured by ELISA. Sera from immunized mice in the H1-HA groups were collected and tested with H1-HA proteins of (<b>A</b>) H1N1 A/Puerto Rico/8/1934, (<b>B</b>) H1N1 A/California/7/2009, and (<b>C</b>) H1N1 A/Brisbane/59/2007. Sera from immunized mice in the H3-HA groups were collected and tested with H3-HA proteins of (<b>D</b>) H3N2 A/Perth/16/2009, (<b>E</b>) H3N2 A/Wisconsin/67/2005, and (<b>F</b>) H3N2 A/New York/55/2004.</p>
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<p>IgM responses in sera against panels of human H1-HA or H3-HA proteins after vaccination as measured by ELISA. Sera from immunized mice in the H1-HA groups were collected and tested with H1-HA proteins of (<b>A</b>) H1N1 A/Puerto Rico/8/1934, (<b>B</b>) H1N1 A/California/7/2009, and (<b>C</b>) H1N1 A/Brisbane/59/2007. Sera from immunized mice in the H3-HA groups were collected and tested with H3-HA proteins of (<b>D</b>) H3N2 A/Perth/16/2009, (<b>E</b>) H3N2 A/Wisconsin/67/2005, and (<b>F</b>) H3N2 A/New York/55/2004.</p>
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<p>IgA responses in lung supernatants against panels of human H1-HA or H3-HA proteins after vaccination as measured by ELISA. DDT-treated lung supernatants from immunized mice in the H1-HA groups were tested with H1-HA proteins of (<b>A</b>) H1N1 A/Puerto Rico/8/1934, (<b>B</b>) H1N1 A/California/7/2009, and (<b>C</b>) H1N1 A/Brisbane/59/2007. DDT-treated lung supernatants from immunized mice in the H3-HA groups were tested with H3-HA proteins of (<b>D</b>) H3N2 A/Perth/16/2009, (<b>E</b>) H3N2 A/Wisconsin/67/2005, and (<b>F</b>) H3N2 A/New York/55/2004.</p>
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<p>Total T-cell responses with different panels of human HA peptide libraries. Splenocytes from the H1-HA groups were isolated and analyzed using ELISpot IFN-γ with human H1 influenza peptide libraries: (<b>A</b>) H1N1 A/Puerto Rico/8/1934 and (<b>B</b>) H1N1 A/Brisbane/59/2007. Similarly, splenocytes from the H3-HA groups were isolated and analyzed with human H3 influenza peptides libraries: (<b>C</b>) H3N2 A/Uruguay/716/2007 and (<b>D</b>) H3N2 A/Wisconsin/67e5/2005. Dashed lines represent the cut-off values (≥50 SFC/10<sup>6</sup> splenocytes).</p>
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<p>Protection against historical H1 influenza A viruses in mice. Mice were primed and boosted with immunization at days 0 and 21, respectively. Two weeks after boost immunization, mice were challenged intranasally with 10 MLD<sub>50</sub> of H1N1 A/Puerto Rico/8/1934 (panels (<b>A</b>–<b>C</b>)) or H1N1 A/Fort Monmouth/1/1947 (panels (<b>D</b>–<b>F</b>)). The figures depict the percentage of weight loss and area under the curve monitored over 14 days post-challenge. Animals that exhibited 25% or more weight loss were humanely euthanized.</p>
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<p>Protection against historical H3 influenza A viruses in mice. Mice were primed and boosted with immunization at days 0 and 21, respectively. Two weeks after boost immunization, mice were challenged intranasally with 10 MLD<sub>50</sub> of H3N1 A/Texas/1/1977 (panels (<b>A</b>–<b>C</b>)) or H3N2 A/Aichi/2/1968 (panels (<b>D</b>–<b>F</b>)). The figures depict the percentage of weight loss and area under the curve monitored over 14 days post-challenge. Animals that exhibited 25% or more weight loss were humanely euthanized.</p>
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