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The Recent Development of Influenza Vaccine: 2nd Edition

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

Deadline for manuscript submissions: closed (31 March 2026) | Viewed by 27752

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Dr. Ramireddy Bommireddy

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Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
Interests: influenza; older population; adjuvants; universal vaccine
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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 (9 papers)

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Research

Jump to: Review

13 pages, 1163 KB

Open AccessArticle

Influenza Vaccination and Cardiovascular Outcomes in Patients with Coronary Artery Diseases: A Placebo-Controlled Randomized Study, IVCAD

by Mohammadmoein Dehesh, Sharareh Gholamin, Seyed-Mostafa Razavi, Ali Eskandari, Hossein Vakili, Mohammad Rahnavardi Azari, Yunzhi Wang, Ethan K. Gough and Maryam Keshtkar-Jahromi

Vaccines 2025, 13(5), 472; https://doi.org/10.3390/vaccines13050472 - 27 Apr 2025

Cited by 3 | Viewed by 3879

Abstract

Background/Objectives: Influenza infection is associated with cardiovascular morbidity and mortality; however, the effect of influenza vaccination on cardiovascular outcomes is not fully understood. This clinical trial aimed to investigate the correlation between cardiovascular outcomes and influenza vaccine (FluVac) in coronary artery disease (CAD) subjects. Methods: This was a randomized single-blinded placebo-controlled trial. Enrolled CAD subjects received 0.5 mL of 2007–2008 trivalent FluVac (15 µg hemagglutinin of each of Solomon Islands/3/2006 (H1N1), Wisconsin/67/2005 (H3N2), and Malaysia/2506/2004 (B)). The subjects were followed up at 1 month (hemagglutinin (HA) antibody titers) and at 12 months post-vaccination for evaluation of outcomes (influenza-like episodes, acute coronary syndrome (ACS), myocardial infarction (MI), coronary revascularization, and death). Results: In total, 278 eligible CAD subjects were randomized to receive either FluVac (n = 137) or a placebo (n = 141), of which consequently 131 and 135 subjects completed the study. Cardiovascular deaths (3/131 [2.29%] vs. 3/135 [2.22%]) and all-cause deaths (4/131 [3.05%] vs. 4/135 [2.96%]) were similar in both groups. Adverse cardiovascular events, including ACS, MI, and coronary revascularization, were less frequent in the vaccine group but did not reach statistical significance. The magnitude of the antibody change and serologic response (≥4-fold HI titer rise) of all three antibodies were significantly higher in the vaccine group compared to the placebo but did not correlate with cardiovascular outcomes in the FluVac group. Conclusions: The influenza vaccine may improve cardiovascular outcomes, though this improvement is not correlated with post-vaccination antibody titers. Despite the controversy, influenza vaccination is recommended in the CAD population (clinicaltrials.gov; NCT00607178). Full article

(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)

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15 pages, 3655 KB

Open AccessArticle

Truncated NS1 Influenza A Virus Induces a Robust Antigen-Specific Tissue-Resident T-Cell Response and Promotes Inducible Bronchus-Associated Lymphoid Tissue Formation in Mice

by Anna-Polina Shurygina, Marina Shuklina, Olga Ozhereleva, Ekaterina Romanovskaya-Romanko, Sofia Kovaleva, Andrej Egorov, Dmitry Lioznov and Marina Stukova

Vaccines 2025, 13(1), 58; https://doi.org/10.3390/vaccines13010058 - 10 Jan 2025

Cited by 4 | Viewed by 2839

Abstract

Background: Influenza viruses with truncated NS1 proteins show promise as viral vectors and candidates for mucosal universal influenza vaccines. These mutant NS1 viruses, which lack the N-terminal half of the NS1 protein (124 a.a.), are unable to antagonise the innate immune response. This creates a self-adjuvant effect enhancing heterologous protection by inducing a robust CD8+ T-cell response together with immunoregulatory mechanisms. However, the effects of NS1 modifications on T-follicular helper (Tfh) and B-cell responses remain less understood. Methods: C57bl/6 mice were immunised intranasally with 10 μL of either an influenza virus containing a truncated NS1 protein (PR8/NS124), a cold-adapted influenza virus with a full-length NS1 (caPR8/NSfull), or a wild-type virus (PR8/NSfull). Immune responses were assessed on days 8 and 28 post-immunisation by flow cytometry, ELISA, and HAI assay. Results: In this study, we demonstrate that intranasal immunisation with PR8/NS124 significantly increases tissue-resident CD4+ and CD8+ T cells in the lungs and activates Tfh cells in regional lymph nodes as early as day 8 post-immunisation. These effects are not observed in mice immunised with caPR8/NSfull or PR8/NSfull. Notably, PR8/NS124 immunisation also leads to the development of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs by day 28, characterised by the presence of antigen-specific Tfh cells and GL7+Fas+ germinal centre B cells. Conclusions: Our findings further underscore the potential of NS1-truncated influenza viruses to drive robust mucosal immune responses and enhance vaccine efficacy. Full article

(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)

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16 pages, 3076 KB

Open AccessArticle

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

Cited by 4 | Viewed by 3272

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 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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13 pages, 991 KB

Open AccessArticle

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

Cited by 3 | Viewed by 2366

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 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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27 pages, 6621 KB

Open AccessArticle

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

Cited by 3 | Viewed by 2690

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 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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16 pages, 1793 KB

Open AccessArticle

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

Cited by 7 | Viewed by 4275

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 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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20 pages, 7048 KB

Open AccessArticle

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

Cited by 6 | Viewed by 3625

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). 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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Review

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11 pages, 884 KB

Open AccessReview

Shifting Perspective in Influenza Vaccines Efficacy: How Risk Difference Shows an Alternative View of the Comparative Efficacy Profile of Newer and Enhanced Influenza Vaccines Compared to Standard, Egg-Based Vaccines

by Laura Colombo, Abraham Palache and Sanjay Hadigal

Vaccines 2026, 14(1), 108; https://doi.org/10.3390/vaccines14010108 - 22 Jan 2026

Viewed by 1058

Abstract

Annual influenza vaccination remains critical for mitigating severe illness and reducing healthcare strain, particularly among high-risk populations. Despite advancements in vaccine platforms, the comparative efficacy of novel vaccines—such as high-dose (HD-IIV), recombinant (rIV), cell-based (cIV), and adjuvanted (aIV) influenza vaccines—versus standard-dose non-adjuvanted (SD-IIV) vaccines remains a public health concern. Traditional Relative Vaccine Efficacy (rVE) metrics, though robust, may overestimate population-level benefits. This short communication explores alternative comparative efficacy measures: risk difference (ΔRD) and number needed to vaccinate (ΔNNV). Analysis of data derived from randomized controlled trials (RCTs), or robust pragmatic trials, shows that while rVE values for newer vaccines often indicate superior efficacy, ΔRD and ΔNNV highlight the limits in incremental protection at the population level, with ΔRD generally below 10 cases per 1000 vaccinated. These findings underline the sustained relevance of SD-IIV in immunization programs and emphasize the need for broader vaccine coverage to highlight the benefits of vaccination and enhance population health outcomes. Full article

(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)

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17 pages, 633 KB

Open AccessReview

Brief Comparison of Novel Influenza Vaccine Design Strategies

by Shiqi Chai, Chuantao Ye, Chao Fan and Hong Jiang

Vaccines 2025, 13(11), 1164; https://doi.org/10.3390/vaccines13111164 - 15 Nov 2025

Cited by 2 | Viewed by 2348

Abstract

Influenza viruses remain a major global public health concern, causing significant morbidity and mortality annually despite widespread vaccination efforts. The limitations of current seasonal vaccines, including strain-specific efficacy and manufacturing delays, have accelerated the development of next-generation candidates aiming for universal protection. This review comprehensively summarizes the recent progress in universal influenza vaccine research. We first outline the key conserved antigenic targets, such as the hemagglutinin (HA) stem, neuraminidase (NA), and matrix proteins (M2e, NP, and M1), which are crucial for eliciting broad cross-reactive immunity. We then delve into advanced antigen design strategies, including immunofocusing, multi-antigen combinations, computationally optimized broadly reactive antigens (COBRA), and nanoparticle-based platforms. Furthermore, we evaluate evolving vaccine delivery systems, from traditional inactivated and live-attenuated vaccines to modern mRNA and viral vector platforms, alongside the critical role of novel adjuvants in enhancing immune responses. The convergence of these disciplines—structural biology, computational design, and nanotechnology—is driving the field toward a transformative goal. We conclude that the successful development of a universal influenza vaccine will likely depend on the strategic integration of these innovative approaches to overcome existing immunological and logistical challenges, ultimately providing durable and broad-spectrum protection against diverse influenza virus strains. Full article

(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)

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