scholarly journals Strategies Targeting Hemagglutinin as a Universal Influenza Vaccine

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 257
Author(s):  
Brianna L. Bullard ◽  
Eric A. Weaver
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Vaccine Efficacy ◽  
Influenza Season ◽  
Surface Protein ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Viral Diversity ◽  
Universal Influenza Vaccine ◽  
Ha Protein

Influenza virus has significant viral diversity, both through antigenic drift and shift, which makes development of a vaccine challenging. Current influenza vaccines are updated yearly to include strains predicted to circulate in the upcoming influenza season, however this can lead to a mismatch which reduces vaccine efficacy. Several strategies targeting the most abundant and immunogenic surface protein of influenza, the hemagglutinin (HA) protein, have been explored. These strategies include stalk-directed, consensus-based, and computationally derived HA immunogens. In this review, we explore vaccine strategies which utilize novel antigen design of the HA protein to improve cross-reactive immunity for development of a universal influenza vaccine.

scholarly journals An Antigenic Thrift-Based Approach to Influenza Vaccine Design

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 657
Author(s):  
Jai S. Bolton ◽  
Hannah Klim ◽  
Judith Wellens ◽  
Matthew Edmans ◽  
Uri Obolski ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Influenza Season ◽  
Vaccine Design ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Immune Protection ◽  
Immune Selection ◽  
Drift Theory ◽  
Gradual Accumulation ◽  
Additional Constraints

The antigenic drift theory states that influenza evolves via the gradual accumulation of mutations, decreasing a host’s immune protection against previous strains. Influenza vaccines are designed accordingly, under the premise of antigenic drift. However, a paradox exists at the centre of influenza research. If influenza evolved primarily through mutation in multiple epitopes, multiple influenza strains should co-circulate. Such a multitude of strains would render influenza vaccines quickly inefficacious. Instead, a single or limited number of strains dominate circulation each influenza season. Unless additional constraints are placed on the evolution of influenza, antigenic drift does not adequately explain these observations. Here, we explore the constraints placed on antigenic drift and a competing theory of influenza evolution – antigenic thrift. In contrast to antigenic drift, antigenic thrift states that immune selection targets epitopes of limited variability, which constrain the variability of the virus. We explain the implications of antigenic drift and antigenic thrift and explore their current and potential uses in the context of influenza vaccine design.

scholarly journals Host Factors Impact Vaccine Efficacy: Implications for Seasonal and Universal Influenza Vaccine Programs

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Santosh Dhakal ◽  
Sabra L. Klein
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Virus Vaccine ◽  
Vaccine Efficacy ◽  
Public Health Problem ◽  
Influenza Virus Vaccine ◽  
Host Factors ◽  
Influenza Vaccines ◽  
Vaccine Type ◽  
Induced Immunity

ABSTRACT Influenza is a global public health problem. Current seasonal influenza vaccines have highly variable efficacy, and thus attempts to develop broadly protective universal influenza vaccines with durable protection are under way. While much attention is given to the virus-related factors contributing to inconsistent vaccine responses, host-associated factors are often neglected. Growing evidences suggest that host factors including age, biological sex, pregnancy, and immune history play important roles as modifiers of influenza virus vaccine efficacy. We hypothesize that host genetics, the hormonal milieu, and gut microbiota contribute to host-related differences in influenza virus vaccine efficacy. This review highlights the current insights and future perspectives into host-specific factors that impact influenza vaccine-induced immunity and protection. Consideration of the host factors that affect influenza vaccine-induced immunity might improve influenza vaccines by providing empirical evidence for optimizing or even personalizing vaccine type, dose, and use of adjuvants for current seasonal and future universal influenza vaccines.

scholarly journals Designed Nanoparticles Elicit Cross-Reactive Antibody Responses To Conserved Influenza Virus Hemagglutinin Stem Epitopes

2019 ◽  
Author(s):  
Dustin M. McCraw ◽  
Mallory L. Myers ◽  
Neetu M. Gulati ◽  
John R. Gallagher ◽  
Alexander J. Kim ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Vaccine Development ◽  
Cross Reactivity ◽  
Surface Glycoprotein ◽  
Influenza Vaccines ◽  
Health Concern ◽  
Public Health Issue ◽  
Lethal Challenge ◽  
Universal Influenza Vaccine

AbstractDespite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that an alpha-helical fragment (helix-A) from the conserved stem region can be displayed on nanoparticles. The stem region of HA on these nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, H1-nanoparticles protected mice from lethal challenge with H1N1 influenza virus. Importantly, antibodies elicited by these nanoparticles demonstrated homosubtypic and heterosubtypic cross-reactivity. The helix-A stem nanoparticle design represents a novel approach to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens up opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes.SignificanceInfluenza virus is a public health issue that affects millions of people globally each year. Commercial influenza vaccines are based on the hemagglutinin (HA) surface glycoprotein, which can change antigenically every year, demanding the manufacture of newly matched vaccines annually. HA stem epitopes have a higher degree of conservation than HA molecules contained in conventional vaccine formulations and we demonstrate that we are able to design nanoparticles that display hundreds of HA stem fragments on nanoparticles. These designed nanoparticles are heat-stable, elicit antibodies to the HA stem, confer protection in mouse challenge models, and show cross-reactivity between HA subtypes. This technology provides promising opportunities to improve seasonal vaccines, develop pandemic preparedness vaccines, and facilitate the development of a universal influenza vaccine.

scholarly journals M2e-Based Influenza Vaccines with Nucleoprotein: A Review

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 739
Author(s):  
Mei Peng Tan ◽  
Wen Siang Tan ◽  
Noorjahan Banu Mohamed Alitheen ◽  
Wei Boon Yap
Keyword(s):  
T Cell ◽  
Influenza Vaccine ◽  
Matrix Protein ◽  
Severe Disease ◽  
Chimeric Protein ◽  
Influenza Vaccines ◽  
Cell Responses ◽  
Hospitalization Rates ◽  
Humoral Responses ◽  
Universal Influenza Vaccine

Discovery of conserved antigens for universal influenza vaccines warrants solutions to a number of concerns pertinent to the currently licensed influenza vaccines, such as annual reformulation and mismatching with the circulating subtypes. The latter causes low vaccine efficacies, and hence leads to severe disease complications and high hospitalization rates among susceptible and immunocompromised individuals. A universal influenza vaccine ensures cross-protection against all influenza subtypes due to the presence of conserved epitopes that are found in the majority of, if not all, influenza types and subtypes, e.g., influenza matrix protein 2 ectodomain (M2e) and nucleoprotein (NP). Despite its relatively low immunogenicity, influenza M2e has been proven to induce humoral responses in human recipients. Influenza NP, on the other hand, promotes remarkable anti-influenza T-cell responses. Additionally, NP subunits are able to assemble into particles which can be further exploited as an adjuvant carrier for M2e peptide. Practically, the T-cell immunodominance of NP can be transferred to M2e when it is fused and expressed as a chimeric protein in heterologous hosts such as Escherichia coli without compromising the antigenicity. Given the ability of NP-M2e fusion protein in inducing cross-protective anti-influenza cell-mediated and humoral immunity, its potential as a universal influenza vaccine is therefore worth further exploration.

scholarly journals Start of the influenza season 2008-9 in Europe - increasing influenza activity moving from West to East dominated by A(H3N2)

2009 ◽  
Vol 14 (3) ◽  
Author(s):  
N Goddard ◽  
P Zucs ◽  
B Ciancio ◽  
F Plata ◽  
O Hungnes ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Northern Hemisphere ◽  
Virus Type ◽  
Influenza Season ◽  
Type A ◽  
Neuraminidase Inhibitors ◽  
Influenza Activity

The influenza season 2008-9 started in week 49 of 2008 and is so far characterised by influenza virus type A subtype H3N2. Isolates of this subtype that were tested proved susceptible to neuraminidase inhibitors, but resistant to M2 inhibitors. The circulating A(H3N2) viruses are antigenically similar to the component in the current northern hemisphere influenza vaccine.

scholarly journals Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Virus Infections ◽  
Head Region ◽  
Immune Pressure ◽  
Stalk Domain ◽  
Ha Protein

Abstract The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.

scholarly journals Relative Effectiveness of the Cell-Cultured Quadrivalent Influenza Vaccine Compared to Standard, Egg-derived Quadrivalent Influenza Vaccines in Preventing Influenza-like Illness in 2017–2018

2020 ◽  
Vol 71 (10) ◽  
pp. e665-e671 ◽  
Author(s):  
Constantina Boikos ◽  
Gregg C Sylvester ◽  
John S Sampalis ◽  
James A Mansi
Keyword(s):  
Cell Culture ◽  
Health Status ◽  
Influenza Vaccine ◽  
Influenza Season ◽  
Relative Effectiveness ◽  
Geographic Region ◽  
Influenza Vaccines ◽  
Study Cohort ◽  
Influenza Like Illness ◽  
Adaptive Mutations

Abstract Background Influenza antigens may undergo adaptive mutations during egg-based vaccine production. In the 2017–2018 influenza season, quadrivalent, inactivated cell-derived influenza vaccine (ccIIV4) vaccine was produced using A(H3N2) seed virus propagated exclusively in cell culture, thus lacking egg adaptive changes. This United States study estimated relative vaccine effectiveness (rVE) of ccIIV4 vs egg-derived quadrivalent vaccines (egg-derived IIV4) for that season. Methods Vaccination, outcome, and covariate data were ascertained retrospectively from a electronic medical record (EMR) dataset and analyzed. The study cohort included patients ≥ 4 years of age. rVE was estimated against influenza-like illness (ILI) using diagnostic International Classification of Diseases, Ninth or Tenth Revision codes. The adjusted odds ratios used to derive rVE estimates were estimated from multivariable logistic regression models adjusted for age, sex, race/ethnicity, geographic region, and health status. Results Overall, 92 187 individuals had a primary care EMR record of ccIIV4 and 1 261 675 had a record of egg-derived IIV4. In the ccIIV4 group, 1705 narrowly defined ILI events occurred, and 25 645 occurred in the standard egg-derived IIV4 group. Crude rVE was 9.2% (95% confidence interval [CI], 4.6%–13.6%). When adjusted for age, sex, health status, comorbidities, and geographic region, the estimated rVE changed to 36.2% (95% CI, 26.1%–44.9%). Conclusions ccIIV4, derived from A(H3N2) seed virus propagated exclusively in cell culture, was more effective than egg-derived IIV4 in preventing ILI during the 2017–2018 influenza season. This result suggests that cell-derived influenza vaccines may have greater effectiveness than standard egg-derived vaccines.

scholarly journals A Real-World Clinical and Economic Analysis of Cell-derived Quadrivalent Influenza Vaccine Compared to Standard Egg-derived Quadrivalent Influenza Vaccines During the 2019-20 Influenza Season in the United States

2021 ◽  
Author(s):  
Victoria Divino ◽  
Vamshi Ruthwik Anupindi ◽  
Mitch DeKoven ◽  
Joaquin Mould-Quevedo ◽  
Stephen I Pelton ◽  
...  
Keyword(s):  
High Risk ◽  
Influenza Vaccine ◽  
Influenza Season ◽  
The United States ◽  
Vaccine Effectiveness ◽  
Influenza Vaccines ◽  
Sensitivity Analyses ◽  
Administrative Claims ◽  
Adaptive Mutations ◽  
Quadrivalent Influenza Vaccine

Abstract Background Cell-derived influenza vaccines are not subject to egg adaptive mutations that have potential to decrease vaccine effectiveness. This retrospective analysis estimated the relative vaccine effectiveness (rVE) of cell-derived quadrivalent influenza vaccine (IIV4c) compared to standard egg-derived quadrivalent influenza vaccines (IIV4e) among recipients aged 4-64 years in the US during the 2019-20 influenza season. Methods The IQVIA PharMetrics® Plus administrative claims database was utilized. Study outcomes were assessed post-vaccination through the end of the study period (March 7, 2020). Inverse probability of treatment weighting (IPTW) was implemented to adjust for covariate imbalance. Adjusted rVE against influenza-related hospitalizations/emergency room (ER) visits and other clinical outcomes was estimated through IPTW-weighted Poisson regression models for the IIV4c and IIV4e cohorts and for the subgroup with ≥1 high-risk condition. Sensitivity analyses modifying the outcome assessment period as well as a doubly-robust analysis were also conducted. IPTW-weighted generalized linear models were used to estimate predicted annualized all-cause costs. Results The final sample comprised 1,138,969 IIV4c and 3,926,357 IIV4e recipients following IPTW adjustment. IIV4c was more effective in preventing influenza-related hospitalizations/ER visits as well as respiratory-related hospitalizations/ER visits compared to IIV4e. IIV4c was also more effective for the high-risk subgroup and across the sensitivity analyses. IIV4c was also associated with significantly lower annualized all-cause total costs compared to IIV4e (-$467), driven by lower costs for outpatient medical services and inpatient hospitalizations. Conclusions IIV4c was significantly more effective in preventing influenza-related hospitalizations/ER visits compared to IIV4e and was associated with significantly lower all-cause costs.

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