Influenza Vaccines Have a Short but Illustrious History of Dedicated Science Enabling the Rapid Global Production of A/Swine (H1N1) Vaccine in the Current Pandemic

2010 ◽  
pp. 115-147 ◽  
Author(s):  
John Oxford ◽  
Anthony Gilbert ◽  
Robert Lambkin-Williams
Keyword(s):  
Influenza Vaccines ◽  
H1n1 Vaccine ◽  
History Of

Design of the Recombinant Influenza Neuraminidase Antigen is Crucial for its Biochemical Properties and Protective Efficacy

2021 ◽  
Author(s):  
Jin Gao ◽  
Laura Klenow ◽  
Lisa Parsons ◽  
Tahir Malik ◽  
Je-Nie Phue ◽  
...  
Keyword(s):  
Single Dose ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Biochemical Properties ◽  
Cell System ◽  
Influenza Vaccines ◽  
H1n1 Vaccine ◽  
Protective Properties ◽  
Head Domain ◽  
Tetramerization Domain

Supplementing influenza vaccines with recombinant neuraminidase (rNA) antigens remains a promising approach for improving the suboptimal vaccine efficacy. However, correlations among rNA designs, properties, and protection have not been systematically investigated. Here, we performed a comparative analysis of several rNAs produced using the baculovirus/insect cell system. The rNAs were designed with different tetramerization motifs and NA domains from a recent H1N1 vaccine strain (A/Brisbane/02/2018) and were compared for enzymatic property, antigenicity, stability, and protection in mice. We found that distinct enzymatic properties are associated with rNAs containing the NA head-domain versus the full-ectodomain, formation of higher order rNA oligomers is tetramerization domain-dependent, whereas protective efficacy is more contingent on the combination of the tetramerization and NA domains. Following single-dose immunizations, a rNA possessing the full-ectodomain and the tetramerization motif from the human vasodilator-stimulated phosphoprotein provided much better protection than a rNA with ∼10-fold more enzymatically active molecules that is comprised of the head-domain and the same tetramerization motif. In contrast, these two rNA designs provided comparable protection when the tetramerization motif from the tetrabrachion protein was used instead. These findings demonstrate that individual rNAs should be thoroughly evaluated for vaccine development, as the heterologous domain combination can result in rNAs with similar key attributes but vastly differ in protection. IMPORTANCE For several decades it has been proposed that influenza vaccines could be supplemented with recombinant neuraminidase (rNA) to improve the efficacy. However, some key questions for manufacturing stable and immunogenic rNA remain to be answered. We show here that the tetramerization motifs and NA domains included in the rNA construct design can have a profound impact on the biochemical, immunogenic and protective properties. We also show that the single-dose immunization regimen is more informative for assessing the rNA immune response and protective efficacy, which is surprisingly more dependent on the specific combination of NA and tetramerization domains than common attributes for evaluating NA. Our findings may help to optimize the design of rNAs that can be used to improve or develop influenza vaccines.

scholarly journals Challenges of Making Effective Influenza Vaccines

2020 ◽  
Vol 7 (1) ◽  
pp. 495-512
Author(s):  
Sigrid Gouma ◽  
Elizabeth M. Anderson ◽  
Scott E. Hensley
Keyword(s):  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Influenza Season ◽  
Viral Evolution ◽  
Influenza Vaccines ◽  
Antigen Production ◽  
Production Processes ◽  
Vaccine Antigens ◽  
History Of ◽  
Viral Vaccines

Seasonal influenza vaccines prevent influenza-related illnesses, hospitalizations, and deaths. However, these vaccines are not as effective as other viral vaccines, and there is clearly room for improvement. Here, we review the history of seasonal influenza vaccines, describe challenges associated with producing influenza vaccine antigens, and discuss the inherent difficulties of updating influenza vaccine strains each influenza season. We argue that seasonal influenza vaccines can be dramatically improved by modernizing antigen production processes and developing models that are better at predicting viral evolution. Resources should be specifically dedicated to improving seasonal influenza vaccines while developing entirely new vaccine platforms.

scholarly journals Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein–Based Influenza Vaccines During the 2017–2018 Season

2019 ◽  
Vol 71 (6) ◽  
pp. 1447-1453 ◽  
Author(s):  
Sigrid Gouma ◽  
Seth J Zost ◽  
Kaela Parkhouse ◽  
Angela Branche ◽  
David J Topham ◽  
...  
Keyword(s):  
Recombinant Protein ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Influenza Vaccines ◽  
Vaccine Antigen ◽  
H3n2 Virus ◽  
High Dose ◽  
Wild Type ◽  
H1n1 Vaccine ◽  
Antibody Titers

Abstract Background The H3N2 component of egg-based 2017–2018 influenza vaccines possessed an adaptive substitution that alters antigenicity. Several influenza vaccines include antigens that are produced through alternative systems, but a systematic comparison of different vaccines used during the 2017–2018 season has not been completed. Methods We compared antibody responses in humans vaccinated with Fluzone (egg-based, n = 23), Fluzone High-Dose (egg-based, n = 16), Flublok (recombinant protein–based, n = 23), or Flucelvax (cell-based, n = 23) during the 2017–2018 season. We completed neutralization assays using an egg-adapted H3N2 virus, a cell-based H3N2 virus, wild-type 3c2.A and 3c2.A2 H3N2 viruses, and the H1N1 vaccine strain. We also performed enzyme-linked immunosorbent assays using a recombinant wild-type 3c2.A hemagglutinin. Antibody responses were compared in adjusted analysis. Results Postvaccination neutralizing antibody titers to 3c2.A and 3c2.A2 were higher in Flublok recipients compared with Flucelvax or Fluzone recipients (P < .01). Postvaccination titers to 3c2.A and 3c2.A2 were similar in Flublok and Fluzone High-Dose recipients, though seroconversion rates trended higher in Flublok recipients. Postvaccination titers in Flucelvax recipients were low to all H3N2 viruses tested, including the cell-based H3N2 strain. Postvaccination neutralizing antibody titers to H1N1 were similar among the different vaccine groups. Conclusions These data suggest that influenza vaccine antigen match and dose are both important for eliciting optimal H3N2 antibody responses in humans. Future studies should be designed to determine if our findings directly impact vaccine effectiveness. Clinical Trials Registration NCT03068949.

scholarly journals Comparative Immunogenicity of the 2014–2015 Northern Hemisphere Trivalent IIV and LAIV against Influenza A Viruses in Children

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 87 ◽  
Author(s):  
Jann Catherine Ang ◽  
Biao Wang ◽  
Joanne J.F. Wang ◽  
Peter Yu Fan Zeng ◽  
Florian Krammer ◽  
...  
Keyword(s):  
Northern Hemisphere ◽  
Influenza A ◽  
Geographic Location ◽  
High Risk Group ◽  
Influenza Vaccines ◽  
Influenza A Viruses ◽  
H1n1 Vaccine ◽  
Specific Serum ◽  
Serum Iga ◽  
H3n2 Vaccine

Both inactivated influenza vaccines (IIV) and live-attenuated influenza vaccines (LAIV) have been recommended for administration to children. Children are a high-risk group for severe influenza, and a major source of transmission. Therefore, prevention of infection by vaccination is particularly important. However, efficacy and immunogenicity of these vaccines are known to vary by season and geographic location. We compared the immunogenicity of the 2014–2015 Northern Hemisphere trivalent IIV and LAIV against influenza A virus in Canadian Hutterite children aged 2 to 17 using hemagglutination inhibition (HAI) assays, and enzyme-linked immunosorbent assays to measure hemagglutinin-specific serum IgA and mucosal IgA. Both vaccine formulations induced significant increases in HAI titers against H1N1 and H3N2 vaccine strains. Serum IgA titers against H3N2 were significantly boosted by both IIV and LAIV, while only IIV induced a significant increase in serum IgA specific to the H1N1 vaccine strain. While HAI titers correlated with protection conferred by IIV, mucosal IgA titers correlated with protection conferred by LAIV (mucosal IgA titers could not be established as a correlate for IIV due to sample size limitations). IIV and LAIV were previously reported to be equally efficacious in this cohort, although the immunogenicity of IIV was generally superior.

scholarly journals Comparison of a Live Attenuated 2009 H1N1 Vaccine with Seasonal Influenza Vaccines against 2009 Pandemic H1N1 Virus Infection in Mice and Ferrets

2011 ◽  
Vol 203 (7) ◽  
pp. 930-936 ◽  
Author(s):  
Grace L. Chen ◽  
Ji-Young Min ◽  
Elaine W. Lamirande ◽  
Celia Santos ◽  
Hong Jin ◽  
...  
Keyword(s):  
Virus Infection ◽  
Seasonal Influenza ◽  
H1n1 Virus ◽  
Influenza Vaccines ◽  
Pandemic H1n1 ◽  
H1n1 Vaccine ◽  
2009 H1n1 ◽  
H1n1 Virus Infection

scholarly journals Balancing the influenza neuraminidase and hemagglutinin responses by exchanging the vaccine virus backbone

2021 ◽  
Vol 17 (4) ◽  
pp. e1009171
Author(s):  
Jin Gao ◽  
Hongquan Wan ◽  
Xing Li ◽  
Mira Rakic Martinez ◽  
Laura Klenow ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibody ◽  
Vaccine Virus ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Influenza Vaccines ◽  
Inhibitory Antibody ◽  
H1n1 Vaccine ◽  
Systematic Analysis ◽  
Vaccine Antigens

Virions are a common antigen source for many viral vaccines. One limitation to using virions is that the antigen abundance is determined by the content of each protein in the virus. This caveat especially applies to viral-based influenza vaccines where the low abundance of the neuraminidase (NA) surface antigen remains a bottleneck for improving the NA antibody response. Our systematic analysis using recent H1N1 vaccine antigens demonstrates that the NA to hemagglutinin (HA) ratio in virions can be improved by exchanging the viral backbone internal genes, especially the segment encoding the polymerase PB1 subunit. The purified inactivated virions with higher NA content show a more spherical morphology, a shift in the balance between the HA receptor binding and NA receptor release functions, and induce a better NA inhibitory antibody response in mice. These results indicate that influenza viruses support a range of ratios for a given NA and HA pair which can be used to produce viral-based influenza vaccines with higher NA content that can elicit more balanced neutralizing antibody responses to NA and HA.

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