Influenza vaccines: the potential benefits of cell-culture isolation and manufacturing

Abstract

Influenza continues to cause severe illness in millions and deaths in hundreds of thousands annually. Vaccines are used to prevent influenza outbreaks, however, the influenza virus mutates and annual vaccination is required for optimal protection. Vaccine effectiveness is also affected by other potential factors such as the human immune system, a mismatch with the chosen candidate virus, and egg adaptation associated with egg-based vaccine production. This article reviews the influenza vaccine development process and describes the implications of the changes to the cell-culture process and vaccine strain recommendations by the World Health Organization since the 2017 season. The traditional manufacturing process for influenza vaccines relies on fertilized chicken eggs that are used for vaccine production. Vaccines must be produced in large volumes and the complete process requires approximately 6 months for the egg-based process. In addition, egg adaptation of seed viruses occurs when viruses adapt to avian receptors found within eggs to allow for growth in eggs. These changes to key viral antigens may result in antigenic mismatch and thereby reduce vaccine effectiveness. By contrast, cell-derived seed viruses do not require fertilized eggs and eliminate the potential for egg-adapted changes. As a result, cell-culture technology improves the match between the vaccine virus strain and the vaccine selected strain, and has been associated with increased vaccine effectiveness during a predominantly H3N2 season. During the 2017–2018 influenza season, a small number of studies conducted in the United States compared the effectiveness of egg-based and cell-culture vaccines and are described here. These observational and retrospective studies demonstrate that inactivated cell-culture vaccines were more effective than egg-based vaccines. Adoption of cell-culture technology for influenza vaccine manufacturing has been reported to improve manufacturing efficiency and the additional benefit of improving vaccine effectiveness is a key factor for future policy making considerations.

COVID-19 vaccines: The status and perspectives in delivery points of view

“…Viruses of choice must first be propagated in cells, isolated, and purified. For the influenza vaccine, the propagation is accomplished in fertilized chicken eggs [ 327 ]. However, SARS-CoV-2 does not replicate in chicken eggs [ 328 ] and demands an alternative scalable production method which is typically costly to develop and often requires specialized equipment.…”

Adaptation of influenza viruses to human airway receptors

“…Presence of additional steric bulk above the H3 RBS appears to reinforce selectivity for extended human-type receptors, since H3N2 strains produced in eggs (though not within MDCK cells) for subsequent seasonal vaccines resulted exclusively in reversion to 160K, removing the N158 glycan and presumably enabling improved growth in eggs through binding to short glycan receptors ( 57 ). Analyses of antibodies produced in both humans and ferrets vaccinated with the egg-grown vaccine showed reactivity to mutant T160K HA, but poor reactivity and neutralization of viruses containing wild-type T160 HA ( 56 , 57 ). CDC data shows that vaccine effectiveness (VE) against H3N2 strains has been steadily decreasing over the last several years ( https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html , June 2020), in part due to the highly evolved receptor specificity now prevalent within these strains.…”

“…Mismatches in receptor specificity of IAVs for their natural receptors in humans and receptors present in laboratory hosts are not new ( 51 , 52 , 53 , 54 , 55 ), having been described in 1949 by Burnet upon passage of H1N1 viruses in eggs resulting in a switch from the “O” (original) to “D” (derived) specificity, as measured by acquisition of hemagglutination with chicken erythrocytes ( 51 ). For recent H3N2 viruses, specificity mismatches are particularly consequential since commercial vaccines are produced in eggs, and primary H3N2 isolates grow poorly in these hosts due to the absence of extended α2-6 sialic acid receptors found in humans ( 56 , 57 , 58 ). Indeed, it is well documented that N-linked glycans found on cells lining the amniotic membrane of chicken eggs contain both human type (α2-6) and avian type (α2-3) sialic acid linkages; however, these receptors are found exclusively on short trisaccharide extensions attached to the Man 3 GlcNAc 2 Asn core ( 59 ).…”

Optimization of the human colorectal carcinoma antigen GA733-2 production in tobacco plants

“…Compare to bacterial system, mammalian cell system allows proper folding and authentic post-translational modification of recombinant protein (Lomonossoff and D'Aoust 2016 , Shanmugaraj et al 2020 ). Based on the advantages, mammalian cell system have contributed to produce many commercially available vaccines (Francis 2018 ; Rajaram et al 2020 ; Zost et al 2017 ). Despite of the advantages, high production cost and possible contamination of human pathogens have been regarded as hurdles for application of mammalian cell system for vaccine production (Schillberg et al 2019 ).…”