Influenza Vaccine Manufacturing: Effect of Inactivation, Splitting and Site of Manufacturing. Comparison of Influenza Vaccine Production Processes.
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ABSTRACT:
SUBMITTER: Kon TC
PROVIDER: S-EPMC4784929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Millions of seasonal and pandemic influenza vaccine doses containing oil-in-water emulsion adjuvant have been administered in order to enhance and broaden immune responses and to facilitate antigen sparing. Despite the enactment of a Global Action Plan for Influenza Vaccines and a multi-fold increase in production capabilities over the past 10 years, worldwide capacity for pandemic influenza vaccine production is still limited. In developing countries, where routine influenza vaccination is not fully established, additional measures are needed to ensure adequate supply of pandemic influenza vaccines without dependence on the shipment of aid from other, potentially impacted first-world countries. Adaptation of influenza vaccine and adjuvant technologies by developing country influenza vaccine manufacturers may enable antigen sparing and corresponding increases in global influenza vaccine coverage capacity. Following on previously described work involving the technology transfer of oil-in-water emulsion adjuvant manufacturing to a Romanian vaccine manufacturing institute, we herein describe the preclinical evaluation of inactivated split virion H5N1 influenza vaccine with emulsion adjuvant, including immunogenicity, protection from virus challenge, antigen sparing capacity, and safety. In parallel with the evaluation of the bioactivity of the tech-transferred adjuvant, we also describe the impact of concurrent antigen manufacturing optimization activities. Depending on the vaccine antigen source and manufacturing process, inclusion of adjuvant was shown to enhance and broaden functional antibody titers in mouse and rabbit models, promote protection from homologous virus challenge in ferrets, and facilitate antigen sparing. Besides scientific findings, the operational lessons learned are delineated in order to facilitate adaptation of adjuvant technologies by other developing country institutes to enhance global pandemic influenza preparedness.
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Project description:Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.
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Project description:BackgroundInfluenza vaccination is recommended for all US residents aged ≥6 months. Vaccine effectiveness (VE) varies by age, circulating influenza strains, and the presence of high-risk medical conditions. We examined site-specific VE in the US Influenza VE Network, which evaluates annual influenza VE at ambulatory clinics in geographically diverse sites.MethodsAnalyses were conducted on 27 180 outpatients ≥6 months old presenting with an acute respiratory infection (ARI) with cough of ≤7-day duration during the 2011-2016 influenza seasons. A test-negative design was used with vaccination status defined as receipt of ≥1 dose of any influenza vaccine according to medical records, registries, and/or self-report. Influenza infection was determined by reverse-transcription polymerase chain reaction. VE estimates were calculated using odds ratios from multivariable logistic regression models adjusted for age, sex, race/ethnicity, time from illness onset to enrollment, high-risk conditions, calendar time, and vaccination status-site interaction.ResultsFor all sites combined, VE was statistically significant every season against all influenza and against the predominant circulating strains (VE = 19%-50%) Few differences among four sites in the US Flu VE Network were evident in five seasons. However, in 2015-16, overall VE in one site was 24% (95% CI = -4%-44%), while VE in two other sites was significantly higher (61%, 95% CI = 49%-71%; P = .002, and 53%, 95% CI = 33,67; P = .034).ConclusionWith few exceptions, site-specific VE estimates aligned with each other and overall VE estimates. Observed VE may reflect inherent differences in community characteristics of the sites and highlights the importance of diverse settings for studying influenza vaccine effectiveness.
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Project description:Through its Global Action Plan for Influenza Vaccines (GAP), the World Health Organization (WHO) in collaboration with the United States Department of Health and Human Services has produced a checklist to support policy-makers and influenza vaccine manufacturers in identifying key technological, political, financial, and logistical issues affecting the sustainability of influenza vaccine production. This checklist highlights actions in five key areas that are beneficial for establishing successful local vaccine manufacturing. These five areas comprise: (1) the policy environment and health-care systems; (2) surveillance systems and influenza evidence; (3) product development and manufacturing; (4) product approval and regulation; and (5) communication to support influenza vaccination. Incorporating the checklist into national vaccine production programmes has identified the policy gaps and next steps for countries involved in GAP's Technology Transfer Initiative. Lessons learnt from country experiences provide context and insight that complement the checklist's goal of simplifying the complexities of influenza prevention, preparedness, and vaccine manufacturing.
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Project description:BackgroundIn some settings, research methods to determine influenza vaccine effectiveness (VE) may not be appropriate because of cost, time constraints, or other factors. Administrative database analysis of viral testing results and vaccination history may be a viable alternative. This study compared VE estimates from outpatient research and administrative databases.MethodsUsing the test-negative, case-control design, data for 2017-2018 and 2018-2019 influenza seasons were collected using: 1) consent, specimen collection, RT-PCR testing and vaccine verification using multiple methods; and 2) an administrative database of outpatients with a clinical respiratory viral panel combined with electronic immunization records. Odds ratios for likelihood of influenza infection by vaccination status were calculated using multivariable logistic regression. VE = (1 - aOR) × 100.ResultsResearch participants were significantly younger (P < 0.001), more often white (69% vs. 59%; P < 0.001) than non-white and less frequently enrolled through the emergency department (35% vs. 72%; P < 0.001) than administrative database participants. VE was significant against all influenza and influenza A in each season and both seasons combined (37-49%). Point estimate differences between methods were evident, with higher VE in the research database, but insignificant due to low sample sizes. When enrollment sites were separately analyzed, there were significant differences in VE estimates for all influenza (66% research vs. 46% administrative P < 0.001) and influenza A (67% research vs. 49% administrative; P < 0.001) in the emergency department.ConclusionsThe selection of the appropriate method for determining influenza vaccine effectiveness depends on many factors, including sample size, subgroups of interest, etc., suggesting that research estimates may be more generalizable. Other advantages of research databases for VE estimates include lack of clinician-related selection bias for testing and less misclassification of vaccination status. The advantages of the administrative databases are potentially shorter time to VE results and lower cost.
| S-EPMC7825890 | biostudies-literature
Project description:Cell culture is now available as a method for the production of influenza vaccines in addition to eggs. In accordance with currently accepted practice, viruses recommended as candidates for vaccine manufacture are isolated and propagated exclusively in hens' eggs prior to distribution to manufacturers. Candidate vaccine viruses isolated in cell culture are not available to support vaccine manufacturing in mammalian cell bioreactors so egg-derived viruses have to be used. Recently influenza A (H3N2) viruses have been difficult to isolate directly in eggs. As mitigation against this difficulty, and the possibility of no suitable egg-isolated candidate viruses being available, it is proposed to consider using mammalian cell lines for primary isolation of influenza viruses as candidates for vaccine production in egg and cell platforms. To investigate this possibility, we tested the antigenic stability of viruses isolated and propagated in cell lines qualified for influenza vaccine manufacture and subsequently investigated antigen yields of such viruses in these cell lines at pilot-scale. Twenty influenza A and B-positive, original clinical specimens were inoculated in three MDCK cell lines. The antigenicity of recovered viruses was tested by hemagglutination inhibition using ferret sera against contemporary vaccine viruses and the amino acid sequences of the hemagglutinin and neuraminidase were determined. MDCK cell lines proved to be highly sensitive for virus isolation. Compared to the virus sequenced from the original specimen, viruses passaged three times in the MDCK lines showed up to 2 amino acid changes in the hemagglutinin. Antigenic stability was also established by hemagglutination inhibition titers comparable to those of the corresponding reference virus. Viruses isolated in any of the three MDCK lines grew reasonably well but variably in three MDCK cells and in VERO cells at pilot-scale. These results indicate that influenza viruses isolated in vaccine certified cell lines may well qualify for use in vaccine production.
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Project description:Zika virus (ZIKV) infection remains a public health concern necessitating demand for long-term virus production for diagnostic assays and R&D activities. Inactivated virus constitutes an important component of the Trioplex rRT-PCR assay and serological IgM assay (MAC-ELISA). The aim of our study is to establish standard methods of ZIKV inactivation while maintaining antigenicity and RNA integrity. We tested viral supernatants by four different inactivation methods: 1. Heat inactivation at 56 °C and 60 °C; 2. Gamma-Irradiation; 3. Chemical inactivation by Beta-propiolactone (BPL) and 4. Fast-acting commercial disinfecting agents. Effectivity was measured by cytopathic effect (CPE) and plaque assay. RNA stability and antigenicity were measured by RT-PCR and MAC-ELISA, respectively. Results: Heat inactivation: Low titer samples, incubated at 56 °C for 2 h, showed neither CPE or plaques compared to high titer supernatants that required 2.5 h. Inactivation occurred at 60 °C for 60 min with all virus titers. Gamma irradiation: Samples irradiated at ≥3 Mrad for low virus concentrations and ≥5Mrad for high virus titer completely inactivated virus. Chemical Inactivation: Neither CPE nor plaques were observed with ≥0.045 % BPL inactivation of ZIKV. Disinfectant: Treatment of viral supernatants with Micro-Chem Plus™, inactivated virus in 2 min, whereas, Ethanol (70 %) and STERIS Coverage® Spray TB inactivated the virus in 5 min.
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Project description:Recently developed devices mimic neuromuscular and neurosensory systems by integrating hydrogels and hydrophobic elastomers. While different methods are developed to bond hydrogels with hydrophobic elastomers, it remains a challenge to coat and print various hydrogels and elastomers of arbitrary shapes, in arbitrary sequences, with strong adhesion. Here we report an approach to meet this challenge. We mix silane coupling agents into the precursors of the networks, and tune the kinetics such that, when the networks form, the coupling agents incorporate into the polymer chains, but do not condensate. After a manufacturing step, the coupling agents condensate, add crosslinks inside the networks, and form bonds between the networks. This approach enables independent bonding and manufacturing. We formulate oxygen-tolerant hydrogel resins for spinning, printing, and coating in the open air. We find that thin elastomer coatings enable hydrogels to sustain high temperatures without boiling.
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Project description:The scale-up of laboratory procedures to industrial production is the main challenge standing between ideation and the successful introduction of novel materials into commercial products. Retaining quality while ensuring high per-batch production yields is the main challenge. Batch processing and other dynamic strategies that preserve product quality can be applied, but they typically involve a variety of experimental parameters and functions that are difficult to optimize because of interdependencies that are often antagonistic. Adaptive Bayesian optimization is demonstrated here as a valuable support tool in increasing both the per-batch yield and quality of short polymer fibers, produced by wet spinning and shear dispersion methods. Through this approach, it is shown that short fiber dispersions with high yield and a specified, targeted fiber length distribution can be obtained with minimal cost of optimization, starting from sub-optimal processing conditions and minimal prior knowledge. The Bayesian function optimization demonstrated here for batch processing could be applied to other dynamic scale-up methods as well as to cases presenting higher dimensional challenges such as shape and structure optimization. This work shows the great potential of synergies between industrial processing, material engineering, and machine learning perspectives.
| S-EPMC6906790 | biostudies-literature
Project description:BackgroundInfluenza virus is a globally important respiratory pathogen that causes a high degree of annual morbidity and mortality. Significant antigenic drift results in emergence of new, potentially pandemic, virus variants. The best prophylactic option for controlling emerging virus strains is to manufacture and administer pandemic vaccines in sufficient quantities and to do so in a timely manner without impacting the regular seasonal influenza vaccine capacity. Current, egg-based, influenza vaccine production is well established and provides an effective product, but has limited capacity and speed.ObjectivesTo satisfy the additional global demand for emerging influenza vaccines, high-performance cost-effective technologies need to be developed. Plants have a potential as an economic and efficient large-scale production platform for vaccine antigens.MethodsIn this study, a plant virus-based transient expression system was used to produce hemagglutinin (HA) proteins from the three vaccine strains used during the 2008-2009 influenza season, A/Brisbane/59/07 (H1N1), A/Brisbane/10/07 (H3N2), and B/Florida/4/06, as well as from the recently emerged novel H1N1 influenza A virus, A/California/04/09.ResultsThe recombinant plant-based HA proteins were engineered and produced in Nicotiana benthamiana plants within 2 months of obtaining the genetic sequences specific to each virus strain. These antigens expressed at the rate of 400-1300 mg/kg of fresh leaf tissue, with >70% solubility. Immunization of mice with these HA antigens induced serum anti-HA IgG and hemagglutination inhibition antibody responses at the levels considered protective against these virus infections.ConclusionsThese results demonstrate the feasibility of our transient plant expression system for the rapid production of influenza vaccine antigens.
| S-EPMC4941669 | biostudies-literature