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According to data from the World Health Organization (WHO) every year, millions of people are affected by flu. Flu is a disease caused by influenza viruses. For preventing this, seasonal influenza vaccinations are widely considered the most efficient way to protect against the negative effects of the flu. To date, there is no “one-size-fits-all” vaccine that can be effective all over the world to protect against all seasonal or pandemic influenza virus types. Because influenza virus transforms its genetic structure and it can emerges as immunogenically new (antigenic drift) which causes epidemics or new virus subtype (antigenic shift) which causes pandemics. As a result, annual revaccination or new subtype viral vaccine development is required. Currently, three types of vaccines (inactivated, live attenuated, and recombinant) are approved in different countries. These can be named “conventional influenza vaccines” and their production are based on eggs or cell culture. Although, there is good effort to develop new influenza vaccines for broader and longer period of time protection. In this sense these candidate vaccines are called “universal influenza vaccines”. In this article, after we mentioned the short history of flu then virus morphology and infection, we explained the diseases caused by the influenza virus in humans. Afterward, we explained in detail the production methods of available influenza vaccines, types of bioreactors used in cell culture based production, conventional and new vaccine types, and development strategies for better vaccines.

mRNA-based vaccines can be rapidly manufactured and have been demonstrated clinically to raise robust immune responses to COVID-19 and protect against severe COVID-19 disease. The clinical immunogenicity and efficacy of self-amplifying mRNA (sa-mRNA) vaccines have also been demonstrated, along with a longer duration of action than mRNA vaccines. However, a detailed understanding of differences between sa-mRNA and conventional mRNA vaccines with modified bases is lacking. Compared with a N1ψ-modified mRNA platform, when using an sa-mRNA approach, we observed a > 100-fold greater transfection efficiency for multiple antigens by sa-mRNA, all of which also showed high durability for gene-of-interest (GOI) production. The enhanced magnitude and durability of GOI expression by sa-mRNA compared with modified mRNA was also analysed in vivo using a luciferase reporter construct. In this experiment, sa-mRNA produced >100-fold cumulative bioluminescence compared with an mRNA construct. The elevation in GOI production translated into greater in vivo immunogenicity, where a 10-fold lower dose of sa-mRNA generated similar binding and neutralizing titers for the avian pandemic influenza H5N1 strain in both mouse and rat models. The sa-mRNA construct also generated comparable or higher antigen-specific CD8 T cell responses at 10-fold lower doses than mRNA. The lower doses of sa-mRNA generated a reduced elevation of reactogenic biomarkers while still generating similar or higher immunogenicity in rats and mice compared with modified mRNA. The current study suggests the potential of leveraging dose sparing, improved durability, enhanced immunogenicity, and possibly reduced reactogenicity of the sa-mRNA platform for vaccine applications. •GOI expression with sa-mRNA vaccine is more potent and durable vs. mRNA vaccine.•Antibody titers and CD8 T cell responses are greater with sa-mRNA vs. mRNA vaccines.•sa-mRNA vaccine generates similar immunogenicity as mRNA vaccine at smaller doses.•Dose-spared sa-mRNA vaccine induces lower cytokine release than mRNA vaccine.

To overcome pandemics, such as COVID-19, vaccines are urgently needed at very high volumes. Here we assess the techno-economic feasibility of producing RNA vaccines for the demand associated with a global vaccination campaign. Production process performance is assessed for three messenger RNA (mRNA) and one self-amplifying RNA (saRNA) vaccines, all currently under clinical development, as well as for a hypothetical next-generation saRNA vaccine. The impact of key process design and operation uncertainties on the performance of the production process was assessed. The RNA vaccine drug substance (DS) production rates, volumes and costs are mostly impacted by the RNA amount per vaccine dose and to a lesser extent by the scale and titre in the production process. The resources, production scale and speed required to meet global demand vary substantially in function of the RNA amount per dose. For lower dose saRNA vaccines, global demand can be met using a production process at a scale of below 10 L bioreactor working volume. Consequently, these small-scale processes require a low amount of resources to set up and operate. RNA DS production can be faster than fill-to-finish into multidose vials; hence the latter may constitute a bottleneck.

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the “Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs”. To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just “pandemic vaccines”. Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first.

In an effort to improve pandemic preparedness and health security, many low- and middle-income countries (LMICs) have launched initiatives to expand regional vaccine manufacturing. A number of elements relating to vaccine markets, production, value chains, and ecosystems significantly impact the ability to generate economically viable and sustainable vaccine manufacturing in LMICs. This paper provides an overview of vaccine manufacturing characteristics and global vaccine markets dynamics. Establishing vaccine manufacturing is a complex undertaking due to a variety of factors including intense competition, associated uncertainty regarding the ability to capture market share and substantial capital investment requirements. Substantive government commitment and investment are essential to ensure new local entrants compete successfully. In the medium to long run, the role of government should shift from supporting individual firms to strengthening local science ecosystems as this bolsters economic sustainability in three ways. First, investment in science promotes technological advances which can reduce production costs, e.g., through process innovations for vaccine manufacturing. Second, strong science ecosystems help to address the skills gap faced by manufacturers. And third, strong science ecosystems enable research and development of new vaccines that address local unmet needs and open new markets. Furthermore, developing a regional approach to vaccine manufacturing and procurement, with associated regulatory harmonization, is crucial to achieving economically viable and distributed vaccine manufacturing. Importantly, investment in research and development and fostering of regional collaborations drives innovation, feeding into new product discovery and consequently a strong pipeline of new vaccine products, driving economically sustainable regional vaccine manufacturing. This offers the potential to prevent endemic infectious diseases with significant socioeconomic and health burden or to develop therapeutic vaccines, generating regular interpandemic demand for regional vaccine manufacturers, consequently sustaining capacity retention and associated pandemic preparedness.

Vaccination is a critical part of the response to an influenza pandemic. Future influenza pandemics will likely leverage existing production processes and manufacturing facilities for seasonal influenza to make pandemic vaccines. Therefore, pandemic influenza vaccine response is heavily dependent on seasonal influenza vaccine production capacity. WHO monitors global vaccine production to inform pandemic preparedness by regularly surveying influenza vaccine manufacturers to estimate both seasonal and potential pandemic vaccine production capacity overall and by region, vaccine type, and manufacturing process. The last survey estimates were for 2019; here, we report updated estimates based on data from the 2023 survey and compare to estimates from previous surveys. Our analysis estimates that annual seasonal influenza vaccine production capacity has remained relatively stable since 2019 at 1.53 billion doses and pandemic vaccine capacity at 4.13 and 8.26 billion doses for moderate and best case scenarios, respectively. Over 80 % of seasonal and pandemic vaccine production capacity relies on embryonated eggs, and inactivated influenza virus vaccines comprise the majority of vaccine supply. There is influenza vaccine manufacturing capacity in all WHO regions, except for the African Region, though influenza vaccine production is concentrated in high and upper-middle income countries. The ability to achieve maximum production capacity could be hindered by access to eggs and other ancillary supplies. While influenza vaccine production capacity has been sustained since 2019, significant gaps persist in its distribution, especially in low and lower-middle income countries, and most notably in the African region. This imbalance in production could result in unequal access to vaccines in the event of a pandemic. Strengthening local vaccine manufacturing, promoting seasonal vaccination programmes, and investing in research and development of next-generation influenza vaccines or improved production platforms are essential to improve pandemic preparedness, sustain the influenza vaccine market, and enable more robust local responses.

PurposeAfrica has the most deaths from infections yet lacks adequate capacity to engage in vaccine development, production and distribution, the cornerstone of efficiently managing and eliminating several infectious diseases. Research has scarcely explored the role of institutional logics in vaccine development, production and distribution, collectively known as end-to-end vaccine manufacturing. This study aims to explore how institutional logics influence firms to engage in the vaccine manufacturing value chain in Africa.Design/methodology/approachWe conducted multiple case study research using five vaccine manufacturing firms from four African countries in three regions. Qualitative interviews were conducted among 18 executives in 5 vaccine manufacturing firms.FindingsWe identified that the state, corporate and market institutional logics disparately influence the different parts of the vaccine manufacturing value chain. These institutional logics co-exist in a constellation that also shapes the organizational forms. Their constellation has dominant logics that guide behavior, while subdominant and subordinate logics influence behavior to a limited extent. The findings show that institutional logics are a function of contextual factors, such as historical events, technological changes and pandemics.Originality/valueThe study developed a typology that identifies vaccine manufacturing firm archetypes, institutional logics and their constellations underpinned by contextual factors. The findings have implications for firms and policymakers, as they may guide the end-to-end vaccine manufacturing interventions adapted for their regions.

Chinese Hamster Ovary (CHO) cells, employed primarily for manufacturing monoclonal antibodies and other recombinant protein (r-protein) therapeutics, are emerging as a promising host for vaccine antigen production. This is exemplified by the recently approved CHO cell-derived subunit vaccines (SUV) against respiratory syncytial virus (RSV) and varicella-zoster virus (VZV), as well as the enveloped virus-like particle (eVLP) vaccine against hepatitis B virus (HBV). Here, we summarize the design, production, and immunogenicity features of these vaccine and review the most recent progress of other CHO-derived vaccines in pre-clinical and clinical development. We also discuss the challenges associated with vaccine production in CHO cells, with a focus on ensuring viral clearance for eVLP products.

With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 10⁷ cells/mL or even 10⁸ cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.

The Influenza viruses affect many people annually. This has a high impact on society, both in terms of morbidity and mortality. Therefore, vaccines are gaining prominence as a means of preventing influenza outbreaks. However, due to the high demand for vaccines, achieving rapid, high-quality, and economical production presents a challenge. While egg-based systems are used in the production of influenza vaccines, more controlled systems are needed to overcome the drawbacks of animal-based products. As a response to this need, cell cultures are emerging as candidate expression platforms. However, regulatory bodies deem the use of animal-derived components in industrial production as undesirable for licensing cell culture-based products. Therefore, it is crucial that cells can be cultivated in serum-free media. Thus, ideally, the most suitable expression platform needs to be identified in terms of highest production yield, ease of production parameters (low raw material usage, scalability, etc.), and natural susceptibility. In this study, various human-originated cell lines, along with positive and negative controls, were initially adapted to grow in serum-free media, and metabolic analyses were conducted to examine their changing characteristics. Subsequently, infection studies were conducted with clinically isolated H1N1 subtype influenza A virus. After confirming that all cell lines, both original and adapted, were infected with the virus, the success of virus production was compared using RT-qPCR, TCID50, and plaque assay. Based on these results, their suitability for bioprocessing in the production of a potential influenza vaccine was assessed. [Display omitted] •Optimal host cells identified for influenza vaccine bioprocessing.•Human-derived cell lines adapted to serum-free growth conditions.•Serum-free systems analyzed for scalability and process suitability.•H1N1 infection efficiency evaluated across multiple cell platforms.•Viral productivity assessed via RT-qPCR, TCID50, and plaque assays.