The role of stakeholders in the development of ChAdOx1-S Covid-19 vaccine: reflection for future pandemics

doi:10.21203/rs.3.rs-4714523/v1

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The role of stakeholders in the development of ChAdOx1-S Covid-19 vaccine: reflection for future pandemics

https://doi.org/10.21203/rs.3.rs-4714523/v1

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COVID-19, an infectious disease caused by the virus SARS-CoV-2, has become a global pandemic and has been classified as a Public Health Emergency of International Concern. Considering vaccines as an effective action to shorten viral transmission and to reduce mortality, stakeholders have worked together to develop vaccines, which played a vital role in containing this pandemic worldwide. In the development of the adenovirus-based ChAdOx1-S vaccine, it is interesting to note the speed at which it was created, with safety, breaking paradigms, relying on connections and influences at various levels, showing that a vaccine can be produced in a very short period of time if there are specific stakeholder dynamics. Herein, we combined the concepts and methods of Stakeholder Theory and Social Network Analysis within this complex scenario, indeed, the positive results delivered to society reinforce the principles of the Stakeholder Theory. Moreover, Social Network Analysis revealed that the ChAdOx1-S vaccine ecosystem had 30 nodes of interconnection. Overall, the data summarized presently discussed indicate the need for preparedness within the vaccine development ecosystem, important for future research into the management and development process of vaccines designed to cope with future global or regional health emergencies.

Key points related to the complexity of a health emergency, considering its risks to public health and society. A coordinated, interdisciplinary, and systemic response between the different actors is emphasized. This study focuses on analyzing the actors involved in the activities related to the development of the ChAdOx1-S vaccine against COVID-19, taking into account the paradigms of time and the pandemic emergency. Considering the network analysis, for this vaccine, new institutional arrangements have emerged, significantly expanding the limits of knowledge, since the initial research was based on more than a decade of knowledge production.

A health emergency can be defined as an extraordinary event as it constitutes a public health risk through the national and international spread of disease and should require a coordinated international response [1]. It can cause social changes, establishing itself as a health crisis of economic, social and humanitarian nature, requiring interaction between different stakeholders to solve transdisciplinary challenges in a systemic way. These stakeholders develop processes with the aim of monitoring, proposing and carrying out actions to prevent or reduce the likelihood of the spread or propagation of diseases [2]. With COVID-19, called severe acute respiratory syndrome caused by the virus the new coronavirus 2 (SARS-CoV-2) and classified as a Public Health Emergency of International Concern (PHEIC), it was not different, especially after variant of the Coronavirus were identified. Thus, on January 30, 2020, following the recommendations of the Emergency Committee, the Director-General of the World Health Organization (WHO) declared the outbreak of SARS-CoV-2 as being of international concern [3]. To contain the spread of the virus, WHO published a series of guidance documents on how to manage this outbreak, presenting the main guidelines for accelerating product development and providing a guide for prioritizing vaccine development [4–5].

The complexity of the development and production of this vaccine involved movements of numerous actors, from basic research to the distribution chain, seeking to apply it to the target populations. Several initiatives were carried out, such as Operation Warp Speed, in the United States; and COVAX, co-led by the Coalition for Epidemic Preparedness Innovations (CEPI), World Health Organization (WHO), and the Vaccine Alliance (GAVI). In addition to these, other efforts emerged in the public and private sectors and on the part of experts, in a networked cooperation capable of developing, advancing, and producing such an important immunobiological tool [6].

In the context of the Health Emergency, it has been highlighted the existence of different types of Stakeholders with specific functions and characteristics involved in disaster operations and in the context of the pandemic [7]. Among them is the WHO [8], which acted on several fronts since drawing up and implementing the global preparedness plan to accelerate the availability of diagnostics, vaccines, and medicines. Also, it has been stressed that all partnerships and stakeholders involved in vaccine development form ecosystems, revealing the importance of capturing, illustrating, and analyzing these ecosystems for characterizing strengths and weaknesses, as well as measuring existing influences and implications [9]. According to Gordon and Samant [10], vaccine development has a hierarchical organization, which requires solid systems and controls and a set of necessary skills, in addition to the interaction of stakeholders with stages/phases related to research, development, and preclinical studies, clinical trials, regulatory approval, production and manufacturing, as well as the distribution chain. It is necessary to understand, illustrate, analyze and characterize this system in order to understand which stakeholders are involved in the development and acquisition of vaccines and the consequences, which ecosystem it is part of, as well as its relationship structure, allowing for measuring its strengths and weaknesses and thus suggest the improvements the system needs to mitigate the latter.

The development and production of the adenovirus-based ChAdOx1-S Oxford-AstraZeneca vaccine by the Oswaldo Cruz Foundation (Fiocruz), subject of the present case study, involved partnerships including various stakeholders, with a fast timeline, from the notification of the virus and corresponding disease to the production of the vaccine in Brazil, and delivered to the Brazilian Unified Health System, as summarized in Fig. 1.

We looked at the network of this complex system, mapping it and identifying stakeholders in a social network analysis, (involving nodes and ties (connections) between the nodes. The nodes are represented in this network by their corresponding actors, such as individuals and groups of individuals, as well as organizations or entities. This analysis sought to identify the networks in view of the development stages of the ChAdOx1-S vaccine and the most active stakeholders throughout the process, their interactions, and partnerships, thus enabling at contributing to the identification and relevance of stakeholders and to assess one or more of the three relationship attributes: power, legitimacy, and urgency.

Accordingly, our aim was to understand how stakeholders interacted to produce vaccines quickly and safely during a pandemic, with the premise that integration and coordination for vaccine development constituted a paradigm in which positive results were delivered to society in less than a year, reinforcing the principles of Stakeholder Theory. We then combined the concepts and methods of Stakeholder Theory and social network analysis within this complex scenario, so that to identify the flow of relationships between the different actors, characterizing the type of attribute and illustrating its dynamics, which is summarized later, in Fig. 2.

The evolution in the development and acquisition/distribution of vaccines has different stages and, in this specific case, they were superimposed for a faster result without losing their effectiveness. Concomitantly, industries optimized their production capacity for large scale, in order to facilitate the distribution of the vaccine without delay once it had been approved [11]. In view of this, the competent national authorities carry out Good Manufacturing Practice inspections to ensure that producers were complying with the standards, licenses, and conditions of manufacturing and marketing authorization. The legacy left by the development and global distribution of the anti-COVID-19 vaccine contributes not only to new products, but also to preparing for responses to new pandemics and infectious diseases.

According to Kaslow [12], there are still many barriers to the development and global dissemination of vaccines in response to infectious threats. With regard to COVID-19, there was a unique opportunity to take advantage of existing data and technologies from different targets, intelligent and flexible clinical trial designs, as well as regulatory issues, even before the demonstration of the safety and efficacy of vaccines, with the aim of accelerating their development [13].

The initial stage of the Oxford-AstraZeneca-Fiocruz vaccine was carried out by the University of Oxford, with various actors involved and cooperation between international organizations such as the WHO, CEPI, GAVI, and the Accelerating COVID-19 Therapeutic Interventions & Vaccines (ACTIV), together with the participation of the Bill & Melinda Gates Foundation, among others [14].

In its clinical stage, simultaneous clinical trials were carried out in the UK (COV001 and COV002), Brazil (COV003), and South Africa (COV005). It should be noted that for the global development, production, and supply of this vaccine, AstraZeneca committed to providing a wide and equitable supply worldwide, including in Brazil, at cost price during the Pandemic period [15].

The methodology used in the present work was based on the Stakeholder Theory and the Social Network Analysis, in the context of the development of the ChAdOx1-S vaccine, integrating approaches and techniques aimed at understanding the complexity of the public health ecosystem.

2.1 The Stakeholder Theory and its application on the development of the ChAdOx1-S vaccine

As mentioned above, COVID-19 has brought a faster pace to the creation of vaccines, in a short space of time and globally, with very clear geopolitical and geo-economic repercussions [16]. In this context, and with the need to focus on creating value for society, the Stakeholder Theory becomes opportune, given the challenges and impacts of the pandemic. The term Stakeholder is commonly used in various areas of knowledge and can be translated as "interested parties" or "intervening parties", focused on both projects and collaborations [17]. Actually, the central purpose of the theory is to promote the balance and integration of different interests, expectations, and needs by the parties [18]. In this context, precise planning and stakeholder engagement are key factors to understand the whole process and its complexity [19].

The applicability of this theory in the context of development in health emergencies poses the challenge of identifying and analyzing the stakeholders involved, including groups such as government entities and agencies, community groups, companies, public institutions, and the society in general [20], although the specific components depend on the different relationships and interactions between all actors involved in the operation. The COVID-19 pandemic has shown that a vaccine can be developed in a very short period of time if there are specific dynamics between the parties involved, including a variety of interests that encompass political and economic ones.

Our study was conducted in a descriptive manner, using qualitative procedures outlined in an exploratory investigation divided into stages. Bibliographic research (secondary data) was therefore carried out on books, articles, individual publications, newsletters, and journal portals such as Web of Science, Scielo, Pubmed, Cochrane and Capes journals, as well as news articles and institutional documents from the WHO, Fiocruz, CEPI Reports, GAVI, and the University of Oxford, enabling the identification of stakeholders through the content analysis of documents, as recommended by Bardin [21]. Literature search and retrieve was carried out using two sets of descriptors, the first related to vaccine development – "coronavirus vaccine", "AstraZeneca", "COVID-19 vaccine developer", "approved vaccines", and the second to stakeholders – "stakeholders" combined with keywords such as "coordination", "cooperation", "partnership", "COVID-19 vaccine manufacturing", and "SNA". The search was conducted in both Portuguese and English. The selection of documents extended to titles, abstracts, or keywords of documents published between December 2011 and July 2023 for the development of vaccines, while the literature related to stakeholders comprehended articles and books published between 1997 and 2023. For the latter, only official partnerships related to AstraZeneca – recognized by the stakeholders involved in the partnership, were included, as institutions with a specific focus on health. Exclusion criteria comprised studies not related to vaccine stakeholders, studies written in languages other than English or Portuguese, as well as documents that did not focus on partnerships aiming at the COVID-19 vaccine. It is worth mentioning that the networks were identified based on research carried out in the Vaccine Landscape Database and Tracker [22], which shows the most important actors.

2.2 Nodes and ties connecting the actors: a network analysis

Social Network Analysis (SNA) is a process with a long history and has evolved because of contributions from different disciplines [23]. It is a tool or process often used in areas such as psychology, engineering, computer science, anthropology, and health. In this analysis, actors are connected to others through social relations. The structure consists of representing networks through "nodes" and "ties” [24]. According to the authors, the "nodes" are the actors (individuals, groups of individuals, organizations, or entities) whereas the ties are their connections, representing these relationships. The SNA allows us to observe how various actors interact, in addition to analyzing individual phenomena, including the influence of individuals' social positions on their formation and mobilization of resources, as well as their perception of how information flows [25].

Some uses of SNA have been reported by public health organizations during the Human Immunodeficiency Virus (HIV) pandemic and on vaccination against the Human Papillomavirus, which were considered invaluable [23, 26, 9].

This involvement of key actors and their interactions in this systemic and dynamic process could fluctuate according to the political and institutional environment in which they were engaged. In this regard, connecting the network approach and comparing it to the pandemic paradigm [27], allow a better understanding of the multiple relationships in the processes related to this production connection.

After the bibliographic search, the SNA involved in the development of the ChAdOx1-S vaccine for COVID-19 by Fiocruz, was carried out based on the information obtained in the documentary and content analysis, as recommended by Bardin [21], who highlighted the following requirements: pre-analysis; analysis of the material; treatment of the results, inference and interpretation, seeking to analyze the senses and meanings of communications. For a better understanding, the SNA was divided into two stages. In stage 1, data were collected aiming at understanding how the process of developing, regulating, and manufacturing the vaccine took place, considering the actors involved and putting them into context. In stage 2, the groups were considered according to the definitions of the attributes proposed by Boaventura et al [28], which in turn, are related to three keywords: a) power, strength-related, effective, efficient, competence, decision, hierarchy; b) legitimacy, with the keywords: contract, agreement, commitment, institutions, decree, and security and c) urgency, which is directly related to the keywords: agility, punctuality, speed, advance, urgency, anticipate, relevance.

2.3 Graphic plotting of the networks

The stakeholders identified were recorded in a list of nodes, while the connections between them were represented by edges. These nodes were identified, mapped, and recorded by their characteristics (such as name and attribution), by means of bibliographic research and other studies already carried out (secondary sources) focused on the development of vaccines, considering each stage, compiling the data in supporting tables, to organize them according to the units of analysis, in this case, the stakeholders, within each stage with their nodes and edges, considering the attributes power, legitimacy, and urgency. For better visualization, the stakeholders have been presented in four distinct groups (development, clinical trials, regulatory approval, as well as production and distribution chain), according to the dynamics in which they operate. As seen below, we will highlight the most important attributes in each stage.

2.4. Data analysis in Gephi software

The information collected in the documentary analysis was necessary for producing the network graph. Text mining and content analysis were carried out, recorded, and categorized according to the stages in an Excel spreadsheet, with their characteristics (name and main function of the stakeholder) creating a list of nodes. An ID was assigned to each one so that to correlate them according to the literature and then create the edges. The lists of nodes and edges were exported into the Gephi software (version 0.9.2) and network graphs were generated according to the stages and attributes. The modularity calculation to identify the communities was carried out according to Lambiotte and coworkers [29].

Focusing on the main direction of Stakeholder Theory, the scope of the study was to analyze the structure of the stakeholders engaged in AstraZeneca's COVID-19 vaccine development system, identifying their interactions and dynamics. The network was mapped according to the operating structure for the development of vaccines and a network graph was generated, allowing the most influential nodes to be visualized. Figure 2 shows the interactions within the three attributes, in their totality of nodes and edges, in a highly complex and interconnected network segmented into two clusters, obtained with the help of the software. Considering the perspective of network cooperation, these interactions unraveled how complex the entire development process was, within a sharing of knowledge, skills and information, key resources in this COVID-19 vaccine related process. The cluster on the right side of the figure concentrates the interactions between international institutions and, on the left, the greater interaction between national organizations. We can observe a greater ramification of the Stakeholders, according to their characteristics, being more predominant in the development and clinical trials stages, as in these, there is an emphasis on the entire vaccine structuring chain.

The ChAdOx1-S vaccine ecosystem had 30 nodes, which in turn received various vertex incident connections from other "nodes". For a better visualization, the stakeholders were presented in four (04) distinct clusters, according to their dynamics of action, as shown in Table 1. The degree and centrality of the vector were calculated for each stakeholder in the network, which shows the number of edges, divided by attributes.

Table 1

Number of edges per attribute in the clusters formed for the development of the ChAdOx1-S vaccine
Stages	Power (edges)	Legitimacy (edges)	Urgency (edges)
Development	72	86	91
Clinical trials	124	57	65
Regulatory approval	31	31	31
Production + Manufacturing and Distribution Chain	57	28	46

Within a network, the higher the degree of centrality a stakeholder has, the more prominence it has in relation to its partners, given the direct contact between the actors. Nevertheless, this does not mean that it obtains more power to mediate network flows [30]. Based on the information collected, identified, and categorized in each stage, a network graph was generated, allowing better visualization of the most influential nodes. In the ChAdOx1-S vaccine development stage, the role of University of Oxford and the Jenner Institute standed out, whereas WHO appointed as the major stakeholder and liaison, given its degree of centrality. Kelkar [9] pointed out that the network's connecting institutions have a key role in the collective results, playing a coordinating role within the system. AstraZeneca was also among the top five stakeholders, thus highlighting the role of industry and vaccine developers, who were arguably the most influential in general terms.

The funders, both through CEPI and Gates, also had influence related to power, with great preponderance. Figures 3, 4, and 5 depict which institutions, in the development stage, appear by degree of importance in the analysis of the three attributes power, legitimacy, and urgency, in respect to the ChAdOx1-S.

In a second vein, some documents, such as those produced by CEPI [31] and GAO [6], dealt with the subject in a generalized way, i.e. involving all approved vaccines, but treating them in separate topics, according to the type of vaccine and manufacturer. This network demonstrates that the stakeholders took the necessary risks in an interdisciplinary and systemic approach to develop a vaccine in record time. Thus, at this early stage, relations were much more localized between the UK and other European countries, given the early stage of development. International agencies and universities, in this case, began to accelerate and generate greater scientific knowledge in view of the accumulated knowledge generated on the SARS and MERS diseases. In this stage, the University of Oxford, the World Health Organization, and the United Kingdom Government standed out (Fig. 3).

Also noteworthy is the union of leaders from the National Institutes of Health (NIH) who met with research and development leaders, seeking a task force for the development of the vaccine. Collins [32] also highlighted the ACT accelerator partnership (which supported the prioritization of candidates for therapies and vaccines).

Legitimacy, on the other hand, is related to the generalized perception or presumption that an entity's actions are desirable, adequate, or appropriate within a social system of norms, values, beliefs, and definitions [33], there being a relevance of those institutions related to regulation and efforts in this direction, with a view to pre-clinical trials (Fig. 4).

Developing inventories for pre-clinical trials considered standardization, sharing of resources, and methods, which accelerated the clinical trial stages. In this respect, we highlight herein the connecting institutions, such as the WHO and University of Oxford, in addition to ACT, which supported the initiatives proposed by the NIH, and was connected to other efforts with the FDA, among other institutions.

The implementation of a vaccine requires the action of various stakeholders who may have different levels of knowledge, intention, and motivation regarding a new vaccine [34]. In the case of COVID-19, in the development stage, urgency became a central attribute, sometimes not technical but related to political interactions and decision-making thus influencing the network. Figure 5 depicts these relationships

The urgency attribute is aligned with the development of the vaccine for the COVID-19 pandemic; delaying this process was considered a bad decision in a state of urgency, given the uncertainty caused by the pandemic. Excler [35] highlighted the compromised economic activities that were affected by the restrictive measures, such as the lockdown and the shutdown of air networks. According to Hu et al [36], the lines of connections and interactions among these social actors should be highlighted. To justify this attribute, CEPI [31] declared an ambitious goal: a vaccine should be ready for initial authorization and large-scale production within 100 days of the recognition of a pathogen. Indeed, the AstraZeneca vaccine was produced in 354 days after sequencing the virus, with innovations that were categorized by three fundamental principles: Prior knowledge available for development; multiple processes carried out totally or partially in parallel; and significant collaboration between stakeholders around the world, in addition to investment undertaken, where it should be highlighted the role of the CEPI, which conducted a study on global vaccine production capacity [37].

Clinical trials were carried out through a combination of stages 1 and 2, with tests on hundreds of people from various countries, such as Brazil, USA, India, and South Africa, in addition to the UK. It should be noted that AstraZeneca signed initial production and technology transfer agreements in April 2020, in parallel with initial development, as well as process development and manufacturing expansion. Regulatory authorities in the countries of origin adopted a proactive approach to quickly establish minimum clinical data requirements for access to safe and effective vaccines [35]. The proactive approach was to revise the regulations, especially as to deadlines and greater flexibility in submitting and prioritizing the evaluation of requests.

Table 2 summarizes the relationships within the stages and their attributes, considering the scores with nodes and edges recorded, highlighting the stakeholders with the highest degree of centrality, with a key and central role in the network.

As stated by Hawe; Webster and Shiell [38], degree and mediation centrality measures identify key and influential stakeholders.

The most important attribute in the stage of clinical trials is legitimacy, considering issues related to regulatory organization, with a greater predominance of agencies. This includes the institutions that led the clinical trials, such as CEPI, which monitored the randomized trials and their standardization, as well as the funding institutions, since clinical trials are the costliest of all stages.

Table 2

Main stakeholders in the clinical trials, regulatory approval, production + manufacturing and distribution chain stages for the ChAdOx1-S anti-SARS-CoV2 vaccine
Stages	Main stakeholders identified	Degree of centrality
Stages	Main stakeholders identified	Power	Legitimacy	Urgency
Clinical trials	0 – World Health Organization 1 – University of Oxford 2 – AstraZeneca 3 – Coalition for Epidemic Preparedness Innovations 4 – NIHR - National Institute for Health and Care Research 5 – UK Research and Innovation 6 – European Medicines Agency 7 – UK Regulatory Agency 8 – Food and Drug Administration 9 – UK Government 10 – ANVISA 11 – German Center for Infection Research (DZIF) 12 – NIHR Oxford Biomedical Research Centre 13 – Thames Valley and South Midlands. 14 – NIHR Clinical Research Network South Midlands 15 – Oswaldo Cruz Foundation 16 – Reference Centers for Special Immunobiologicals 17 – Brazilian Ministry of Health 18 – Lemann Foundation (Brazil) 19 – Rede D'Or (Brazil) 20 – Brava & Telles Foundation (Brazil)	0 –World Health Organization 1 – University of Oxford 2 – AstraZeneca 6 – European Medicines Agency 8 – Food and Drug Administration	0 – World Health Organization 1 – University of Oxford 2 – AstraZeneca 6 – European Medicines Agency 7 – UK Regulatory Agency. 8 – Food and Drug Administration 12 – NIHR Oxford Biomedical Research Centre 13 – Thames Valley and South Midlands. 14 - South Midland NIHR Clinical Research Network 15 – Oswaldo Cruz Foundation	0 – World Health Organization 1 – University of Oxford 2 – AstraZeneca 6 – European Medicines Agency 7 – UK Regulatory Agency 8 – Food and Drug Administration 10 – Brazilian National Program of Immunization 12 – NIHR Oxford Biomedical Research Centre 13 – Thames Valley and South Midlands 14 - South Midland NIHR Clinical Research Network 15 – Oswaldo Cruz Foundation
Regulatory approval	0 – University of Oxford 1 – World Health Organization 2 – AstraZeneca 3 – UK Regulatory Agency 4 – Food and Drug Administration 5 – European Medicines Agency 6 – ANVISA 7 – Oswaldo Cruz Foundation 8 – Brazilian Ministry of Health	0 – University of Oxford 1 – World Health Organization 3 – UK Regulatory Agency 4 – Food and Drug Administration 5 – European Medicines Agency	0 – University of Oxford 1 – World Health Organization 4 – Food and Drug Administration 5 – European Medicines Agency	1 – World Health Organization 3 – UK Regulatory Agency 4 – Food and Drug Administration 5 – European Medicines Agency 6 – Brazilian National Program of Immunization
Production + Manufacturing and Distribution Chain	0 – AstraZeneca 1 – University of Oxford 2 – World Health Organization 3 – Fiocruz/Biomanguinhos 4 – Serum Institute 5 – Brazilian Government 6 – Coalition for Epidemic Preparedness Innovations 7 – GAVI 8 – Brazilian Ministry of Health 9 – Brazilian National Program of Immunization 10 – COVAX 11 – ANVISA	0 – AstraZeneca 2 – World Health Organization 3 – Fiocruz/Biomanguinhos 4 – Serum Institute 6 – Coalition for Epidemic Preparedness Innovations 10 – COVAX	2 – World Health Organization 3 – Fiocruz/Biomanguinhos 6 – Coalition for Epidemic Preparedness Innovations 8 – Brazilian Ministry of Health 10 – COVAX 11 – Brazilian National Program of Immunization	0 – AstraZeneca 2 – World Health Organization 8 – Ministry of Health 10 – COVAX

In Brazil, the trials were organized by the CRIE – Unifesp and Fiocruz – with funding from the Lemann Foundation, D'or Institute, and the Brazilian Government. It should be noted that this stage revealed the alignment of regulatory institutions, such as the UK Regulatory Agency, EMA, and ANVISA, with established pre-clinical standards and the development of harmonized clinical trial protocol models that could be quickly adapted by developers and used globally [11]. We observed the interaction of institutions such as WHO [12] with guidelines related to efficacy, safety, access, and quality, four pillars that underpine the production of medicines and immunobiologicals. The Brazilian National regulatory agency (ANVISA) and the United Kingdom, both institutions with their own health regulatory framework also played a key tole. AstraZeneca also reviewed the study data in all countries where trials were carried out. It should also be noted that the coordination of the program and the execution of the trials in the United Kingdom would not have been possible without the support of the National Institute for Health and Care Research [39]. Another key and actively supportive actor was FDA, which indicated that it would license a vaccine against the pandemic virus with at least 50% effectiveness.

The power attribute highlights the action of supranational institutions and their integration, with a view to increasing the number of clinical trials carried out in other countries, aimed at contributing to regulatory harmonization and credibility. In the area of regulatory approval, we highlight the attribute of urgency, with countries' regulatory institutions having greater involvement, such as in the clinical trials stage, with regulatory flexibility, controls, and continuous action on results and clinical protocols. These emergency-related regulatory procedures required frequent dialog and involvement between developers and regulators from the very beginning of the process. This alignment merges with the urgency attribute, since feedback loops took place faster for real-time data analysis and improved planning for post-authorization commitments. It is also worth noting that the vaccine undergoes strict safety, efficacy, and quality controls, even after it has been approved by the regulatory bodies. The approvals made by the MHRA (Medicines and Healthcare products Regulatory Agency), FDA, EMA, and ANVISA were crucial in this stage, as they established greater flexibility in the regulatory channels by improving processes and creating an emergency path for mobilizing these actors.

Finally, the last stages focus on the manufacturing and distribution chain stages, which also have specificities and peculiarities according to the platform chosen to develop the ChAdOx1-S vaccine. Standardizing facilities and manufacturing systems were essential, both in terms of the supply chain and compatible quality systems and good manufacturing practices for rapid technology transfers. We also considered the urgency attribute at this stage to be the most preponderant and most aligned among the stakeholders. In order for the AstraZeneca vaccine to be produced in Brazil by Fiocruz/Biomanguinhos and quickly supply PNI, it had to simultaneously negotiate the transfer of production technology and carry out specific adjustments for the new purposes in its final processing area, complying with all Good Manufacturing Practices standards approved by ANVISA [40]. Moreover, the Sérum Institute exported 2 million doses of the vaccine already bottled, to be rapidly made available to the PNI. Large-scale production began in March 2021 and the technology transfer agreement was signed in June of the same year.

By 2022, Fiocruz had already been approved by the national evaluation of PNI, according to the full technology transfer agreement. The need to realign and coordinate funding to support vaccine development was directly linked to the emergence of the global market in the search for approved vaccines. Thus COVAX, an initiative led by WHO, GAVI, and CEPI, brought together key stakeholders such as governments, global health agencies, manufacturers, among others, providing and facilitating equitable access and distribution of the vaccine to all countries, but prioritizing those with low incomes and people in greater vulnerability. COVAX, through its early involvement and funding, allowed for much faster timelines for clinical development. Much of this distribution was of AstraZeneca's vaccine. The funds invested by the Covax Facility amounted to around US$2 billion [41]. In Brazil, distribution of the ChAdOx1-S vaccine was carried out by the PNI.

The present study focused on analyzing the stakeholders involved in the activities related to the development of the AstraZeneca-Oxford-Fiocruz vaccine, considering the paradigms of time and pandemic urgency, from the beginning of the outbreak to the development and approval and distribution of the first vaccine data package, with the involvement of various stakeholders, in an multinstitutional effort never seen before.

There are traditional barriers associated with the ecosystem of vaccine stakeholders, notably in terms of time and funding from design to approval. Considering the network analysis, for the ChAdOx1-S COVID-19 vaccine, new institutional arrangements have emerged, crossing the boundaries of knowledge in a significant way, as the initial safe research was not random but based on more than a decade of knowledge production.

Regarding the attributes analyzed and as the metrics were applied, the relationships were interconnected, and when locating central actors, we highlighted power in the first stage, given the significant number of relationships between the verious stakeholders. Along with this, the degree of influence and decision-making in order to regroup and coordinate the entire process, seeking to keep up with the global market for approved vaccines. Legitimacy can be highlighted as central to this new paradigm and is related to a major shift towards preparing not only institutions, but also the entire regulatory framework, within the global network of clinical trials, with established and coordinated processes and protocols. The urgency attribute, one of the most relevant, has led to joint action by stakeholders, including governments, R&D institutions, funders, regulators, and industry, to overcome the traditional challenges faced by vaccine candidates from development to regulatory approval. It should be noted that urgency and legitimacy were attributes that complemented each other, given the time between development and availability of the product. The health crisis has highlighted the importance of coordinated actions and comprehensive, adapted, collaborative, and participatory knowledge.

The results were relevant to researchers involved in Stakeholder management as shown by the social network analysis in the context of vaccine development. While the first allowed an integrated view of the strategies used and covered the parties that are directly or indirectly involved in the context in order to meet the needs (or objectives), in this case, the vaccine for the population, the second investigated to what extent each actor can influence and impact each other, as well as the degree of cohesion and connection in the network.

More broadly, the results structurally demonstrated the ability of Stakeholder Theory to be associated with coordination capacity in response to public health emergencies, in the specific case of vaccine development. On the other hand, it was possible to see that this ecosystem had weaknesses, especially in the manufacturing supply chain. In addition to the global vaccine working group, future vaccine ecosystems should strive to achieve alignment and coordination between stakeholders to create common standards and support the execution of processes at all stages. Finally, we suggest that future studies deepen this discussion through other sources of information, as well as comparative analyses between the two vaccines that were developed and distributed by Brazilian public laboratories.

Funding Not applicable.

Conflicts of InterestsThe authors have no competing interests to declare relevant to the content of this article.

Availability of Data and Material Not applicable.

Ethics Approval Not applicable.

Authors’ Contribution All authors contributed to the study conception and design. Ayres performed the literature search, and screened papers and documents. The first draft of the manuscript was written by Ayres, and all authors commented on previous versions of the manuscript. All the authors authors critically revised the manuscript and approved the final version.

Informed consent Not applicable.

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No competing interests reported.

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The role of stakeholders in the development of ChAdOx1-S Covid-19 vaccine: reflection for future pandemics

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Abstract

Figures

1. Introduction

2. Methodology

2.1 The Stakeholder Theory and its application on the development of the ChAdOx1-S vaccine

2.2 Nodes and ties connecting the actors: a network analysis

2.3 Graphic plotting of the networks

2.4. Data analysis in Gephi software

3. Results and Discussion

4. Final Considerations

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References

Additional Declarations

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