Technology transfer programme for influenza vaccines - Lessons from the past to inform the future.

In 2006, to address the global inequitable access to influenza vaccines in the event of an influenza pandemic, WHO, with support of donors and partners, embarked on an ambitious project, the Technology Transfer Initiative (TTI), to facilitate influenza vaccine production capacity-building in low- and middle-income countries (LMICs). This commentary briefly summarizes the high-level lessons learned, key challenges encountered, and critical components needed for success.

Recognizing the potential impact of an influenza pandemic, especially considering the widespread reemergence of the highly pathogenic avian influenza A(H5N1) in the early 2000s, in 2005, the 58th World Health Assembly adopted resolution WHA58.5 to strengthen pandemic influenza preparedness and response, including through technology transfer of pandemic influenza vaccines to LMICs. As a result, WHO launched the Global Action Plan for Influenza Vaccines (GAP) 2006–2016 to increase global influenza vaccine production capacity so that 70% of the world’s population could be immunized with two doses of pandemic vaccine within six months of the availability of the vaccine virus strain [1].

Over the course of 13 years and through several rounds of proposals, 14 developing country vaccine manufacturers (DCVMs) (see Table 1) received seed funding, licenses and technical assistance, including regulatory system strengthening, from WHO and partners to develop or strengthen their influenza vaccine production [2]. Each manufacturer was unique in the level and type of assistance required, which included assistance with facility design, funding of facility construction, equipment procurement, process development, assay development, preclinical studies, clinical trials, and development of regulatory market applications. Additional technical assistance was provided to assist the DCVMs and countries with identifying strengths, challenges, and opportunities for sustaining production capacity of influenza vaccines [3]. The GAP was sunset in 2016 [4] followed by TTI in 2019.

Table 1

DCVMs in the WHO Influenza TTI.

Manufacturer	Country	Year of entry into TTI	Status of influenza vaccine production
Instituto Butantan	Brazil	2007	Seasonal IIV approved in Brazil in 2012 and WHO Prequalified in 2021.Evaluated H1N1 and H7N9 vaccines in clinical trials.
Changchun BCHT	China	2013	Seasonal LAIV approved in China in 2020.
Vacsera	Egypt	2009	Influenza vaccine development halted before completion.
Serum Institute of India	India	2007	Seasonal LAIV approved in India in 2014 and WHO Prequalified in 2015.H1N1 pandemic LAIV approved in India in 2010 and WHO Prequalified in 2012.H1N1 pandemic IIV approved in India in 2010 (inactivated programme discontinued).
Bio Farma	Indonesia	2007	Seasonal IIV approved in Indonesia in 2009 (fill-finish of bulk produced by BIKEN).Local bulk production facility not completed.
Razi Institute	Islamic Republic of Iran	2009	Influenza vaccine development halted before completion.
Research Institute for Biological Safety Problems	Kazakhstan	2011	Clinical trials of seasonal IIV completed using vaccine produced at lab scale.GMP facility under construction.
Birmex	Mexico	2007	Local vaccine production in collaboration with Sanofi.
Green Cross Corporation (now GC Pharma)	Republic of Korea	2009	Established producer of seasonal vaccines.H1N1 pandemic vaccine approved in Republic of Korea in 2009 and WHO Prequalified in 2010.H1N1 adjuvanted pandemic vaccine approved in 2010.H5N1 pre-pandemic vaccine approved in 2015.
Cantacuzino Institute	Romania	2009	H1N1 pandemic IIV approved in Romania in 2011.No longer in production; ongoing investment in production facility.
Institute of Virology, Vaccines and Sera Torlak	Serbia	2009	Seasonal IIV approved in 2020.
Biovac	South Africa	2011	Influenza vaccine development halted before completion.
Government Pharmaceutical Organization (GPO)	Thailand	2007	Seasonal IIV clinical trials ongoing (Phase III).H1N1 pandemic LAIV approved in Thailand in 2011.H5N2 pre-pandemic LAIV approved in Thailand in 2015.
Institute of Vaccines and Medical Biologicals (IVAC)	Viet Nam	2007	Seasonal IIV approved in Viet Nam in 2019.H5N1 pre-pandemic IIV approved in Viet Nam in 2019.

Each participating manufacturer had its own unique context, objectives, priorities, strengths, and challenges. However, selected DCVMs were required to demonstrate governmental support of the project and previous experience with producing at least one human vaccine approved by the national regulatory authority (NRA). In 2006, WHO commissioned a review of influenza vaccine technologies and related intellectual property (IP). Following these reviews, WHO advised the selected DCVMs to pursue egg-based inactivated influenza vaccine (IIV) or live attenuated influenza vaccine (LAIV) production as the technologies and associated processes and supplies were accessible and well-established [1]. Since then, some DCVMs are evaluating, or have begun, the transition to cell-culture based production.

Because the technologies were well-established in terms of market availability and regulatory approval pathways, IP was not considered a barrier for egg-based IIV and LAIV production; rather, access to the production know-how was identified as the primary barrier. Therefore, WHO encouraged or facilitated technology transfer partnerships. For those DCVMs that did not enter into bilateral partnerships, WHO established technology transfer hubs for influenza vaccines (in 2008 at the Netherlands Vaccine Institute [NVI] [5]) and adjuvants (in 2010 at the University of Lausanne, Switzerland [6]). Nine of the 14 grantees received training at NVI, which was decommissioned in 2013 once grantees moved from process development into preclinical and clinical trials. Supplementary to this, the US Biomedical Advanced Research and Development Authority, a key partner and donor of the project, partnered with academic institutions to provide on-site manufacturing training to the DCVMs [7], [8].

While several DCVMs were successful in getting their influenza vaccines approved, some were unsuccessful (often for reasons beyond their control), and others are still progressing. Table 2 provides an overview of the critical activities and capacities that influenced the participating manufacturers’ success in the programme.

Table 2

Critical activities and capacities that influenced success in the TTI.

Thematic areas	Activities and capacities[2], [3], [9]
Policy and political landscape	Coherence among health, industrial, and economic policies
	Government/public sector subsidies for local production
	Inclusion of seasonal vaccination in health insurance schemes
	International sanctions and border control issues
	Political will and stability; long-term political vision and strategic planning
Product development and manufacturing	Access to R&D networks and partnerships
	Business and strategic plans to address supply chain issues, market opportunities, risk mitigation strategies
	Chemistry, manufacturing, and controls: seed development, bulk manufacturing, formulation, yields, process validation
	Competition with multinational manufacturers
	Development or sourcing of egg supply facilities
	Egg-based manufacturing does not allow rapid ramp-up of production
	Facility design and construction
	Funding for R&D, process optimization, expansion of capacities
	Maintenance of equipment
	Procurement, installation, and validation of equipment
	Quality management, including compliance with Good Manufacturing Practices
	Skilled workforce availability, training, and retention
Product approval and regulation	Capacity to conduct preclinical and clinical trials
	Capacity to prepare and submit regulatory filings
	Export know-how and processes
	NRA strengthening and maturity
Acceptance, demand, and delivery of influenza vaccines	Awareness of local manufacturer/locally produced influenza vaccine
	Demand forecasting and marketing strategy for seasonal influenza vaccines
	Influenza disease and economic burden data
	Influenza vaccination policies and programmes, including identification of target populations
	Market access/healthy markets for sustainability
	Vaccine procurement and delivery strategies and infrastructure

Based on the lessons learned from the programme, we identified two critical needs that influenced success in influenza vaccine technology transfer:

whole-of-government and multisectoral coordination and collaboration as influenza vaccine production goes beyond just increasing supply; and

long-term planning, support, and vision as technology transfer is not always a quick solution for increasing access to influenza vaccines in the event of a pandemic.

To date, nine of the 14 DCVMs were able to produce and obtain approval of at least one influenza vaccine (seasonal or pandemic), and four of those nine had multiple approvals throughout the project. If only taking product approvals into consideration for the project's goal, including the pandemic influenza vaccines approved during the 2009–10 influenza A(H1N1) pandemic, this represents a 64.3% success rate, but one manufacturer of the nine has since ceased production. However, an additional manufacturer is still constructing its GMP facility and may seek approval at a later date. It is clear that building and sustaining manufacturing capacity is a long-term process with many challenges, but the project galvanized global attention on inequitable access to vaccines during a pandemic and highlighted the importance of and complexities with technology transfer as a mechanism for increasing access to vaccines in LMICs. This was evident by the global support of GAP/TTI throughout the project as well as the national commitments to local production of influenza vaccines; for example, the overall investment by WHO was approximately US$ 50 million compared to close to US$ 1 billion by national governments and other bodies [2]. Additionally, the impact of GAP and TTI has been demonstrated by the leveraging of available manufacturing capacity of egg-based IIV in Instituto Butantan (Brazil), GPO (Thailand), and IVAC (Viet Nam) to evaluate and produce egg-based COVID-19 vaccine candidates with the support of PATH and Dynavax.1

As of 2019, the world had not yet achieved the production capacity goal set by GAP; the annual potential pandemic influenza vaccine production capacity was estimated to be 8.31 billion doses for a best-case scenario, with 80% of that capacity being concentrated in high-income countries [10]. When looking at the six TTI grantees that currently produce licensed seasonal influenza vaccines, they can contribute a combined total of 675.2 million doses of pandemic vaccine in 12 months, based on data provided in 2019. Given the current reliance on seasonal influenza vaccine capacity to estimate pandemic influenza vaccine production capacity, that number will not increase until there is greater demand for seasonal influenza vaccines or a technology is available which enables companies to de-couple pandemic vaccine production capacity from their seasonal vaccine demand.

A deeper dive into lessons learned from the programme, including the drivers of success, challenges, and barriers, is currently underway and will be completed in 2022; this analysis will include inputs from all relevant stakeholders involved in the TTI programme. The lessons can be leveraged for future decision-making around technology transfer and local production of vaccines in the context of COVID-19, other epidemic and pandemic diseases, and next-generation influenza vaccines.

Acknowledgements

We would like to acknowledge and thank our partners from across the world for their contributions to GAP and TTI: Asian Development Bank, Bill and Melinda Gates Foundation, Government of Japan, Government of the Netherlands, PATH, Public Health Agency Canada; TTI Technical Advisory Group Members; UNICEF; United Kingdom Department of Health; United States Department of Health and Human Services; and WHO staff in Headquarters, Regional Offices, and Country Offices. We would also like to acknowledge and thank the DCVM grantees and their governments for their commitments to the project.

Disclaimer

The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.