Improving Middle-Income Countries Access to Vaccines. A Blueprint to Overcome Current Challenges

The Global Health Consortium at Florida International University developed an end-to-end solution framework based on the input of a diverse panel of experts from middle-income country (MIC) government agencies, public health think tanks, academia, and nonprofit organizations to identify mechanisms to help MIC governments and stakeholders increase access to novel vaccines for infectious diseases. The resultant layout can be deployed to improve vaccine discovery and development, strengthen regulatory processes, and boost vaccine production, access, and implementation. Mechanisms include policies and incentives MIC governments can use to stimulate vaccine investment and activity, as well as actions government agencies can take together with other stakeholders to coordinate efforts or build capabilities. Through a series of individual virtual interviews, we engaged diverse experts from MIC government agencies, public health think tanks, academia, and nonprofit organizations who understand the vaccine ecosystem, immunization policies, and population health financing at global, regional, and country levels. Responses were mapped, and in-depth questions were prepared for a group virtual discussion. This paper is the result of such a group discussion. The panel identified clear opportunities for MICs to improve locally-driven innovations and future access to novel vaccines. It proposes a solution framework for countries considering investing in vaccine research and development and innovation to use as a guide to evaluate the steps they could take to improve such an environment and incentivize innovation in vaccine development. It is hoped that this end-to-end solution framework will become a key resource to help MICs strengthen policies and take more actions to make such improvements.


INTRODUCTION
Recent available data from WHO and UNICEF based on estimates of national immunization coverage indicate that more than one out of four children in middle-income countries (MICs) fails to complete the basic vaccine schedule.As a result, about 25 million children, more than 60 percent of them living in just 10 countries (India, Nigeria, Indonesia, Ethiopia, the Philippines, the Democratic Republic of the Congo, Brazil, Pakistan, Angola, and Myanmar), were un-or undervaccinated in 2021.Worse still, in the same year, more than 18 million children did not receive any vaccines (zero-dose children), an increase of 5 million from 2019, a situation worsened by the pandemic when many children were not properly vaccinated [1].
As new vaccines become available, more countries are making efforts to incorporate them into their immunization programs.However, issues such as unaffordability, lack of technical capacity in forecasting and planning, unreliability of local vaccine suppliers, and limited and/or unpredictable funding represent serious challenges for MICs to achieve universal immunization coverage.
The emergence of the COVID-19 pandemic represented an unprecedented global challenge with appalling health and socioeconomic consequences.The rapid development and production of effective vaccines against the disease over the past two years offered a unique opportunity to reduce its impact; however, vaccines did not reach all parts of the world equally, curtailing the possibility of effectively controlling viral spread.Indeed, according to the information collected by the WHO and the United Nations, most vaccine doses were distributed in high-and uppermiddle-income countries, while other most-needed areas, especially African countries, still lag in the vaccination process [2,3].
Lack of vaccination due to unequal access generates economic and social disadvantages, which could instead increase other inequalities [4].In this regard, COVID-19 vaccine inequality will continue to profoundly impact socio-economic recovery in low-income countries if urgent actions to assure equitable access worldwide are not taken; it would also delay progress towards the Sustainable Development Goals (SDGs) [5][6][7][8].
Many activities are underway to increase equitable access to COVID-19 vaccines and improve preparations for future pandemics.Global actors and institutions are driving new collaborations, policies, and funding mechanisms to deliver COVID-19 vaccines and increase support for lowincome countries (LICs) and MICs.In parallel, efforts at country and regional levels are exploring ideas to improve vaccine procurement, manufacturing capacity, and implementation.This presents an opportunity to help MICs look beyond pandemics to strengthen policies and actions that drive vaccine innovation and access for unsolved infectious diseases affecting developing countries.

METHODOLOGY
During the first half of 2022, the Florida International University Global Health Consortium organized the Access to Vaccine Innovation Framework (AVIF), engaging diverse experts with a background in vaccine-related work, development, or regulatory frameworks from MIC government agencies, public health think tanks, academia, and nonprofit organizations who understand the vaccine ecosystem, immunization policies, and population health financing at global, regional, and country levels.A one-hour virtual interview was conducted with each of the 14 experts, followed by a 2.5hour virtual roundtable with all participants.Initial discussions focused on the challenging task of stimulating the development of novel vaccines for neglected tropical diseases (NTDs) and unsolved infectious diseases that mainly affect developing countries.While scientific technology is available, investments in new vaccines to prevent such diseases are constrained by a low return on investment (ROI) and a lack of aligned end-to-end incentives for R&D, access, and implementation.However, experts' discussions revealed that MIC interest in improving vaccine technologies and capabilities is broader than NTDs.Many MICs want the ability to develop novel vaccines for future pandemics and endemics, The discussions and recommendations by the experts are grouped under I. Barriers impacting MIC Stakeholders, where several barriers were detected, and II.an End-to-End Solution Framework, structured into three sections to reflect the full continuum from vaccine discovery and development through sustainable access and implementation: a) Front-End Drivers of R&D Capabilities, b) Regulatory Drivers, and c) Downstream Market Drivers.

BARRIERS IMPACTING MIC STAKEHOLDERS
Discussions among panel experts explored obstacles that limit MIC stakeholders from doing more to encourage vaccine innovation and access.This revealed multiple all-encompassing, front-end, regulatory, and downstream barriers throughout the MIC vaccine ecosystem, such as financing for R&D and economic constraints, political motivations and focus on the short term, stakeholder interests, over-reliance on multinational pharmaceutical corporations, regulatory weaknesses, and market size.Considerations are to be taken to overcome these barriers.(See Tables 1a-1b, 2).

Financial and economic constraints
• Economic restrictions worsened by COVID-19 pandemic  Assessing which barriers any particular MIC is facing is an important step to fine-tune the application of the end-to-end solution framework in order to aim for improvement in specific capabilities.3).

END-TO-END SOLUTION FRAMEWORK TO HELP MICS INCREASE ACCESS TO FUTURE NOVEL VACCINES
For the Front-End Drivers for RD Capabilities, four objectives were suggested for discussion for recollecting recommendations on actions and/or policies and incentives by addressing the suggested objectives (Table 3).Among the suggested actions for governments were to define a long-term State vision for vaccine R&D and production, place focus on improving weaker areas of the vaccine chain, increase investment and funding for vaccine R&D platforms and research centers, and exercise a coordinating role and research priority setting among all stakeholders.
Policies and incentives are to be strengthened by fostering the formation of future scientists and researchers, enabling the incorporation of researchers from other countries, incentivizing technology transfers, and tying fund allocation to universities and research centers to their research efforts.Regarding specific actions recommended to be implemented, these were to forge R&D partnerships and consortia with key stakeholders, establish centers to train a workforce for vaccine R&D and production, such as the Partnerships for African Vaccine Manufacturing (PAVM), conduct science and vaccine diplomacy to link global actors, and participate in learning and best practice networks.
The need to explore and form Public-Private Partnerships (PPP), and/or Production Development Partnerships to increase capabilities and encourage partnerships to accelerate vaccine development, mainly with academic institutions working around vaccines, was stressed.
Experts recommended increasing government funding for vaccine R&D through various mechanisms, providing tax incentives, tax credits or subsidies to those developing vaccines or investing in vaccine R&D, as well as de-risking through multiple funding sources, such as the Right Fund in Korea, pooling regional funds for R&D and innovation, risk sharing with high-income countries and companies, and embedding vaccine experts in governments, parliamentary roles, and diplomacy.
Regarding the Regulatory Drivers, a much-needed perception, not only in countries but multicountry, is that strengthening regulatory agencies towards a fast WHO prequalification is essential, as is improving regional regulatory capabilities and harmonization.The lack of a regional regulatory body, such as EMA, weakens the regions; however, Africa has taken steps towards implementing the new African Medicines Agency, and Mexico has proposed, during the recent 7th Summit of Heads of State and Government of the Community of Latin American and Caribbean States (Celac), the creation of a Latin American Medicines Agency [9,10].
Countries should cooperate in facilitating a practical network to share advances and common knowledge to foster regulatory processes both at country and regional levels.They also should aim to apply policies that incentivize the acceleration of vaccine innovation by rewarding successful  producers by various methods and providing an exclusive extended period to limit competition and reward local developers.An expedited review, such as the US FDA Fast Track review, could be implemented.
Another aspect to consider is the need to have strong intellectual property laws along with proper management and enforcement for significant R&D investments and to protect scientific innovations.
When discussing the Downstream of Market Drivers, focus was placed on promoting incentives through advance market commitments to procure a certain volume of a vaccine for an established price once it meets certain conditions.Higher purchase commitments are needed as an incentive for more involved local production that goes beyond the fill-and-finish stage.
Pooled funding through a special program to create incentives for multi-national corporations to develop vaccines for NTDs and secure a return on investment ought to be explored, as well as leveraging regional pooled models of innovation by creating a regional pooled procurement capability that encourages MIC vaccine innovation and exportation through new models incentivizing the development of novel vaccines [11].
MICs countries may also benefit from the pooling of emergency response funds to stockpile vaccines and investment in solutions for future pandemics that could be started immediately, as ASEAN countries are already discussing.
Tier pricing is seen as an effective mechanism that provides incentives for vaccine producers and affordability for countries based on differing income levels.An attractive and sustainable trade environment is needed by reducing restrictions, import duties, and taxes on vaccine inputs.
A key element is the support of sustainable access and vaccine implementation by national health systems and services, along with training to overcome vaccine implementation barriers.Countries should strengthen or incorporate laws to protect funding for new vaccines in their current schedules, secure financing for novel vaccines, and improve vaccine coverage.Plans should be set in place to secure the introduction of emergency vaccines and the implementation of novel vaccines, considering technical training as well as a communication strategy.Lessons learned should be shared through community practice.

Case for action
In addition to providing input on the policies and actions in the solution framework, program participants identified three primary motivations that compel MICs governments and stakeholders to take actions that improve access to vaccine innovations.(Table 4) Countries will need to have strong data and perform the needed analysis to move forward, making sure they can improve the vaccine landscape locally and/or regionally.To support this, WHO recently developed the Full Value of Vaccine Assessments (FVVA) framework to help country authorities evaluate vaccine value beyond individual health benefits and include the broader socioeconomic and indirect impacts mentioned above, along with strong economic modeling [12].

Relevant comments
Government stakeholders must be convinced that the burden of an infectious disease makes preventing it a high priority.
Decision makers must have access to data and projections to understand the full impact and value of prevention.
This requires a strong evidence-based business case and health economic modeling to support MIC government decision making.
Throughout the pandemic, MICs were reliant on MNCs, NGOs, and HICs for COVID-19 vaccines and had to either wait their turn or fend for themselves to receive supply.
MICs want the ability to develop novel vaccines for future pandemics/endemics, and to produce several vaccines on their EPI/NIP.This is motivating MICs to make investments and deepen partnerships to improve their end-to-end vaccine value chain capabilities.
Some MIC governments view science, biotechnology, and vaccines as strategic enablers of economic growth.
These MICs want to diversify their economic output beyond their historical base and shift toward a more knowledgebased economy.

Table 1a
During the AVIF interviews and roundtable, participants in the expert panel identified numerous mechanisms that have successfully driven vaccine innovation, access, and implementation.Input was based on direct experiences working in LMICs, knowledge of what works well in benchmark high-income countries, as well as lessons learned throughout the COVID-19 pandemic.
The resulting current end-to-end solution framework is structured into three sections that reflect the full continuum from vaccine discovery and development through sustainable access and implementation.Each section was further organized into specific objectives, underneath which are corresponding mechanisms to help MICs strengthen their capabilities to advance vaccine innovation.Each objective involves two types of mechanisms: policies and incentives for an MIC government to

Table 1b
• Lack of stringent regulatory agencies in the Global South*, affects timing to review and approve vaccines, which vaccines countries have access to, availability of vaccines for exportation, and impacts the willingness of stakeholders to invest in R&D.In Latin America at least six countries (Argentina, Brazil, Chile, Colombia, Cuba and Mexico) with level 4 regulatory agencies, could be further strengthened to become a stringent supervisory body for the region • Pooled procurement agencies^ may paradoxically limit exportation opportunities for new vaccines from MICs because of regulatory aspects and WHO prequalification process

Table 2
encourage actions or investments by other stakeholders, and recommended actions that MIC government agencies, together with other stakeholders, can implement to coordinate efforts or build or expand capabilities.Overall, four objectives were presented for discussion under three main areas: Front-End Drivers for R&D Capabilities, Regulatory Drivers, and Downstream Market Drivers (Table

Table 3
End-to-end Solution Framework to Help MICs Increase Access to Future Novel Vaccines.Espinal et al.

Table 4
Case for action.