Evolution of WHO Influenza Antiviral Stockpile: Rapid Access and Use in Low- and Middle-Income Countries for Pandemic Preparedness and Response

Abstract

The SARS outbreak and influenza A(H5N1) infections (2003–2004) prompted WHO to establish a global influenza antiviral stockpile, enabling rapid distribution to 72 countries during the 2009 A(H1N1) pandemic. To improve access in low- and middle-income countries, WHO added antivirals to the WHO Model List of Essential Medicines and included them in the Prequalification Programme. The 2011 Pandemic Influenza Preparedness Framework refined strategies for equitable access and rapid response. Lessons from COVID-19 led to a new WHO-led mechanism—the Interim Medical Countermeasures Network (i-MCM-net)—which supports integrated supply chains, real-time data sharing, research and development, and equitable access. WHO continues to emphasise equity and global solidarity, highlighting the need for accessible, effective, and affordable antivirals alongside vaccines to protect vulnerable populations and mitigate the impact of future pandemics.

Influenza antivirals and supportive medicinal products may be useful life saving countermeasures for severe influenza response, particularly for novel and pandemic influenza [1]. Here we describe World Health Organization (WHO) efforts to make influenza antivirals available for the low- and middle-income countries (LMICs) to prevent the spread and mitigate the impact of influenza virus infections.

HISTORICAL BACKGROUND AND EVOLUTION OF THE WHO GLOBAL STOCKPILE OF INFLUENZA ANTIVIRALS

Consideration for use and stockpiling influenza antivirals appeared already in WHO's first Influenza Pandemic Preparedness Plan published in 1999; this was based on earlier recommendations on prophylaxis and treatment of influenza [2]. Amantadine and rimantadine were listed as the available antiviral drugs with preference given to rimantadine because of its better tolerability profile. At that time neuraminidase inhibitors (NAIs) were undergoing large-scale clinical trials to support applications for licensure. Upon declaration of an influenza pandemic, the intention was that WHO would issue guidance on the best use of available antivirals against the pandemic virus, update this guidance throughout the pandemic, and estimate the availability of antiviral drugs for subsequent waves.

The 1999 plan argued that national policy decisions would need to address pharmaceutical supply and logistical issues, including whether to establish strategic stockpiles of antiviral drugs like rimantadine for laboratory workers or medical staff at high risk of exposure to a new subtype before vaccines could be manufactured. Procedures for using such drugs if not yet licensed in the country were also considered.

However, the conclusion stated that keeping stocks of anti-influenza drugs sufficient to treat entire population groups worldwide was unrealistic due to cost, shelf-life, and supply problems. Prophylactic, postexposure, and early treatment were recognized as intervention strategies, but widespread prophylactic use was deemed unrealistic for the same reasons. Nevertheless, as part of national pandemic planning, it was recommended that mechanisms existed to ensure the importation, licensure, and use of drugs already approved in some countries and that a supply adequate for critical needs, such as protecting healthcare staff and laboratory workers exposed to a new virus, be maintained.

The WHO Global Influenza Preparedness Plan published in 2005 [3] reflected lessons learned from the severe acute respiratory syndrome (SARS) 2003 outbreak experience and the evolving situation with reappearance of influenza A(H5N1) causing increasingly frequent zoonotic infections since 2003. Antivirals were considered a key resource along with vaccines to form core pharmaceutical interventions, and their use was integrated systematically throughout the plan. The development of a global stockpile was also discussed. The newer class of antivirals, primarily NAIs (oral oseltamivir and inhaled zanamivir), replaced amantadine and rimantadine as the first-line influenza antivirals because of the frequently observed antiviral resistance to the former medications in both seasonal and zoonotic influenza viruses, and because of their clinical potential for adverse effects. WHO published interim clinical guidelines for the use of antivirals for H5N1 infection in 2004 and these interim guidelines were updated in 2006 [4]. The key recommendations included: oseltamivir was strongly recommended for treatment due to its effectiveness in reducing severity and mortality; zanamivir was recommended as an alternative if oseltamivir was not available; amantadine and rimantadine were not recommended due to high levels of resistance in H5N1 strains; and the NAIs (eg, oseltamivir, zanamivir) were strongly recommended for chemoprophylaxis for high-risk exposure populations to prevent infection. Additionally, the importance of maintaining adequate stockpiles of antiviral drugs for timely treatment was emphasized.

During 2005, changes were observed in the epidemiology of H5N1 disease in animals, and human cases continued to occur with high mortality (33% to > 50% case fatality). The virus evolved and expanded its geographical range and became endemic in poultry in parts of Asia, increasing the size of the population at risk. Considering the impact of a pandemic caused by the highly pathogenic virus, WHO was asked to explore the establishment of an international stockpile of antivirals for strategic use during an evolving outbreak in an attempt to contain it at the source or at least delay spread.

The NAIs were not easily accessible in most of the countries and were expensive at that time. Considering the ease of oral administration, storage, transport, and broader clinical use in terms of age group, oseltamivir was considered as the primary antiviral for stockpiling. Two pivotal publications based on modeling approaches for the containment or mitigation of the impact of an influenza pandemic with antiviral agents prompted WHO Member States and WHO to develop stockpiles of antivirials [5, 6]. The recommendations suggested early or prophylactic use of antivirals as a containment measure, along with social distancing measures such as school closures, workplace distancing, and reducing public gatherings to help slow transmission. Some high-income countries developed their own national stockpiles. By November 2007, according to a media survey, antiviral national stockpiles reached treatment coverage of 5% of the global population.

The manufacturer of oseltamivir (F. Hoffmann-La Roche, AG) offered a donation to WHO in 2006 (3 million treatment courses) to develop a rapid response and containment stockpile. Later, the manufacturer donated additional doses to establish regional stockpiles (2 million treatment courses), which were equally distributed to the 6 regions (WHO Member States are divided into 6 regions: Africa, Americas, Europe, East Mediterranean, Europe, South-East Asia, and Western Pacific) and stored at designated regional hubs to enable rapid deployment. Pediatric capsules were also added to the central stockpile. A task force, composed of operational teams of the manufacturer, WHO, World Food Programme, and the United Nations Children's Fund, planned distribution and transportation of the stockpile. Regulatory and customs clearance were mapped across the countries and obstacles were resolved prior to the onset of a pandemic. When in 2009 the A(H1N1)pdm09 virus quickly spread globally, the entire 3 million rapid response global stockpile was distributed to the 72 countries (71 GAVI eligible countries plus Mexico where the pandemic hit the hardest in the early days of the pandemic) within 14 days from the declaration of phase 4 by the Director-General of WHO, demonstrating the value of having a such a mechanism in place. The regional stockpiles were deployed to countries based on the regional criteria along with the other international stocks developed by partners. The manufacturer made efforts to replenish the totality of the stockpile, which was deployed throughout the subsequent severe waves of the A(H1N1)pdm09 virus upon the requests from the affected Member States.

WHO has worked to enhance the accessibility of influenza antivirals in LMICs by adding them to the WHO Model List of Essential Medicines (EML) [7]. Being included on the WHO EML offers several significant benefits such as global recognition, guidance for national lists, improved access, and quality assurance. These advantages facilitate their procurement and use in public health programs, especially in resource-limited settings. Oseltamivir has been included in the EML since 2010; however, it was moved from the core list to the complementary list of the EML in 2017. This decision was based on additional evidence indicating that the beneficial effect of oseltamivir on relevant outcomes, such as hospital admissions and mortality, was lower than previously estimated [8]. The WHO Prequalification Program ensures that medical products, including medicines, vaccines, and diagnostics, meet global standards of quality, safety, and efficacy. Since the first prequalified NAI oseltamivir in 2009, a total of 20 manufacturers of oseltamivir and zanamivir have been prequalified by WHO [9].

The calls for greater equity of access to pandemic response products, notably vaccines and antivirals, by countries triggered a global discussion among WHO Member States starting in 2007. The 4-year negotiations to address public health security through the dual lens of sharing of influenza viruses with pandemic potential, on the one hand, and access to vaccines and other benefits, on the other, resulted in the adoption of the Pandemic Influenza Preparedness (PIP) Framework [10], an access and benefit sharing instrument that has equity at its core. The PIP Framework has since played a crucial role in refining WHO's antiviral stockpile strategy, emphasizing the importance of equity as the driver for global cooperation and partnership for pandemic influenza preparedness and response. The PIP Framework has been instrumental in enhancing the resilience of LMICs in the face of novel influenza outbreaks and pandemics.

PIP FRAMEWORK

Negotiated by WHO's 194 Member States and adopted by the World Health Assembly in 2011, the PIP Framework is an access- and benefit-sharing arrangement to enhance global preparedness for, and equitable response to, pandemic influenza. The Framework ensures access to pandemic influenza vaccines and antiviral treatments, particularly for LMICs, based on public health risk and need. Its key components and mechanisms aim to increase equity in the preparedness for, and response to, a future influenza pandemic through, inter alia, the following:

• Strengthening the WHO-coordinated Global Influenza Surveillance and Response System (GISRS) by promoting the rapid timely and systematic sharing of influenza viruses with pandemic potential by Member States with GISRS;

• Securing funds to support pandemic influenza preparedness capacities: The PIP Framework establishes an annual Partnership Contribution mechanism that provides sustainable financing to WHO from influenza vaccine, diagnostic and pharmaceutical manufacturers that use GISRS. WHO implements the funds through High-Level Implementation Plans that define public health objectives, with indicators and milestones, to strengthen specific pandemic influenza preparedness and response capacities at the global level and in countries where they are weak;

• Securing real-time access to future life-saving pandemic response products, such as vaccines and antivirals: WHO signs advance supply contracts with influenza product manufacturers to secure real-time access to specific percentages of future production of pandemic influenza response products for distribution to countries, particularly developing countries, based on public health risk and need;

• Promoting transparency and partnership through a robust governance mechanism that includes regular interaction with relevant stakeholders, notably GISRS, manufacturers, and civil society;

• Securing other benefits, including but not limited to laboratory and surveillance capacity building, regulatory capacity building, and antiviral stockpile development.

Antivirals Under the PIP Framework

The Framework promotes access to antivirals by seeking commitments from manufacturers to contribute to, or maintain, antiviral stockpiles for use in containment of outbreaks of influenza viruses with pandemic potential or response to an influenza pandemic. Antivirals secured by WHO are allocated to countries based on public health risk and need, and in accordance with evidence-based guidance and recommendations.

To achieve this goal, the PIP Framework requests that the WHO Director-General engages with relevant manufacturers to develop advance supply agreements for future access to antiviral supplies. An agreement was recently signed to provide WHO with access to relevant influenza antivirals at the time of an influenza pandemic. In May 2024, the first antiviral donation agreement under the PIP Framework was signed with F. Hoffmann-La Roche, Ltd. The commitment is for up to 5 million treatment courses over a 2-year period. These antiviral treatment courses would be critical in the early stages of the response to an influenza pandemic [11].

The inclusion of antivirals under the PIP Framework underscores the commitment of WHO Member States to pandemic preparedness and the equitable distribution of medical countermeasures (MCM) during a pandemic emergency—promoting equity of access by all, based on public health need, and thereby avoiding the inequities that have resulted from differences in economic development status. Through strategic partnerships and continuous monitoring, the Framework ensures that antivirals are available where they are most needed, enhancing the global response to influenza outbreaks and pandemic emergencies.

THE NEW APPROACH—INTERIM MEDICAL COUNTERMEASURES NETWORK

The Access to COVID-19 Tools (ACT) Accelerator [12], commonly referred to as ACT-A, was launched in April 2020 in response to the COVID-19 pandemic. This global collaboration aimed to accelerate the development, production, and equitable access to COVID-19 diagnostics, treatments, and vaccines. ACT-A brought together health organizations, scientists, businesses, civil society, and philanthropists to pool their expertise and resources, fostering an unprecedented level of cooperation.

ACT-A's vaccine arm, COVAX [13] delivered more than 1 billion COVID-19 vaccine doses to LMICs by the end of 2021 and 2 billion doses by the end of 2023 [14], significantly reducing the global inequity in vaccine distribution. Additionally, ACT-A facilitated the distribution of 92 million COVID-19 tests and provided critical treatments to millions of patients worldwide. The World Health Assembly adopted WHO Pandemic Agreement in May 2025. Pending entry into force of the WHO Pandemic Agreement, WHO is working with Member States and relevant partners to ensure the interim Medical Countermeasures Network (i-MCM net) is operational to respond to public health events requiring a coordinated international response [15].

Drawing on past experience, notably the lessons learned from the COVID-19 pandemic, there is a recognition of the broad capabilities that exist in the medical countermeasures ecosystem. These include innovation, research, production, distribution, and delivery of health products during pandemics.

The i-MCM-net will focus on several key areas to enhance global pandemic preparedness and response:

1. Coordinate availability of, equitable access to, and timely allocation of medical countermeasures at the global level: strengthen coordination efforts and provide strategic orientation to ensure a coherent response to pandemic threats, with a focus on the global level, but mindful of regional developments and approaches, maximizing the impact of collective actions.

2. Promote and develop collaboration platforms, frameworks, and tools: establish platforms, frameworks, and tools that encourage collaboration among existing key MCM networks, facilitating the sharing of knowledge, resources, and expertise to avoid duplication, streamline processes, and enhance the overall efficiency of MCM-related initiatives.

3. Catalyze action across networks: address strategic priorities by catalyzing partnerships and collaborations, ensuring concerted effort to address pandemic threats and achieve the shared goal of global access to quality MCMs.

4. Leverage collective expertise: encourage the pooling of expertise from diverse stakeholders, fostering a collaborative environment that drives equity across the end-to-end value chain of MCMs.

5. Monitor and evaluate progress: establish a robust monitoring and evaluation framework to assess progress and ensure transparency and accountability in achieving the aim of global access to MCMs.

During the mpox public health emergency of international concern in 2024 to the present [16], the i-MCM-net operationalized the mpox Access and Allocation mechanism to secure 2.4 million doses of vaccine to be allocated to the most affected countries on the African continent [17].

The i-MCM-net provides a forward-looking mechanism to leverage Member State collaboration, and to address pandemics and other public health crises, pending entry into force of the WHO Pandemic Agreement.

PERSPECTIVES FOR THE FUTURE

Pandemic influenza has the potential to cause severe global morbidity and mortality, leading to significant social and economic disruptions. The establishment of a global antiviral stockpile proved beneficial during the A(H1N1)pdm09 influenza pandemic, allowing for rapid and equitable access to necessary treatments. Lessons learned from this experience have been incorporated into WHO influenza control strategies and the PIP Framework.

The COVID-19 pandemic further underscored the need for global solidarity and the importance of working towards timely and equitable access to life-saving interventions. Member States highlighted the necessity of establishing mechanisms through which Member States can collaborate to make the value chain—from research and development to manufacturing, allocation, and delivery—resilient and equitable for populations most at risk during emergencies.

WHO is committed to continuously update its evidence-based guidance for the use of influenza antivirals, including novel influenza antivirals such as endonuclease inhibitors [18] to inform its mechanisms for access. In the situation where antivirals can save lives of severely ill patients and provide hope for survival, with improved access and availability, their true utility can be enjoyed fully by affected populations. While vaccines are crucial, the global health community must also draw more attention to the critical need for access to antivirals—their role to prevent illness and transmission is often under recognized. Ensuring that both vaccines and antivirals are readily available and accessible to all countries based on public health risk and need, particularly developing countries, is vital for an effective response to future pandemics.