Introduction

The World Health Organization (WHO) Prequalification (PQ) Units’ Emergency Use Listing (EUL) is a unique WHO-facilitated regulatory pathway that can only be used in a declared public health emergency of international concern (PHEIC) or other public health emergency designated by the WHO Director-General1. This emergency scenario allows for a product to be listed based on an earlier package of safety and efficacy data than is the norm.

In both 2019 and 2020, the Bill & Melinda Gates Foundation (BMGF) worked closely with multiple product development partners to support P.T. Bio Farma’s submission to the WHO EUL for the novel oral polio vaccine type 2 (nOPV2) vaccine. The nOPV2 vaccine was developed to better address the evolving risk of type 2-circulating, vaccine-derived poliovirus, a risk that elicited a declaration of a PHEIC by the WHO in 20142. The novel vaccine became the first and, to-date, an only vaccine to be submitted for WHO EUL under the revised procedure. It is widely anticipated that a novel COVID-19 vaccine will be the second vaccine type to utilize the WHO EUL procedure3.

The EUL will likely play a critical role in accelerating equitable access to COVID-19 vaccines, enabling manufacturing countries to use an emergency pathway to authorize products1. Many governments with nascent regulatory systems, such as those in low- and middle-income countries (LMICs), rely on the routine WHO PQ program and the programmatic utilization recommendations to guide procurement and implementation decisions4,5. The EUL procedure can be an effective tool for assuring quality and accelerating access to COVID-19 vaccines. Despite this opportunity, not all vaccine developers may be familiar with navigating the WHO EUL for a successful submission.

In this Perspective, we seek to draw on our lessons learned from the nOPV2 WHO EUL experience and provide recommendations to those interested in accelerating COVID-19 vaccine development with the goal of WHO EUL submission. Specifically, we share our observations on key lessons learned in the areas of regulatory, clinical development, chemistry manufacturing and controls (CMC), and post-deployment monitoring with respect-to a WHO EUL. We hope that these insights will help developers effectively plan for WHO EUL interactions and submissions and, thus, accelerate development and global access to safe, effective, quality COVID-19 vaccines.

Why EUL?

As with many new medical interventions, it is likely that COVID-19 vaccines will be widely available in high-income countries much earlier than in LMICs6,7 This issue will be exacerbated if there are vaccine supply constraints, and vaccine manufacturers prioritize high-income country markets. The WHO EUL procedure could help address this potential imbalance by providing a route through which manufacturers, particularly those aiming to supply low-income country markets, can diversify access to their vaccines in the absence of an alternative stringent regulatory agency (SRA) pathway; or, WHO EUL can streamline the process to accelerate global market access following SRA or National Regulatory Agency (NRA) approval.

We acknowledge that some frontrunner COVID-19 vaccine candidates, if successful, are unlikely to follow the WHO EUL and PQ pathways. They may instead opt for approval from an SRA. However, given the unprecedented scale and speed of the need for COVID-19 vaccines, continued vaccine development will likely be necessary to meet global demand8. The need to generate affordable vaccines for large-scale, long-term distribution may also be a key driver for continued vaccine innovation. Several promising candidates are currently being developed by Developing Countries Vaccine Manufacturers (DCVMs) at low cost and, for which, the first registration will not be via an SRA. While some vaccine manufacturers may prefer to prepare submissions directly for WHO PQ9, the WHO EUL procedure represents an opportunity to accelerate the availability of vaccines by months or, even, years compared to WHO PQ.

Overall, candidates for WHO EUL must demonstrate initial human efficacy (typically phase 2 data), as well as early human safety data. Though a decision is generally made within 90 days, the listing is not intended to circumvent the need for full clinical trial enrollment and analysis, WHO PQ, or other full market authorization processes (Fig. 1b). Under the EUL, a vaccine at an earlier stage of product development might only be listed for use in specific at-risk populations for a time-limited duration, provided the demonstrated benefits continue to outweigh the risks in post-listing studies. Given the high mortality rate and transmissibility of SARS-CoV-2 and the paucity of prophylactic or therapeutic modalities10,11,12, the WHO EUL is clearly suited to the COVID-19 pandemic scenario. Its relatively rapid turnaround time may make the WHO EUL a superior option for accelerated and facilitated regulatory assessment.

Fig. 1: Potential for acceleration across all aspects of development for an EUL submission.
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Comparison of the traditional drug and vaccine development timeline adapted from Heaton4 (a) with an idealized vaccine development timeline targeting World Health Organization Emergency Use Listing submission based on nOPV2 and COVID-19 experiences (b). Symbols are used to indicate key stages in the vaccine development process; orange-red shading for clinical and blue shading for CMC activities.

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In this paper, we describe the recommendations on how to approach a submission for WHO EUL and the accelerated pathways for vaccine development for COVID-19 vaccines based on our observed experience for nOPV2. The WHO continues to provide guidance on their EUL process3. It will be important for readers to refer to those resources for the most up-to-date information.

Regulatory framework

The WHO EUL has pre-emergency, emergency, and post-listing phases1. Since the emergency phase begins once a PHEIC is declared, and COVID-19 has already been declared a PHEIC, it follows COVID-19 vaccine development will take place in the emergency phase. While the pre-emergency phase is over, the pre-emergency activities are still critical to successful EUL submission and should be completed during the emergency phase.

Strategy for the pre-emergency phase

The pre-emergency phase involves establishing platforms for collaborations between the WHO, the subject matter experts, the national regulatory agencies (NRAs) with special expertise, and the NRAs where the products will be used (where they differ). These platforms are leveraged for the pre-submission meetings/activities, product selection, and assessment of submitted data. A key benefit of these platforms is that all regulatory agencies that will be involved in the submission are included as early as possible and, then, throughout the tenure of preparation of the EUL data package. These agencies, WHO, and the manufacturers can align on appropriate non-clinical models and clinical study design, allowing for Phase 2b and Phase 3 trials to commence quickly. This approach can help to define the most relevant clinical trial endpoints for informing EUL by WHO and in target countries13,14.

Strategy for emergency phase

In the emergency phase, it is important for the product developers, regulatory agencies, and subject matter experts to align early on the content and the format of the regulatory submission. Best practices for quickly and efficiently preparing regulatory submissions should be agreed upon. Examples include defining the structure of data tables and developing the document “shells” in advance of clinical data becoming available to enable the rapid completion of data tables and reports. The regulatory strategy should articulate what is the level of authorization (if any) that will be required in the manufacturing country prior to EUL filing. For example, it should be decided whether the product will be submitted to a WHO Maturity Level 4 (ML4) regulator and will, therefore, come to EUL with an emergency authorization from the ML4 regulator15. If the vaccine will be manufactured in a country whose regulatory agency is not ML4 but is considered “functional for purposes of vaccine oversight”, it should be determined as early as possible what was the level of authorization (if any) in the manufacturing country that will be required prior to EUL filing. The applicants should clarify which regulatory agency will perform batch release and whether all agencies will rely on that release decision.

The scientific advice and pre-submission meetings are invaluable for reaching an agreement, not only on the content of the submission, but also on the filing strategy. Agreement on the timing and details of a rolling submission, and a review process that allows staggered submission of preclinical, CMC, and clinical data, could be useful in accelerating the overall timeline. If, for example, the CMC and preclinical data are available for review earlier than are the clinical data, a rolling submission could allow assessors to begin and potentially complete their review of those elements sooner than leave it for a later date.

Strategy for post-listing phase

If the data available at the time of the EUL are considered insufficient to support licensure or WHO PQ, then the developer must reach an agreement with the WHO PQ unit on the nature and timing of data to be submitted for assessment post-listing to support a request for WHO PQ.

A plan to monitor safety and efficacy in the field must be included as part of the EUL submission16. However, some countries seeking to adopt the vaccine under EUL may have limited monitoring infrastructure17. The NRAs in such countries should engage with experts in safety monitoring and vaccine deployment and with ongoing product assessment and oversight post-EUL under emergency circumstances. Depending on the scientific robustness with which post-listing monitoring data are collected and analyzed, these data may provide primary and/or supplementary data to support decisions on full licensure or removal from the EUL.

Updates based on emergency status

Following the authorization of the first few COVID-19 vaccines, the ability of later candidates to quality for facilitated regulatory approaches, through the definitions of “unmet clinical need”, will decline: therefore, the rationale for use of the EUL pathway will be impacted. Simultaneously, the applicants will need to demonstrate that COVID-19 remains a PHEIC, perhaps due to supply/demand challenges, or that their product offers superior safety, efficacy, administration, and/or feasibility. Garnering a WHO vaccine program, World Health Assembly resolution, or Strategic Advisory Group of Experts on Immunization recommendation may be important for the procurement agencies and the country’s adoption of the new vaccine under EUL.

Clinical development

Overall strategy

When pursuing an EUL, the clinical development group should align with WHO PQ and the primary regulatory authority on the requisite data set in target age groups to support an initial, perhaps restricted, EUL. Specifically, it is crucial to align on the intended wording of the EUL with respect to the target population(s) for use of the vaccine and to include plans for developing data supporting special populations (e.g. children, women of child-bearing age)18,19. This will be of particular importance for COVID-19 vaccines which will have a wide-range of target populations and use-cases.

Another strategic goal should be to accelerate clinical studies as much as possible to shorten the timeline to EUL. Table 1 outlines many potential acceleration approaches that can be employed through all stages of clinical development. Several of the strategies address the novel targets and manufacturing approaches associated with COVID-19, which clinical data will help validate.

Table 1 Strategies for accelerating clinical development.
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Chemistry manufacturing and controls considerations

Overall strategy

There is no abbreviated CMC EUL path based on risk/benefit criteria20. Manufacturers and facilities will be held to established commercial standards, requiring strict adherence to guidelines that are not well-understood by the general public. Large amounts of human and financial capital must be dedicated to programs with high risk of delays or failure.

The CMC strategy should aim for the fastest path to EUL with a plan to manufacture at the scale required to address the pandemic. When pursuing accelerated timelines under heavy public scrutiny, it is important to develop a clear CMC strategy and communication plan. Procurers and implementers need to be aligned with the strategy and commit to it early (even before efficacy readouts) to reduce the risk of supply being delayed or insufficient.

The practices described below are intended to help anticipate and mitigate some of this risk. These recommendations are derived from experience with nOPV2 manufacturing and submission, and are supported by findings from Merck’s experience with their Ebola vaccine manufacturing and submission21.

Regulatory alignment for clinical trials, initial doses, and subsequent use

Manufacturing for a public health emergency must take place much faster than the traditional process development and scale-up22,23. EUL CMC standards are based on routine GMP standards for both pilot- and commercial-scale plants1,24. It is therefore critical to align with WHO PQ and the relevant regulatory bodies on expectations for standards, documentation, and inspection, as well as process- and analytical-comparability assays and any flexibilities that might apply.

Manufacturers and regulators must align on the use of material produced, in pilot-scale and/or alternate facilities, to accelerate the availability of EUL-approved material. Circumstances might require launching doses from pilot-scale and/or alternate-commercial-scale facilities; while commercial-scale and/or additional facilities, commercial processes, and presentations are still being finalized, and, as the regulatory submission is happening (Fig. 2). Because the material used in clinical studies may have been made in a different facility than those being planned for ongoing commercial production, it is necessary to pre-establish parameters for demonstrating adequate process, and analytical comparability, and to continue to improve mechanisms that can accommodate changes while the product is rolled out25. In addition, it could be important to plan for a rolling EUL submission that allows for initial review of pilot-scale and/or alternate facilities, with the inclusion of commercial/large-scale production data as it becomes available and validated (Fig. 1).

Fig. 2: Example of vaccine production for EUL—concurrent activities needed for pilot and commercial facility scale-up and regulatory submissions.
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Assumptions in this scenario include: rolling EUL submission is allowed, and that pilot-scale process development and engineering and validation runs completed prior to month 1.

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If possible, manufacturers could agree with WHO PQ and the relevant national authorities on the types of release assays necessary. If these assays require specialized expertise, such as genetic sequencing, it could be beneficial for the manufacturer to bring this capacity in-house early to minimize any testing delays.

Site selection and capacity planning

Depending on volumes needed, it may be necessary to secure multiple sites for promising candidates, and account for factors such as those outlined in Table 2.

Table 2 Factors to consider in site selection and capacity planning.
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Presentation options

Different manufacturing bottlenecks and supply issues may limit flexibility on initial vaccine presentation. For example, adequate drug-substance production but limited filling capacity could require higher dose-per-vial presentations that might not be ideal for routine immunization but could be suitable in campaign settings26,27. Maintaining flexibility for changing presentations based on the evolution of the epidemic requires careful consideration of the features in Table 3.

Table 3 Presentation features that may change post-initial EUL.
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Scaling up/at-risk funding

To ensure sufficient volumes of vaccine are produced and allocated equitably, manufacturers need to be shown the money through some combination of push-and-pull funding28. For COVID-19, much of this funding has been supplied through direct government subsidy and commitments to purchase a significant number of doses, post authorization. Some will also be governed by the ACT Accelerator COVAX facility29. Currently, there are no UNICEF processes to procure an unlicensed vaccine30,31, yet some form of financing is needed to build a stockpile at-risk that can be used upon emergency/conditional authorization (recognizing that the stockpile will have a shelf-life and need to be replenished regularly, even if unused). This risk could be shared between different stakeholders, and might involve some form of a purchase order or guarantee in the event of technical or regulatory failure and/or funding discrete components of long-lead-time equipment and freezers or storage equipment. It may also be useful to procure and stockpile supplies with long shelf-life in non-pandemic times (e.g., syringes)—these items might be impacted by supply chain breakdowns in the pandemic, but do not require highly specialized storage or risk rapid expiration32. In addition, to determine the size of investment and reservation, it is important to have reliable demand projections that are backed by purchase orders33,34. The stockpile mechanism itself does not own or store doses, which places an additional onus on suppliers to store and prepare vaccines for distribution in future scenarios.

Cost of goods sold/Pricing for global access

Vaccine pricing must enable broad access, so investments should aim to secure company commitment to pricing at cost of goods sold (COGS) plus a specific margin (COGS + pricing) for LMICs. For scaled, lower-cost access, manufacturers could consider planning for technology transfer to a DCVM or increasing production scale to decrease COGS in the future35. Additionally, funders can require contractual definitions for pricing at COGS + pricing at certain volumes.

Post-deployment product monitoring

Overall strategy

Ongoing safety monitoring is a key aspect of deploying any new vaccine36. A post-deployment monitoring plan is required by WHO for EUL approval. EUL post-deployment product monitoring must include the use of a reporting system for adverse events following immunization (AEFIs), and the option for using active surveillance to investigate specific safety concerns37. These systems must report outcomes in a timely manner to both WHO and relevant NRAs.

Like other aspects of the EUL submission, the post-deployment product monitoring plan should be discussed with the WHO PQ unit during pre-licensing meetings to ensure early alignment with EUL requirements. Since EUL candidates must commit to advancing the product to WHO PQ whenever possible, the post-deployment safety monitoring plan should also align with the collection of the remaining clinical data needed for assembling the full WHO PQ dossier.

Strong product monitoring procedures will be crucial for vaccines rolled out under the EUL pathway prior to WHO PQ, or those having full licensure by an SRA. Many COVID-19 vaccine candidates use novel technologies such as an mRNA-based platform38, which will require even closer scrutiny because of the lack of historical safety data from similar vaccines39. While most high-income countries are equipped with well-established adverse event reporting systems40, many LMICs using the EUL pathway lack strong existing reporting systems, making collecting safety data for a newly deployed vaccine in these geographies difficult41,42.

Special considerations for COVID-19

The roll-out of COVID-19 vaccines will be unprecedented in scale and breadth. Never before has the global community attempted to deploy vaccines across so many countries and target populations so quickly. This deployment will be further complicated by multiple vaccines for COVID-19 likely to co-exist under different forms of licensure and authorization.

This unique scenario creates many considerations on how to evaluate risk benefit for different populations, especially in locations with weak safety surveillance systems43. Equitable access considerations should be balanced against safety concerns for special populations (such as pregnant women), and the ability to monitor and report AEFIs in the selection of the initial deployment country and populations.

There are also many scientific complexities presented by the multiple vaccine candidate landscape for COVID-19. It is likely that certain COVID-19 vaccines will be rolled out under emergency use authorization while clinical trials for other vaccines are ongoing or in preparation. This presents a challenge on how to design clinical trials for experimental vaccines. Restricting access of trial participants to the available vaccine may be deemed unethical. Thus, the trial design will need to be adaptive, and may be required to compare the experimental vaccine against authorized vaccines rather than placebo.

Alongside safety monitoring, the effectiveness of COVID-19 vaccines will need to be monitored over time. The duration of immunity will not initially be known for new COVID-19 vaccines. Studies will need to be conducted to monitor duration of immunity for each vaccine, post-deployment. Guidance on boosters and the relative performance of different authorized vaccines may subsequently be required.

Strategies for active surveillance

The considerations above apply largely to passive surveillance of AEFIs. Ideally, comprehensive post-deployment product monitoring of a COVID-19 vaccine would also involve active surveillance and epidemiological studies of vaccine safety outcomes and long-term efficacy44. Since pharmacovigilance capacity varies greatly in LMICs17, widespread active surveillance of vaccine outcomes in some areas will be challenging. In such areas, there should be additional provision for training to enable active surveillance. Strategies for active surveillance in areas with limited pharmacovigilance capacity include conducting surveillance via sentinel sites such as government immunization centers45, leveraging existing epidemiological networks41, and implementing targeted cohort studies using local investigators to examine possible safety signals46,47.

Reporting

It will be important for manufacturers to ensure that they have adequate capacity to bring together safety data reported from all geographies in which their vaccines are deployed, whether higher- or lower-income. Those data should be reported to in-country regulators, the manufacturing country’s NRA, and the WHO to ensure that appropriate actions for further investigation can occur.

Conclusion

The goal of this work was to highlight strategies for streamlining vaccine development and to encourage COVID-19 vaccine developers to consider mechanisms by which they can achieve accelerated access for their products in LMICs. By virtue of BMGF’s involvement with the P.T. Bio Farma nOPV2 EUL submission, we have gained insights into vaccine development acceleration and WHO EUL submission that can be applied to the race for a COVID-19 vaccine and which, we hope, may accelerate the use of the novel vaccines under development to protect at-risk populations. It is anticipated that the vaccine development and global health community will learn a lot about emergency authorization and listing procedures over the next 12–18 months as vaccine candidates for COVID-19 advance. There are many opportunities to leverage these experiences and strengthen procedures for future epidemic preparedness beyond the current COVID-19 pandemic.