We conducted 3 key activities to collect the necessary data for this assessment. Activity 1 was a literature review and stakeholder mapping exercise of key procurement agencies and manufacturers involved in diphtheria antitoxin procurement and implementation activities for diphtheria outbreaks, by country or region. Activity 2 was surveys of the identified key procurement agencies and manufacturers involved in diphtheria antitoxin supply and procurement and implementation activities for diphtheria outbreaks. Activity 3 was key informant interviews with the developers of monoclonal antibodies currently in development for diphtheria.

The surveys and key informant interviews highlight that prices and availability of DAT vary widely and that prediction of demand is challenging for both manufacturers and procurement agencies. Procurement agencies raised concerns over the inability to obtain sufficient amounts of DAT to respond to increasing global outbreaks (19–26). Related factors raised included broad variability in pricing, a lack of procurement agency resources available to engage with manufacturers, and the absence of prequalified or stringent regulatory authority–approved DAT. There was no clear indication of why prices varied so widely, although there appeared to be some correlation between larger contract volumes and lower prices, as would be expected in contracting practices.

With respect to product specifications, procurement agencies noted that the product’s relatively short shelf-life resulted in a purchase risk for the organization, and given the lower quantities typically procured in comparison to other public health products and the challenges with supply availability, many procurement agencies were not well placed to take that risk. Suggested ways to mitigate those risks included the coordination of a global stockpile, as was done for cholera vaccines (27), from which multiple agencies could draw, which would coordinate demand, introduce supportive financing mechanisms, and increase consistency across prices. Such a stockpile could also mitigate another concern raised, the necessary lead time for manufacturing, which proves challenging for outbreak response purposes. There is also a need to discuss the roles and responsibility for management of such a stockpile, similar to Gavi’s International Coordination Group (ICG) on Vaccine Provision, as well as distribution responsibilities, because diphtheria infections are not a high priority for response compared with other pathogens requiring vaccines or therapeutics. The stockpile approach would also require the definition of transportation requirements and responsibilities as well as funding authorities.

Although manufacturers overall expressed fewer concerns, the lack of response from several manufacturing organizations could mean that there are unexpressed concerns from other manufacturers. Some of the contacted manufacturers could no longer be involved in DAT supply, which would represent a further reduction in DAT availability from several years ago (Appendix). Manufacturers who responded to the survey indicated some forecasting or future estimates for manufacturing but did not identify any substantive ability to expand manufacturing capacity in a timely manner (e.g., surge capacity during outbreaks requiring increased production). Manufacturers also identified GMP requirements as a rate-limiting step for timely surge DAT production that would require increased speed of production. Those requirements should be considered nonnegotiable for procurement; however, there is a potential role for increasing prequalification of suppliers or enabling coordination with suppliers to promote capacity to meet GMP requirements in advance of increases in production needs or surge requirements.

Those solutions might help to mitigate some manufacturing issues, but they do not address other concerns with DAT, namely batch-to-batch variability of product, risk for hypersensitivity or allergic reactions, and timely ability to manufacture in response to outbreaks. Both organizations currently developing a monoclonal antibody product for DAT are making progress in development; however, both are hampered by a lack of available funding for research, lack of clarity around the potential implementation of a randomized control trial in outbreak situations to enable comparison against DAT, and lack of a clear path for manufacturing upon licensure. With respect to a potential clinical trial for mAbs, there is also an ethical concern of carrying out trials for market authorization in geographic locations for which the product may be too expensive, as was noted during clinical trials for Ebola viral disease treatment with mAbs. Although both products show great scientific promise, cost per treatment would likely be substantially higher than that of DAT.

The introduction of diphtheria vaccine has greatly reduced global incidence of diphtheria and contributed to improved childhood health. However, because of inconsistency in vaccine access, supply, and confidence, childhood immunization rates have waned globally in recent years and diphtheria outbreaks have risen, driving increased but unpredictable DAT demand and causing subsequent issues with consistent and rapid access to sufficient DAT. The importance of maintaining DAT manufacturing, supply, and access for health security of a vaccine-preventable disease should be recognized in the short term in tandem with a long-term understanding of the benefits of DAT replacement by more effective and safe toxin-targeting monoclonal antibodies that offer the promise of a 21st Century solution to DAT limitations.

Transition from DAT to monoclonal antibodies could be accomplished by supplementation of DAT supplies with laboratory-produced mDAT; 2 candidates are currently in clinical development. However, both mDAT candidates face challenges in advancing their clinical and manufacturing progress, such as an unclear value proposition and business case, lack of preferred product characteristics guidelines, lack of clear regulatory guidance, and the challenge of clearly communicating the unmet need in the face of an effective vaccine.

The perspectives we learned through surveys and interviews were invaluable. Our review was limited by nonresponse of some manufacturers, lack of ability to use publications or information in other languages, and lack of historical data about manufacturers no longer producing therapeutics.

Although WHO is maintaining a small stock of DAT to respond to urgent requests, no specific financial and allocation mechanism similar to an ICG has been established for diphtheria antitoxin. We noted a need to reconvene a group of experts drawn from manufacturers, procurement agencies, multilateral agencies, regulatory bodies, and philanthropic organizations. The mission of such a group would be to assess proposed options for viability and develop a shared commitment to increase financing for advancing mDAT product development while ensuring access to sufficient DAT supply.