Could Fractional Dosing Be the Key to Addressing the Mpox Vaccine Shortage?

As the world grapples with the mpox outbreak, recently declared a public health emergency of international concern by the WHO, the urgency for effective vaccines has never been greater. Yet, despite efforts to boost donations and scale up production, there’s an unsettling sense of déjà vu, reminiscent of the early COVID-19 response when vaccine supply fell woefully short of demand. With Africa CDC estimating that at least 10 million doses are needed to contain the mpox outbreak, the current global supply is just a drop in the bucket. Even as WHO, UNICEF, and Gavi fast-tracked their processes to deliver vaccines to the DRC in the next few days, the gap remains significant.

In this critical moment, fractional dosing (FD)—a strategy that involves administering smaller doses of vaccines, mainly to stretch limited supply—could be a game-changer. This approach was successfully employed during the 2022 mpox emergency with the MVA-BN vaccine, one of the two vaccines approved for mpox in high-income countries, allowing countries like the US and UK to extend their vaccine coverage despite severe shortages.

During the 2022 outbreak, the FDA and EMA approved a smaller 0.1 mL dose administered intradermally—just below the top layer of the skin—rather than subcutaneously—under the skin—based on a 2015 Phase 2 trial that showed similar antibody responses and safety profiles for both methods. This swift move enabled the rapid and widespread rollout of fractional dosing across the US and UK in 2022 and 2023. The results were clear: fractional dosing not only expanded vaccine coverage but also maintained efficacy and safety, with consistent completion rates for the two-dose regimen, despite the change in administration method.

Why fractionation is so important now

The potential benefits of FD are substantial. First and foremost, FD could dramatically increase the number of people vaccinated, potentially up to five-fold. This would be a crucial step in meeting the urgent demand for 10 million doses. By making the most of available supply, FD could help bridge the gap until additional production capacity can be mobilized.

Speed is another critical advantage of FD. Even if new vaccine doses are produced or donated, they will take time to reach the at-risk populations. In contrast, FD can be implemented immediately, as soon as doses become available, allowing for quicker coverage. In the 2022 mpox emergency, modeling in the US showed that when supply is constrained, FD could prevent up to 70 percent of infections. This rapid response capability could mean the difference between containment and further spread of the virus.

Cost-effectiveness is a third major benefit. With the price of mpox vaccination as high as $100 per person, the financial burden on global health funders is significant. FD could reduce these costs substantially, making it a more feasible option for widespread vaccination campaigns, especially in affected African countries.

Challenges to overcome

Despite its promise, FD is not without challenges. Decision-makers considering large-scale FD implementation will need to address three key issues:

1. Lack of data: There is currently insufficient data on FD’s effectiveness in certain key populations, such as children and individuals living with HIV. Additionally, there are no established correlates of protection against mpox, meaning we do not fully understand how well mpox virus-neutralizing antibodies protect against disease or transmission. This uncertainty complicates public health decision making. Importantly, lack of data is an issue that goes beyond FD and applies to any mpox vaccination.
2. Complex delivery: Administering vaccines intradermally (ID), as required for FD, is more complex than traditional methods. It necessitates specialized needles and syringes, as well as additional training for healthcare workers to ensure proper administration. However, it’s worth noting that ID delivery has been successfully used in other vaccine campaign, including during polio vaccine shortages in many low- and middle-income countries. Despite initial concerns, large-scale FD rollouts during the 2022 mpox emergency were largely successful.
3. Stigma and side effects: Local reactions to ID injections can leave visible marks at the injection site, potentially increasing the stigma for vaccinated individuals. This is a particularly important consideration in communities where vaccine-related stigma may already be a barrier to uptake. However, it’s important to recognize that the alternative vaccine, produced by Japan’s KM Biologics, also presents challenges in administration.

The path forward

As the mpox outbreak continues to spread in Africa, FD offers a promising strategy to maximize vaccine impact in the short term. The potential benefits—up to a fivefold increase in vaccine supply, faster coverage, and significant cost savings—make it a strategy worth serious consideration. However, the global health community must act quickly to overcome the challenges associated with FD. Here are three critical steps that can be taken:

• Rapid regulatory and recommendation on ID delivery: African regulators and policy makers should swiftly review the latest evidence from the 2022-2023 emergency to determine whether it is sufficient to recommend FD in the current context. This effort could be led by the East African Community, a subregional economic bloc that includes several affected countries such as Kenya, Burundi, Rwanda, and Uganda belong, with support from WHO, the FDA, and the EMA where these decisions have already been made.  
• Further research: whether or not large-scale FD roll-out is implemented, it’s crucial to conduct further trials of ID delivery in African countries. These trials must be tailored to the specific needs and contexts of affected countries, with backing from funders like CEPI and collaboration with African regulators and organizations such as Africa CDC.
• Modeling benefits: it’s essential to build models that demonstrate the potential benefits of deploying an FD strategy for mpox vaccination in affected African countries. These models can help guide decision-making and ensure that the strategy is effectively implemented.

By addressing these challenges head-on, the global health community can maximize the impact of limited vaccine supplies and move closer to containing the mpox outbreak in Africa. Fractional dosing is not just a stopgap measure—it could be the key to ensuring equitable access to vaccines and protecting vulnerable populations during this critical time.