Preparing for the Unknown

In 2018, the World Health Organization (WHO) added a striking element to its list of priority diseases: “Disease X.” Unlike all other items on that list, Disease X does not refer to a specific pathogen or a known illness. Rather, it is a provisional concept: a deliberate acknowledgment that the next major pandemic could be caused by something science has not yet identified.

The concept captures a fundamental truth about infectious diseases: the greatest threat may be the one we are not yet monitoring. Disease X represents the possibility that a pathogen currently unknown to medicine could emerge and spread globally, potentially more rapidly, and virulently than any other we have encountered to date. It may also refer to a previously known pathogen that has altered its behavior, becoming more transmissible, more severe, or with a broader geographic distribution than it previously had.

Far from being a vague or abstract idea, Disease X serves a specific purpose in global health planning. Its inclusion on the WHO’s priority list indicates that preparedness efforts must go beyond known threats and invest in flexible, adaptable tools: vaccines that can be rapidly reformulated, diagnostic platforms effective against multiple types of pathogens, and surveillance systems capable of detecting the unexpected. SARS-CoV-2, the virus responsible for the COVID pandemic, is now widely regarded as the first real manifestation of Disease X: It emerged from an unidentified source and caused global devastation before any specific countermeasures existed.

Why the WHO Needs a Priority List

The WHO Action Plan for Research and Development to Prevent Epidemics, commonly known as the Research and Development Roadmap, was launched in 2015 at the request of the organization’s member states. Its central objective is to reduce the time between the identification of a new outbreak and the availability of effective diagnostics, treatments, and vaccines.

The Roadmap focuses specifically on serious emerging diseases for which there is currently little or no medical response. Established diseases that have their own research programs such as influenza, tuberculosis, or human immunodeficiency virus fall outside its scope not because they lack importance but because they already have funding, established regulatory pathways, and resources for the development of control measures. The Roadmap is designed to fill gaps, not to duplicate existing efforts.

An essential component of the Roadmap is its list of priority diseases. This list identifies which threats most urgently require investment in new tools, and it is reviewed annually to incorporate the latest scientific advances and changes in real-world conditions.

A Rigorous Method for Measuring Uncertainty

In the 2018 review, the most detailed one publicly documented, brought together specialists in microbiology, infectious diseases, epidemiology, public health policy, animal health and veterinary medicine, anthropology, and defense and security. This breadth of expertise reflects a fundamental principle: Pandemic risk cannot be assessed from an exclusively biological perspective.

The selection process follows a methodology based on three main tools. First, experts use the Delphi technique, which is a structured method for reaching consensus through successive rounds of anonymous feedback, to propose and narrow down the list of candidate diseases. Second, detailed context analyses are commissioned for each disease included on the shortlist, covering its biology, epidemiology, transmission characteristics, and existing countermeasures. Third, Multicriteria Decision Analysis is applied — a formal analytical method that scores each disease according to a set of weighted criteria, making the relative importance of the various factors explicit and transparent.

The criteria used to score the diseases reflect what makes a pathogen particularly dangerous from a public health perspective. In 2018, the greatest relative weight was assigned to person-to-person transmissibility, which accounted for nearly a quarter of the total score. Next is severity, measured by the case fatality rate. Other criteria include the degree of contact between humans and animals, the public health capacity of the affected regions, the potential for social disruption, and the pathogen’s evolutionary potential — that is, the likelihood that it will change and become more dangerous over time. A final category encompasses additional factors such as geographic distribution, the absence of protective immunity in the population, and any historical or potential links to biological weapons programs.

In addition, candidate diseases are also screened to determine whether they fall within the scope of the Master Plan. For example, cholera was excluded because a major global control initiative already existed. Leishmaniasis was redirected to the WHO’s Neglected Tropical Diseases program. Plague and West Nile virus disease were excluded by a committee vote as it was determined that countermeasures already existed or that the threat profile did not align with the Roadmap’s objectives.

The Eight Threats the WHO Is Closely Monitoring

Following this process, the committee identified eight diseases or categories of diseases that required accelerated research and development as a matter of urgency. These are, in no particular order of priority: Crimean-Congo hemorrhagic fever, Ebola virus disease, Marburg virus disease, Lassa fever, Middle East Respiratory Syndrome and SARS, diseases caused by the Nipah virus and other related henipaviruses, Rift Valley fever, Zika virus disease, and Disease X.

Each of these diseases poses a significant threat. Ebola and Marburg are filoviruses that cause severe hemorrhagic fevers, with historical case fatality rates of up to 90% in some outbreaks. The Nipah virus causes severe encephalitis and respiratory distress, with case-fatality rates ranging from 33% to 100% depending on the outbreak. Lassa fever is endemic in West Africa, with tens of thousands of cases annually; although most infections are mild, severe disease is associated with considerable mortality. Crimean-Congo hemorrhagic fever is transmitted by ticks, affects a vast geographic area stretching from Africa to Central Asia through the Middle East, and kills between 10% and 40% of those who develop severe disease. Rift Valley fever primarily affects livestock, but it can cause severe and sometimes fatal illness in humans, especially following floods that promote the proliferation of mosquitoes. Not only that but also it is the one that affects us most directly: despite its name, it is also endemic in Spain, with documented cases of infection dating back to 2016. The Zika virus, although typically mild in adults, garnered international attention due to its association with microcephaly in newborns of infected mothers.

The most recent addition to the list is SARS-CoV-2, added following the declaration of the COVID pandemic in 2020.

What Experts Fear Most

Specialists’ opinions on which of these diseases poses the greatest pandemic risk reveal some significant differences from the WHO’s formal ranking. In a survey conducted in 2023 among 187 infectious disease specialists from 57 countries by the VACCELERATE clinical trials network, influenza viruses received the highest score, cited by nearly four out of five participants as one of the most concerning threats, despite not appearing on the Roadmap list. Disease X ranked second, selected by nearly half of the respondents. SARS-CoV-2 and its predecessor, SARS-CoV, followed closely behind.

The absence of influenza from the Blueprint’s list is not an oversight. It reflects the fact that we already have vaccines, a dedicated global surveillance system, and a mature research and development pipeline — precisely the conditions that place a disease outside the Blueprint’s scope. Even so, the expert consensus that influenza poses the greatest pandemic risk highlights a tension at the heart of public health preparedness: the most well-studied diseases may still pose the greatest threat, while the Master Plan’s most urgent work concerns diseases that are poorly understood and controlled.

This tension is the essence of what Disease X represents. The WHO’s priority list does not aim to predict which pathogen will cause the next pandemic. It aims to ensure that, when something new and potentially dangerous emerges — whether from a bat colony, a live animal market, climate change, or a completely unforeseen source — the world will not have to start from scratch.

The authors’ conflicts of interest can be found in the original texts.

This story was translated from Univadis Spain, part of the Medscape Professional Network.