Investing in sepsis science for future pandemic preparedness

Published on January 30th, 2025

High-quality and relevant data are fundamental to evidence-based planning for people-centered, cost-effective, results-oriented, and measurable policies and clinical interventions. This is particularly true for policy decisions aimed at alleviating significant human suffering, death, and disability caused by global health threats or medical emergencies.

Sepsis is a global health challenge estimated to affect 48.9 million children and adults every year and account for at least 11 million deaths—approximately 20% of all global deaths. Sepsis is a life-threatening medical emergency when the body’s immune system has an extreme response to an infection, damaging its own tissues and organs. Sepsis can lead to shock, multi-organ failure, disability and death, especially if not recognized early and treated effectively. It is a major cause of death both from endemic and pandemic infections. As such, sepsis needs urgent investments in real-time clinical epidemiology, as well as research and development (R&D) for novel vaccines, diagnostics, and therapeutic solutions (1, 2). The recent experience of the COVID-19 pandemic, which highlighted insufficient capacity to effectively respond to SARS-CoV-2-associated sepsis, further underscores the need for increased R&D focused on sepsis prevention, early detection, and effective treatment through a holistic approach spanning surveillance and early warning systems, vaccination, antimicrobial, immunomodulatory, and precision medicine approaches—as highlighted in the Frontiers in Science lead article by Hancock et al (3).

The 2030 Global Agenda for Sepsis (4), the first multi-year global strategy in this area launched by the Global Sepsis Alliance at the German Bundestag in September 2024, provides a roadmap for addressing these critical gaps. The Agenda prioritizes political leadership and multilateralism to ensure increased political and financial investments in sepsis responses, including through robust measurement and accountability mechanisms for this global health threat. It urges United Nations (UN) Member States to invest in sepsis research and innovation, and in sepsis response capacities during pandemics and other health emergencies. Figure 1 summarizes the five strategic pillars of the Agenda.

Lessons from COVID-19 pandemic vis-à-vis sepsis

The COVID-19 pandemic, with its high burden of SARS-CoV-2-associated sepsis, has led to a growing consensus that severe COVID-19 causing organ dysfunction was appropriate to label as sepsis (4). Overall, 78% of COVID-19 patients in intensive care units met diagnostic criteria for sepsis (5) and SARS-CoV-2-associated sepsis proved strikingly similar to sepsis caused by other pathogens in terms of the acute manifestations, phenotypes, complex immune responses, clinical outcomes, and long-term sequelae (6–9).

Sepsis is challenging to diagnose and treat in part because it is so heterogeneous and multifaceted, particularly in the context of pandemics. This underscores the need for prioritizing R&D in multiomics, machine learning, network biology, and novel diagnostics. These innovations will enable early detection and facilitate immune-directed therapies tailored to specific sepsis subtypes (endotypes) and disease stages over time, including epigenetic factors, as Hancock et al. emphasize (3).

Immune dysregulation was an important component of COVID-19 pathophysiology and immune-based therapies showed well-documented successes (10). As an example, monoclonal antibody-based immunotherapies have significantly improved survival among mechanically ventilated patients and targeted immunotherapies in patients with moderate or severe COVID-19 significantly reduced the risk of worse clinical outcomes (10, 11). However, research investments in sepsis are generally limited, especially when it comes to developing effective immunomodulatory therapies.

Decision-makers continue to underestimate that, similar to COVID-19, every future disease outbreak or pandemic—regardless of the primary pathogen—will increase the risk of sepsis as a final common pathway to death and disability from infectious diseases. For effective future pandemic preparedness, it is therefore crucial to invest in surveillance and rapid response systems as well as systems immunology, pathogen-agnostic, and precision medicine approaches to reduce pandemic-related mortality, alongside R&D of new vaccines, infection prevention measures, and antimicrobial therapies. Moreover, long COVID and post-sepsis syndrome of other infectious etiologies confers a high societal burden, shares many similarities and demands attention.

Global health authorities must prioritize sepsis research for effective pandemic response

The historic Sepsis Resolution adopted in 2017 at the 70th Session of the World Health Assembly (WHA70.7) urges UN Member States “to develop and implement standard and optimal care and strengthen medical countermeasures for diagnosing and managing sepsis in health emergencies, including outbreaks, through appropriate guidelines with a multisectoral approach” (13).

The treatment of sepsis and antimicrobial resistance (AMR) are intimately linked. It is encouraging that the R&D agenda for antimicrobial therapies, including those targeting resistant pathogens with pandemic potential, has been prioritized in the draft Pandemic Accord currently under the negotiations by 194 Member States of World Health Organization (WHO). The critical link between pandemic preparedness and AMR is also reflected in the political declaration of the high-level meeting on AMR submitted to the 79th Session of the UN General Assembly in September 2024.

However, sepsis—the major cause of pandemic- and AMR-related deaths—has not been addressed in either of these documents that will shape the future global frameworks for pandemic preparedness. Neither the Pandemic Accord nor the AMR political declaration calls for R&D into novel immune diagnostics or therapies, which are essential for the effective treatment of septic patients during outbreaks or pandemics, regardless of the causative pathogens. We call on UN Member States, especially donor governments of countries within the Organisation for Economic Co-operation and Development (OECD), to increase both political and financial commitments to sepsis research.

The Biomedical Advanced Research and Development Authority (BARDA) of the United States is an example of a national agency that provides an integrated, systematic approach to the development of vaccines, therapies, and diagnostic tools for public health emergencies. Through its Division of Research, Innovations, and Ventures (DRIVe), BARDA launched the "Solving Sepsis Strategy" initiative in 2018 and has since announced new partnerships to advance host-based diagnostic research aimed at early detection of sepsis and improved clinical outcomes (14).

Government entities with similar mandates, such as the European Commission's Health Emergency Preparedness and Response Authority (HERA) or national and regional centers for disease control, should also consider making similar investments in sepsis R&D through their pandemic prevention, preparedness, and response programs.

Summary of policy recommendations

UN Member States, in coordination with the UN Secretariat, WHO, other specialized UN agencies, and stakeholders from public, private, academic, and civil society sectors, should prioritize sepsis as a critical global health threat.

Given the significantly high incidence and mortality rates of sepsis during pandemics, R&D for sepsis should be a key component of pandemic prevention, preparedness, and response measures at national, regional and global levels—building on the 2017 World Health Assembly Resolution (13) and the 2030 Global Agenda for Sepsis (4).

To address the complex immune pathophysiology of sepsis, global health authorities should prioritize systems immunology and precision medicine research to enhance early sepsis detection and pathogen-agnostic, individualized treatment. New, effective immune diagnostics and therapeutics could significantly improve survival rates among sepsis patients, regardless of the nature of the pandemic pathogen.

Sepsis immunology research for future pandemic preparedness should account for the disproportionately high burden of sepsis in low- and middle-income countries (LMICs), where healthcare systems face significant resource constraints. Financial assistance and subsidies, such as those provided through the Pandemic Fund or other multilateral mechanisms, should help LMICs to reduce these disparities and ensure effective sepsis management to limit future pandemic deaths.

Generative AI statement 

Generative AI was not used in the development of this article. 

Copyright statement 

Copyright: © 2024 [author(s)]. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in Frontiers Policy Labs is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.     

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