Which Virus Will Cause the Next Pandemic?

The paper addresses the question of which viruses are most likely to cause the next pandemic. The authors frame pandemics as WHO-declared events (or historically recognized pandemics prior to the WHO framework) and emphasize that, despite advances in infectious disease research, societies have repeatedly been unprepared, incurring high mortality and socioeconomic costs. To inform future preparedness, the paper reviews past pandemics of the 20th and 21st centuries, outlines the WHO International Health Regulations and Public Health Emergencies of International Concern (PHEIC), and examines WHO priority diseases. It then compares pandemic viruses, PHEIC agents, and WHO-priority pathogens to identify common traits—particularly zoonotic origins and airborne human-to-human transmission—that can guide assessment of pandemic risk.

The authors briefly review major pandemics with identified causative viruses: the 1918–1919 influenza A/H1N1 pandemic (~50 million deaths), the 1957 A/H2N2 pandemic (~1 million deaths), the 1968 A/H3N2 pandemic (~1 million deaths), the 1977 reemergence of A/H1N1, the 2009 A/H1N1 pandemic (~284,000 deaths), and the SARS-CoV-2 pandemic (by late August 2022, >600 million cases and ~6.5 million deaths). They describe how influenza pandemics arose via zoonotic introduction and reassortment, largely involving avian reservoirs, with potential reassortment in pigs or poultry. They summarize WHO’s International Health Regulations and seven PHEIC declarations since 2005, including the 2009 H1N1 pandemic, West Africa Ebola (2013–2016; >11,000 deaths), ongoing poliomyelitis PHEIC since 2014, Zika in South America (2016; ~600 microcephaly cases), Ebola in DRC (2018–2020; ~2,300 deaths), the SARS-CoV-2 pandemic, and the 2022 mpox outbreak (>16,000 cases in 75 countries). The current WHO priority disease list includes COVID-19, Crimean-Congo hemorrhagic fever, Ebola, Marburg, Lassa, SARS, MERS, Nipah and henipaviral diseases, Rift Valley fever, Zika, and “Disease X.” The review highlights reservoirs implicated in past and priority threats—wild waterfowl for influenza A, bats for multiple high-consequence viruses, arthropods for arboviruses, and rodents for Lassa virus—and notes vaccine availability and gaps.

• Most pandemics and priority threats are zoonotic; viruses already circulating widely in humans are unlikely to cause pandemics due to preexisting immunity.
• Reservoirs: wild waterfowl (influenza A), bats (e.g., Ebola, Marburg, Nipah, SARS/MERS/SARS-CoV-2), arthropods (e.g., Zika, CCHF, Rift Valley fever), and rodents (e.g., Lassa). Eradication is feasible only for human-only reservoirs (e.g., smallpox; polio near-eradication), not for zoonotic reservoirs.
• Influenza pandemics originated from avian viruses or reassortants with avian gene segments (notably HA and PB1), occasionally involving pigs as intermediate hosts.
• Human immunity is narrow and may wane; antigenic novelty enables pandemics even within known subtypes (e.g., 2009 H1N1). Most of the global population is immunologically naïve to H2N2 due to its absence since 1968; discontinuation of some vaccinations (e.g., polio in some regions around 2000) increases susceptibility.
• Airborne human-to-human transmission characterizes all recorded viral pandemics; non-airborne routes (vectors, direct contact/body fluids) have caused PHEICs and outbreaks but have not produced pandemics to date.
• Airborne transmission is difficult to curb and entails high socioeconomic costs when strict measures are applied; vehicle/contact-based transmission can often be mitigated through hygiene and behavioral interventions, though cultural practices can challenge implementation.
• Vaccines: strain-specific influenza vaccines exist; SARS-CoV-2 vaccines are widely available but face variant-related efficacy challenges; a licensed vaccine exists for Zaire ebolavirus in some African countries; many PHEIC/priority diseases lack widely deployed vaccines. The 100-day vaccine goal may be attainable via mRNA platforms but will not prevent initial waves.
• Molecular predictors remain limited: receptor usage and innate immune antagonism matter, but sequence data alone cannot reliably predict spillover/pandemic potential. Zoonotic threats are more often RNA than DNA viruses.
• Quantitative context: 1918–1919 H1N1 (~50 million deaths); 1957 H2N2 (~1 million); 1968 H3N2 (~1 million); 2009 H1N1 (~284,000 deaths); COVID-19 by late Aug 2022 (>600 million cases; ~6.5 million deaths); West Africa Ebola (2013–2016; >11,000 deaths); DRC Ebola (2018–2020; ~2,300 deaths); 2022 mpox (>16,000 cases across 75 countries); Zika-linked microcephaly (~600 cases).

By comparing past pandemics, PHEICs, and WHO priority diseases, the paper narrows the characteristics most associated with pandemic risk: zoonotic origin from mammals or birds, immune naïveté in the human population, and efficient airborne human-to-human transmission. These insights directly address the central question by indicating that future pandemic threats are most likely to emerge from respiratory RNA viruses with established or attainable airborne spread in humans (e.g., influenza A lineages from avian reservoirs, coronaviruses from bats). The analysis underscores that while many high-consequence zoonoses spread via vectors or direct contact with body fluids, such transmission modes have not historically produced pandemics. The discussion also highlights practical implications for public health: difficulties of controlling airborne spread; the importance of vaccine platforms that can be rapidly adapted; and the necessity of surveillance focused on animal reservoirs with high zoonotic potential (especially bats and birds).

The next pandemic will most likely arise from a zoonotic virus originating in mammals (notably bats and rodents) or birds, with efficient airborne human-to-human transmission. Preparedness should prioritize: (i) surveillance and metagenomic cataloging of animal reservoirs and human-infecting viruses; (ii) development of animal models for candidate pandemic viruses; (iii) basic molecular virology to understand host range, transmission, and immune evasion; (iv) early-stage vaccine development and testing, leveraging rapid platforms (e.g., the 100-day target); and (v) broad-spectrum antivirals as first-line defenses. A prototype pathogen approach across priority virus families is advocated to accelerate countermeasure readiness. Even with accelerated vaccine timelines, initial pandemic waves are likely unavoidable, underscoring the need for sustained, coordinated global preparedness.

This is an opinion/narrative synthesis without primary experimental methods. Predictive power is limited by incomplete knowledge of viral determinants of host range, transmission, and immune evasion; receptors are known for relatively few viruses, and data on interferon antagonism and other virulence factors exist for a limited set. Sequence analysis alone cannot reliably predict spillover or pandemic potential. Many conclusions are based on historical patterns that may not capture future evolutionary paths or ecological changes (e.g., habitat encroachment, climate-driven vector shifts).