Ending respiratory infections

A century ago, waterborne diseases levied similar costs to those posed by respiratory viruses like colds and influenza today: endemic, periodically epidemic, and widely accepted as an inevitable feature of human life. Then, at the turn of the twentieth century, we decided they didn’t have to be. Pharmaceutical advances and clean water infrastructure made cholera, typhoid, and dysentery rare across much of the world within a matter of decades.Why haven’t we already seen the same kind of transformation with respiratory viruses? Last August we hosted a symposium at Stripe with ~40 leading scientists, pharma R&D leaders, biotech venture capitalists, and regulatory experts to better understand if this is technically possible and, if so, why it hasn’t happened yet.We heard two main reasons. First, it’s just technically very challenging: respiratory viruses represent hundreds of distinct, mutating strains across several families. Fortunately, new platform technologies, advances in our understanding of human immunology, biological data sets, and protein design tools mean we have our strongest ever suite of approaches for tackling it.Second, the development of the broad-spectrum solutions needed to solve the first problem has historically been underfunded, neither a great fit for philanthropic nor commercial funding. While COVID generated a burst of activity around preventing and understanding respiratory infections through an influx of new funding, that hasn’t been sustained.We believe that with enough focus and funding, these problems are tractable. Intercept is a $500 million philanthropic initiative that will take advantage of these new tools to catalyze the development of two types of products: broad-spectrum preventatives and air cleaning technologies. Together, these technologies can radically reduce the burden of respiratory infections, and can eventually help eliminate them altogether.Today, we treat respiratory infections like the cold and influenza as a minor nuisance. The evidence increasingly suggests otherwise.Healthy people spend roughly 15-25 days each year—about 5% of their lives—sick with respiratory infections like the common cold and influenza.1Common respiratory infections can lead to severe outcomes.

In 2021 alone, there were 12.8 billion infections globally, mostly caused by viruses.2 Annually, over 65 million3 4 of these progress to serious lower respiratory disease and account for around 7% of deaths from major causes in the U.S.5 6 7Respiratory infections raise our risk of serious illness, often years later. While researchers are still early in establishing these connections, it seems plausible that society has meaningfully underestimated the significance of seemingly benign infections on short and long-term health, e.g.:9.8x asthma risk by age 6 if infected with HRV between birth and age 3 in a high-risk cohort86.1x heart attack risk for 7 days after influenza infection94.5-5x dementia risk after severe influenza102.6-4.1x Alzheimer’s risk after severe influenza and pneumonia112.2-3x schizophrenia potential risk for infant if mother is infected by influenza during pregnancy12 131.3x risk of heart failure after RSV infection compared to influenza14Routine respiratory illness imposes a massive, persistent economic burden, driving 1–1.5% annual productivity losses—roughly $600B globally, or ~0.6% of global GDP—in non-pandemic years.15Emerging evidence suggests that severe prenatal16 17 and early postnatal18 respiratory infections might lead to reduced adult earnings and educational attainment later in life.Achieving broad protection against respiratory pathogens would meaningfully reduce pandemic risk, serving as a critical first line of defense—alongside air disinfection—against both natural outbreaks and increasingly accessible engineered biological threats.No single technology can accomplish population-level infection reduction across all of these pathogens. A shot or pill that provided >90% protection against >90% of respiratory viruses (we’ll call these broad-spectrum preventatives or BSPs), but achieved ~60% uptake (a realistic ceiling based on existing vaccine uptake), would still fall short of of the population immunity required to dramatically reduce sustained transmissions.This is because there are so many different kinds of respiratory viruses, many of which are highly contagious. It’s helpful to revisit the concept of R0 from the COVID pandemic: the number of people an infected person will infect in a fully unprotected population.

While we can’t change the intrinsic R0 of a given virus, we can reduce any given virus’s effective reproduction number (Re): how infective a virus is in a given environment inclusive of interventions. To eliminate a virus, its Re needs to drop below 1. The vast majority of seasonal respiratory viruses have an R0 between 1 and 3. To eliminate an R3.0 virus, you need roughly 67% of the population to be protected.So, to get closer to elimination, we also need a way to reduce the virions circulating in high density environments. During COVID the world experimented with various interventions like social distancing and personal protective equipment. But to reduce transmission durably for a large number of common respiratory viruses that are perennially circulating, we need solutions that are convenient and minimally disruptive.We think the most promising category of products that accomplish these goals are those that remove pathogens from the air, particularly in high-density environments like offices, schools, and public transit. We’ll call these air cleaning technologies (ACTs) like air filtration and far-UVC antimicrobial light.The uptake required for BSPs or for ACTs to be effective by themselves is extremely high. As a benchmark, commercial fire sprinkler penetration is about 40% in the US. Getting to 100% uptake would be extremely difficult. But when deployed together at realistic levels, BSPs and ACTs could achieve our goals.These are products—a shot, a nasal spray, a pill—that defend individuals against rhinoviruses, influenza, coronaviruses, and other respiratory viruses simultaneously. Our goal is to catalyze the development of safe and tolerable preventatives that will prevent more than 75% of symptomatic respiratory infections in as few doses as possible, via easy-to-administer modalities, and that have a credible path to ~60% uptake.19 We will prioritize approaches that are convenient with minimal side effects to support the goals of widespread adoption and uptake. This will be the core technical challenge some of these drug candidates face: they need to find the sweet spot between being too narrow (targeting only one viral strain like most vaccines today) and being too broad (causing unwanted side effects, e.g., via excessive stimulation of the immune system or unwanted off target effects on the host).Prior to 2020, efforts to develop broad-spectrum preventatives were limited.

Then a rapid injection of capital during the pandemic catalyzed a major expansion of research and prototyping. Examples of these include vaccine prototypes designed to elicit broadly neutralizing antibodies across all sarbecoviruses,20 21 small molecule antivirals targeting host proteins with broad antiviral activity,22 engineered interferon-like molecules with broad antiviral activity,23 and siRNA candidates designed for SARS-CoV2.24 Unfortunately, many of these did not progress through clinical development as funding dwindled when effective but strain-specific COVID-19 vaccines became available, but they did provide useful signals on where we might want to focus our efforts.Adaptive immunity is the arm of the immune system that is targeted to a specific pathogen or parts of a pathogen, leads to long-lasting immunity against re-infection, and is mediated by cellular (T cells) and/or humoral (B cell) responses. Substantial effort and investment has gone into developing “universal vaccines” that aim to elicit broadly neutralizing antibodies for single virus families,25 but these will offer no protection against other respiratory viruses. Emerging evidence suggests that CD8 T cells stationed at the site of infection can stop an infection from establishing after exposure.26 27 New approaches are now being explored to elicit these types of cells in lung tissues to prevent infection by respiratory viruses. Importantly, these platforms must work across diverse populations and account for population-level immune diversity.Direct-acting antivirals is a wide category of antiviral interventions that lead to direct inhibition of the viral life cycle. While antivirals such as monoclonal antibodies target proteins on the surface of viruses, new nucleic acid degrader28 29 approaches like small-interfering RNA (siRNA) unlock new antiviral targets like viral RNA inside cells that are highly conserved across viruses. Another modality includes broad-spectrum small molecules,30 31 32 33 34 which target conserved virus proteins like RNA polymerase or have broad virucidal activity through membrane disruption. Other modalities include receptor decoys. The main barrier we will aim to address is how to optimally expand (or combine) these platforms to protect across multiple viral families while minimizing unwanted off-target effects.Innate immunity modulators aim to put the immune system on high alert, but without causing the accompanying cold-like symptoms.

New protein design capabilities can engineer interferon, the master regulators of innate immunity, with improved product profiles to generate antiviral responses (interferon-stimulated genes) without the associated inflammatory cytokines. Alternative approaches also include small molecule agonists to activate innate signaling pathways such as cGAS/RIG-I, many of which are actively being evaluated as immunological adjuvants for oncology. Proving that longer-term activation of innate immunity will not lead to chronic immune dysregulation and/or inflammation will be key for this category of preventatives.Host-directed antivirals work by acting on human targets that viruses depend on to enter or replicate inside cells. The main challenges in this field are identifying host proteins that are shared across multiple viral families and finding ways to target them safely without causing harmful side effects. Anti-PD-L1 antibodies, which have transformed cancer treatment, are among the best-known examples of host-directed therapeutics.Physical barrier formulations prevent entry of viruses into the body, which is generally achieved through the nasal passage (less frequent transmission can occur through the eyes and mouth). The main challenge this approach will likely face is durability—providing sufficiently long-lasting protection on a reasonable dosing schedule. Options include sprays or gels that coat the nasal lining and enhance natural mucosal protections. Other approaches include exploring high-affinity viral-binding proteins—lectins, mucin domains, neutralizing fragment scaffolds, and sialic acid-presenting glycoproteins—as formulation additives that increase the kinetics and completeness of viral particle capture across the full diversity of respiratory viruses.The science is promising. What’s holding back progress?Last August at Stripe we co-hosted a symposium with David Veesler, inviting ~40 leading scientists, pharma R&D leaders, biotech venture capitalists, and regulatory experts. The goal was to understand if it’s technically possible to prevent infections from most common respiratory viruses and, if so, what it’d take to do it.We surveyed attendees ahead of the symposium. One of our questions was: if this doesn’t happen in the next ~10 years, what will the primary reason be? The number one reason cited was lack of funding, followed by technical feasibility.Why hasn’t this field attracted sufficient funding, especially given the enormous societal burden? Common respiratory viruses largely fall through the cracks between government, philanthropic, and commercial funding.