Mitigating Future Respiratory Virus Pandemics: New Threats and Approaches to Consider

Abstract

Despite many recent efforts to predict and control emerging infectious disease threats to humans, we failed to anticipate the zoonotic viruses which led to pandemics in 2009 and 2020. The morbidity, mortality, and economic costs of these pandemics have been staggering. We desperately need a more targeted, cost-efficient, and sustainable strategy to detect and mitigate future zoonotic respiratory virus threats. Evidence suggests that the transition from an animal virus to a human pathogen is incremental and requires a considerable number of spillover events and considerable time before a pandemic variant emerges. This evolutionary view argues for the refocusing of public health resources on novel respiratory virus surveillance at human-animal interfaces in geographical hotspots for emerging infectious diseases. Where human-animal interface surveillance is not possible, a secondary high-yield, cost-efficient strategy is to conduct novel respiratory virus surveillance among pneumonia patients in these same hotspots. When novel pathogens are discovered, they must be quickly assessed for their human risk and, if indicated, mitigation strategies initiated. In this review, we discuss the most common respiratory virus threats, current efforts at early emerging pathogen detection, and propose and defend new molecular pathogen discovery strategies with the goal of preempting future pandemics.

Keywords: emerging viruses; molecular detection; pathogen discovery; respiratory viruses.

Figure 1

A model for zoonotic pathogen genesis. Viral evolutionary theory suggests the generation of novel animal viruses often fail to cause infection in humans. It is a rarity that a virus will succeed in colonizing or infecting a human. For that virus or its progeny to cause limited human-to-human infection will be rarer still. Finally, it will be incredibly rare for that virus or its progeny to move from limited human-to-human transmission to become highly transmissible among humans. The selection of such animal viruses that become human pathogens is likely to occur incrementally over long periods of time. Hence, evolutionary theory supports the notion that “time is on our side” if we conduct surveillance for novel respiratory viruses at the animal–human interface where this viral “pinging” is occurring. This would be an effective strategy to detect prepandemic viruses before they fully adapt to humans and become highly transmissible. By repeatedly surveilling both animals and humans, one can determine which viruses are becoming successful in adapting to humans and subsequently develop interventions to mitigate transmission.

Figure 2

A graphic depicting three strategies for detecting prepandemic pathogens. The Wildlife Pathogen Discovery Focus has been embraced by USAID with its PREDICT I and II, STOP Spillover, and DEEP VZN projects, as well as a very ambitious proposed Global Virome Project. It has been criticized as not having precise human illness relevance. The Know Human Pathogen Focus has been embraced by the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers of Disease Control and prevention (CDC) in their various centers and large pathogen-centric research teams. It, too, missed foreseeing the 2009 and 2020 pandemic threats. While we recognize that both of these two rather polar approaches have greatly helped in the response to respiratory virus epidemics and pandemics, we argue that a more efficient, cost-effective, and sustainable approach is conducting surveillance for novel respiratory virus threats in geographical hotspots using a One Health approach. Should such studies not be possible, alternatively, pneumonia etiology studies should be performed in these same geographical hotspots to identify emerging respiratory viruses.

Figure 3

Flow diagram for field specimen study. Our international partners conduct most of the real-time RT-PCR/PCR screening work and some of the pan-species molecular work. If a virus is not yet identified but suspected, next-generation sequencing may be employed for pathogen discovery. Where we see evidence of the same respiratory viruses in both the animal workers and their animals, we next intensely study those viruses for their prepandemic potential. This may involve attempts at viral culture in multiple human and animal cells lines and full genome sequencing. If further risk assessment is warranted, this may involve seroepidemiological studies of other animal workers, the development of specific molecular assays for geographical prevalence studies, and pathogenesis studies in animal models.

Figure 4

Sample processing workflow. Swab samples are collected in 1.5 mL viral transport media (VTM), 2 mL of saliva is collected as-is, and bioaerosol samples are collected in a wet stage (15 mL VTM) or a dry stage, which is then suspended in 1 mL phosphate-buffered saline (PBS) with 0.5% bovine serum albumin (BSA). Subsequently, these samples are divided for DNA/RNA extraction, inoculation in cell culture to obtain live virus, or stored as an archival sample at −80 °C.

Figure 5

Molecular detection algorithm for influenza viruses and pan-Paramyxoviridae/Pneumoviridae viruses. The influenza virus assay utilizes real-time (q) RT-PCR to differentiate the various strains of influenza virus. For influenza A, C, and D viruses, this is followed by conventional RT-PCR assays for subtyping. In contrast, the Paramyxoviridae/Pneumoviridae algorithm begins with a pan-species conventional RT-PCR approach to identify human and animal viruses of the Paramyxoviridae and Pneumoviridae families. Viruses are further characterized with Sanger sequencing.

Figure 6

Molecular detection assays for adenovirus (Ad), enterovirus (EV), and coronavirus (CoV). In these algorithms, we combine qPCR/qRT-PCR, and conventional pan-species PCR/qRT-PCR work to detect and characterize both previously recognized and novel human or animal viruses.