key: cord-0971988-kenp2xz2
authors: Wu, Fuqing; Lee, Wei Lin; Chen, Hongjie; Gu, Xiaoqiong; Chandra, Franciscus; Armas, Federica; Xiao, Amy; Leifels, Mats; Rhode, Steven F; Wuertz, Stefan; Thompson, Janelle; Alm, Eric J
title: Making Waves: Wastewater Surveillance of SARS-CoV-2 in an Endemic Future
date: 2022-05-03
journal: Water Res
DOI: 10.1016/j.watres.2022.118535
sha: f4ff10a17fecf652a23f458e403c44df99d6dec9
doc_id: 971988
cord_uid: kenp2xz2

Wastewater-based surveillance (WBS) has been widely used as a public health tool to monitor the emergence and spread of SARS-CoV-2 infections in populations during the COVID-19 pandemic. Coincident with the global vaccination efforts, the world is also enduring new waves of SARS-CoV-2 variants. Reinfections and vaccine breakthroughs suggest an endemic future where SARS-CoV-2 continues to persist in the general population. In this treatise, we aim to explore the future roles of wastewater surveillance. Practically, WBS serves as a relatively affordable and non-invasive tool for mass surveillance of SARS-CoV-2 infection while minimizing privacy concerns, attributes that make it extremely suited for its long-term usage. In an endemic future, the utility of WBS will include 1) monitoring the trend of viral loads of targets in wastewater for quantitative estimate of changes in disease incidence; 2) sampling upstream for pinpointing infections in neighborhoods and at the building level; 3) integrating wastewater and clinical surveillance for cost-efficient population surveillance; and 4) genome sequencing wastewater samples to track circulating and emerging variants in the population. We further discuss the challenges and future developments of WBS to reduce inconsistencies in wastewater data worldwide, improve its epidemiological inference, and advance viral tracking and discovery as a preparation for the next viral pandemic.

Wastewater-based surveillance (WBS), which was used for detecting the silent circulation of polio and non-polio enteroviruses (Manor et al., 2014; World Health Organization, 2003) , has, with the advent of the COVID-19 pandemic, been adapted as a public health tool for monitoring the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in communities.

The presence of SARS-CoV-2 RNA in wastewater was first demonstrated in the Netherlands, United States, Spain, and Australia in April 2020 (Ahmed et al., 2020; Medema et al., 2020; Randazzo et al., 2020; . Since then, the WBS field has undergone considerable growth in the optimization of experimental protocols (Ahmed et al., 2022; Pérez-Cataluña et al., 2021) , testing scales, and epidemiological modeling analyses (McMahan et al., 2021) as well as numerous observational case studies on a local or national scale (Shah et al., 2022) . In April 2022, the World Health Organization (WHO) published interim guidelines for the environmental surveillance of SARS-CoV-2 as a complementary method to clinical diagnostics, thus further legitimizing WBS as an important public health tool (World Health Organization, 2022) . With the emergence of SARS-CoV-2 variants of concern (VOCs), the applications of WBS have also expanded from merely indicating the presence of the virus to tracking the occurrence and prevalence of VOCs circulating in the community.

Vaccinations have been shown to be the most effective tool available to date to control the COVID-19 pandemic. Reinfections of naturally immunized or fully vaccinated individuals, however, have been frequently reported for the Delta and recently emerged Omicron variants (Brown, 2021; Cavanaugh, 2021; Griffin, 2021; Lafaie et al., 2020; Vitale et al., 2021; Wolfe et al., 2022; Yuan et al., 2020) , suggesting that SARS-CoV-2 will most likely not be completely eradicated and the virus likely persisting in populations and becoming endemic like seasonal influenza or common human coronaviruses. On the other hand, the effectiveness of current COVID-19 vaccines against severe illness and hospitalization (Pilishvili et al., 2021; Thompson et al., 2020) , together with progress in the ongoing global vaccination campaigns, the economic costs of lockdowns, as well as pandemic fatigue among the public (Azzolino and Cesari, 2022; Haktanir et al., 2021) has motivated policy changes towards endemicity.

As the classification of SARS-CoV-2 transitions from pandemic to endemic, the objectives and focus of WBS will necessarily change. Here, we explore the roles of wastewater surveillance in a COVID-19 endemic future, and discuss future developments that are important for the field as preparation for the next viral pandemic.

While clinical testing remains the gold standard, albeit imperfect, for verifying SARS-CoV-2 infection in individuals, the costs associated with reagents, equipment, and personnel pose substantial economic burden for a long-term, population-level surveillance program. On the contrary, WBS, in part due to its 'composite' nature (samples are commonly taken downstream of defined populations including the inflows of wastewater treatment facilities), is comparatively cost-effective (Safford et al., 2022; Shrestha et al., 2021) . Taking a sewershed with 10,000 people as an example, WBS only needs to test one sample for mass screening of SARS-CoV-2.

Clinical testing, on the other hand, may require 10,000 individual tests and bears the associated costs for sample collection and investments in high-throughput infrastructure. While wastewater surveillance programs cost more capital expenditure on infrastructure setup at the start, the need for a long-term surveillance program for endemic SARS-CoV-2 increases the cost effectiveness of such investments. Pragmatically weighing costs and benefits, a well-designed wastewater surveillance program that delivers reliable results would do much to inform pandemic response.

Thus, WBS is especially attractive for longitudinal mass surveillance of SARS-CoV-2 infections.

Second, wastewater sampling on the population level is non-invasive, since samples are collected from wastewater treatment plants and sewers in comparison to nasopharyngeal or anal swabs.

The former also shields individuals from privacy concerns, though these are then relegated to the community level. While the majority of individuals have acquiesced, to a large degree, in the collection of their personal data including locations, personal mobility, and relationship, and health status during the pandemic (Bentotahewa et al., 2021) , it would be challenging to maintain this over a long endemic phase, due to potential concerns over its impact on civil liberties (Gable et al., 2020) . Moreover, sampling wastewater affords an opportunity to avoid the potential social stigma experienced by some COVID-19 patients and healthcare workers (Bhanot et al., 2021; Thompson et al., 2020) .

Further, the acceptance of COVID-19 as endemic will likely be accompanied by the roll back of routine diagnostics for communities from current emergency / pandemic response levels ( Fig. 1 ).

Subsequently, a reduction in the frequency of clinical PCR tests, in part due to increasing substitution by at-home rapid tests, and decreased societal willingness to get tested are to be expected. The antigen-based self-tests with reduced sensitivity, coupled with decreased testing behaviour, could also impact the accuracy of government estimates of disease incidence. Thus, decentralization of individual testing and asymptomatic carriage and viral shedding despite vaccination (Riemersma et al., 2021) consolidate the relevance of WBS as an independent indicator of infection trends. These practical considerations suggest that WBS will be the most feasible and effective tool for monitoring SARS-CoV-2 infection in the population in an endemic future. However, caveats and challenges to the implementation of WBS, in the form of nonunified standards, uncertainty and variability of measurements remain to be overcome, and these will be discussed in the later section. 

As SARS-CoV-2 becomes endemic, municipal wastewater signals for the virus may perpetually stay positive, impairing the utility of qualitative information like the binary presence or absence of detectable viral shedding within a targeted community. Instead, quantitative monitoring of the longitudinal trends of viral concentrations in wastewater may yield more effective health information. Accurate trending would require a framework for regular wastewater sampling and virus quantification to establish a reference level of viral concentration corresponding to a certain infection incidence (such as 1 new case a day in 10,000 people) in each sewershed. Rising trends would then suggest the onset of emerging infections in a population and subsequently trigger (non-pharmaceutical) infection control and interventions, such as localized quarantine or mass swabbing orders. Falling trends, on the other hand, would indicate the adequacy of ongoing health management policies.

Differences in geography, climate (i.e., precipitation, and temperature), population size and vaccine coverage (including rationing of boosters), imply that the concentration of SARS-CoV-2 RNA that forms the reference line may be specific and dynamic for each sewershed and dependent on the sample logistics and processing methods. Moreover, the reference levels of SARS-CoV-2 in wastewater can be influenced by the difference in viral shedding rates amongst variants of concern and the proportion of vulnerable and immunized individuals in a population.

Thus, developing a response framework to deal with the baseline levels of SARS-CoV-2 "variant de jour" and to detect the inflexion point in the temporal trends of viral concentrations would be essential for wastewater surveillance for population health in the endemic future.

In a SARS-CoV-2 endemic future, we anticipate increased emphasis on wastewater sampling upstream of the wastewater treatment plant ( Fig. 2A) . Depending on the extent of granularity desired for the targeted populations, wastewater samples would be collected at multiple levels like neighborhoods (Rios et al., 2021) , schools (Gibas et al., 2021; Harris-Lovett et al., 2021; Karthikeyan et al., 2021) , and housing estates (Wong et al., 2021) , down to the individual building level (Gibas et al., 2021) , at prisons, care homes, and food manufacturing sites for instance. Such flexibility enables precision in pinpointing locations where infections are taking place (Liu et al., 2022; Thompson et al., 2020; Yeager et al., 2021) . Compared to large wastewater treatment plants, collecting samples from smaller sewersheds allows for the identification of neighborhood hotspots and enables the public health authorities to prioritize areas for more focused clinical testing, possibly ring fencing disease prior to the onset of larger outbreaks (Mota et al., 2021) , and importantly, increases sensitivity for detecting changes in viral trends (Hewitt et al., 2022) . However, it also poses challenges for sampling such as installation and maintenance in limited space as well as safety concerns, and passive sampling could be an alternative strategy because of its flexibility and ease of use (Habtewold et al., 2022; .

We anticipate a modular system whereby qualitative assessment of positivity at catchments of different sizes could be used to identify disease incidence during the early outbreak of an emergent variant. The probability of SARS-CoV-2 detection in wastewater is impacted by infection incidence and population size in the sewershed, and the highest detection rate is mostly achieved from high incidence rate and large population size ( , Fig. 2B ). Such a qualitative relationship could help us to evaluate the detection efficiency and potentially to estimate new infections in the sub-catchments Claro et al., 2021) .

It is expensive and challenging to maintain a clinical testing program with the current capacity for an endemic SARS-CoV-2. A long term COVID-19 surveillance program needs to be economically sustainable, of which wastewater surveillance and clinical testing should be integrated to achieve mass surveillance of infected individuals in the population in a costefficient way. This would be especially useful should containment and ring-fencing be necessary following the emergence of highly virulent variants. To better understand the economics of this integrated system, we developed an equation (Eq1) to measure the total cost of conducting WBS in modular catchments, followed up by conducting clinical tests on individuals living in the WBS-positive catchments. In this equation, the population (with a size N pop ) is divided into different sub-sewersheds (each with a population size of N catch ) and the total cost for WBS (C totWBS ) is the number of sub-sewersheds multiplied by the cost of one wastewater sample (C WBS ).

The total cost of clinical testing (C totind ) relies on the cost of an individual clinical test (C ind ) and the probability of a given sewershed having positive cases (f p ), which is determined by the incidence (v). The relative total per capita cost (C rel_pc ) is measured relative to the cost of an individual clinical test (Eq2).

(1)

where

Setting , we evaluated relative per capita cost over different sewershed sizes (Ncat ch).

We observe a regime of small incidence rates where there is a sewershed size that minimizes total cost by optimizing the tradeoff between WBS cost and individual cost (Fig. 2C ). This optimal situation happens when many sewersheds can be eliminated as negative via WBS, so fewer individuals need to undergo clinical testing. We extend this analysis to a more densely sampled range of incidences and sewershed sizes and find that low incidence rates with sewershed sizes in the thousands minimize total cost, whereas higher incidence rates or larger catchment sizes lead to a relative total cost of 1 (Fig. 2D ). The latter situation is equivalent to applying clinical testing to every individual in the population because all sewersheds are positive by WBS.

However, this model has some limitations. The equation assumes that the incidence rate is equal across sewersheds, that sewersheds are the same size, and does not account for laboratory variability or PCR inhibition when conducting WBS. Additionally, we chose an arbitrary cost ratio where WBS for one catchment is 100-fold more expensive than an individual clinical test.

While these assumptions will not necessarily be fulfilled in all neighborhoods, this simplified model is instructive to show that the size of the sewersheds is a strong determinant of the total cost of combined WBS and clinical surveillance. Thus, when officials are deciding how to implement modular WBS in their population, they should consider optimizing the sewershed sizes to be most cost-effective, given the cost ratio between WBS and individual clinical tests in their municipality. ; the range for v is (10 -6 , 10 -2 ); and range for N catch is (10, 10 6 ).

As COVID-19 transitions into an endemic status, WBS will become an exceedingly important We anticipate that technologies that have been developed for variant monitoring in wastewater will continue to play an important role for monitoring the evolution of SARS-CoV-2 in the endemic phase, when clinical testing and sequencing will probably decrease. WBS, coupled with genomic sequencing, would play a prominent role in maintaining a watchful eye on the evolution and emergence of SARS-CoV-2 variants circulating in the community as has previously been demonstrated (Crits-Christoph et al., 2021; Rothman et al., 2021; Smyth et al., 2022) .

Quantitative, VOC-specific PCR-based assays (Lee et al., , 2021b (Lee et al., , 2021a , RT-ddPCR (Gering et al., 2021; Heijnen et al., 2021) and nested RT-PCR (La Rosa et al., 2021) will continue to provide a cost-effective means for identifying and quantifying the distribution of VOCs in populations. Moreover, inferring transmission fitness of different VOCs from wastewater sequencing data will be another attractive but challenging application in endemic COVID-19 as discussed in the next section.

To date (February 2022), wastewater surveillance of SARS-CoV-2 has been carried out in 58 countries around the world (Naughton et al., 2021) . However, the true utility of WBS for public health decision-making for COVID-19 remains yet to be realized due to sources of uncertainty which impact measurement quality and the interpretation of wastewater data Wade et al., 2022) . This variability is present in almost every step from how the samples are collected and concentrated to the use of different reagents across laboratories and agencies (Ahmed et al., 2022; Wade et al., 2022) . Wastewater composition could also lead to differences in PCR inhibition (Ahmed et al., 2022) . Further, studies on spiked samples suggest that the recovery rate of viruses from wastewater could effectively be less than 10% and vary up to 7 orders of magnitude when tested across laboratories (Pecson et al., 2021) . These sources of variability and limited recovery efficiency pose technical hurdles to relating viral load in wastewater to caseload in the community. Adopting US-EPA methods (US EPA, 2015) to assess the surface water quality into WHO recommendations (Deborah, 1996) and ISO norms (ISO 15216-2, 2019) could be a blueprint for such an endeavor to reduce uncertainties pertaining to wastewater viral measurements.

While WBS may often be mentioned interchangeably or in combination with wastewater-based epidemiology, obtaining epidemiological estimates from wastewater data is challenging to achieve. Some of the attempts to correlate the concentration of SARS-CoV-2 in wastewater to the number of infected individuals have been proposed by Wurtzer et al., 2020; Xiao et al., 2021) , as well as others McMahan et al., 2021; Nourbakhsh et al., 2021; Saththasivam et al., 2021) . The precision of epidemiological estimates extensively relies on the accuracy of quantification for viral RNA shed into wastewater throughout the course of SARS-CoV-2 infection, which is challenging to obtain especially during the pre-symptomatic phase. Using statistical methods, such as a beta or gamma distribution-based fitting, to infer the temporal viral shedding dynamics from clinical data has partially solved the problem (Ferretti et al., 2020; He et al., 2020; Wu et al., 2022) , although more efforts are needed to improve model efficiencies in integrating the heterogeneous clinical datasets subjected to missing data points, methodological biases and inconsistent medical record metadata.

Furthermore, the lack of clinical viral shedding data from vaccinated (single or multiple doses) and unvaccinated individuals, patients with varied severity of symptoms, as well as across SARS-CoV-2 variants also hampers a wide range of WBE endeavours, including calculating the incidence of infection in sewersheds, estimating the effective reproduction number of SARS-CoV-2 in a population (Huisman et al., 2021) and inferring transmission fitness of VOCs from wastewater data . On the other hand, viral concentrations in wastewater are impacted by the transient flow rates, water pH, viral degradation and detention in wastewater lines (Amoah et al., 2022; Khan et al., 2021; Simpson et al., 2021) , further undermining WBS data applications.

All in all, these uncertainties call for the development of improved frameworks including optimized viral concentrating methods, accurately quantified viral degradation and recovery efficiency, and rigorous measurement of viral shedding dynamics in infected individuals across symptoms, age groups, and SARS-CoV-2 variants. These efforts will lead to better quantifying the relationship between the virus load in a sewershed and the number of infected individuals present for maximizing the utility of wastewater data for SARS-CoV-2 management.

Using wastewater-based surveillance to monitor the emergence of SARS-CoV-2 variants has the potential to become an exceedingly important and versatile tool in a COVID-19 endemic future.

Accurate quantification of low-frequency variants by WBS remains a technological challenge due to the dilution and decay of SARS-CoV-2 in wastewater and the lack of normalization parameters to confidentially indicate the population equivalents contributing to a sewershed at any given time. To further complicate things, new variants usually start to occur in a small group of people, which necessitates the development of sensitive and reliable bioinformatics approaches to discover the emerging low-frequency variants in wastewater. Metagenomic shotgun sequencing of either untargeted (Crits-Christoph et al., 2021) or targeted amplicons (Bar-Or et al., 2021; Fontenele et al., 2021; Nemudryi et al., 2020; Pérez-Cataluña et al., 2022; Swift et al., 2021) enables the discovery of viral genetic mutations to infer variants that are circulating in the sewershed. Reliable lineage assignment from viral metagenomic dataset remains putative (Fontenele et al., 2021) though methodological improvements have been made . This is further hampered by the low concentration and impaired integrity of SARS-CoV-2 RNA in wastewater samples. Thus, optimizations in experimental protocol and bioinformatics analysis are necessary to promote wastewater surveillance to be a more feasible tool for timely proactive variant tracking.

The COVID-19 pandemic has brought to the fore the need to develop expansive yet costeffective methods for the detection and discovery of emerging zoonotic agents. To this end, WBS coupled with next generation sequencing represents a highly promising tool. As wastewater is a complex matrix containing a myriad of microorganisms, the detection of the pathogens requires either amplification or metagenomics with an implemented viral nucleotide acid enrichment (Crits-Christoph et al., 2021; Rothman et al., 2021) , both of which rely on, and are biased by, a priori knowledge of genomic information on those biological agents. Pathogen detection using molecular methods independent of prior knowledge need to be developed for early warning surveillance of novel viruses with risk to human health.

We have discussed the utility of and needed methodologies for WBS as COVID-19 and its epidemiology evolve into endemicity and identified the following key conclusions:

• WBS continues to be a cost-effective and non-invasive tool for mass surveillance of SARS-CoV-2 infection in the long run.

• Decentralization of individual testing and asymptomatic carriage despite vaccination underscore the importance of WBS of SARS-CoV-2 as an independent indicator of infection trends.

• The objectives and potential of WBS in an endemic phase will shift from early case detection to providing situational assessment about the trend of viral infection in the population.

• Cost-effective integration of wastewater and clinical surveillance could be achieved through optimizing sewershed size.

• WBS remains essential for population level variant tracking to anticipate emerging variants of concern, although further improvements in methodologies are necessary for proactive variant tracking.

• Wastewater research should optimize frameworks to improve recovery efficiency and reduce inconsistencies in wastewater data towards improving epidemiological inference.

• Methods developed in the context of SARS-CoV-2 and its analyses could be of invaluable benefit for future wastewater monitoring work on discovering emerging zoonotic pathogens and for early recognition of future pandemics.

E.J.A. is an advisor to Biobot Analytics, Inc. and holds shares in the company. 

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