Miguel I. Paredes

Sporadic cases of clade IIb mpox continue to be notified among men who have sex with men, with most lacking identifiable transmission links. To resolve underlying dynamics, we tested prospectively for evidence of monkeypox virus infection in anorectal swabs from a cohort of men who have sex with men in Los Angeles, whom we monitored concurrently for clinical mpox diagnoses during summer, 2024. Here we estimate that infections exceeded reported mpox cases by a 33-fold margin (95% confidence interval: 16-68). Independent estimates derived from phylogenetic reconstruction and a meta-analysis of surveillance studies corroborated this extensive under-reporting. We estimate that undiagnosed infections must cause at least 31-44% of all transmission to explain observed monkeypox virus phylogenies; under realistic modeling assumptions, this proportion rises to 61-97%. Contrary to current guidance, our findings suggest a substantial proportion of monkeypox virus circulation may be associated with subclinical infections, challenging the feasibility of current mpox elimination targets.

In 2022, mpox clade IIb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the increased immunity within sexual networks, mpox continues to persist in North America without extinction, raising concerns of future outbreaks. We combined phylodyamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023 to 2024. Our Bayesian phylodynamic analysis revealed a time-varying pattern of viral importations into the county, which seeded mpox outbreak clusters that display “stuttering chains” dynamics. Our phylodynamics-informed microsimulation model demonstrated that the mpox cases in LAC can be explained by a combination of waves of viral introductions, a median effective reproductive rate below one, and a return to near-baseline sexual behaviors after the 2022 epidemic. Our counterfactual scenario modeling showed that frequent public health interventions that either promote increased isolation of infectious individuals or enact behavior-modifying campaigns during the periods with the highest viral importation intensity are actionable and effective at curbing mpox cases. Our work highlights the factors that maintain present-day mpox dynamics in a large, urban US county and describes how to leverage these results into community-centered public health interventions.

Motivation: Genome sequencing provides an exceptional window into the evolutionary and epidemiological dynamics of endemic and emerging pathogens, and thus allows for better, more targeted, public health interventions. Online genomic surveillance platforms can provide near real-time insight into these dynamics. Results: Nextstrain provides continually updated real-time genomic surveillance for 21 viruses and the bacterial pathogen Mycobacterium tuberculosis, with most analyses relying solely on open sequence data. Each pathogen includes steps to fetch and curate open data, classify sequences using established nomenclature systems, perform phylodynamic analyses, and share the results publicly. These analyses are automated, with most running daily to provide continually updated snapshots of pathogen evolution. Availability and Implementation: All source code is available at https://github.com/nextstrain. Phylodynamic results can be visualized and downloaded at https://nextstrain.org/pathogens, and open sequence data and curated metadata are available at https://nextstrain.org/pathogens/files.

In 2022, mpox clade IIb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the accumulation of immunity within queer sexual networks, mpox continues to persist at low incidence in North America without extinction, raising concerns of future outbreaks. We combined phylodynamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023–2024. Our Bayesian phylodynamic analysis revealed a time–varying pattern of viral importations into the county that seeded a skewed distribution of mpox outbreak clusters that display a ″stuttering chains″ dynamic. Our phylodynamics–informed microsimulation model demonstrated that the persistent number of mpox cases in LAC can be explained by a combination of waves of viral introductions, a median Rt significantly below one, and a return to near–baseline sexual behaviors that were altered during the 2022 epidemic. Finally, our counterfactual scenario modeling showed that public health interventions that either promote increased isolation of symptomatic, infectious individuals or enact behavior–modifying campaigns during the periods with the highest viral importation intensity are both actionable and effective at curbing mpox cases. Our work highlights the heterogeneous factors that maintain present–day mpox dynamics in a large, urban US county and describes how to leverage these results to design timely and community–centered public health interventions.

SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.

The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level changes associated with controlling spread, we built phylogeographic and phylodynamic models to analyze MPXV genomes from five global regions together with air traffic and epidemiological data. Our models reveal community transmission prior to detection, changes in case-reporting throughout the epidemic, and a large degree of transmission heterogeneity. We find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that mpox transmission in North America began declining before more than 10% of high-risk individuals in the USA had vaccine-induced immunity. Our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases and of joint integration of genomic and epidemiological information for early outbreak control.

SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape. One Sentence Summary: Analysis of SARS-CoV-2 genomes in King County, Washington show that diverse areas in the same metropolitan region can have different epidemic dynamics.

Background: The coronavirus disease 2019 (COVID-19) pandemic is dominated by variant viruses; the resulting impact on disease severity remains unclear. Using a retrospective cohort study, we assessed the hospitalization risk following infection with 7 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: Our study includes individuals with positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) in the Washington Disease Reporting System with available viral genome data, from 1 December 2020 to 14 January 2022. The analysis was restricted to cases with specimens collected through sentinel surveillance. Using a Cox proportional hazards model with mixed effects, we estimated hazard ratios (HR) for hospitalization risk following infection with a variant, adjusting for age, sex, calendar week, and vaccination. Results: In total, 58 848 cases were sequenced through sentinel surveillance, of which 1705 (2.9%) were hospitalized due to COVID-19. Higher hospitalization risk was found for infections with Gamma (HR 3.20, 95% confidence interval [CI] 2.40–4.26), Beta (HR 2.85, 95% CI 1.56–5.23), Delta (HR 2.28 95% CI 1.56–3.34), or Alpha (HR 1.64, 95% CI 1.29–2.07) compared to infections with ancestral lineages; Omicron (HR 0.92, 95% CI .56–1.52) showed no significant difference in risk. Following Alpha, Gamma, or Delta infection, unvaccinated patients show higher hospitalization risk, while vaccinated patients show no significant difference in risk, both compared to unvaccinated, ancestral lineage cases. Hospitalization risk following Omicron infection is lower with vaccination. Conclusions: Infection with Alpha, Gamma, or Delta results in a higher hospitalization risk, with vaccination attenuating that risk. Our findings support hospital preparedness, vaccination, and genomic surveillance.

Background: The COVID-19 pandemic is dominated by variant viruses; the resulting impact on disease severity remains unclear. Using a retrospective cohort study, we assessed the hospitalization risk following infection with seven SARS-CoV-2 variants. Methods: Our study includes individuals with positive SARS-CoV-2 RT-PCR in the Washington Disease Reporting System with available viral genome data, from December 1, 2020 to January 14, 2022. The analysis was restricted to cases with specimens collected through sentinel surveillance. Using a Cox proportional hazards model with mixed effects, we estimated hazard ratios (HR) for hospitalization risk following infection with a variant, adjusting for age, sex, calendar week, and vaccination. Findings: 58,848 cases were sequenced through sentinel surveillance, of which 1705 (2.9%) were hospitalized due to COVID-19. Higher hospitalization risk was found for infections with Gamma (HR 3.20, 95%CI 2.40-4.26), Beta (HR 2.85, 95%CI 1.56-5.23), Delta (HR 2.28 95%CI 1.56-3.34) or Alpha (HR 1.64, 95%CI 1.29-2.07) compared to infections with ancestral lineages; Omicron (HR 0.92, 95%CI 0.56-1.52) showed no significant difference in risk. Following Alpha, Gamma, or Delta infection, unvaccinated patients show higher hospitalization risk, while vaccinated patients show no significant difference in risk, both compared to unvaccinated, ancestral lineage cases. Hospitalization risk following Omicron infection is lower with vaccination. Conclusion: Infection with Alpha, Gamma, or Delta results in a higher hospitalization risk, with vaccination attenuating that risk. Our findings support hospital preparedness, vaccination, and genomic surveillance. Summary: Hospitalization risk following infection with SARS-CoV-2 variant remains unclear. We find a higher hospitalization risk in cases infected with Alpha, Beta, Gamma, and Delta, but not Omicron, with vaccination lowering risk. Our findings support hospital preparedness, vaccination, and genomic surveillance.