research

Integrating virus genomics into public health

Virus evolution and diversity can impact outbreak dynamics and control efforts. This has been thoroughly demonstrated during COVID-19 pandemic, in particular with the emergence of variants. Monitoring evolutionary processes can provide answers that are hidden from traditional epidemiology, both on a small scale by investigating the details of transmission chains and uncovering the pathways of spread on a global scale. Genomic data also has the potential to enhance disease forecasting models and has been critical for development of vaccines, therapeutics, and molecular diagnostic assays. The overall goal of our lab is to apply virus sequencing and genomic analysis to better design, apply, and evaluate strategies to mitigate transmission and disease. While our primary interests are mosquito- and tick-borne viruses, like dengue, West Nile, and Powassan, we are broadly interested in genomic epidemiology across many viruses, including SARS-CoV-2.

Tracking outbreaks using genomics

Genomics has become an important tool to track the emergence and spread of viruses (Grubaugh et al., 2019). At the core of our lab is the routine sequencing of viruses to facilitate public health decision making and epidemiological investigations. When SARS-CoV-2 emerged in the US, we partnered with the Yale New Haven Hospital and the Connecticut Department of Public health to create the Yale SARS-CoV-2 Genomic Surveillance Initiative (CovidTrackerCT). Our data provided real-time information to the public about the emergence of variants and important data to understand the epidemiology of the virus. For example, sequencing the first COVID-19 cases from the state revealed that the introductions were likely from domestic rather than international locations (Fauver et al., 2020), and expanded sequencing revealed the patterns of introductions of new variants (Alpert et al., 2021). We also built a framework to connect our sequencing data to other epidemiological data to measure the transmissibility of variants (Petrone et al., 2022; Earnest et al., 2022). Looking forward, our group received a prestigious NIH New Innovator Award in 2022 to apply these techniques to better understand the dynamics of dengue virus. Following the Zika epidemic, we discovered that the dengue resurgence was caused by cryptic viruses circulating locally for years (Brito et al., 2021). With more routine sequencing, we aim to discover how the emergence of dengue virus lineages is associated with outbreaks. To do these projects, we will collaborate with many awesome labs from around the world (see a list of our collaborators at the bottom of the “team” page).

Impact of genetic diversity on control measures

Virus evolution and genetic diversity can significantly impact control measures, as clearly demonstrated during the COVID-19 pandemic. In particular, we showed how new variants can alter serum neutralization from vaccinated individuals (Lucas et al., 2021) and have higher potential to cause vaccine breakthrough infections (Chaguza et al., 2022). We are now working with colleagues at the Yale School of Medicine and Public Health to routinely track the impact of SARS-CoV-2 variants on vaccines and outbreak potential. As vaccines and other control measures are developed and deployed for dengue and other viruses, we must adapt these systems to study the impact of genetic diversity. For example, we are using both experimental and field-based designs to determine how dengue virus diversity impacts the transmission control of Wolbachia-infected mosquitoes, and we aim to apply the same framework to study dengue vaccine candidates.

Ecological drivers of emergence and spread

Mosquito and tick-borne viruses have complex ecologies which can define the speed and range of their spread. Several years ago, we started the WestNile4K project to sequence West Nile virus from throughout the Americas to better define “transmission zones” and the ecological barriers that define them. Our work revealed the initial rapid spread of West Nile virus across the US and how it evolved into distinct lineages (Hadfield et al., 2019). Using this network, we expanded to include eastern equine encephalitis virus and the tick-borne Powassan virus. Our sequencing and phylogenetics revealed the (re)emergence of Powassan virus into the Northeast US and that transmission is limited to tight geographical foci (Vogels et al., 2022). Furthermore, we are incorporating environmental data into mosquito-borne virus transmission models to better inform outbreak predictions.

Sequencing tools to support public health

During the Zika epidemic, we helped to develop a highly multiplexed PCR approach to amplify the virus genome in many small pieces (i.e., “RNA jackhammering”), greatly enhancing our sequencing sensitivity (Quick et al., 2017). Later, we validated its use for measuring intrahost virus diversity and developed a data processing pipeline called iVAr (Grubaugh et al., 2019). These tools helped to facilitate the massive genomic surveillance, and now we are looking to apply them towards creating a modular framework for sequencing. For example, we modified the COVIDSeq protocol to sequence human monkeypox virus, even though has a DNA genome about 10x larger (Chen et al., 2022). Along these lines, our group was selected as an academic partner for the Northeast Regional Pathogen Genomic Center of Excellence hosted by the Massachusetts Department of Health and funded by the CDC. Our goals are to develop pan-sequencing methods and to integrate cost-effective approaches into public health labs to enable rapid response systems.

Current funding

New England Pathogen Genomics Center of Excellence (Massachusetts DPH)

1 NU50CK000629-01-00
Sub-award PI: Grubaugh
09/30/2022-09/29/27

Enhancing dengue virus genomic surveillance to uncover circulating genetic diversity

1DP2AI176740-01
PI: Grubaugh
09/21/2022-08/31/2025

Transmissibility and immune escape of emerging SARS-CoV-2 variants

75D30122C14697
PI: Grubaugh
09/19/2022-09/18/2024

SARS-CoV-2 whole genome sequencing (Yale Center for Genome Analysis)

21PSX0049
PI: YCGA
9/1/2021 – 6/30/2023

Genomic epidemiology of SARS-CoV-2 in the National Basketball Association

Sponsored Research Agreement
PI: Grubaugh
4/14/2021 – 6/30/2024