Vincent C. Marconi, MD

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.