COVID-19 Updates

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

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

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

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

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.