Summer 2024 SeroNews

As FLiRT Cases Increase, We Should Apply Powerful Data and Past Lessons to Current Preparedness Efforts

The Clinical and Translational Serology Task Force has continued to work together in reviewing the current COVID-19 situation and discussing emerging data in the areas of COVID-19 and cancer, including research in adaptive immunity on T cells; artificial intelligence/machine learning; and the current and future activities of COVID-19 and pandemic preparedness consortia.

According to the U.S. Centers for Disease Control and Prevention, the amount of SARS-CoV-2 virus in wastewater has been increasing in recent weeks, just in time for summer vacation season.

The increase is largely driven by the new FLiRT subvariants, offshoots of JN.1, which are now the dominant variants in circulation. These new variants appear to be producing an increase in transmission and a rise in COVID-related emergency department visits and hospitalizations, but death rates are still relatively low.

New updated monovalent vaccines are expected this fall, and will target the JN.1 lineage, possibly KP.2, based on recommendations from the Food and Drug Administration (FDA) after a recent advisory committee meeting.

With these new variants, there is a need for continued research to better understand COVID-19 immunity and protection, especially for at-risk populations.

We at the CTTF look forward to continued discussions, engagements, and collaborations, and—of course—we welcome your suggestions, comments, and requests!

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CRWDi Collects Real-World Data for Studying COVID-19 in Immunocompromised Populations

Immunocompromised populations, including people with cancer, people with systemic autoimmune rheumatic conditions, and transplant recipients, have an increased risk of SARS-CoV-2 infection and severe disease outcomes. There is a relative lack of large-scale, real-world clinical data on the efficacy of the COVID-19 vaccines and their ability to induce and maintain an effective serological response in these groups.

To help address this gap, identified by the leaders of the SeroNet Clinical and Translational Serology Task Force (CTTF), the National Cancer Institute developed a COVID-19 Real-World Data Infrastructure (CRWDi), under the leadership of NCI’s Lynne Penberthy, M.D., and SeroNet member James Crawford, M.D., Ph.D.

CRWDi houses all available comprehensive longitudinal real-world data, held in a single data platform, from a broad set of data providers. Its assets are linked through secure privacy-preserving record linkage (PPRL) technology. Overall, the goal is to provide data on the impact of COVID-19 infection and immunization against SARS-CoV-2 in immunocompromised patient populations, with a special focus on people with cancer.

To that end, CRWDi seeks to collect standardized, immunologically relevant data from validated serology assays to enable researchers to answer evolving questions about the impact of COVID-19 on vulnerable populations. The platform’s proponents hope to spur the development of evidence-based diagnostic evaluation guidelines for patients across varying risk strata, including guidance on the role of boosters and/or treatment.

Beyond the specific insights that can be gained through CRWDi, this project serves as a pilot study for assessing the potential value of having such a national data infrastructure in place for future events. Something of this nature may be relevant for tracking and managing other vaccine-addressable pathogens that affect vulnerable individuals.

“CRWDi is a U.S. data resource that was desperately needed through the height and length of the COVID-19 pandemic. This resource has now been built, serving as a pilot for how the U.S. can maintain readiness for future pandemics. In the immediate time frame, CRWDi now gives researchers an opportunity to examine the impact of COVID-19 on vulnerable immunocompromised populations at a level of granularity not previously available. This includes examination of the efficacy of vaccination, research which may have broader relevance for other vaccine-addressable pathogens and may serve as an example of the broader need for a national data infrastructure of this nature,” said Crawford, who is also a professor of pathology and chair emeritus at Northwell Health.

A Rich Resource

CRWDi has collected data through two main partners: HealthVerity, whose resources include medical claims, pharmacy claims, COVID-19-relevant lab data, and vaccination data on over 250 million unique individuals, and NCI’s Surveillance, Epidemiology, and End Results (SEER) project, which is supported by the Surveillance Research Program (SRP) in NCI’s Division of Cancer Control and Population Sciences and represents nearly 50% of the U.S. population affected by cancer, with 800,000 new cancer cases per year.

The infrastructure harmonizes the HealthVerity and SEER data sets for those patients for whom there are COVID-19-relevant data, including diagnostic and serological testing for SARS-CoV-2, electronic health records of COVID-19-relevant conditions, and COVID-19 vaccination records.

CRWDi data span medical claims (health plan records, benefits enrollment); pharmacy claims (prescriptions, pharmacy benefit managers); vaccination records; laboratory results (SARS-CoV-2 testing performed by the two major national commercial laboratories: LabCorp and Quest Diagnostics); and SEER-based cancer data, such as detailed tumor characterization, stage at diagnosis, therapy initiation and type, and risk analysis for people treated for cancer from 2018–2023.

CRWDi also has access to SARS-CoV-2 diagnostic and serological results from an additional 460,000 patients through a data set collected via Northwell Health, a major integrated health care delivery network whose records are harmonized with the HealthVerity data set.

Full of Potential

CRWDi was constructed to support research on vulnerability to SARS-CoV-2 infection and severe disease in people, aged 0 to 89, with immunocompromising conditions who fall into three general groups: cancer under active treatment (1.3 million patients), rheumatic disease under active treatment (1.6 million patients), and solid organ and stem cell transplantation for reasons other than cancer (300,000 patients). A U.S. census–based general population group (2 million people) serves as a comparison group for further cohort construction.

For all unique patient records (5.2 million people in total, plus the 460,000 from Northwell Health), the data focus on patients who have at least 180 days of continuous health plan enrollment for both medical and pharmacy claims. The goal is to have robust health care data to illuminate the chronological relationships between their immunocompromised condition and COVID-19 status and outcomes. In certain cases, CRWDi data may also provide insights into post-acute sequelae of COVID-19 (“Long COVID”).

The availability of these data represents an important resource for researchers seeking to better understand the impact of COVID-19 on these vulnerable immunocompromised populations. Such a proximate near-real-time U.S. data resource would have been invaluable during the first years of the pandemic, alleviating substantial gaps in the medical community’s ability to translate diagnostic testing for COVID-19, especially serological testing, into practical guidance for treating and helping all patients, immunocompromised or not.

“This is the first time, to my knowledge, a data infrastructure has been built including standardized SARS-CoV-2 serology data from EUA [Emergency Use Authorization] approved tests which are linked to demographic and clinical patient data from a very large number of people with immunocompromising conditions. These efforts were a product of fruitful collaborations fostered through CTTF and will contribute to advance understanding of immune response to infection and vaccines in people with immunocompromising conditions, including people with cancer, in a real-world setting,” said Ligia Pinto, Ph.D., a CTTF co-chair and the director of the Vaccine, Immunity, and Cancer Directorate at Frederick National Laboratory for Cancer Research.

Proof-of-Concept Ready to Demonstrate Its Value

CRWDi is serving as a proof-of-concept for gathering wide-ranging data as the scientific and medical communities maintain readiness for potential future pandemics.

For now, however, the greatest hurdle is making sure the scientific community knows how to take advantage of this powerful tool. If an effective argument is to be made that such data infrastructure is truly of value, CRWDi must now be used by the research community.

The CTTF leadership team strongly encourages any who are interested to explore CRWDi and to ask questions or request data access by contacting crwdiuseraccess@nih.gov. The more this resource gets used, the more knowledge will be gained, and the more likely similar tools will be developed in the future!

Remaining Vigilant in a COVID-19-Endemic World

The COVID-19 pandemic brought an unprecedented threat to the entire world, but some populations, such as people diagnosed with cancer, were more vulnerable to developing severe disease than others. At the height of the pandemic, many laboratories across the globe, including cancer laboratories, temporarily pivoted to battle the aggressive SARS-CoV-2 virus. As the pandemic shifted to endemic status and restrictions eased, many of these laboratories returned to their original research interests. However, COVID-19 continues to be a major concern for immunocompromised populations as the virus becomes a constant, if less conspicuous, threat.

Infectious diseases have long been a major concern in cancer clinics because some therapeutic interventions can leave patients susceptible to potentially deadly infections. Many of these deaths can be attributed to septicemia, pneumonia, and influenza (flu). Respiratory viral infections—such as flu virus, respiratory syncytial virus (RSV), parainfluenza virus, metapneumovirus, rhinovirus, and SARS-CoV-2—are receiving a great deal of attention in regards to patient populations.

Some of these infections, including flu, RSV, and COVID-19, can be mitigated with currently available vaccines. However, comprehensive research into the effects of these viruses and their respective vaccines in people with cancer is still lacking. These questions fall in an important research area: the intersection between the fields of oncology and infectious diseases.

Outcomes for People with Cancer and COVID-19

Since people with cancer and SARS-CoV-2 infections present with even more severe outcomes, including death, compared to people with cancer infected with seasonal flu viruses, the COVID-19 pandemic has highlighted the need for a focus on infectious diseases in oncology.

As research into SARS-CoV-2 infection in people with cancer has been advancing, evidence has accumulated that cancer type and treatment can affect COVID-19 outcomes. People with lung cancer have a high risk for severe outcomes from SARS-CoV-2 infection. Active or progressing cancer was also linked to higher mortality from COVID-19 compared to mortality rates in people in cancer remission. People with hematological cancers were also at higher risk of death attributable to COVID-19 compared to people with solid tumors.

Vaccine Responses in People with Cancer

Research has shown that responses to COVID-19 vaccination among people with cancer vary depending on cancer and treatment type. People with solid tumors appear to be more likely than people with blood cancers to develop higher antibody responses after vaccination. However, people with solid tumors receiving immune checkpoint inhibitors prior to vaccination had lower sustained antibody responses compared to those who received similar treatment after vaccination.

Among other cancer types, many people undergoing treatment for B-cell lymphoma did not develop substantial antibody responses after primary vaccination, especially if they were receiving anti-CD20 therapy. However, booster doses did increase antibody responses.

People with multiple myeloma had highly variable anti-SARS-CoV-2 neutralizing antibody titers post-vaccination, and vaccine responses depended on therapy type. Individuals receiving anti-CD38-containing or BCMA-targeted therapy had significantly higher likelihood of having no antibody response to vaccination.

In one study of people with chronic lymphocytic leukemia, participants were about half as likely to produce an antibody response to COVID-19 mRNA vaccination compared to healthy controls, and those treated with Bruton’s tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody had low antibody response rates.

Treating COVID-19 in People with Cancer

There are few available options for treating COVID-19 in people with cancer, and cancer treatment cannot be compromised to treat SARS-CoV-2 infection. Remdesivir has been approved for treatment of patients hospitalized with COVID-19, and a new monoclonal antibody was recently given emergency use authorization for pre-exposure prophylaxis in immunocompromised patients. However, the effectiveness of these therapies in people with cancer, as well as how long they remain effective against currently circulating variants, continues to be under investigation.

Thus, prevention continues to be key, with recommendations for general best practices, such as handwashing and watching for signs and symptoms of infection. If people with cancer are concerned that they do have an infection, they should take a COVID-19 test and contact their doctor if they test positive.

Although funding opportunities for research on SARS-CoV-2 are scarce, there is still much research to be done and many unknowns on how to care for people with cancer in a COVID-19-endemic world—or really in the wake of any infectious disease. Research must continue to serve vulnerable populations, especially as the world remains at risk for COVID-19 and future pandemics.

Standardization Is Key to Clarifying Role of Mucosal Immunity in Preventing SARS-CoV-2 Infections

Currently available COVID-19 vaccines have been successful at preventing severe disease, hospitalization, and death; however, SARS-CoV-2 infections continue to be a global public health threat. Mounting evidence suggests that the key to preventing infection may lie in the local immune system of the mucosa (such as the mucous membrane  of the nose) where the virus enters and infects the host. Consequently, scientists have been gathering to discuss how to better study and target these areas of immunity, as well as to identify the elements and roles of the different arms of the immune system in combating infection and disease.

T cells, which can be resident in mucosal and barrier sites, play a role in the body’s defense against viral respiratory infections. Recently, Nature Medicine reported that T cell responses, in combination with neutralizing antibody levels and memory B cell responses, may be reliable correlates of protection against symptomatic SARS-CoV-2 infection in children.

Other studies highlight the potential of T-cell-based immunity. For example, in one study, individuals who became resistant to SARS-CoV-2 infection post-exposure were more likely to possess populations of circulating T cells against common cold viruses that were also cross-reactive against SARS-CoV-2. The effects of cross-reactive T cells have also been reported in other studies.

Children appear more resistant than adults to developing severe COVID-19 and exhibit substantially greater immunity to SARS-CoV-2 in the upper airway, which some data attribute to innate immune mechanisms and the presence of certain T cell populations.

These and other studies call attention to the importance of studying T cells as possible correlates of protection against SARS-CoV-2 infection, both in the blood and in the oral and nasopharyngeal fluids. Unfortunately, T cell assay standardization, which is necessary to bring such measures into clinical use, is highly complex and, thus, still a work in progress.

Nonstandardized Procedures Create Challenges

Every step involved in measuring patient T cells, from sample collection to data analysis, can contribute to the great variability associated with cell-based tests—which currently lack robust standardization due to their complexity. However, this issue must be addressed because there is an urgent need for T cell collection and assay standardization to generate reliable, comparable data that can be leveraged to inform public health decisions.

For example, blood collection to isolate peripheral blood mononuclear cells (PBMCs) is common, but different laboratories and studies use varying collection procedures. If oral or nasal fluids are needed, their collection requires mucosal sampling, another procedure that is not yet fully standardized. T cells can be isolated from lung mucosa using bronchoalveolar lavage, but in the absence of validated and standardized protocols, it is difficult to interpret and compare test results.

Once the cells are collected, there are a number of assays available to study T cell quantity and function, and the assay choice depends upon the question being posed. These assays and derived data also need to be standardized and validated.

Current T Cell Assays Yield Range of Data

Three of the most well-characterized T cell assays are the ELISpot assay, the intracellular staining (ICS) assay, and the activation-induced marker (AIM) assay. Each presents, depending on the scientific question being investigated, advantages and disadvantages and are best for addressing different types of T cell questions.

ELISpot assays measure individual cytokine levels on a single-cell basis and are relatively simple and robust. However, they have limited sensitivity and depth, providing no information regarding the phenotypes of the cytokine-producing T cells detected. ICS assays measure multiple cytokines and T cell phenotypes. AIM assays analyze T cells that produce cytokines in response to specific antigens. ICS and AIM assays can be combined to capture antigen-specific responses and cytokine production in the same cells. ELISpot assays can be performed on a high-throughput platform, as can flow-based assays such as ICS and AIM (with the appropriate setup), an important option for population-level studies.

Both ELISpot and ICS analyses require research and development efforts to define the cytokine responses to the specific target of interest, an extra step when analyzing T cell responses to a novel antigen or virus, such as SARS-CoV-2. Similarly, AIM assays require optimization to best understand which marker combinations are indicative of T cell activation by the target viral antigen.

Overall, a great deal of information needs to be gathered first before the selection of key relevant markers of interest and their subsequent validation and application to large, well-designed epidemiological studies can begin.

T Cell Standards and Assay Standardization Are Critical

Although proficiency panels and harmonization guidelines have been developed for ELISpot assays, there are still many gaps in T cell immunity assay standardization. ICS and AIM assays are both flow-cytometry-based tests, which are subject to a number of variables that can lead to inconsistent results. Advances in standardization of ICS assays include the use of centralized analysis/standardized gating templates and lyophilized reagents. Unfortunately, while these methods allow for assay standardization if participating laboratories follow the guidelines, data harmonization between laboratories is still difficult without the use of appropriate sets of T cell standards, controls, and critical reagents, such as those available for SARS-CoV-2 serology.

Another complicating factor is that, while antibodies are proteins that can be measured and stored, T cells are living entities that must be carefully maintained and are subject to change depending upon the conditions in which they are kept and used, emphasizing a need for standardized protocols for their utilization in this research arena.

Nevertheless, T cells appear to play key roles in protection against COVID-19, so the challenges inherent in moving T-cell-based assays to the clinical setting are worth tackling. T cell standards development and T cell assay standardization are critical to fully leveraging the information generated by these types of tests. These tools will be essential to further our goal to better understand SARS-CoV-2 T cell immunity and its role in protection against infection and disease at the population level.