Fall 2023 SeroNews

Collaborative research, updated vaccines help shield at-risk populations

The Clinical and Translational Serology Task Force continues in its commitment to meet regularly to review and discuss new findings and gaps in research on COVID-19 immunity and protection.

As the updated vaccines roll out and the strategies for COVID-19 vaccine development continue to evolve, CTTF has maintained an interest in the issues surrounding protection from COVID-19 infection, especially in immunocompromised populations. Patients with immunocompromising conditions such as cancer are at higher risk for reinfection and poorer outcomes. CTTF has been hosting a speaker series on COVID-19 immunity and cancer to better understand immune responses against infection after vaccination and/or infection—as well as post-acute sequelae in immunocompromised individuals. As SARS-CoV-2 evolves, continued vaccine development and efforts to prevent infection will be key in protecting these vulnerable populations. Vaccination remains our strongest tool against COVID-19.

In addition, CTTF has been discussing the role of cellular immunity in fighting COVID-19 disease and how complex, cell-based assays can be standardized. Applying the lessons learned from advances in standardizing serology for COVID-19 and other pathogens will be important for translating cell-based assays’ utility into clinical practice.

As always, we look forward to further engagement, discussion, and collaboration as new results and strategies develop to address COVID-19. We continue to welcome your suggestions, comments, and requests, and we hope you reach out!

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Roundtable recaps COVID-19 consortia developments and lessons learned

Meta-analyses, consortia, and biobanks: to anyone familiar with the terms, they convey a sense of power and potential, of large quantities of data and specimens revealing patterns or yielding crucial information. Put into practice, they tell scientists a lot about disease and are powerful tools in cases such as the COVID-19 pandemic. However, a tool is only useful if those who need it know that it exists, what it’s good for, how to use it, and how to apply it in the future.

The Clinical and Translational Serology Task Force sought to spread that information within its community earlier this year, convening a roundtable meeting about COVID-19 consortia and biospecimen banks. The discussion highlighted their scientific findings and explored their accomplishments, the lessons learned, and potential future uses.

Key points from the meeting are below.

Value in networks and communication

The U.K. Coronavirus Immunology Consortium, with its 20 academic units working in tandem, was presented as an example of what a broad network can achieve.

The consortium worked with the SIREN and VIVALDI studies and various populations in the U.K. All told, it had data from health care workers, elderly and frail populations (including care home residents), children and adolescents, immunosuppressed populations, and healthy adults vaccinated against SARS-CoV-2.

Thanks to that approach, the consortium’s researchers were able to measure the decrease in antibody efficacy to the BA.4 and BA.5 sublineages among people vaccinated with the AZD1222 or BNT162b2 vaccines. They also identified the neutralizing EY6A antibody and its target antigen, charting a path for future monoclonal antibody research and treatments. Some additional work characterized the immune response in elderly and frail people, and other efforts showed that children develop robust immune responses against SARS-CoV-2 that also react to other coronaviruses.

On the management side, the main takeaway was the value of organized teamwork with tight, constant communication, resulting in contributions much bigger than the sum of their parts. Networks like these would be valuable in the future. While the U.K. consortium didn’t have a centralized biorepository for storing specimens from all studies, future initiatives could benefit from that type of infrastructure. That would allow researchers to maintain and study long-term immune responses to infection and vaccination, as well as provide valuable contextual samples and controls should another pandemic hit.

Hub-and-spoke model rolls on

The Serological Sciences Network (SeroNet), the United States’ largest coordinated effort to expand the national capacity for SARS-CoV-2 serology testing and research, was another topic of discussion.

Established in 2020, SeroNet uses a hub-and-spoke type of model to unite government and academic partners’ capabilities. Designated centers of excellence and capacity-building centers conduct investigator-initiated research and collect biospecimens of healthy and immunosuppressed individuals. The Network Coordinating Center, headquartered at Frederick National Laboratory (FNL), helps consolidate and manage efforts, and the FNL Serology Laboratory leads standardization and assay validation efforts that are critical to conduct translational research, in collaboration with government and private organizations.

So far, SeroNet has produced more than 350 publications on COVID-19, with many now in the National Institute of Allergy and Infectious Diseases’ ImmPort database. The network also established the Clinical and Translational Serology Task Force.

At the FNL Serology Laboratory, scientists have evaluated more than 120 commercial SARS-CoV-2 tests, investigated the immune response to vaccines, and produced the U.S. human SARS-CoV-2 serology standard and assay validation panels. Studies in academic partner laboratories have likewise revealed much about the immune response to the virus and vaccines.

SeroNet has become an example of responding to a pandemic and standardizing scientific efforts via a flexible and agile model with a shared vision. Work under SeroNet is ongoing: studies into B- and T-cell characterization are underway, as are proteomic and transcriptomic analyses.

Putting antibodies in bins

The Coronavirus Immunotherapy Consortium (CoVIC) proved to be a different example. As an international collaboration to compare and study SARS-CoV-2 antibodies, it represented what large-scale comparative analyses can accomplish.

CoVIC aimed to help researchers find potent antibodies that could be developed at low cost for treatments in low-income countries. Under its aegis, scientists collected more than 400 antibodies from over 60 contributors, removed identifying information to avoid bias, and submitted the antibodies to partner labs for study. All results were uploaded to a public dashboard.

The outcome was a database for comparing different antibodies and better understanding their functions. It resembled a well-tested and proven predecessor database created under the Viral Hemorrhagic Fever Immunotherapeutic Consortium, which focused on Ebola outbreaks.

CoVIC classified antibodies based on their target antigens, “binning” them into seven categories that recognized patterns in how they neutralized or attached to SARS-CoV-2. That information helped scientists understand how to measure the antibodies’ activity more efficiently, and it could help them select antibodies or antibody combinations to develop further. For instance, one analysis identified characteristics of COVID-19 antibodies, generated against earlier variants, that neutralized the Omicron variant.

Building on the model used for Ebola research, the consortium has underscored how a large, international “binning,” or comprehensive characterization, approach advances knowledge about antibodies against emerging viruses. As such, it could be a powerful tool in future pandemics.

Long COVID, defined

Mayo Clinic’s Long COVID Program and the National Institutes of Health’s RECOVER initiative rounded out the discussion. Mayo serves as a biorepository for both programs.

As part of its many goals to better understand Long COVID, the RECOVER program created a definition for it by analyzing patient surveys.

The surveys reached 85 clinics and homed in on 12 symptoms with severity ratings to characterize Long COVID. Importantly, patients contributed to planning and refining the surveys, offering a unique and illuminating perspective.

The programs’ additional work pinpointed features associated with Long COVID, such as high levels of interleukin-6, as well as other inflammatory markers that could be biomarkers, depending on the variant that caused the infection. Disrupted metabolic patterns in the brain, cellular aging and immunoaging, and altered arginine metabolism may play a role, as well.

These programs highlighted the relevance of having biorepositories with pre-existing samples, collected prior to the pandemic, to serve as controls. These and similar resources could be deployed in future pandemics, along with developed survey and data collection templates.

Combined with the preceding consortia on the agenda, Mayo’s program and RECOVER illustrate the importance of taking many approaches to studying COVID-19. Such a large biomedical challenge demands a large-scale response: one that’s broad, flexible, diverse, innovative, and thorough. That’s the best way to deliver on the potential of partnerships and biobanks.

New monovalent formulations put to the test

New vaccines are on the scene. In September, the U.S. Food and Drug Administration (FDA) approved and authorized, and the Centers for Disease Control and Prevention (CDC) recommended, updated mRNA COVID-19 vaccines from Moderna and Pfizer–BioNTech for all people 6 months of age or older.

Unlike the bivalent vaccines made available in August of 2022, these vaccines are monovalent, targeting the SARS-CoV-2 Omicron subvariant XBB.1.5 (a.k.a., “Kraken”). This formulation was selected to address the dominant variants circulating in June 2023, in anticipation of a fall and winter COVID-19 surge.

Since Omicron evolves rapidly, it wasn’t surprising that XBB.1.5 was no longer the dominant variant by the time vaccine manufacturers had the doses ready. Fortunately, subsequent testing of the updated Pfizer and Moderna vaccines against newer subvariants, including EG.5 (“Eris”) and BA.2.86 (“Pirola”), showed that the updated vaccine induces neutralizing antibody responses and is expected to protect against severe disease and hospitalization.

Eris is a member of the XBB family; however, recent studies revealed that Pirola is not, and may have evolved from Omicron BA.2. If this variant takes off, Pirola may be the next variant that is given a Greek name by the World Health Organization.

A third updated vaccine, a monovalent, protein-based formulation produced by Novavax, also targeting XBB.1.5 spike protein, was approved by the FDA in October for all people 12 years of age or older.

Why return to a monovalent vaccine?

In June 2022, the FDA recommended that vaccine manufacturers Pfizer and Moderna add Omicron BA.4 and BA.5 spike protein components to their original vaccine compositions against the ancestral SARS-CoV-2 strain, creating a two-component, bivalent booster. The rationale was that the anti-spike protein antibodies to the original vaccine would continue to protect against the ancestral strain while those to Omicron BA.4 and BA.5 spike would extend protection against these then-dominant variants and their descendants.

The idea was sound, and the bivalent booster did offer protection against severe disease and death, but limitations arose that set a path toward developing an updated monovalent vaccine rather than another booster for the fall and winter of 2023.

Uptake of the bivalent booster in the U.S. was low, about 17% as of May 2023, and CDC follow-up data show that, while the booster was highly effective at reducing hospitalization and death rates, even for XBB-related sublineages, vaccine effectiveness waned over time. That makes the development and implementation of updated vaccines targeted to the most recently relevant circulating strains a key public health strategy for protection against COVID-19.

Maintaining vigilance

The winter holidays are here for a large part of the world, complete with crowded travel, more time spent indoors with friends and family, and exposure to other winter “regulars,” such as flu and respiratory syncytial virus, and—now—SARS-CoV-2.

Vaccination is still the best way to protect yourself and those around you from COVID-19. The updated COVID-19 vaccines offer a window of protection against infection and are a key tool in reducing transmission. Since immunity wanes after vaccination, timing a vaccination appointment is an important consideration when heading into a season when infections increase.

COVID-19 is still causing severe disease, and Long COVID remains a factor to reckon with. Even with a mild COVID-19 infection, there’s still a risk of developing Long COVID, and the risk increases with multiple infections.

Protective measures, including vaccination, are always important, especially to help those who are vulnerable, such as children too young to be vaccinated, those who can’t be vaccinated, and immunocompromised people.

Let’s look out for each other and get the updated COVID-19 vaccine. An ounce of prevention is still worth a pound of cure.

The COVID-19 pandemic disrupted life for everyone. But cancer patients and other immunocompromised people have been even more adversely affected.

Researchers and clinicians have worked hard to gather and analyze data on these vulnerable groups to try to better understand immunity and disease outcomes in these patients. As part of that effort, on August 8, 2023, the Clinical and Translational Serology Task Force hosted the first meeting in a two-part series on Cancer and COVID-19, featuring three researchers studying the interplay between cancer and SARS-CoV-2 outcomes and breakthrough infections.

Protracted infections in immunocompromised patients

Ghady Haidar, M.D., from the University of Pittsburgh Medical Center, summarized previous studies showing that immunocompromised patients were highly likely to be hospitalized, have poor outcomes, and have protracted, months-long SARS-CoV-2 infections, with symptoms that wax and wane. Protracted infection with SARS-CoV-2 in immunocompromised patients can also result in increased viral mutation, potentially producing new infectious variants.

An additional concern is the lack of demonstrated effective treatments for these groups, meaning that prevention is key. While use of the bivalent vaccine and multiple vaccine doses appear to be helpful in preventing hospitalization or breakthrough infection, the focus still needs to be on optimization of COVID-19 prevention strategies in these cohorts. Post-vaccination seroconversion, antibody titers, and T-cell responses are low in immunocompromised patients, particularly those with blood cancers (although increasing the number of doses can increase these levels). Since immunocompromised patients are at risk for protracted infections and severe outcomes, vaccine response optimization will be extremely important for protecting these cohorts as variants continue to emerge.

Analyzing risk factors for severe outcomes and breakthrough infections in CCC19

Chris Labaki, M.D., from the Dana-Farber Cancer Institute, presented findings from the COVID-19 and Cancer Consortium (CCC19), which includes more than 19,000 records of patients with cancer and COVID-19. Focusing on factors correlated with worse outcomes for cancer patients, the consortium found that risk factors for severe outcomes in patients with cancer include increased age; being male; comorbidities; and active, advanced, or progressive cancer.

Furthermore, multiple clinical laboratory markers were associated with severe disease or mortality in hospitalized patients. These included abnormal absolute lymphocyte count; high absolute neutrophil count; low platelets; and abnormal creatine, troponin, lactate dehydrogenase, and C-reactive protein. Patients undergoing cytotoxic chemotherapy or DNA methyltransferase inhibitor therapies experienced higher mortality, while immunotherapy regimens increased the risk of worse COVID-19-related outcomes if the patients were already immunosuppressed. Patients who had blood cancers, used immunosuppressive therapies, or had lymphopenia were all at higher risk of worse outcomes from COVID-19 as well.

While patients with cancer have, overall, a poorer vaccine response than the general population, the team concluded vaccination was associated with improved outcomes and lower mortality rates among patients with cancer, with a more profound benefit for patients who received three doses. These results point to an advantage of three versus two vaccine doses for these populations; however, people with active or progressive cancer still fared worse compared to others, despite being vaccinated.

As SARS-CoV-2 continues to integrate itself into the annual viral landscape, it will be important to reassess the impact of newer vaccines on vulnerable groups as the updated formulations are made available. In the case of cancer patients, it’s crucial to emphasize that prevention is vital in these susceptible populations and that vaccination should be encouraged.

Factors associated with worse COVID-19 outcomes or breakthrough infections in N3C data

Rounding out the meeting, Qianqian Song, Ph.D., from Wake Forest University School of Medicine, brought data from the National COVID Cohort Collaborative (N3C). The N3C data enclave represents the largest secure collection of harmonized clinical health data in the U.S., comprising 77 sites, 18.3 million patients, and more than 7.2 million positive COVID-19 cases. Song presented research from this cohort evaluating factors that increase worse outcomes and all-cause mortality from COVID-19 for cancer patients.

In these studies, among people with COVID-19, being over 65 years old, being male, having a blood cancer, having multiple tumor sites, and undergoing recent cytotoxic therapy were associated with increased risk of all-cause mortality. Notably, non-Hispanic Black patients had a lowered risk. Also, patients who received recent immunotherapies didn’t appear to have a higher risk of overall mortality.

Patients with cancer, especially those with hematologic malignancies such as multiple myeloma and lymphoma, were at higher risk of breakthrough infections and severe outcomes. Multiple myeloma, especially, was associated with a higher risk of breakthrough infections and severe outcomes in the N3C cohort. Cancer treatments played a role, too: proteosome inhibitors, immune modulators, monoclonal antibodies, and bone-marrow transplants were associated with higher risk of breakthrough infections.

While researchers studying this challenging disease and vulnerable populations still face many questions, especially as both virus and medicine continue to evolve, the key point from the meeting was that enhanced vaccines and treatments are needed for these populations. For now, prevention against COVID-19 infection remains the best defense for patients with cancer.