SeroNews Summer 2023

To many, the urgency surrounding the COVID-19 pandemic has passed. This spring, the U.S. national emergency response to the COVID-19 pandemic ended, the Centers for Disease Control and Prevention stopped collecting certain types of COVID-related public health data, and the World Health Organization declared the end of COVID-19 as a global health emergency.

While that’s good news for people who are ready for a post-pandemic existence, those who are battling Long COVID are worried about being left behind as the rest of the COVID-weary world moves on.

More than one in five American adults who contract a SARS-CoV-2 infection go on to battle Long COVID symptoms. While the chances of developing Long COVID appear to be lower with the Omicron strains, they’re significant enough to cause concern, as breakthrough infections continue to occur.

Not every person infected with SARS-CoV-2 is equally at risk for Long COVID. Women, Hispanic adults, cancer patients, people living with HIV, and adults over 65 years of age are among those most vulnerable.

Patient Input Remains Key

Obstacles still loom in addressing the major health issues associated with Long COVID, not only for those currently affected—some of whom are still battling symptoms three years out—but also for those who will contract it in the future.

For instance, although the most common problems are extreme fatigue, memory problems (“brain fog”), shortness of breath, sleep problems, and joint pain, the symptoms vary greatly. There won’t—and likely can’t—be a single cure.

Patient input is going to be key in the search for answers. In the U.K., the National Long COVID research working group has high­lighted the importance of patient and public involvement to speed the pace of their epide­miological Long COVID studies.

Collaborative efforts between Long COVID patients and experts have yielded initiatives such as the Long COVID Alliance, a network of patient-advocates, scientists, disease experts, and drug developers committed to accelerating Long COVID research, and the Patient-Led Research Collaborative, a group of Long COVID patients who are also researchers who facilitate patient-led and patient-involved Long COVID research.

Still, laboratories, clinics, and industry will need to stay committed to continue working on this important problem, even as the pandemic shifts.

Progress in Predicting, Preventing, and Treating

Another major challenge lies in determining the biological indicators of Long COVID after an acute SARS-CoV-2 infection. Searches began early in the pandemic. Thankfully, some biomarkers are starting to look like good candidates, possibly even for predicting the Long COVID symptoms a patient might develop.

For example, reactivation of latent viral infec­tions in some individuals may play a role. Studies have shown that Epstein-Barr virus (EBV), which infects most people at some point in their lives, shows signs of reactivation in COVID-19. Antibodies against early and nuclear EBV antigens fall to undetectable levels after acute EBV illness, but they’ve been found in some COVID patients, where they can correlate with development of post- COVID fatigue and neurocognitive dysfunction like that seen in Long COVID.

There also is some forward movement in the search for Long COVID treatments and preventive measures.

Rintatolimod, an experimental drug in the U.S. designed to treat chronic fatigue syndrome, is about to enter Phase II trials to assess its effects on extreme fatigue in Long COVID patients. Meanwhile, clinical trials of an amino acid mix called AXA1125 showed a reduction in this fatigue in participants.

Early treatment with Paxlovid, an FDA-ap­proved medication for mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, also appeared to protect against progression to Long COVID in a study that used more than 280,000 Department of Veterans Affairs records. Treatment not only reduced the risk of death from SARS-CoV-2 infection, it reduced the risk of developing Long COVID by 26%.

In another effort, STIMULATE ICP, a U.K.-based program for the study of Long COVID, is running a Phase III drug trial using combina­tions of anti-inflammatory, antihistamine, antacid, and blood-thinning medications in a nested platform designed to rapidly evaluate possible therapies for Long COVID, and to contribute to a patient-centered, integrated care system.

Staying the Course

The National Institutes of Health have taken steps to keep Long COVID research a priority through the RECOVER Initiative, which is designed to learn about the long-term effects of Long COVID. This nationwide partnership is working to find answers and treatments to help affected people. It’s a multidisciplinary, organized effort across different areas of medicine and biology that Long COVID touches. It has the potential to be impactful due to the extensive data set it has gathered since its inception, and preparations are underway to begin clinical trials.

Other efforts revolve around private ventures, such as the Long COVID Research Initiative, which looks to use an agile approach to study the disease model of Long COVID with the direct goal of producing therapeutics.

Unfortunately, even with these collective efforts underway, patients often still face chal­lenges in finding the most appropriate care.

The global rush to produce vaccines and treatments early in the pandemic was unmatched by any other public health emergency response. Long COVID is still part of the pandemic, and the same commitment and energy will be vital to helping those who are struggling to find treatment, answers, and hope for recovery.

A new wave of COVID-19 vaccines is steadily moving through preclinical and clinical testing. Many of them have yet to capture widespread attention until further data are gathered, but they hold the potential to be crucial players in controlling COVID-19 in the future.

One may question why new vaccines are necessary when the current vaccines are safe and effective, with more than 13 billion doses administered worldwide.

The data stage a stark scene in response, giving a resounding answer in favor of a future need for novel options. Existing vaccine regimens have been shown to induce lower levels of neutralizing antibodies against BQ.1, BQ.1.1, XBB, and XBB.1 variants compared to the original Wuhan strain. Since then, new XBB.1 subvariants have arisen. While existing vaccines still protect against hospitalization and death, their ability to prevent infection with an evolving virus such as SARS-CoV-2 is increasingly limited.

Additionally, existing vaccines are less effective in immunocompromised people, including cancer patients. The dominant Omicron subvariants also dodge convalescent plasma and therapeutic antibodies. It’s still important to focus on vulnerable populations, as there have been 767,518,723 confirmed cases of COVID-19 reported worldwide as of June 28, and 167,628 new cases reported during the last week of June.

New vaccines are far from being under­studies. Many employ different platforms or manufacturing techniques than existing vaccines, presenting several advantages over the current vaccines. Some are easy to make. Some can be readily engineered to protect against more than one strain of the virus. Others are stable at warmer temperatures, avoiding the transportation and storage challenges associated with existing mRNA vaccines. These are meaningful alternatives that still require additional investigation.

Particles Play a Protective Part

Virus-like particles (VLPs) are one option, as VLP-based vaccines have afforded long-term protection, even with a just single dose, against other viruses such as HPV.

SARS-CoV-2 VLP vaccines use small assem­blies of proteins that mimic parts of the virus. While noninfectious, they do, like actual viruses, contain multiple key SARS-CoV-2 proteins. This variety provides the recipient’s immune system with a broad group of targets, including parts of the virus that don’t change much between variants, increasing the likeli­hood of defending against even new variants. So far, the vaccines have shown encouraging results in animal studies.

In one study, mice vaccinated with an adju­vanted VLP had high antibody levels against several parts of the virus, including the spike protein that’s a primary vaccine target. The vaccine also stimulated a strong response of white blood cells called T cells in the mice, another front for fighting the virus and disease. Encouragingly, vaccinated mice had significantly less lung distress and damage than unvaccinated mice after encountering SARS-CoV-2.

Another study of a different VLP vaccine revealed that vaccination stimulated a strong, diverse antibody response in mice and pigs—and that the antibodies targeted key parts of the virus.

Still another study found that VLPs generated a protective immune system response in vaccinated nonhuman primates, a closer model of human disease. T-cell responses were induced in vaccinated and boosted animals, and the animals had lower viral replication and inflammation compared to their unvaccinated counterparts after encoun­tering SARS-CoV-2, suggesting their immune systems better controlled the infection.

Some VLP vaccines have already entered human clinical trials. Results from the Phase I trial of the ABNCoV2 VLP vaccine have been published, showing the vaccine is safe and produces an immune response. Phase III trial results for other VLP-based SARS-CoV-2 vaccines have likewise been published, in which the vaccines prevented moder­ate-to-severe COVID-19.

Engineering Through Other Means

Protein-based vaccines are also poised to enter the scene. As of May 2022, two protein-based vaccines—Nuvaxovid and Covovax—had been approved by the World Health Organization. Nuvaxovid is the most visible, having received Emergency Use Authoriza­tion (EUA) by the FDA and shown protection against SARS-CoV-2 variants.

Many other protein-subunit vaccines are in development or clinical trials. One, called V-01, was proven safe and effective in humans. Another, S-trimer (SCB-2019), was well-tolerated by patients and showed robust neutralizing immune responses against SARS-CoV-2 in a Phase I study. Several others have been evaluated, as well.

Vaccine platforms such as nanoparticles also offer the possibility of designing for broad protection. The currently approved, most-used SARS-CoV-2 vaccines, mRNA-1273 and BNT162b2, are both lipid-nanopar­ticle-formulated, nucleoside-modified mRNA-based vaccines, but many others are in development. For instance, researchers created a vaccine with modified, nonin­fectious pieces of the virus attached to a ferritin-based nanoparticle. After two doses, vaccinated mice had higher neutralizing antibodies than mice that received any of the other candidate vaccines in the study.

In a different study, a team engineered a nanoparticle with spike proteins from the Wuhan strain and the Alpha, Beta, and Gamma variants. Vaccinated mice and nonhuman primates developed neutralizing antibodies against all four strains. The mice were protected against the Wuhan and Beta strains after encountering the virus.

Other nanoparticle-based vaccines, including CVnCOV from CureVac and SK SARS-CoV-2 from SK Bioscience Co., Ltd., have been in clinical trials.

The Right Response at the Right Time

Studies are ongoing for many of these new vaccine types, and trials still need to be done in immunocompromised populations. However, the data so far suggest that some candidates may soon earn a spot in the limelight.

This doesn’t discount existing vaccines or mRNA platforms, which are still valuable. Rather, like choosing the right actor to play the right part, an expanding vaccine reper­toire will give society the means to respond to SARS-CoV-2 as circumstances dictate.

As the virus continues to mutate and evade immunity, a varied, flexible means of vacci­nation will be necessary. It’ll go a long way toward creating broad, enduring protection and finally dropping the curtain on this pandemic—for everyone.

The COVID-19 pandemic has inspired frenzied vaccine production, with researchers trying old and new methods to tamp out the virus. As more and more people have been vacci­nated, infected, or both, it has become harder to gauge vaccine efficacy through random­ized placebo-controlled trials. Determining correlates of protection, immunological markers of whether a person is protected against a virus, is an alternative route to determining efficacy.

Every virus has its own correlates of protec­tion. Scientists have determined them for many viruses with currently licensed vaccines, including hepatitis A and B and measles. Correlates of protection for nearly all currently licensed vaccines, with a few notable exceptions, are associated with antibody responses.

Immunity against the virus likely depends on multiple pathways, though one correlate of protection will probably prove to be more useful than others. While some possible surrogates of protection for COVID-19 have been found, more research is needed to determine the most useful and effective correlates of protection.

Questions and Answers from Antibodies

In particular, both the concentration of IgG antibodies against the SARS-CoV-2 spike protein and the levels of total neutralizing antibodies have been demonstrated to be associated with protection against symptom­atic COVID-19 at the population level.

Yet researchers are still debating whether these can be considered deployable correlates of protection that can reliably be used to measure a vaccine’s efficacy at the individual level. It’s not possible to determine how much virus clinical trial participants are exposed to, so it’s difficult to determine with any certainty how much protection a certain level of antibodies can provide.

Reaching a threshold antibody level for protection against all variants of COVID-19 may be challenging since it is an evolving, rapidly spreading mucosal virus, and anti­bodies decline over time, meaning someone can be infected even after receiving a vaccine. There’s a high incidence of Omicron infection even after triple vaccination.

Nevertheless, a recent study has determined the IgG concentration and neutralizing antibody levels that are thresholds for protec­tion specifically from the SARS-CoV-2 Delta variant, so updated thresholds for emerging variants could be determined in the future.

B Cells and T Cells: Another Threshold?

Meanwhile, scientists are pursuing research around other possible correlates of protec­tion. For instance, nonhuman primates with COVID-19 in laboratory studies have shown a strong response to the vaccines from white blood cells known as B cells and T cells. SARS-CoV-2-specific CD4+ and CD8+ T cells are each associated with milder disease. However, T cells are difficult to standardize in a laboratory, making them challenging to study.

Making Better Vaccines: Protection for All

After researchers identify and pinpoint a correlate of protection based on accumu­lated, strong protection data, it can be used to obtain regulatory approval for a vaccine for a specific use or to ensure consistency between different lots of vaccine production. Such markers can help to bridge the gap from first- to second-generation vaccines based on surrogate measures of protection. In addition, a reliable correlate of protection would help determine when protection afforded by vacci­nation may have waned, and help researchers figure out how administering multiple types of vaccines together affects what each does.

Further, correlates of protection can help determine proper vaccine doses for immu­nocompromised individuals, cancer patients, or other populations for whom vaccines seem to be less effective. Cancer patients are more likely to test positive for SARS-CoV-2 and more likely to experience breakthrough infection after vaccination. Usable correlates could aid clinical determination regarding a need for extra boosting or intervention.

Ultimately, discovering the right correlates of protection will help solve the mystery of how best to protect all populations from SARS-CoV-2. With the virus on its way to becoming a seasonal visitor, like the flu, there’s no time to lose.

As the public health emergency of international concern ended in April in the U.S., the Clinical and Translational Serology Task Force sought to examine the status of serological rapid test development and the remaining limitations and challenges to their implementation.

Accordingly, they convened a roundtable to discuss the latest lateral flow immunoassay (LFIA) developments and their past and future applications for studying and monitoring immune response to SARS-CoV-2 infection. The event, which aligned with the task force’s efforts to highlight the value of population-level serosurveillance and point-of-care testing, featured industry and academic institutions that have developed or used LFIA technology during the pandemic to detect antibodies to SARS-CoV-2 in blood or serum.

LFIAs are rapid tests that can detect active infection or antibodies generated in response to infection or vaccination, depending on the kind of test. They hold potential for under­standing immunity on a large scale, but their use for that faces many obstacles.

Market Woes and Scientific Speed Bumps

From the beginning of the pandemic, serology development took off at a lightning pace. Many SARS-CoV-2 lateral flow tests have received Emergency Use Authorization to detect antibodies developed in response to infection.

However, most of the original tests were designed to detect the binding activity of antibodies to the original SARS-CoV-2 strain. As new variants emerged, some companies have developed new neutralizing antibody tests for point-of-care applications.

Massachusetts Institute of Technology’s Hojun Li, M.D., Ph.D., reported on his group’s development of a LFIA to test for neutralizing antibodies against SARS-CoV-2 as a point-of-care device. While rapid lateral flow assays aren’t necessarily as accurate and sensitive as higher-complexity laboratory assays, they can be cost-efficient and easy to perform. At the time of the presentation, the team hadn’t submitted their test for regulatory approval.

Jianfu Wang, Ph.D., presented Novodiax’s LFIA, CoNAb, which can detect neutralizing antibodies to the spike protein, including the Omicron variant, in whole blood or serum. Testing takes just 15 minutes, and the assay has been harmonized to the World Health Organization International Standard. It hasn’t received Emergency Use Authoriza­tion, however.

In some cases, standardizing the test results is challenging. Enqing Tan, Ph.D., presented on Bio-Techne Corporation’s efforts to develop a LFIA that detects neutralizing antibodies to a single variant, as well as a second LFIA covering 10 variants of the spike protein receptor-binding domain. Both tests are relatively fast, low cost, and deployable, but standardization remained elusive. At the time of the round table, the assay hadn’t obtained Emergency Use Authorization.

In all three of these cases, the technology presented may represent a considerable step toward practical and reliable large-scale rapid serological testing. However, as the pandemic’s emergency phase ends, interest in commercializing new serology assays is waning due to decreasing demand and absence of clinical guidelines for their use. Novodiax pulled CoNAb from develop­ment for the clinical market and limited its availability to only research use due to lack of demand, highlighting some of the barriers to further COVID-19 LFIA development.

Making It Work

Should the technology to accurately evaluate neutralizing antibodies against circulating variants of concern be developed, previous studies have illustrated that LFIAs can be used for immune surveillance in large populations. At the roundtable, Christina Atchinson, Ph.D., and Helen Ward, Ph.D., of Imperial College London, led a discussion based around the REACT-2 study in the United Kingdom. This nationwide effort, previously reported on in SeroNews, recruited participants to take a serological LFIA at home. The study provided a population-level view of SARS-CoV-2 exposure and immune response to the virus during a certain phase of the pandemic.

As such, LFIAs are outstanding candidates for at-home, population-level immuno­logical monitoring. The obstacle is getting them there and ensuring participation. The roundtable suggested that studies like REACT-2 must be conducted to demonstrate the feasibility and utility of widespread LFIA implementation at a population level.

Researchers will also need to make infor­mation easily understood by diverse sets of participants. People need to comprehend a study’s goals and the medical infrastructure—and be willing to participate. Investigators conducting a study must describe it clearly and also explain the specific steps needed to complete an at-home LFIA without error. Drs. Atchinson and Ward underscored that building relationships with communities for things like these was crucial to the success of REACT-2: it demonstrated that these large-scale studies are possible with careful and in-depth planning and development.

Meanwhile, utility on the individual patient level can only be achieved upon development of LFIAs with high specificity and sensitivity for markers identified as correlates of protec­tion against the relevant variants of concern. Collaboration across industry groups, LFIA developers, regulators, and policymakers is key to continue test development and fully leverage and implement these types of testing tools.

No Time to Quit

The ability to monitor population-level trends in immunity as a marker of past exposure becomes increasingly critical as formal reporting and tracking efforts for COVID-19 fall out of vogue. Without them, society risks blinding itself to a virus that’s still causing infections and endangering vulnerable indi­viduals, such as cancer patients or the elderly, worldwide.

Next-generation LFIAs can help fill that gap. Even so, as the discussion indicated, much more work needs to be done to get there.

The public health emergency may be finished, but the job isn’t. Research, resources, and collaboration must forge on.

The Emergency May Have Ended, But the Job Isn’t Over Yet

The Clinical and Translational Serology Task Force continues to meet regularly to review progress and priorities in key areas of collabo­ration in this post-emergency COVID-19 era.

Long COVID, or Post-Acute Sequelae of COVID-19, is one of our topics of intense discussion and interest, given the number of affected people worldwide. Serology and immunology will remain important in better understanding this condition and the mechanisms behind it. CTTF is dedicated to leveraging knowledge in this area that can inform public health decisions.

Although the emergency phase of the pandemic has ended, COVID-19 collabora­tive and coordinated research continues to advance. Public health agencies around the world are carefully monitoring the safety and effectiveness of the COVID-19 vaccines and the evolution of SARS-CoV-2. Based on current evidence, new vaccine booster shots for this fall will be updated to target the currently circulating Omicron subvariant XBB.1.5. New vaccine and serology technology developments will again be key for pandemic preparedness.

We look forward to further engagement, discussion, and collaboration as this new COVID era develops, and—as always—we welcome your suggestions, comments, and requests. Please reach out!

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