Experimental Cancer Vaccine Shows Promise in Animal Studies

An experimental therapeutic cancer vaccine induced two distinct and desirable immune system responses that led to significant tumor regression in mice, report investigators from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.  

The researchers found that intravenous (IV) administration of the vaccine boosted the number of cytotoxic T cells capable of infiltrating and attacking tumor cells and engaged the innate immune system by inducing type I interferon. The innate immune response modified the tumor microenvironment, counteracting suppressive forces that otherwise would tamp down T-cell action. Modification of the tumor microenvironment was not seen in mice that received the vaccine via needle injection into the skin (subcutaneous administration).

Dubbed “vax-innate” by the scientific team, the approach achieves an important goal in the quest for more effective immunotherapeutic vaccines for cancer. The study demonstrates that IV vaccine delivery enables and enhances T-cell immunity by overcoming tumor-induced immunosuppressive activity. The researchers say the candidate vaccine might also be given intravenously to people who have already received tumor-specific T cells as a therapy. It also could improve tumor control by increasing the number of T cells and altering the tumor microenvironment to make them function better, the researchers note. 

Scientists pinpoint mechanisms associated with severe COVID-19 blood clotting

After studying blood samples from 244 patients hospitalized for COVID-19, a group of researchers, including those who work at the National Institutes of Health, identified “rogue antibodies” that correlate with severe illness and may help explain mechanisms associated with severe blood clotting.

The researchers found circulating antiphospholipid antibodies, which can be more common among people with autoimmune disorders, such as lupus. However, these “autoantibodies,” which target a person’s own organs and systems, can also be activated in response to viral infections and activate other immune responses.
 

Scientists compared the blood samples to those from healthy controls and found the COVID-19 samples contained higher levels of the antibody IgG, which works with other immune cells, such as IgM, to respond to immune threats. Higher levels of IgG were also associated with COVID-19 disease severity, such as in patients who required breathing assistance. The researchers observed similar patterns, but to a lesser extent, after analyzing blood samples from 100 patients hospitalized for sepsis, which can leave the body in inflammatory shock following a bacterial or viral infection.  

IgG helps bridge a gap between innate and adaptive immune responses – a process that helps the body recognize, respond to, and remember danger. In normal cases, these features help protect the body from illness and infection. However, in some cases, this response can become hyperextended or altered and exacerbate illness. A unique finding from this study is that when researchers removed IgG from the COVID-19 blood samples, they saw molecular indicators of “blood vessel stickiness” fall. When they added these same IgG antibodies to the control samples, they saw a blood vessel inflammatory response that can lead to clotting.  
 
Since every organ has blood vessels in it, circulating factors that lead to the “stickiness” of healthy blood vessels during COVID-19 may help explain why the virus can affect many organs, including the heart, lungs, and brain. A query of this study was evaluating “upstream” factors involved with severe blood clotting and inflammation among people with severe COVID-19 illness.   
 

The researchers note future studies could explore the potential benefits of screening patients with COVID-19 or other forms of critical illness for antiphospholipids and other autoantibodies and at earlier points of infection. This may help identify patients at risk for extreme blood clotting, vascular inflammation, and respiratory failure. Corresponding studies could then assess the potential benefits of providing these patients with treatments to protect blood vessels or fine-tune the immune system.  

COVID-19 increases the risk of pregnancy complications

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications — in addition to health risks from the virus — than pregnant women without COVID-19, suggests a study funded by the National Institutes of Health.

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications

The study, which included nearly 2,400 pregnant women infected with SARS-CoV-2, found that those with moderate to severe infection were more likely to have a cesarean delivery, to deliver preterm, to die around the time of birth, or to experience serious illness from hypertensive disorders of pregnancy, postpartum hemorrhage, or from infection other than SARS-CoV-2. They were also more likely to lose the pregnancy or to have an infant die during the newborn period. Mild or asymptomatic infection was not associated with increased pregnancy risks.

“The findings underscore the need for women of child-bearing age and pregnant individuals to be vaccinated and to take other precautions against becoming infected with SARS-CoV-2,” said Diana Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which funded the study. “This is the best way to protect pregnant women and their babies.”

The study was conducted by Torri D. Metz, M.D., of the University of Utah, Salt Lake City, and colleagues in the NICHD Maternal-Fetal Medicine Units Network. It appears in the Journal of the American Medical Association. Additional funding was provided by NIH’s National Center for Advancing Translational Sciences.

The study included more than 13,000 pregnant individuals from 17 U.S. hospitals, approximately 2,400 of whom were infected with SARS-CoV-2. Participants delivered between March 1 and December 31, 2020, before SARS-CoV-2 vaccination was available. The researchers compared outcomes among those with COVID-19 to those from uninfected patients and tabulated the study results as a primary outcome — whether the patient had died from any cause or had a serious illness or condition related to common obstetric complications. They also evaluated the results in terms of several secondary outcomes, including cesarean delivery, preterm birth, and fetal and newborn death.

NIH launches first phase of $9.8 million competition to accelerate development of neuromodulation therapies

The National Institutes of Health has launched the first phase of the Neuromod Prize(link is external), a $9.8 million competition to accelerate the development of neuromodulation therapies — targeted treatments that adjust nerve activity to improve organ function. The competition seeks scientists, engineers, and clinicians to submit novel concepts and clinical development plans to demonstrate solutions for precisely stimulating the peripheral nervous system to treat disease and improve human health.

The first phase of the competition will award up to $800,000. NIH plans to launch a second phase awarding up to $4 million, and a third phase awarding up to $5 million, subject to the availability of funds. Details of the requirements and registration for phases 2 and 3 are expected to be announced at a future time. NIH is launching only phase 1 at this time.

The Neuromod Prize is part of the Stimulating Peripheral Activity to Relieve Conditions (SPARC)(link is external) program from the NIH Common Fund. SPARC has made significant progress elevating neuromodulation as a therapeutic approach, closing fundamental knowledge gaps, and offering tools that enable open science(link is external) and innovation. With this competition, NIH hopes to bridge the gap between early-stage research and clinical use for solutions capable of independently targeting multiple functions involving the internal organs of the body.

The nervous system plays a role in all bodily functions, so neuromodulation therapies have the potential to treat a variety of health conditions, ranging from gastrointestinal disorders to heart failure, through targeted regulation of the nerves that connect with all parts of the body. Recent innovations in device technology and improved understanding of the interactions between the nervous system and target tissues and organs have led to a breakthrough moment in the field. As decades of research are applied in new ways, innovators are identifying novel neuromodulation approaches that are capable of selectively targeting multiple organs and functions.

“Through the Neuromod Prize, we’re asking potential solvers to use the foundational knowledge and technologies that have come out of our SPARC program and take it to the next level with their innovative concepts and ideas,” said ​​James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives, which oversees the NIH Common Fund. “This competition is an exciting opportunity to come up with tangible plans for harnessing the power of the body’s electrical system to help transform treatments for millions of people living with chronic or acute illnesses.”

Phase 1 participants will submit concept papers describing their proposed therapeutic approaches and their plans for conducting proof-of-concept studies, rationales for therapeutic use, and expectations for clinical impact. To learn more, potential participants can join a virtual information session(link is external) on February 7, 2022. Submissions through an online portal are due by 4:59 p.m. EDT on April 28, 2022.

A judging panel will select up to eight quarterfinalists to receive a share of the up to $800,000 first-phase prize pool. NIH subsequently plans to launch a second and a third phase, which will be announced at a later date. Phase 1 quarterfinalists will be exclusively invited to participate in the second phase, anticipated to take place starting in 2022, which will translate the winning ideas into preclinical studies. Semifinalist winners from the second phase will be eligible to compete in the final phase, expected to launch in 2023, moving their preclinical work into advanced translational and clinical studies as a critical step towards the regulatory approvals needed to bring new neuromodulation therapies to market.

Lung Autopsies of COVID-19 Patients Reveal Treatment Clues

Lung autopsy and plasma samples from people who died of COVID-19 have provided a clearer picture of how the SARS-CoV-2 virus spreads and damages lung tissue.

Scientists at the National Institutes of Health and their collaborators say the information, published in Science Translational Medicine, could help predict severe and prolonged COVID-19 cases, particularly among high-risk people, and inform effective treatments.

Although the study was small—lung samples from 18 cases and plasma samples from six of those cases—the scientists say their data revealed trends that could help develop new COVID-19 therapeutics and fine-tune when to use existing therapeutics at different stages of disease progression. The findings include details about how SARS-CoV-2, the virus that causes COVID-19, spreads in the lungs, manipulates the immune system, causes widespread thrombosis that does not resolve, and targets signaling pathways that promote lung failure, fibrosis and impair tissue repair. The researchers say the data are particularly relevant to caring for COVID-19 patients who are elderly, obese, or have diabetes—all considered high-risk populations for severe cases. Study samples were from patients who had at least one high-risk condition.

The study included patients who died between March and July 2020, with time of death ranging from three to 47 days after symptoms began. This varied timeframe allowed the scientists to compare short, intermediate, and long-term cases. Every case showed findings consistent with diffuse alveolar damage, which prevents proper oxygen flow to the blood and eventually makes lungs thickened and stiff.

They also found that SARS-CoV-2 directly infected basal epithelial cells within the lungs, impeding their essential function of repairing damaged airways and lungs and generating healthy tissue. The process is different from the way influenza viruses attack cells in the lungs. This provides scientists with additional information to use when evaluating or developing antiviral therapeutics.

Researchers at NIH’s National Institute of Allergy and Infectious Diseases led the project in collaboration with the National Institute of Biomedical Imaging and Bioengineering and the U.S. Food and Drug Administration. Other collaborators included the Institute for Systems Biology in Seattle; University of Illinois, Champaign; Saint John’s Cancer Institute in Santa Monica, California.; the USC Keck School of Medicine in Los Angeles; University of Washington Harborview Medical Center, Seattle; University of Vermont Medical Center, Burlington; and Memorial Sloan Kettering Cancer Center in New York City.

NIH scientists identify mechanism that may influence infectivity of SARS-CoV-2 variants

Scientists at the National Institutes of Health have found that a process in cells may limit infectivity of SARS-CoV-2, and that mutations in the alpha and delta variants overcome this effect, potentially boosting the virus’s ability to spread. The findings were published online in the Proceedings of the National Academy of Sciences. The study was led by Kelly Ten Hagen, Ph.D., a senior investigator at NIH’s National Institute of Dental and Craniofacial Research (NIDCR).

Since the coronavirus pandemic began in early 2020, several more-infectious variants of SARS-CoV-2, the virus that causes COVID-19, have emerged. The original, or wild-type, virus was followed by the alpha variant, which became widespread in the United States in early 2021, and the delta variant, which is the most prevalent strain circulating today. The variants have acquired mutations that help them spread and infect people more easily. Many of the mutations affect the spike protein, which the virus uses to get into cells. Scientists have been trying to understand how these changes alter the virus’s function.

“Throughout the pandemic, NIDCR researchers have applied their expertise in the oral health sciences to answer key questions about COVID-19,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “This study offers fresh insights into the greater infectivity of the alpha and delta variants and provides a framework for the development of future therapies.”

The outer surface of SARS-CoV-2 is decorated with spike proteins, which the virus uses to attach to and enter cells. Before this can happen, though, the spike protein must be activated by a series of cuts, or cleavages, by host proteins, starting with the furin enzyme. In the alpha and delta variants, mutations to the spike protein appear to enhance furin cleavage, which is thought to make the virus more effective at entering cells.

Studies have shown that in some cases protein cleavage can be decreased by the addition of bulky sugar molecules—a process carried out by enzymes called GALNTs—next to the cleavage site. Ten Hagen’s team wondered if this happens to the SARS-CoV-2 spike protein, and if so, whether it changes the protein’s function.

To find out, the scientists studied the effects of GALNT activity on spike protein in fruit fly and mammalian cells. The experiments showed that one enzyme, GALNT1, adds sugars to wild-type spike protein, and this activity reduces furin cleavage. By contrast, mutations to the spike protein, like those in the alpha and delta variants, decrease GALNT1 activity and increase furin cleavage. This suggested that GALNT1 activity may partially suppress furin cleavage in wild-type virus, and that the alpha and delta mutations overcome this effect, allowing furin cleavage to go unchecked.

Further experiments supported this idea. The researchers expressed either wild-type or mutated spike in cells grown in a dish. They observed the cells’ tendency to fuse with their neighbors, a behavior that may facilitate spread of the virus during infection. The scientists found that cells expressing mutated spike protein fused with neighbors more often than cells with the wild-type version. Cells with wild-type spike also fused less in the presence of GALNT1, suggesting that its activity may limit spike protein function.

“Our findings indicate that the alpha and delta mutations overcome the dampening effect of GALNT1 activity, which may enhance the virus’s ability to get into cells,” said Ten Hagen.

To see if this process might also occur in people, the team analyzed RNA expression in cells from healthy volunteers. The researchers found wide expression of GALNT1 in lower and upper respiratory tract cells that are susceptible to SARS-CoV-2 infection, indicating that the enzyme could influence infection in humans. The scientists theorized that individual differences in GALNT1 expression could affect viral spread.

“This study suggests that GALNT1 activity may modulate viral infectivity and provides insight into how mutations in the alpha and delta variants may influence this,” Ten Hagen said. The knowledge could inform future efforts to develop new interventions.

This research was supported by the NIDCR Division of Intramural Research. Support also came from the intramural program of the National Institute of Environmental Health Sciences.

NIH study suggests people with rare diseases face significantly higher health care costs

A new retrospective study of medical and insurance records indicates health care costs for people with a rare disease have been underestimated and are three to five times greater than the costs for people without a rare disease.

The study, led by the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS), provides new evidence of the potential impact of rare diseases on public health, suggesting that nationwide medical costs for individuals with rare diseases are on par with those for cancer and heart failure. The study’s results were published Oct. 21 in the Orphanet Journal of Rare Diseases(link is external).

“There needs to be greater public awareness of the large and growing medical footprint of rare diseases in society,” said senior author Anne Pariser, M.D., director of the NCATS Office of Rare Diseases Research. “Only about 10% of rare diseases have an FDA-approved therapy for their treatment. The findings underscore an urgent need for more research, and earlier and more accurate diagnoses of and interventions for these disorders.”

Most of the approximately 7,000 to 10,000 known rare diseases disproportionately affect children, adolescents and young adults. Individually, most rare diseases might affect only a few hundred to a few thousand people worldwide. However, rare diseases are collectively common, affecting an estimated 25 million to 30 million people in the United States. Many of these diseases have a genetic cause, are serious or life-threatening and are hard to diagnose and treat.

The pilot study was a collaborative effort among NCATS; Eversana Life Sciences, Chicago; Oregon Health & Science University, Portland; Sanford Health, Sioux Falls, South Dakota; and a health insurer in Australia. Pariser and colleagues analyzed patients’ diagnosis information in medical records and billing codes. They used International Classification of Diseases (ICD) codes, which designate a disease diagnosis and other methods, to determine those individuals with rare diseases and their direct medical costs for 14 rare diseases in four health care systems compared to non-rare disease patients of a similar age.

The pilot study aimed to test the feasibility of this approach in analyzing data on rare diseases prevalence and costs. The 14 rare diseases represented a diverse set of disorders that differ in prevalence, organ systems affected, age of onset, clinical course, and availability of an approved treatment or specific ICD code. Examples of the selected rare diseases include sickle cell disease, muscular dystrophy and eosinophilic esophagitis.

The analysis showed wide variations of rare diseases prevalence in the various healthcare systems, which the researchers attributed in part to geographic differences, as well as the use of public versus private insurance, which may include different patient group representation. In addition, some genetic diseases can occur more frequently in certain populations, depending on the demographic make-up of a region.

The team determined approximate medical costs by examining healthcare system data from NCATS and Eversana. In every case, the cost per patient per year (PPPY) for those with a rare disease exceeded costs for non-rare diseases patients of the same age. According to the Eversana healthcare system database, which included estimates from commercial and insurance payors over nearly 15 years, PPPY costs ranged from $8,812 to $140,044 for rare diseases patients compared to $5,862 for those without a rare disease. The NCATS data, which drew from estimates mostly from Florida Medicaid information over five years, indicated PPPY costs ranging from $4,859 to $18,994 for rare diseases patients versus $2,211 for those without a rare disease.

The team reported that extrapolating the average costs estimate for the approximately 25 to 30 million individuals with rare diseases in the United States would result in total yearly direct medical costs of approximately $400 billion, which is similar to annual direct medical costs for cancer, heart failure and Alzheimer’s disease.

The researchers also used patient medical records to trace the diagnostic journeys of four people with a rare disease, including two individuals who had a form of Batten disease, an inherited neurological disorder, and two others with cystic fibrosis, an inherited disease that severely affects the lungs. The journey “maps” provided detailed descriptions of direct medical costs, such as for hospitalizations and procedures associated with these diseases, and provided insights into patient clinical management before and after disease diagnosis.

The researchers noted that analyzing medical records revealed that rare diseases patients often share a consistent group of symptoms (e.g., seizures, infections, and developmental delay) and characteristics, which could help clinicians make diagnoses more quickly and begin treatment earlier. Because many individuals are diagnosed with a rare disease at a young age and because most rare diseases are serious conditions, rare disease patients are likely to require more time in the hospital and incur greater medical expenses over a lifetime than those without rare diseases.

Such commonalities among rare disease patients could point to the potential use of machine learning techniques on healthcare system databases to improve diagnoses, said NCATS Acting Director Joni L. Rutter, Ph.D., a co-author on the study.