NIH begins clinical trial evaluating second COVID-19 booster shots in adults

A Phase 2 clinical trial evaluating various additional COVID-19 booster shots has begun enrolling adult participants in the United States. The trial aims to understand if different vaccine regimens—prototype and variant vaccines alone and in combinations—can broaden immune responses in adults who already have received a primary vaccination series and a first booster shot. The study, known as the COVID-19 Variant Immunologic Landscape (COVAIL) trial, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Colorized scanning electron micrograph of a cell (purple) infected with a variant strain of SARS-CoV-2 virus particles (pink), isolated from a patient sample. NIAID

“We are looking beyond the Omicron variant to determine the best strategy to protect against future variants,” said NIAID Director Anthony S. Fauci, M.D. “This trial will help us understand if we can use prototype and variant vaccines alone or together to shift immune responses to cover existing and emerging COVID-19 variants.”

Despite waning protection against infection and mild illness during the Omicron wave, COVID-19 vaccines available in the United States so far have maintained durable protection against severe COVID-19. However, NIAID is preparing for the possibility of future variants evading protection against currently available COVID-19 vaccines.

COVID-19 vaccine manufacturers can adjust prototype vaccines to target specific variants, a process similar to how manufacturers update seasonal influenza vaccines every year to target circulating strains. However, predicting if, when and where new COVID-19 variants will emerge and how they will affect the population, remains challenging. Studies(link is external) indicate that Omicron has a combination of mutations that make it substantially different from prior SARS-CoV-2 variants. Should a new variant emerge that more closely resembles ancestral SARS-CoV-2 or, for example, the Delta variant, an Omicron-specific vaccine may not offer substantial protection. An individual’s response to booster shots may also be impacted by their history of prior infection and vaccination, or both, and what type of COVID-19 vaccines they received.

Vaccine manufacturers have previously studied some variant vaccine candidates and are currently conducting clinical trials of Omicron-specific vaccines. The COVAIL trial will gather data on the immune responses induced by prototype vaccines and variant vaccine candidates—including bivalent vaccines, which target two SARS-CoV-2 variants—to inform booster shot recommendations.

The first stage of this trial is being conducted in collaboration with Moderna, Inc., based in Cambridge, Massachusetts, and Moderna is manufacturing the study vaccines that will be administered. The trial will be adapted to enroll more participants to evaluate additional vaccine platforms and variant vaccines from other manufacturers as needed to further inform public health decisions. Participants will be monitored for symptoms and adverse events following vaccination and will be asked to return to the clinic during set times over the course of 12-14 months to provide blood samples. Investigators will evaluate the samples in the laboratory to measure and characterize immune responses to SARS-CoV-2 strains. Investigators aim to have initial findings available by August 2022.

Nadine Rouphael, M.D., director of the Hope Clinic at the Emory Vaccine Center in Atlanta, and Angela Branche, M.D., associate professor of medicine at the University of Rochester Medical Center in New York, are leading the trial. Site investigators at 24 clinics are enrolling 600 participants 18 years and older who already have received a primary COVID-19 vaccination series and booster shot. Participants are randomly assigned to one of six vaccine regimens:

NIH launches program to offer molecular characterization of childhood cancers

In support of President Biden’s Cancer Moonshot℠ goal of fostering data sharing in cancer research, the National Cancer Institute, part of the National Institutes of Health, has launched the Molecular Characterization Initiative for pediatric tumors.

The program offers tumor molecular characterization, also called biomarker testing, to children, adolescents, and young adults with newly diagnosed central nervous system tumors who are being treated at hospitals that are affiliated with the Children’s Oncology Group (COG)(link is external), an NCI-supported clinical trials group that includes more than 200 hospitals and institutions that treat most children diagnosed with cancer in the United States.

The Molecular Characterization Initiative is offered through NCI’s Childhood Cancer Data Initiative, which was launched in 2019 to promote data sharing and collection of new data among researchers who study childhood cancers.

Children, adolescents, and young adults diagnosed with a central nervous system cancer across the United States will be eligible to receive molecular characterization of their tumors free of charge through this voluntary program. DNA and RNA from tumor and blood samples will be analyzed to help make an accurate diagnosis and to understand what is causing or driving the cancer. The Molecular Characterization Initiative will expand later in 2022 to include soft tissue sarcomas and other rare tumors.

“The ultimate dream has really been for every child with cancer to have a state-of-the-art diagnosis and the safest and most effective therapy,” said Brigitte C. Widemann, M.D., special advisor to the NCI director for childhood cancer. “The Molecular Characterization Initiative is a transformative collaboration that will entail participation of the entire community.”

Having a precise diagnosis based on the molecular characteristics of a patient’s tumor can help doctors choose the most effective and potentially least toxic treatment for each child. Data on the molecular changes seen across childhood cancers can also help researchers better understand the molecular causes of childhood cancers and accelerate the development of new, more effective, and potentially less toxic treatments, especially for rare childhood cancers for which treatment options are limited. 

“The game changer for patients is that we’re going to understand the patient’s disease precisely and comprehensively in a way that we’ve done piecemeal so far,” said Douglas S. Hawkins, M.D., group chair of COG.

Previously, comprehensive tumor molecular characterization was available to children enrolling in some clinical trials or to those being treated at larger institutions with internal resources to offer such state-of-the-art diagnostics. Data on tumor biomarkers were stored exclusively at the hospital or institution where a child was treated, with limited sharing of data among institutions. The new program will make tumor molecular characterization broadly available for children throughout the country. Moreover, the data collected will be available in a central location so that childhood cancer researchers can learn from the data and use it to inform future studies.

“We can help make molecular characterization available throughout the country so that it will be a standard of care that every child can get,” said Maryam Fouladi, M.D., COG’s central nervous system tumor disease committee leader. “An accurate molecular diagnosis can inform optimal treatment for every child.”

For example, Dr. Fouladi explained, some childhood cancers, such as gliomas, can be misdiagnosed. “We can apply molecular diagnostics to a child diagnosed with a high-grade glioma and find out that it is actually a low-grade glioma or an entirely different tumor, which may need very different treatments and have a very different outcome,” she said. “Molecular diagnostics can really contribute to getting the correct diagnosis, offering the optimal treatment and, ultimately, improving the patient’s outcome.”

In addition to providing detailed information about a cancer to use in making an accurate diagnosis, the data can also be used to determine whether a child is eligible for a clinical trial. Molecular characterization can reveal, for example, whether a child has a specific cancer subtype that is eligible for a clinical trial evaluating a new treatment explicitly designed for that subtype.

Enrollment in the Molecular Characterization Initiative is initially offered through participation in Project:EveryChild(link is external), a childhood cancer registry maintained by COG (APEC14B1). Initial participants will include newly diagnosed children, adolescents, and young adults ages 25 years and younger at the time of diagnosis. Young adults over the age of 25 who are being screened for eligibility into a COG clinical trial may also be included.

Tumor and blood samples from participants will be sent to an accredited lab for analysis, and the results will be available to patients and their families within 21 days. The molecular data will also be aggregated into a database available to researchers for future studies, such as those exploring why some tumors become resistant to therapies they initially responded to or what factors increase the risk of treatment-related side effects. Personal information that could be used to identify a participant will be removed before data are put into the database.

Dr. Widemann said the Molecular Characterization Initiative is a program the childhood cancer community can easily get behind. “To be able to apply the best tools to make the most accurate diagnosis so that the most effective treatment can be prescribed, that’s a goal that I think physicians and families can all align around,” she said.

Hydrocortisone does not prevent lung complications in extremely preterm infants

Hydrocortisone is no more effective than a placebo at preventing damage that can result from oxygen and ventilator therapy necessary to keep preterm infants alive, according to research funded by the National Institutes of Health.

The study of a potential treatment for the condition, known as bronchopulmonary dysplasia, appears in the New England Journal of Medicine.

In recent years, hydrocortisone was considered as a replacement for the widely used drug dexamethasone in the prevention of bronchopulmonary dysplasia. Both drugs inhibit the inflammation thought to contribute to BPD, but animal studies suggested that hydrocortisone would have fewer effects on the developing brain. Infants born preterm have higher rates of death and disability(link is external).

The study enrolled 800 infants born before the 30th week of pregnancy who had been on a ventilator for at least seven days. From 14 days to 28 days, in addition to receiving standard care and ventilator therapy, infants were randomly assigned to receive either hydrocortisone or a placebo.

Of the hydrocortisone-treated infants, 16.6% survived to 36 weeks without moderate or severe bronchopulmonary dysplasia, which did not differ significantly from 13.2% in the placebo group. The rate of neurodevelopmental impairment did not differ significantly between the groups (36.9% vs. 37.3%). The hydrocortisone group was more likely to need drug treatment for hypertension than the placebo group (4.3% vs. 1.0%).

People from racial, ethnic, and other groups report frequent COVID-19–related discrimination

People from all major racial and ethnic minority population groups in the United States report experiencing more COVID-19–related discrimination than white adults, a new study shows.

COVID-19-related discrimination includes experiences of being threatened or harassed based on someone’s perception of another having COVID-19. To date, this is the largest study, with the most diverse participants, to examine discrimination related to COVID-19. The study was led by Paula D. Strassle, Ph.D., of the National Institute on Minority Health and Health Disparities (NIMHD), part of the National Institutes of Health, and was published in the American Journal of Public Health on Feb. 23, 2022.

In the study, researchers measured the prevalence of COVID-19–related discrimination in all major racial and ethnic groups in the United States, using data from the COVID-19’s Unequal Racial Burden (CURB) survey. They also analyzed the impact of other social and demographic factors on COVID-19–related discrimination. People from groups that have been marginalized, such as those who speak little to no English and those with lower levels of education, were also found to face more discrimination due to the pandemic.

Researchers collected information from 5,500 American Indian/Alaska Native, Asian, Black/African American, Hawaiian and Pacific Islander, Latino, white, and multiracial adults. The online survey was administered by YouGov from December 2020 to February 2021 and was available in English and Spanish. The survey asked whether participants had experienced COVID-19–related discriminatory behaviors, such as being called names or insulted, being threatened or harassed, or hearing racist comments, because the perpetrator thought the participant had COVID-19. The survey also asked whether participants felt that others acted afraid of them because they belonged to a racial/ethnic group misconceived to get COVID-19 more often.

Results showed that 22.1% of participants had experienced COVID-19–related discriminatory behaviors, and 42.7% of participants reported that people acted afraid of them. When compared to white adults, people from all racial and ethnic minority groups were more likely to have experienced COVID-19–related discrimination. Participants who identified as Asian or American Indian/Alaska Native were most likely to have experienced this hostile behavior, and participants who identified as Hawaiian or Pacific Islander or Latino were also highly likely to have experienced discrimination. Higher rates of discrimination affected participants who lived in a big city; in a rural area; or in Alabama, Kentucky, Mississippi, or Tennessee.

The results suggest that the COVID-19 pandemic has worsened existing resentment toward racial and ethnic minorities and other minority populations in the United States. The study showcases the need for careful and responsible public health messaging during public health crises to help prevent and address discrimination against groups that have been marginalized.

France and WHO sign new agreement to reinforce health systems to combat COVID-19

The Government of France and WHO have announced a new €50 million contribution agreement that will help countries’ health systems overcome bottlenecks in the COVID-19 response and speed up equitable access to testing, treatments, and vaccines.

WHO is very grateful to the Government of France for its continued commitment to global unity in the response to the COVID-19 pandemic. France has taken a leading role in supporting WHO’s work through the ACT Accelerator, which is crucial for WHO to achieve its mission and safeguard the lives of the most vulnerable around the world.

– Dr Tedros Adhanom Ghebreyesus, WHO Director-General

The agreement, disclosed on the sidelines of the ministerial conference of foreign ministers and health ministers in Lyon, France, aims to support the work of WHO and co-convener’s work in the Health Systems and Response Connector (HSRC) of the Access to COVID-19 Tools Accelerator (ACT-A), aligned with the WHO’s COVID-19 Strategic Preparedness and Response Plan (SPRP).

The HSRC works to ensure that countries have the technical, operational, and financial resources to acquire and efficiently use vaccines and other COVID-19 tools.

France’s contribution will help accelerate equitable access to all COVID-19 tools, by looking at each country’s health system’s bottlenecks and identifying the right responses and solutions to them.

The contribution will work through the HSRC to help countries turn vaccines into well-prioritized vaccination campaigns; turn tests into effective test-and-treat approaches; pursue community-based testing strategies to support public health measures and the platform for disease surveillance, and turn therapeutics into life-saving clinical pathways. This means strengthening national response mechanisms and reinforcing health systems.

H.E. Mr. Jean-Yves Le Drian, Foreign Minister of France said: “Global health is of critical importance to the French presidency of the European Union. This support to WHO aims to provide additional support to countries’ health systems; strengthen cooperation between actors and coordination between ACT-A components; to enhance dialogue with all stakeholders including the civil society and recipient countries; and to accelerate equitable access to new COVID-19 tools and ensure they are made available at a scale and scope in order to save millions of lives.”

France shares key health priorities with WHO, adopting a cross-cutting approach and prioritizing universal health coverage as part of the 2030 Sustainable Development Agenda.

In January 2020, France and WHO signed a new framework agreement for 2020-2025, confirming France’s role as a key actor in global health, along with its strong support for WHO’s Thirteenth General Programme of Work, a five-year strategy that aims to ensure healthy lives and well-being for people of all ages.

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.  

Researchers document third known case of HIV remission involving stem cell transplant

A woman with HIV who received a cord blood stem cell transplant to treat acute myeloid leukemia has had no detectable levels of HIV for 14 months despite cessation of antiretroviral therapy (ART), according to a presentation at today’s Conference on Retroviruses and Opportunistic Infections (CROI).

Scanning electron micrograph of an HIV-infected H9 T cell, colorized in Halloween colors.NIAID

This is the third known case of HIV remission in an individual who received a stem cell transplant. The research was conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) P1107 observational study led by Yvonne Bryson, M.D., of the University of California Los Angeles, and Deborah Persaud, M.D., of Johns Hopkins University, Baltimore. The IMPAACT network is funded by the National Institutes of Health.

The IMPAACT P1107 study began in 2015 and was a U.S.-based observational study designed to describe the outcomes of up to 25 participants living with HIV who underwent a transplant with CCR5Δ32/Δ32 cord blood stem cells for the treatment of cancer, hematopoietic disease, or other underlying diseases. As a result of the genetic mutation CCR5Δ32/Δ32, missing cells lack CCR5 co-receptors, which is what HIV uses to infect cells. By killing off the cancerous immune cells via chemotherapy and then transplanting stem cells with the CCR5 genetic mutation, scientists theorize that people with HIV then develop an HIV-resistant immune system.

The case described today at the CROI meeting involves a woman of mixed race ancestry who had been on ART for HIV infection for four years at the time of her acute myeloid leukemia diagnosis. She achieved acute myeloid leukemia remission after chemotherapy. Prior to receiving the stem cell transplant, the participant’s HIV was well-controlled but detectable.

In 2017, she received a transplant of CCR5Δ32/Δ32 cord blood stem cells supplemented with adult donor cells from a relative (called haplo cells). After receiving the stem cell transplant, she engrafted with 100% cord blood cells at day 100 and had no detectable HIV. At 37 months post-transplant, the patient ceased ART. According to the study team, no HIV was detected in the participant for 14 months except for a transient detection of trace levels of HIV DNA in the woman’s blood cells at 14 weeks after stopping ART. The haplo cells only transiently engrafted and contributed to rapid recovery.

HIV remission resulting from a stem cell transplant had been previously observed in two cases. The first, known as the “Berlin patient” (a Caucasian male), experienced HIV remission for 12 years and was deemed cured of HIV; he died of leukemia in September 2020. The “London patient” (a Latino male) has been in HIV remission for more than 30 months. This third case of HIV remission suggests that CCRΔ5/Δ32 cord stem cell transplantation should be considered to achieve HIV remission and cure for people living with HIV who require such a transplant for other diseases, according to the study team.