Scientists identify characteristics to better define long COVID

A research team supported by the National Institutes of Health has identified characteristics of people with long COVID and those likely to have it.

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient.NIAID

Scientists, using machine learning techniques, analyzed an unprecedented collection of electronic health records (EHRs) available for COVID-19 research to better identify who has long COVID. Exploring de-identified EHR data in the National COVID Cohort Collaborative (N3C), a national, centralized public database led by NIH’s National Center for Advancing Translational Sciences (NCATS), the team used the data to find more than 100,000 likely long COVID cases as of October 2021 (as of May 2022, the count is more than 200,000). The findings appear in The Lancet Digital Health.

Long COVID is marked by wide-ranging symptoms, including shortness of breath, fatigue, fever, headaches, “brain fog” and other neurological problems. Such symptoms can last for many months or longer after an initial COVID-19 diagnosis. One reason long COVID is difficult to identify is that many of its symptoms are similar to those of other diseases and conditions. A better characterization of long COVID could lead to improved diagnoses and new therapeutic approaches.

“It made sense to take advantage of modern data analysis tools and a unique big data resource like N3C, where many features of long COVID can be represented,” said co-author Emily Pfaff, Ph.D., a clinical informaticist at the University of North Carolina at Chapel Hill.

The N3C data enclave currently includes information representing more than 13 million people nationwide, including nearly 5 million COVID-19-positive cases. The resource enables rapid research on emerging questions about COVID-19 vaccines, therapies, risk factors and health outcomes.

The new research is part of a related, larger trans-NIH initiative, Researching COVID to Enhance Recovery (RECOVER), which aims to improve the understanding of the long-term effects of COVID-19, called post-acute sequelae of SARS-CoV-2 infection (PASC). RECOVER will accurately identify people with PASC and develop approaches for its prevention and treatment. The program also will answer critical research questions about the long-term effects of COVID through clinical trials, longitudinal observational studies, and more.

In the Lancet study, Pfaff, Melissa Haendel, Ph.D., at the University of Colorado Anschutz Medical Campus, and their colleagues examined patient demographics, health care use, diagnoses and medications in the health records of 97,995 adult COVID-19 patients in the N3C. They used this information, along with data on nearly 600 long COVID patients from three long COVID clinics, to create three machine learning models to identify long COVID patients.

In machine learning, scientists “train” computational methods to rapidly sift through large amounts of data to reveal new insights — in this case, about long COVID. The models looked for patterns in the data that could help researchers both understand patient characteristics and better identify individuals with the condition.

The models focused on identifying potential long COVID patients among three groups in the N3C database: All COVID-19 patients, patients hospitalized with COVID-19, and patients who had COVID-19 but were not hospitalized. The models proved to be accurate, as people identified as at risk for long COVID were similar to patients seen at long COVID clinics. The machine learning systems classified approximately 100,000 patients in the N3C database whose profiles were close matches to those with long COVID. 

“Once you’re able to determine who has long COVID in a large database of people, you can begin to ask questions about those people,” said Josh Fessel, M.D., Ph.D., senior clinical advisor at NCATS and a scientific program lead in RECOVER. “Was there something different about those people before they developed long COVID? Did they have certain risk factors? Was there something about how they were treated during acute COVID that might have increased or decreased their risk for long COVID?”

The models searched for common features, including new medications, doctor visits and new symptoms, in patients with a positive COVID diagnosis who were at least 90 days out from their acute infection. The models identified patients as having long COVID if they went to a long COVID clinic or demonstrated long COVID symptoms and likely had the condition but hadn’t been diagnosed.

“We want to incorporate the new patterns we’re seeing with the diagnosis code for COVID and include it in our models to try to improve their performance,” said the University of Colorado’s Haendel. “The models can learn from a greater variety of patients and become more accurate. We hope we can use our long COVID patient classifier for clinical trial recruitment.”

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:

NIAID issues new awards to fund “pan-coronavirus” vaccines

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has awarded approximately $36.3 million to three academic institutions to conduct research to develop vaccines to protect against multiple types of coronaviruses and viral variants. The awards are intended to fuel vaccine research for a diverse family of coronaviruses, with a primary focus on potential pandemic-causing coronaviruses, such as SARS-CoV-2.

“The available COVID-19 vaccines have proven to be remarkably effective at protecting against severe disease and death,” said NIAID Director Anthony S. Fauci, M.D. “These new awards are designed to look ahead and prepare for the next generation of coronaviruses with pandemic potential.”

The new awards are funded by NIAID’s Division of Microbiology and Infectious Diseases and its Division of Allergy, Immunology, and Transplantation through the Emergency Awards Notice of Special Interest (NOSI) on Pa.n-Coronavirus Vaccine Development Program Projects. The notice was issued in November 2020 while many SARS-CoV-2 vaccines were still under development because a critical need remained for prophylactic vaccines offering broad protective immunity against other coronaviruses, such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).

The awards are designed to fund multidisciplinary teams at each institution to conduct research focused on incorporating understanding of coronavirus virology and immunology, immunogen design, and innovative vaccine and adjuvant platforms and technologies to discover, design, and develop pan-coronavirus vaccine candidates that provide broad protective immunity to multiple coronavirus strains. Specific programs will address coronavirus diversity and infectious potential in humans, include innovative immunogen design and vaccine platforms, and approaches to elicit potent and durable pan-coronavirus immunity, and evaluate vaccine candidates in preclinical models. The awardees are expected to be flexible in the response to emerging knowledge about SARS-CoV-2 immune responses and infection and factor in new information as vaccines candidates are developed. Additional awards are expected to be issued under the NOSI in 2022 to support pan-coronavirus vaccine research at more institutions.

The new awards build on the $1.2 billion investment NIAID has made in coronavirus vaccine research since the COVID-19 pandemic began, including multiple projects in pan-coronavirus vaccine research in the NIAID intramural and extramural programs.

A key goal of the initiative is to develop multivalent vaccine platforms and strategies suitable for use in vulnerable populations and to understand vaccine-induced responses and efficacy related to a person’s age or sex.

Taskforce on COVID-19 says vaccine inequity driving a dangerous divergence in COVID-19 survival

At its third meeting, the Multilateral Leaders Taskforce on COVID-19 (MLT) – the heads of the International Monetary Fund, World Bank Group, World Health Organization and World Trade Organization -met with the leaders of the African Vaccine Acquisition Trust (AVAT), Africa CDC, Gavi and UNICEF to tackle obstacles to rapidly scale-up vaccines in low- and lower middle-income countries, particularly in Africa, and issued the following statement:

“The global rollout of COVID-19 vaccines is progressing at two alarmingly different speeds. Less than 2% of adults are fully vaccinated in most low-income countries compared to almost 50% in high‑income countries.

These countries, the majority of which are in Africa, simply cannot access sufficient vaccine to meet even the global goals of 10% coverage in all countries by September and 40% by end 2021, let alone the African Union’s goal of 70% in 2022.

This crisis of vaccine inequity is driving a dangerous divergence in COVID-19 survival rates and in the global economy. We appreciate the important work of AVAT and COVAX to try and address this unacceptable situation.

However, effectively tackling this acute vaccine supply shortage in low- and lower middle-income countries, and fully enabling AVAT and COVAX, requires the urgent cooperation of vaccine manufacturers, vaccine-producing countries, and countries that have already achieved high vaccination rates. To ensure all countries achieve the global goals of at least 10% coverage by September and 40% by end-2021:

We call on countries that have contracted high volumes of vaccines to swap near-term delivery schedules with COVAX and AVAT.

We call on vaccine manufacturers to immediately prioritize and fulfill their contracts to COVAX and AVAT, and to provide regular, clear supply forecasts.

We urge G7 and all dose-sharing countries to fulfill their pledges urgently, with enhanced pipeline visibility, product shelf life and support for ancillary supplies, as barely 10% of nearly 900 million committed doses have so far been shipped.

We call on all countries to eliminate export restrictions and any other trade barriers on COVID-19 vaccines and the inputs involved in their production.

We are in parallel intensifying our work with COVAX and AVAT to tackle persistent vaccine delivery, manufacturing and trade issues, notably in Africa, and mobilize grants and concessional financing for these purposes. We will also explore financing mechanisms to cover future vaccine needs as requested by AVAT. We will advocate for better supply forecasts and investments to increase country preparedness and absorptive capacity. And we will continue to enhance our data, to identify gaps and improve transparency in the supply and use of all COVID-19 tools.

NIH launches study of third COVID-19 vaccine dose in kidney transplant recipients

Colorized scanning electron micrograph of a cell (purple) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID

A pilot study has begun to assess the antibody response to a third dose of an authorized COVID-19 mRNA vaccine in kidney transplant recipients who did not respond to two doses of the Moderna or Pfizer-BioNTech COVID-19 vaccine. The Phase 2 trial is sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The lifelong immunosuppressive therapy that organ transplant recipients must take to prevent organ rejection blunts their immune response to both pathogens and vaccines. Research has shown that many organ transplant recipients do not develop antibodies against SARS-CoV-2, the virus that causes COVID-19, after receiving an authorized COVID-19 vaccine regimen. The purpose of the new study is to determine whether a third dose of one of the mRNA COVID-19 vaccines could overcome this problem for at least some kidney transplant recipients. This is particularly important because this population has a high prevalence of conditions that are risk factors for severe COVID-19, such as cardiovascular disease and diabetes.

The pilot study also aims to identify characteristics that could help distinguish those kidney transplant recipients who would benefit from a third dose of an mRNA vaccine from those who will require a different approach to achieve protection. The pilot study findings will inform a subsequent, larger phase of the trial that includes higher-risk strategies to induce a protective immune response against SARS-CoV-2 in solid organ transplant recipients who do not respond to a third dose of an mRNA vaccine.

The third-dose vaccine intervention was chosen because of the demonstrated safety of the two-dose mRNA vaccine regimen in solid organ transplant recipients as well as the efficacy of additional doses of other vaccines, such as those for hepatitis and influenza, in immunocompromised people.

The pilot study, called COVID Protection After Transplant (CPAT), is being conducted at Johns Hopkins University in Baltimore under the leadership of Dorry Segev, M.D., Ph.D. Dr. Segev is the Marjory K. and Thomas Pozefsky professor of surgery and epidemiology, associate vice chair of the department of surgery, and director of the Epidemiology Research Group in Organ Transplantation at Johns Hopkins University. 

The CPAT study team will enroll up to 200 adults ages 18 years or older who received a kidney transplant a year or more prior to enrollment and have had no recent organ rejection or change in immunosuppression. Between 50 and 100 participants will have had no detectable antibody response to two doses of an mRNA COVID-19 vaccine, and 50 to 100 participants will have had a low response. All participants will receive a third dose of the same COVID-19 vaccine that they received previously. Thirty days later, investigators will measure participants’ antibody response to the third dose. The goal is to determine the proportion of participants who achieve a designated antibody response at the 30-day mark. The study team will follow participants for one year after enrollment. Preliminary results are expected in September 2021.

Sierra Leone: One-month nationwide curfew imposed to control the new COVID variant

Sierra Leone president Julius Maada Bio on Thursday announced a one-month nationwide curfew in Sierra Leone to control spread of Covid-19 effective Monday 5th July 2021 from 11 pm to 5 am daily.

a) Congregational worship in churches, mosques and other religious places are suspended for a period of one month effective Friday 2nd July 2021.

b) Restaurants and bars are encouraged to use takeaway services and they shall close at 9 pm daily.

c) Attendance at funerals, weddings, and other social events shall be limited to no more than fifty persons.

d) Drivers and passengers are strongly urged to get their COVID-19 vaccination prior to all traveling from one town to the other.

Bio: not taking chances

The president said all prior NACOVERC measures and advisories on proper face-masking, handwashing, and social distancing remain in full force and that NaCOVERC will enforce these measures strictly.

“I, therefore, call on all citizens to cooperate with these interventions. These measures will be reviewed from time to time based on scientific data and expert advice.

“COVID-19 vaccines that are available in this country are safe and efficacious. They have been approved by our Pharmacy Board and the World Health Organisation. I, senior members of Government, over a hundred thousand citizens have been fully vaccinated. This vaccine will protect you against COVID-19 and protect your life. I, therefore, strongly urge every eligible citizen to take the free COVID-19 vaccines that are widely available throughout the country.”

All prior NACOVERC measures and advisories on proper face-masking, handwashing, and social distancing remain in full force and that NaCOVERC will enforce these measures strictly.

The president pointed out that together as a nation, and in peace, the country has coped with financial and social constraints, restrictions on movement, and the general global uncertainties and anxieties caused by the pandemic.

 “We did not renew the state of emergency once it elapsed. We eased restrictions on worship and travel and completely lifted the curfew. We did so then based on our assessment of COVID-19 infections.

 “So far, we have kept our children in schools and colleges at all levels; kept hospitals and all Government offices open; kept public services running; kept congregational worship centers open, kept businesses open; and, supported the most vulnerable of our citizens throughout this period. Our Quick Action Economic Recovery Programme has mitigated the impact of the pandemic and maintained our economy on an even keel.

 “All Covid-19 emergency response pillars from the national to district levels have remained active. All our policies as a Government have been well-thought-out to minimize the economic and other burdens of the pandemic, to save lives, and to protect livelihoods”.

The president said international partners and institutions have unreservedly praised the government’s competent handling of the first and second waves of the pandemic as the fatality ratios at under 3%, but noted that according to the World Health Organisation, the third wave of COVID-19 may impact the country and the Delta variant has been recently detected in Sierra Leone. “That variant is easily transmitted and it is very deadly.”

 He said people have tested positive for COVID-19 in the last few weeks with more people hospitalized and 72% of beds in treatment and care centers already occupied.

 “We have assessed the data. We have carefully examined the patterns of infection. We have closely looked at the trends. We believe we must take urgent and necessary steps to stem this third wave of the COVID-19 pandemic in Sierra Leone and thus save lives and protect livelihoods,” he said.

Adjuvant Developed with NIH Funding Enhances Efficacy of India’s COVID-19 Vaccine

An adjuvant developed with funding from the National Institutes of Health has contributed to the success of the highly efficacious COVAXIN COVID-19 vaccine, which roughly 25 million people have received to date in India and elsewhere. Adjuvants are substances formulated as part of a vaccine to boost immune responses and enhance a vaccine’s effectiveness. COVAXIN was developed and is manufactured in India, which is currently suffering a devastating health crisis due to COVID-19. 

“Ending a global pandemic requires a global response,” said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “I am pleased that a novel vaccine adjuvant developed in the United States with NIAID support is part of an efficacious COVID-19 vaccine available to people in India.” 

The adjuvant used in COVAXIN, Alhydroxiquim-II, was discovered and tested in the laboratory by the biotech company ViroVax LLC of Lawrence, Kansas with support exclusively from the NIAID Adjuvant Development Program. The adjuvant comprises a small molecule attached in a unique way to Alhydrogel, a substance frequently called alum that is the most commonly used adjuvant in vaccines for people. Alhydroxiquim-II travels to lymph nodes, where the small molecule detaches from alum and activates two cellular receptors. These receptors, TLR7 and TLR8, play a vital role in the immune response to viruses. Alhydroxiquim-II is the first adjuvant in an authorized vaccine against an infectious disease to activate TLR7 and TLR8. In addition, the alum in Alhydroxiquim-II stimulates the immune system to search for an invading pathogen.

Molecules that activate TLR receptors stimulate the immune system powerfully, but the side effects of Alhydroxiquim-II are mild. This is because, after COVAXIN is injected, the adjuvant travels directly to nearby lymph nodes, which contain white blood cells that play an essential role in identifying pathogens and fighting infection. Consequently, only a small amount of Alhydroxiquim-II is needed in each dose of vaccine, and the adjuvant does not circulate throughout the body, thereby averting more widespread inflammation and undesirable side effects. 

COVAXIN comprises a disabled form of SARS-CoV-2 that cannot replicate but still stimulates the immune system to make antibodies against the virus. Published results from a Phase 2 trial of the vaccine indicate that it is safe and well tolerated. Safety data from a Phase 3 trial of COVAXIN in 25,800 participants in India will become available later this year. Meanwhile, unpublished interim results from the Phase 3 trial indicate that the vaccine has 78% efficacy against symptomatic disease, 100% efficacy against severe COVID-19, including hospitalization, and 70% efficacy against asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19. Results from two studies of blood serum from people who had received COVAXIN suggest that the vaccine generates antibodies that effectively neutralize the B.1.1.7 (Alpha) and B.1.617 (Delta) variants of SARS-CoV-2, first identified in the United Kingdom and India, respectively. 

The NIAID Adjuvant Program has supported the research of the founder and chief executive officer of ViroVax―Sunil David, M.D., Ph.D.―since 2009. His work has focused on searching for novel molecules that activate innate immune receptors and developing them as vaccine adjuvants. 

The collaboration between Dr. David and the company that makes COVAXIN, Bharat Biotech International Ltd. of Hyderabad, was initiated during a 2019 meeting in India coordinated by the NIAID Office of Global Research under the auspices of NIAID’s Indo-U.S. Vaccine Action Program. A delegation of five NIAID-funded adjuvant investigators including Dr. David; two members of the NIAID Division of Allergy, Immunology, and Transplantation; and the NIAID India representative visited four leading biotechnology companies to learn about their work and discuss potential collaborations. The delegation also attended a consultation in New Delhi co-organized by NIAID and India’s Department of Biotechnology and hosted by India’s National Institute of Immunology.

Among the scientific collaborations sparked by these activities, Bharat Biotech signed a licensing agreement with Dr. David to use Alhydroxiquim-II in their candidate vaccines. This license was expanded during the COVID-19 pandemic to include COVAXIN, which has received Emergency Use Authorization in India and more than a dozen other countries. Bharat Biotech developed COVAXIN in collaboration with the Indian Council of Medical Research ‒ National Institute of Virology. The company conducted extensive safety studies of Alhydroxiquim-II and undertook the complex process of scaling up production of the adjuvant under Good Manufacturing Practice standards. Bharat Biotech expects to produce an estimated 700 million doses of COVAXIN by the end of 2021.