Virus World

NIH researchers explore hidden, vulnerable region of influenza neuraminidase.

Researchers at the National Institutes of Health have identified antibodies targeting a hard-to-spot region of the influenza virus, shedding light on the relatively unexplored “dark side” of the neuraminidase (NA) protein head. The antibodies target a region of the NA protein that is common among many influenza viruses, including H3N2 subtype viruses, and could be a new target for countermeasures. The research, led by scientists at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center, part of NIH, was published today in Immunity. Influenza, or flu, sickens millions of people across the globe each year and can lead to severe illness and death. While vaccination against influenza reduces the burden of the disease, updated vaccines are needed each season to provide protection against the many strains and subtypes of the rapidly evolving virus. Vaccines that provide protection against a broad range of influenza viruses could prevent outbreaks of new and reemerging flu viruses without the need for yearly vaccine reformulation or vaccinations. One way to improve influenza vaccines and other countermeasures is to identify new targets on the virus’s surface proteins in “conserved” regions—portions that tend to be relatively unchanged between different strains of the virus. Influenza NA is a surface protein containing a globular head portion and a narrow stalk portion. The underside of the NA head contains a highly conserved region with targets for antibodies—known as epitopes—that make it vulnerable to antibody binding and inhibition of the virus, as well as not being impacted by mutations common in drug-resistant strains. This region is termed the “dark side” due to its partially hidden location and relatively unexplored characteristics.

The researchers isolated human antibodies that target the NA dark side from the blood of two people who had recovered from influenza type A subtype H3N2, a major subtype of seasonal flu viruses. In lab tests, the antibodies inhibited propagation of viruses from subtype H2N2, the subtype that caused pandemic influenza in 1957-58, and H3N2 viruses from humans, swine, and birds. The antibodies also protected mice from lethal infection by a subtype H3N2 virus when given to the animals either one day before or two days after infection, showing that the antibody may treat and prevent influenza in this model. The scientists analyzed the structure of two of the antibodies while bound to NA using advanced microscopy techniques known as cryogenic electron microscopy. Each antibody targeted different, nonoverlapping regions of the dark side, demonstrating that this region has multiple areas that may be useful to explore for countermeasure development. These findings show that the NA dark side has unique, previously untapped epitopes that could be applied to the development of new vaccine and therapeutic strategies. They suggest that antibodies targeting the NA dark side could be useful in combination with antivirals or other types of antibodies for interventions against influenza, as they are effective against influenza viruses with drug-resistant mutations. The researchers also note that NA dark side targets could be included in the next generation of broadly protective vaccines against influenza.

Study published in Immunity (March 24, 2024):

https://doi.org/10.1016/j.immuni.2024.02.003 

The Antiviral Program for Pandemics (APP) team, along with experts from across the National Institutes of Health (NIH) and Biomedical Advanced Research and Development Authority (BARDA), has drafted Target Product Profiles (TPPs) for potential direct-acting antiviral therapeutics candidates targeting several key viruses of pandemic potential.  These TPPs should be considered ‘living documents’ that are never final but may be useful starting points for consideration by therapeutics developers who are drafting TPPs for their specific candidates.  Also, the example TPPs are not intended to provide details about product requirements for funding or other support from USG or other funders.  Instead, these sample TPPs are being provided as tools for scientists working toward therapeutics product development of direct-acting antivirals for use in potential future outbreaks or pandemics. We are happy to receive feedback on these sample TPPs and may make updates/revisions or add TPPs for additional clinical indications in the future, so please monitor this page for updates and send any feedback to APPSubmissions@mail.nih.gov

Advocates ask the US biomedical agency to rethink the design of its RECOVER initiative, citing possible harm and funding waste. Patients and patient advocates are calling on the US National Institutes of Health (NIH) to reconsider its decision to include exercise trials in its RECOVER initiative, which aims to study and find treatments for long COVID. They argue that a large proportion of people with long COVID have reported experiencing post-exertional malaise (PEM) — a worsening of symptoms such as fatigue, difficulty regulating body temperature and cognitive dysfunction, after even light exercise — and worry that putting certain RECOVER participants through exercise trials could cause them harm. In a petition and multiple letters, the advocates request that the NIH and affiliated physicians explain their rationale for this testing and share the trial protocols. Up to 23 million people in the United States have developed long COVID, according to a report from the US Government Accountability Office. The condition has affected their lives and livelihood: an analysis of people with long COVID who filed workers’ compensation claims in New York State between 1 January 2020 and 31 March 2022 found that 18% of them had still not returned to work more than a year after being infected with the coronavirus SARS-CoV-2. Advocates want to see the RECOVER exercise protocols because they are concerned that trial participants will not be adequately informed about the potential risks; that participants will not be properly screened for PEM; and that researchers will not sufficiently monitor people for harm in the hours after the exercise regimen or after the trial concludes. “In a world where there’s hundreds of things to trial, why are we choosing this one thing that we know has the potential to cause harm to a substantial portion of patients?” asks Lisa McCorkell, a co-founder of the Patient-Led Research Collaborative for long COVID, a research and advocacy group based in Washington DC.

The RECOVER Clinical Trials Data Coordinating Center at the Duke Clinical Research Institute in Durham, North Carolina, sent Nature a statement on behalf of the NIH saying that the trials being planned for RECOVER — which stands for Researching COVID to Enhance Recovery — have not yet launched and that the agency is working with patient representatives in shaping the exercise trial protocol. The statement also says that the study’s investigators are meeting with those representatives to discuss the concerns expressed in the letters and petition. The NIH did not make the representatives available to Nature for an interview by the time this story was published and said that the full protocols for the trial would be released publicly only after they have been reviewed by an institutional review board.

Hitting a wall

Long COVID isn’t the first disease for which people have reported experiencing PEM. People who have myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), have long reported exacerbation of symptoms after overexertion that make their day-to-day functioning difficult. Similar to long COVID, ME/CFS often develops after a viral illness; its symptoms include PEM, cognitive impairment and joint and muscle pain. Jaime Seltzer, who has ME/CFS, first experienced PEM after some gentle exercise. “It felt fine until I hit my wall, after which I experienced a drop in core body temperature, started shaking, had trouble thinking,” says Seltzer, who is scientific and medical outreach director for the international advocacy organization #MEAction USA, based in Santa Monica, California, which sent the letters to the NIH. “It was like I had suddenly been dropped in the Arctic.” She then slept for 18 hours, after which she was unable to get out of bed. Although it seems counter-intuitive that exercise — normally considered an ingredient of good health — can cause harm, researchers have confirmed some of the physical effects of PEM through controlled studies. Scientists have measured people’s heart rate and oxygen intake during 2 maximal-exertion exercise tests spaced 24 hours apart. They found that those with PEM perform noticeably worse on the second day1. Meanwhile, for those without PEM — a group that included athletes, sedentary people and people with conditions such as heart failure and cystic fibrosis — results were similar, if not identical, on both days. Studies have also shown unusual patterns in gene expression2, metabolism3 and cognitive functioning4 after exertion for those with PEM.

Exercise overload

As researchers find out more about long COVID, it has become clear that many people with the condition meet the criteria for ME/CFS. In a study published online late last year5, researchers reported that of the 465 people with long COVID surveyed, 58% could be categorized as having ME/CFS. And in a 2021 study, researchers at the Patient-Led Research Collaborative, including McCorkell, surveyed 3,762 people with long COVID and found that, over a 7-month period, one of the most frequent symptoms reported was PEM6. Around 89% of participants reported experiencing PEM at some point during the course of their illness, with 72% of them still reporting it at month 7. All of this has advocates concerned about the inclusion of exercise trials in the RECOVER initiative. According to the NIH, RECOVER is the most expansive long-COVID study yet, with the trials expected to last four years, and to enrol more than 15,000 adults and 6,000 children. The statement from the NIH to Nature said that the exercise trial would use “inclusion and exclusion criteria to make sure that people who could be harmed by exercise will not be included in that platform trial”. But patient advocates still worry that the trials are a waste of time and money. “Every dollar is precious” when seeking treatments, says JD Davids, co-founder of the advocacy organization Long COVID Justice, which is based in New York City, and author of the petition, which began circulating in December and now has more than 1,600 signatures. “It is evident the NIH RECOVER initiative is made up of many folks who are dedicated and determined to crack open effective treatments for long COVID,” says Charles McCone, an advocate based in San Francisco who Nature identified as a patient representative for the RECOVER trial. But it is “baffling and discouraging” that the initiative is including exercise — a treatment that has been largely ineffective and often harmful for those with ME/CFS, he says. “Dozens of drugs [for long COVID] have been identified as promising candidates that need immediate further study,” but funding is limited, he adds. McCone could not discuss the exercise trial protocol with Nature because he signed a non-disclosure agreement with the NIH. The US Congress allocated US$1.15 billion to support RECOVER for four years, $172 million of which is being used to conduct clinical trials at the Duke Clinical Research Institute; the NIH declined to tell Nature how much of that money would be used to fund the exercise trials.

NIH-supported studies show variations in symptoms and diagnostic experiences among different racial and ethnic groups. Black and Hispanic Americans appear to experience more symptoms and health problems related to long COVID(link is external), a lay term that captures an array of symptoms and health problems, than white people, but are not as likely to be diagnosed with the condition, according to new research funded by the National Institutes of Health. The findings – from two different studies by NIH’s Researching COVID to Enhance Recovery(link is external) (RECOVER) Initiative – add to a growing body of research aimed to better understand the complex symptoms and other issues associated with long COVID that millions have experienced. “This new evidence suggests that there may be important differences in how long COVID manifests in different racial and ethnic groups,” said Mitchell S.V. Elkind, M.D., a professor of neurology and epidemiology at Columbia University, New York City, and chief clinical science officer for the American Heart Association. “However, further research is needed to better understand the mechanisms for these differences in symptoms and access to care, and also if diagnostic codes assigned by clinicians may play a role.” 

In one analysis, published in the Journal of General Internal Medicine(link is external), researchers looked at the health records of 62,339 adults who received a positive COVID-19 test at one of five academic health centers in New York City, all between March 2020 and October 2021. They tracked the patients’ health for one to six months after the positive test and compared the findings to 247,881 adults who never had COVID. Among 13,106 adults who had severe COVID that required hospital care, the researchers found Black and Hispanic adults were disproportionately represented. Of those who had these severe cases, for example, 1 in 4 were Black adults, 1 in 4 were Hispanic adults, and 1 in 7 were white adults. In the months following infection, Black adults with severe disease were more likely than white adults to be diagnosed with diabetes and experience headaches, chest pain and joint pain, but less likely to have sleep disorders, cognitive problems, or fatigue. Similarly, Hispanic adults who required hospital care were more likely than white adults to have headaches, shortness of breath, joint paint, and chest pain, but less likely to have sleep disorders, cognitive problems, or fatigue. Similar patterns emerged among people with mild to moderate disease. Among patients who were not hospitalized, Black adults were more likely to have blood clots in their lungs, chest pain, joint pain, anemia, or be malnourished. Hispanic adults were more likely than white adults to have dementia, headaches, anemia, chest pain, and diabetes. Conversely, white adults were most likely to have conditions such as cognitive impairment (sometimes referred to as “brain fog”) and fatigue.

The researchers also found that in comparison to people who did not have COVID, those who did were more likely to experience conditions affecting their nervous system, respiratory function, and circulation, and more likely to feel fatigued or have joint pain. “It’s not clear what's behind these symptom variations,” said Dhruv Khullar, M.D., a study author and physician and assistant professor of health policy and economics at Weill Cornell Medicine, New York City. “We hope this work draws attention to possible differences across racial and ethnic groups, stimulates research into the potential mechanisms, and sparks discussion among patients, clinicians, and policymakers.” In the second study, which published in BMC Medicine(link is external), researchers analyzed data from the electronic health records of 33,782 adults and children who received a diagnosis for long COVID between October 2021 and May 2022 at one of 34 U.S. medical centers. All had been given a diagnosis – Post COVID-19 condition, unspecified – the code for the condition first introduced in U.S. health care systems in October 2021. In studying the profile of these patients and their symptoms, the researchers found multiple patterns. Among the more striking: most of the patients were white, female, non-Hispanic, and likely to live in areas with low poverty and greater access to health care. Given what researchers already knew about the disproportionate impact of COVID on people of color and economically disadvantaged populations, the findings stood out. Emily Pfaff, Ph.D., a study author and assistant professor in the Division of Endocrinology and Metabolism at the University of North Carolina, Chapel Hill, said the pattern suggested that not all patients who have long COVID are being diagnosed. The reasons vary. In addition to long-documented health disparities based on race and other factors, she said, women are more likely than men to seek health care in general, and patients with the time and resources to access health care tend to be disproportionally represented in clinical data.

“You can see all the different ways these diagnostic codes can provide insight, but they can also skew the whole story,” Pfaff said. Still, she added, the insights help. She and her team found, for example, that most of the patients with long COVID had just mild to moderate, not severe, symptoms of acute infection. They also discovered that long-term symptoms could be grouped into common clusters – cardiopulmonary, neurological, gastrointestinal, and coexisting conditions – as well as by age. Children and teens were more likely to experience gastrointestinal and upper respiratory problems, including stomach aches and coughing. Adults ages 21-45 commonly experienced neurological problems, such as brain fog and fatigue. Adults ages 66 and older were more likely to have coexisting conditions, such as heart problems and diabetes, which the authors suspect is more likely present because of age than long COVID.  The authors of both papers said additional studies are needed to confirm and further categorize these trends. “This research contributes to our understanding of symptom clusters in long COVID that may be differentiated by race, ethnicity, and influenced by social determinants of health,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute. “It also provides vital insights into the utility, as well as the constraints, of the diagnostic code now in use for long COVID.” Both studies were funded by RECOVER (HL161847-01). The National Center for Advancing Translational Sciences provided additional support for the review published in BMC Medicine through the National COVID Cohort Collaborative (N3C) Data Enclave (U24TR002306).

Cited Studies:

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-023-02737-6 

https://link.springer.com/article/10.1007/s11606-022-07997-1 

A COVID-19 autopsy study from NIAID and many other collaborators helped researchers rethink where SARS-CoV-2 spread in the body and how long its remnants persisted. Autopsies of 44 people who died from COVID-19 in the first year of the pandemic showed researchers that disease-causing SARS-CoV-2 virus spread throughout the body – beyond just a respiratory disease – and remained in tissue for months. The study, from the National Institutes of Health and published in Nature, helped scientists broaden their perspectives on where SARS-CoV-2 could cause infection and persist, including the brain. The work also supported the rationale for a clinical trial evaluating the antiviral drug Paxlovid for the treatment of post-acute sequelae of COVID-19, also known as Long COVID.  Findings from the autopsies, which took place between April 2020 and March 2021, confirmed that SARS-CoV-2 primarily infected and damaged the airway and lungs. But scientists also found virus fragments (viral RNA) in 79 of 85 body locations, with some virus found up to 230 days after patient’s symptoms began. Scientists found virus in cardiovascular, lymphoid, gastrointestinal, renal, endocrine, reproductive, muscle, brain and other tissue – although none of these areas sustained significant inflammation compared to what they found in the respiratory tract. Scientists from NIH’s National Institute of Allergy and Infectious Diseases and Clinical Center led the work, closely collaborating with National Cancer Institute (NCI) pathologists, four other NIH institutes, the University of Maryland, and Maryland health care facilities in Salisbury and Towson. “We show SARS-CoV-2 disseminates across the human body and brain early in infection at high levels and provide evidence of virus replication at multiple extrapulmonary sites during the first two weeks following symptom onset,” their study states. Virus can spread throughout the body and viral RNA may remain detectable for months even in cases with mild or no symptoms, they say.

Senior study author Dr. Daniel Chertow said prior to the work, “the thinking in the field was that SARS-CoV-2 was predominantly a respiratory virus.” Finding the viral fragments in tissue throughout the body – and sharing those findings with colleagues a year ago – helped scientists explore a relationship between the viral fragments and Long COVID. Long COVID gets its name from the persistent symptoms some people experience after having COVID-19; symptoms can be debilitating, and the cause is not known. Though the study in Nature did not specifically explore Long COVID, finding the viral RNA throughout the body raised speculation that those fragments might contribute to the persistent symptoms, according to Dr. Chertow. Treating people with an effective COVID-19 antiviral such as Paxlovid could, therefore, eliminate the persistent symptoms. The Paxlovid trial, now underway at Duke University, is part of the NIH-funded RECOVER project – Researching COVID to Enhance Recovery – and includes an extension of the autopsy work, according Dr. Stephen Hewitt of NCI, who collaborated on the paper in Nature, and serves on a steering committee for the RECOVER project. He said one branch of RECOVER includes tissue pathology studies, and obtaining material from autopsies is in progress; these autopsies include people who both were vaccinated and infected with variants of concern – data not available in the earlier study that Dr. Chertow’s group led. “We’re hoping to replicate the data on viral persistence and study the relationship with Long COVID,” Dr. Hewitt said, adding that the project is scheduled to last four years. “Less than a year in we have about 85 cases, and we are working to expand these efforts.”

Published (Dec. 14, 2022) in Nature:

https://doi.org/10.1038/s41586-022-05542-y 

The National Institutes of Health has chosen Pfizer's antiviral drug Paxlovid as the first treatment it will study in patients who experience prolonged symptoms of COVID-19, known as "long COVID," under its RECOVER Initiative tasked with looking into the causes of the largely unexplained medical condition. The trial, which will start next year, will investigate whether portions of the COVID-19 virus remain in the body after infection, causing the long-lasting symptoms associated with long COVID that are wide-ranging, including cognitive impairment or lethargy.  The Duke Clinical Research Institute will oversee the trial, which will involve 1,700 patients 18 and up. Experts theorize that antivirals such as Paxlovid might be used to help treat long COVID symptoms and clear the coronavirus from a patient's system, according to a study description. Paxlovid, which has been used to treat mild and moderate COVID-19 already, has been named by physicians as a possible drug for treatment, though this will be the first time a study tests it on long COVID patients, per Reuters. The underlying causes of long COVID have mostly remained a mystery to experts. The NIH maintains a webpage compiling possible symptoms of long COVID, such as swelling in the legs or feet and loss of appetite. The Centers for Disease Control and Prevention estimated in June that nearly 1 in 5 adults in the United States who have had a COVID-19 infection continue to experience lingering symptoms after first contracting the virus. The trial is estimated to start on Jan. 17, 2023.

J&J's HIV vaccine, using the same technology as its COVID vaccine, failed to meet its goal of reducing the chance of HIV infection by 50%. An HIV vaccine using the same basic technology as Johnson & Johnson’s Covid shot failed to prevent infection, the company said Tuesday, dealing yet another blow to efforts to create a vaccine against the virus.  The study, called Imbokodo, enrolled 2,600 women in southern Africa who were at very high risk of HIV infection. J&J and its partners, including the National Institutes of Health and the Bill & Melinda Gates Foundation, launched the study in 2017 and announced that all participants had received either a vaccine or a placebo last year. The goal of the vaccine was not to completely prevent infection, but to reduce the chance of infection by half. “If a vaccine is 50% efficacious it can curb the future of the HIV pandemic,” said Paul Stoffels, J&J’s chief scientific officer and, before that, an HIV researcher. He said that the actual efficacy seen was 25.2%, meaning those that received the vaccine had their odds of becoming infected reduced that much compared to the placebo group 24 months after the first dose. That difference was not statistically significant, indicating that it is possible the result is due to chance. A second study, called Mosaico, that is testing a somewhat different vaccine regimen in men who have sex with men and transgender people in the Americas and Europe, will continue. 

“The development of a safe and effective vaccine to prevent HIV infection has proven to be a formidable scientific challenge,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said in a statement. “Although this is certainly not the study outcome for which we had hoped, we must apply the knowledge learned from the Imbokodo trial and continue our efforts to find a vaccine that will be protective against HIV.” Scientists have been trying for decades to develop an HIV vaccine. After a Merck vaccine failed to prove effective in 2007, researchers looked back at the data and found it raised the risk of people developing the disease. Hopes were buoyed by a 2009 study in Thailand, which showed limited but significant efficacy, reducing the rate of infection by about 30%. But last year, an effort combining vaccines from Sanofi and GlaxoSmithKline also failed to prove effective.  J&J had repeatedly expressed optimism about its vaccine. In 2015, Johan Van Hoof, who leads J&J’s vaccine R&D, pointed to data showing that, in animals, the vaccine could reduce infection by 90%, “suggesting it might be a real breakthrough with regard to a future HIV vaccine.” On calls with financial analysts in 2020 and 2021, Stoffels listed the HIV project among the company’s vaccine efforts, calling it “very encouraging.” When the trial began five years ago, Fauci had said “the development and delivery of a preventive HIV vaccine that is safe and at least moderately effective would help bring about a durable end to the HIV/AIDS pandemic.” Imbokodo means “rock” in isiZulu, and refers to a proverb about women’s strength and the need for community. In the study, 63 of 1,109 volunteers in the placebo group developed HIV, while 51 of the 1,079 volunteers who received the vaccine developed HIV. That difference leaves a great deal of uncertainty as to whether there was an effect. The 95% confidence interval, used by researchers to define a range of likely outcomes, ranged from -10.5% to 49.3%. However, J&J said in its release that no vaccine-related safety issues were identified. Stoffels told STAT that it was clear the vaccine did not increase the risk of HIV.  Larry Corey, the principal investigator of the HIV Trials Network, which helped run the study, and a professor at the Fred Hutchinson Cancer Research Center in Seattle, said that he saw the result as a disappointment but also a sign of progress. It had been hoped that non-neutralizing antibodies – those that bound to the virus but did not entirely stop infectivity – would be enough to slow the rate of HIV infection, he said, but it is beginning to appear that vaccine developers will need to figure out how to generate antibodies that neutralize the virus.

“It is telling us that non-neutralizing antibodies are not decreasing acquisition and maybe demonstrates how difficult and different HIV is than Covid-19,” Corey said. Like the Covid-19 vaccine that Johnson & Johnson developed, this HIV vaccine delivers genetic code for proteins to a recipient’s cells using a type of virus called an adenovirus, which then makes proteins that the immune system learns to recognize and attack. The strain of adenovirus used, called Ad26, is also used in Johnson & Johnson’s experimental vaccine against respiratory syncytial virus, which can be very serious in infants.  The HIV vaccine regimen tested repeated dosing. It was given four times, and included genetic code for a “mosaic” of proteins from different strains of the HIV virus. Patients also received soluble protein injections at the third and fourth visit. The ongoing Mosaico study – the one in the Americas and Europe – uses a different mixture of soluble proteins at the vaccination visits three and four. Stoffels said that this is one reason that the vaccine might perform better in that study. Another is that the volunteers in the Mosaico study are at lower risk of infection, which may make the vaccine’s work less difficult. Corey also said there was hope Mosaico would succeed where Imbokodo failed. He said that the new formulation had led, in earlier studies, to higher levels of antibodies against HIV. Stoffels said that he doesn’t believe that the result should color people’s feelings about J&J’s adenovirus vaccine platform, which, he pointed out, has proven effective against Covid-19 and Ebola. (In Covid-19, the broad use of the vaccine also was linked to a rare but severe side effect that involves both the formation of clots and excessive bleeding. That side effect is so rare even large clinical trials might not detect it.) “It shows again that the HIV virus is a very special virus, very unique, escaping the immune system and finding its way to infect people and it’s very difficult to mount immunity against acquisition of HIV,” Stoffels said. But researchers will continue to try. Moderna recently began human trials of an HIV vaccine that relies on the mRNA technology behind its Covid vaccines. Corey pointed out that even under Covid lockdowns, women in the study still had a 4% chance of contracting HIV. That underscores the need for a vaccine, he said. “Vaccines really do make a difference when you have an effective vaccine, look at what happened with Covid,” Corey said. “I think we can’t give up.”

The NIH on Wednesday announced the start of a phase 1 clinical trial evaluating Moderna’s variant-specific COVID-19 vaccine, saying the shot has been administered to trial participants. Moderna shipped doses of the vaccine — a modified version of its mRNA-1273 vaccine, which has been authorized for use in the U.S. since December — to the NIH last month for testing. The vaccine was tweaked to target the B.1.351 variant, which was first identified in South Africa.  According to the NIH, the new trial will enroll 210 healthy adults at four clinical research sites in Atlanta, Cincinnati, Nashville and Seattle. Investigators at the four sites anticipate that the trial will be fully enrolled by the end of April, the NIH said. The modified vaccine will be studied in both vaccinated and unvaccinated adults. The vaccinated adults already received mRNA-1273 last year as part of a clinical trial. They will be randomly assigned to receive either a single booster vaccination of 50 µg of the modified vaccine, mRNA-1273.351, or a single vaccination containing one 25 µg dose of mRNA-1273 and one 25 µg dose of mRNA-1273.351. A separate clinical trial will assess a booster shot of the original vaccine in the remaining vaccinated study participants. According to National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD, the B.1.351 variant has been detected in at least nine U.S. states. The NIAID, which co-developed the vaccine with Moderna, is leading and funding the new trial. “Preliminary data show that the COVID-19 vaccines currently available in the United States should provide an adequate degree of protection against SARS-CoV-2 variants,” Fauci said in the NIH release. “However, out of an abundance of caution, NIAID has continued its partnership with Moderna to evaluate this variant vaccine candidate should there be a need for an updated vaccine.”

NIH Press Release (March 31, 2021):

https://www.nih.gov/news-events/news-releases/nih-clinical-trial-evaluating-moderna-covid-19-variant-vaccine-begins 

Convalescent plasma taken from Covid-19 survivors should not be considered a standard of care for coronavirus, an NIH panel says. A National Institutes of Health panel said there's no evidence backing the use of convalescent plasma to treat coronavirus patients and that doctors should not treat it as a standard of care until more study has been done. "There are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19," the panel of more than three dozen experts said in a statement posted on the NIH website Tuesday. The statement, which was posted quietly, contradicts the Trump Administration's characterization of the treatment as "historic" and a "major advance" and directly refers to last week's emergency use authorization by the US Food and Drug Administration. "Convalescent plasma should not be considered standard of care for the treatment of patients with COVID-19," the committee, which evaluates treatments for coronavirus, said in the statement. "Prospective, well-controlled, adequately powered randomized trials are needed to determine whether convalescent plasma is effective and safe for the treatment of COVID-19. Members of the public and health care providers are encouraged to participate in these prospective clinical trials." 

Last week, President Trump declared that the FDA's emergency use authorization was historic. "Today I am pleased to make a truly historic announcement in our battle against the China virus that will save countless lives," Trump said at a White House news conference. "Today's action will dramatically increase access to this treatment." Health and Human Services Secretary Alex Azar was equally effusive. "This is a major advance in the treatment of patients. A major advance," he said at last week's briefing. The timing raised suspicions the White House had pressured FDA -- something FDA Commissioner Dr. Stephen Hahn denied several times. Trump had also said politics held up the FDA's EUA. But Hahn had also made misleading comments about the data supporting the use of convalescent plasma -- which is the antibody-rich serum taken from the blood of people who have recovered from an infection. The hope is infusing this plasma into new patients will kickstart their immune response. It's a treatment that dates back more than 100 years and has never been used broadly.

The NIH panel, led by Dr. Clifford Lane, the head of research at the National Institute of Allergy and Infectious Diseases; Dr. Roy Gulick, chief of the Division of Infectious Diseases at Weill Medical College of Cornell University; and Dr. Henry Masur, chief of the Critical Care Medicine Department at NIH, said much more research is needed into whether the treatment works. Data published so far don't really show whether it helps patients, they said. "The long-term risks of treatment with COVID-19 convalescent plasma and whether its use attenuates the immune response to SARS-CoV-2, making patients more susceptible to reinfection, have not been evaluated," the statement added. Plus, different patients have differing levels of antibodies, so the treatment is highly variable, they said....

Patients admitted with COVID-19 at select hospitals may now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treatment for the disease. The Phase 3 randomized, controlled trial is known as ACTIV-3, and as a “master protocol,” it is designed to expand to test multiple different kinds of monoclonal antibody treatments. It also can enroll additional volunteers in the middle of the trial, if a specific investigational treatment shows promise. The new study is one of four ongoing or planned trials in the National Institutes of Health’s. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership to speed development of the most promising treatments and vaccine candidates. It also is receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19.

The trial will take place at select hospitals around the world that are part of existing clinical trial networks. They include the lead network, the International Network of Strategic Initiatives in Global HIV Trials (INSIGHT), operated by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health. Collaborating clinical trial networks include the Prevention and Early Treatment of Acute Lung Injury network (PETAL) and Cardiothoracic Surgical Trials Network (CTSN), supported by the NIH’s National Heart, Lung and Blood Institute through the Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) program, and the U.S. Department of Veterans Affairs Medical Centers. ACTIV-3 uses an adaptive two-stage Phase 3 protocol design. The ACTIV-3 trial can be modified to test additional experimental therapeutics and flexibly allow novel therapeutics to enter at either stage 1 or stage 2. In addition, if a treatment appears to be safe and effective in the initial stage after review by an independent data and safety monitoring board (DSMB), the investigational therapeutic proceeds to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped...

The initial stage of the ACTIV-3 clinical trial aims to enroll approximately 300 volunteers who have been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Once their COVID-19 infections have been confirmed and they have consented to take part in the study, participants will be randomly assigned to receive either an intravenous (IV) infusion of LY-CoV555 or a saline placebo infusion. Participants also will receive standard care for COVID-19, including the antiviral remdesivir. After five days, participants’ symptoms will be assessed, as will their need for supplemental oxygen, mechanical ventilation, or other supportive care. Volunteers will be followed for 90 days after enrollment and will receive regular examinations and have blood samples taken periodically during this time to analyze their response to the investivational therapeutic. Data collected on the fifth day of the volunteers’ participation will determine whether the investigational therapeutic will be administered to a larger group of volunteers. If LY-CoV555 appears to be safe and appears to be effective, the trial will enroll an additional 700 participants. It also will begin enrolling more severely ill participants, such as those with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs. The primary endpoint of the trial is the participants’ sustained recovery for 14 days after release from the hospital. The principal investigator of ACTIV-3 is Jens Lundgren, M.D., of the University of Copenhagen and Rigshospitalet. Leads of the participating networks include James Neaton, Ph.D., of the INSIGHT network, Taylor Thompson, M.D., of the PETAL network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the CTSN, and Rachel Ramoni, D.M.D., Sc.D., of the U.S. Department of Veterans Affairs. To ensure that the trial is being conducted in a safe and effective manner, an independent DSMB will oversee the trial and conduct periodic reviews of the accumulating data...

Remdesivir sped recovery of patients by several days, although it’s “not a home run. A candidate treatment for COVID-19 has shown convincing—albeit modest—benefit for the first time in a large, carefully controlled clinical trial in hospitalized patients. The infected people who received remdesivir, an experimental drug made by Gilead Sciences that cripples an enzyme several viruses use to copy their RNA, recovered in an average of 11 days versus 15 in patients who received a placebo. “Although a 31% improvement doesn’t seem like a knockout, 100% [success], it is a very important proof of concept,” said Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), during an Oval Office meeting in which President Donald Trump was asked by media about a statement Gilead had released on the results. The patients treated with remdesivir also had a lower mortality rate—8% versus 11.6% in the group given the placebo—but this positive trend did not reach statistical significance, Fauci noted. (The full results from the trial have not been made public in a preprint or peer-reviewed paper.)

NIAID sponsored the study, which began on 21 February and enrolled 1063 patients at 68 sites in the United States, Europe, and Asia. A board that monitors safety and data from the trial informed investigators on 27 April that remdesivir was better than the placebo. Fauci says the board is releasing the overall results early in part on ethical grounds: Given the positive data, remdesivir must now be offered to all study participants, and trials of other treatments now underway must start to offer the drug instead of a placebo, Fauci said. The search for COVID-19 treatments that can do better than remdesivir remains a top priority. “It’s a promising signal, but we do not need to get hyperexcited—this is not a home run,” says Carlos del Rio, an infectious disease clinician at Emory University, one of the larger sites that participated in the remdesivir trial. In essence, he says, the study showed that patients who received the drug, which is given intravenously, could stop receiving supplemental oxygen earlier. Del Rio, a veteran of HIV drug development, which gradually advanced from nothing to effective treatments, hopes the results mark a first step for COVID-19. But he does not expect remdesivir will significantly ease the demands that COVID-19 is putting on hospitals, or brighten prospects for lifting shelter-in-place orders...

The National Institutes of Health and the Bill and Melinda Gates Foundation will together invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV with an attribute even rarer in the world of genetic medicine than efficacy, the groups announced on Wednesday: The cures, they vowed, will be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

The effort reflects growing concerns that scientific advances in genetic medicine, both traditional gene therapies and genome-editing approaches such as CRISPR, are and will continue to be prohibitively expensive and therefore beyond the reach of the vast majority of patients. Spark Therapeutics’ Luxturna, a gene therapy for a rare form of blindness, costs $425,000 per eye, for instance, and genetically engineered T cells (CAR-Ts) to treat some blood cancers cost about the same.  With CRISPR-based treatments already being tested in clinical trials for sickle cell disease, the blood disorder beta thalassemia, and another form of blindness, and with additional CRISPR treatments in development, scientists, ethicists, and health policy experts have grown increasingly concerned that the divide between haves and have-nots will grow ever-wider.

Gene-based treatments “are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries,” the NIH said in a statement. To help right that, its collaboration with the Gates Foundation aims to develop “curative therapies that can be delivered safely, effectively and affordably in low-resource settings.” Scientists whose research focuses on gene-based cures welcomed the infusion of funding and the recognition that genetic cures are on track to be unaffordable to the majority of patients. But they noted one irony. The most effective sickle cell drug, hydroxyurea, has hardly even been studied in sub-Saharan Africa, let alone made widely available. Yet a 2019 study found that giving children the drug cut their death rate by two-thirds and halved the pain crises that are common in sickle cell disease, caused by misshapen red blood cells that cannot flow through blood vessels. The NIH-Gates collaboration “is tremendously exciting and has the potential to have a great impact on sickle cell disease in sub-Saharan Africa,” said Dr. Vijay Sankaran of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who has done pioneering research on genetic cures for the disease. “But my hesitation is that even the inexpensive therapies we have today, such as hydroxyurea, are largely unavailable there. The question is, how do we best approach this disease, with therapies that are working today or with genetic therapies that might work?”...

A novel experimental vaccine against respiratory syncytial virus (RSV), a leading cause of severe respiratory illness in the very young and the old, has shown early promise in a Phase 1 clinical trial. The candidate, DS-Cav1, was engineered and developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, who were guided by their atomic-level understanding of the shape of an RSV protein. An interim analysis of study data showed that one dose of the investigational vaccine prompted large increases in RSV-neutralizing antibodies that were sustained for several months. 

First described in 1956 as a cause of infant pneumonia, the health burden of RSV has long been underappreciated. In fact, the virus is an important contributor to serious illness worldwide and causes as many as 118,000 deaths annually among young children. In the United States each year, RSV infections account for approximately 57,000 hospitalizations and 2 million outpatient clinic visits among children younger than five years old, according to the Centers for Disease Control and Prevention. 

“A vaccine to prevent RSV is a long-sought goal that has eluded us for decades,” said NIAID Director Anthony S. Fauci, M.D. “The early results of this trial suggest that this structure-based strategy for developing an RSV vaccine may bring that goal within reach.”  After four weeks, levels of RSV-neutralizing antibodies in those who received 50 µg of vaccine (with or without alum) had increased sevenfold over the levels present prior to vaccination. A single dose of 150 µg without alum boosted neutralizing antibody levels 12-fold, while alum-adjuvanted vaccine at that dose prompted a 15-fold surge in neutralizing antibodies. The vaccine-induced antibody levels greatly exceed those seen following natural RSV infection in human challenge trials (where healthy volunteers are exposed to pathogens under carefully controlled conditions in order to observe the course of infection), when neutralizing antibody levels merely triple over those present before infection.

Original findings were published in Science on 02 August 2019:

https://doi.org/10.1126/science.aav9033 

The clinical trials are designed to evaluate multiple treatments simultaneously to identify more swiftly those that are effective....

NIH-funded research effort identifies most common symptoms, potential subgroups, and initial symptom-based scoring system – with aim of improving future diagnostics and treatment. Initial findings from a study of nearly 10,000 Americans, many of whom had COVID-19, have uncovered new details about long COVID, the post-infection set of conditions that can affect nearly every tissue and organ in the body. Clinical symptoms can vary and include fatigue, brain fog, and dizziness, and last for months or years after a person has COVID-19. The research team, funded by the National Institutes of Health, also found that long COVID was more common and severe in study participants infected before the 2021 Omicron variant. The study, published in JAMA(link is external), is coordinated through the NIH’s Researching COVID to Enhance Recovery (RECOVER)(link is external) initiative, a nationwide effort dedicated to understanding why some people develop long-term symptoms following COVID-19, and most importantly, how to detect, treat, and prevent long COVID. The researchers hope this study is the next step toward potential treatments for long COVID, which affects the health and wellbeing of millions of Americans.

“Americans living with long COVID want to understand what is happening with their bodies,” said ADM Rachel L. Levine, M.D., Assistant Secretary for Health. “RECOVER, as part of a broader government response, in collaboration with academia, industry, public health institutions, advocacy organizations and patients, is making great strides toward improving our understanding of long COVID and its associated conditions.”

Researchers examined data from 9,764 adults, including 8,646 who had COVID-19 and 1,118 who did not have COVID-19. They assessed more than 30 symptoms across multiple body areas and organs and applied statistical analyses that identified 12 symptoms that most set apart those with and without long COVID: post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic cough, chest pain, and abnormal movements. They then established a scoring system based on patient-reported symptoms. By assigning points to each of the 12 symptoms, the team gave each patient a score based on symptom combinations. With these scores in hand, researchers identified a meaningful threshold for identifying participants with long COVID. They also found that certain symptoms occurred together and defined four subgroups or “clusters” with a range of impacts on health. Based on a subset of 2,231 patients in this analysis who had a first COVID-19 infection on or after Dec. 1, 2021, when the Omicron variant was circulating, about 10% experienced long-term symptoms or long COVID after six months. The results are based on a survey of a highly diverse set of patients and are not final. Survey results will next be compared for accuracy against an array of lab tests and imaging.....

Not long after Moderna kicked off its COVID-19 vaccine launch, questions started swirling around the origins of the company's mRNA technology and the intellectual property rights to its vaccines. In Moderna's earnings release Thursday, the company said it recently paid the National Institute of Allergy and Infectious Diseases (NIAID) a $400 million "catch-up payment" under a new royalty-bearing license agreement between the parties. The payment is part of a license agreement between Moderna and NIAID inked late last year. With the deal, Moderna is paying the U.S. government to access “certain patent rights concerning stabilizing prefusion coronavirus spike proteins,” Moderna Chief Financial Officer Jamie Mock said on a conference call Thursday.  Going forward, Moderna agreed to pay NIAID “low single-digit royalties” on COVID-19 vaccine sales, Mock added. This agreement does not put Moderna out of the woods on the patent litigation front. Even after this deal, the vaccine maker is fighting with the U.S. National Institutes of Health over the origins of the core technology in the vaccine, The New York Times points out. 

Within the industry, the company is facing patent suits from mRNA rivals Pfizer and BioNTech, plus a separate case from Arbutus and Roivant’s Genevant Sciences. One case between Pfizer and Moderna is heading to trial in London next April, Reuters reported last week. Moderna pulled down around $36 billion in COVID-19 vaccine sales across 2021 and 2022, its two big launch years. While the $400 million payment represents only around 1% of the company's total COVID-19 vaccine sales over that span, the lump-sum nature of the "catch-up payment" drove up Moderna's fourth quarter's costs. The payment was a "key driver" in pushing the company's cost of sales—as a proportion of total sales—to 39% in the fourth quarter, Mock said. That compared with 14% during the same period in 2021. Aside from the license payment, Moderna also suffered financially from demand declines last year. For all of 2022, the company recorded around $2.8 billion in charges related to slouching demand. That figure included a $1.3 billion charge for inventory write-downs plus $725 million for contract cancellations.  The company also paid $776 million related to unused manufacturing capacity and CDMO charges. 

The National Institutes of Health, in collaboration with the Administration for Strategic Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services, has launched the Home Test to Treat program, an entirely virtual community health intervention that will provide free COVID-19 health services—at-home rapid tests, telehealth sessions and at-home treatments—in selected communities. The program, first announced by the White House(link is external) in September 2022, will make antiviral treatment available for eligible individuals who receive a positive test result, which could prevent severe illness, hospitalization or death. “At-home testing for COVID-19 is now widely available in the United States, as are antiviral treatments, and this program combines easy home access to both,” said Bruce Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) at the National Institutes of Health and leader of the Rapid Acceleration of Diagnostics (RADx®) Tech program. “The Home Test to Treat program allows those who are sick an alternative to venturing out for testing or treatment, potentially reducing the spread of COVID-19 in the community.” Later this month, local and state officials in Berks County, Pennsylvania, will be the first to pilot the Home Test to Treat program. Up to 8,000 eligible residents are anticipated to participate in the program. Program organizers will gather information from participants to identify best practices and make improvements to the Home Test to Treat model that can be used to implement the program on a larger scale. Additional communities across the country will be selected to participate based on level of community need, access to healthcare treatment, expected COVID-19 infection rates and socio-economic factors.

Through collaborations with local health departments, Home Test to Treat aims to offer services to approximately 100,000 people across the United States in the coming year. Telehealth services provider eMed will implement the Home Test to Treat program. Their services are provided under a contract award by NIBIB contractor, VentureWell. Having administered millions of verified at-home telehealth sessions during the pandemic, eMed will host the user-friendly Home Test to Treat website, where participants can sign up for the program, report symptoms, receive telehealth and antiviral treatment delivery, and coordinate telehealth enabled test kits. NIBIB also has issued a contract with UMass Chan Medical School, whose researchers, in collaboration with eMed, will analyze data collected from each participating community, including the impacts of a home-based process for testing and treatment, individual attitudes about the Home Test to Treat program, and clinical outcomes from treatments. HHS, through ASPR, has led a national COVID-19 Test to Treat initiative since March 2022, that includes thousands of treatment access points nationwide. These include CDC’s Increasing Community Access to Testing (ICATT) program, composed of federally funded health centers, long-term care facilities and community-based sites. Participants in the Home Test to Treat program can be tested at local ICATT centers. The Test to Treat initiative has evolved to include more mobile and telehealth-based models that reduce barriers to access for the highest-risk individuals. NIH’s Home Test to treat program will provide an important additional pathway to rapidly access lifesaving treatments for COVID-19 in vulnerable communities.

Home Test to Treat will promote equitable solutions and help to identify best practices that may save lives in this and future pandemics. In each community, the research team will identify and implement improvements that leave us in a much better position to respond to specific needs at the local, state and federal levels. The National Institute of Biomedical Imaging and Bioengineering (NIBIB) has supported development of Home Test to Treat through the RADx Tech program. About the Rapid Acceleration of Diagnostics (RADx®) initiative: The RADx initiative was launched on April 29, 2020, to speed innovation in the development, commercialization, and implementation of technologies for COVID-19 testing. The initiative has four programs: RADx Tech, RADx Advanced Technology Platforms, RADx Underserved Populations and RADx Radical. It leverages the existing NIH Point-of-Care Technology Research Network. The RADx initiative partners with federal agencies, including the Office of the Assistant Secretary of Health, Department of Defense, the Biomedical Advanced Research and Development Authority, and U.S. Food and Drug Administration. Learn more about the RADx initiative and its programs: https://www.nih.gov/radx. 

About the National Institute of Biomedical Imaging and Bioengineering (NIBIB): NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website: https://www.nibib.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

A new discovery in the fight against COVID could lead to a long-lasting vaccine that works on all variants of the ever-mutating virus. With new COVID variants and subvariants evolving faster and faster, each chipping away at the effectiveness of the leading vaccines, the hunt is on for a new kind of vaccine—one that works equally well on current and future forms of the novel coronavirus. Now researchers at the National Institutes of Health in Maryland think they’ve found a new approach to vaccine design that could lead them to a long-lasting jab. As a bonus, it also might work on other coronaviruses, not just the SARS-CoV-2 virus that causes COVID-19. The NIH team reported its findings in a peer-reviewed study that appeared in the journal Cell Host & Microbe earlier this month. The key to the NIH’s potential vaccine design is a part of the virus called the “spine helix.” It’s a coil-shaped structure inside the spike protein, the part of the virus that helps it grab onto and infect our cells. Lots of current vaccines target the spike protein. But none of them specifically target the spine helix. And yet, there are good reasons to focus on that part of the pathogen. Whereas many regions of the spike protein tend to change a lot as the virus mutates, the spine helix doesn’t. That gives scientists “hope that an antibody targeting this region will be more durable and broadly effective,” Joshua Tan, the lead scientist on the NIH team, told The Daily Beast. Vaccines that target and “bind,” say, the receptor-binding domain region of the spike protein might lose effectiveness if the virus evolves within that region. The great thing about the spine helix, from an immunological standpoint, is that it doesn’t mutate. At least, it hasn’t mutated yet, three years into the COVID pandemic. So a vaccine that binds the spine helix in SARS-CoV-2 should hold up for a long time. And it should also work on all the other coronaviruses that also include the spine helix—and there are dozens of them, including several such as SARS-CoV-1 and MERS that have already made the leap from animal populations and caused outbreaks in people.

To test their hypothesis, the NIH researchers extracted antibodies from 19 recovering COVID patients and tested them on samples of five different coronaviruses, including SARS-CoV-2, SARS-CoV-1 and MERS. Of the 55 different antibodies, most zeroed in on parts of the virus that tend to mutate a lot. Just 11 targeted the spine helix. But those 11 that went after the spine helix worked better, on average, on four of the coronaviruses. (A fifth virus, HCoV-NL63, shrugged off all the antibodies.) The NIH team isolated the best spine-helix antibody, COV89-22, and also tested it on hamsters infected with the latest subvariants of the Omicron variant of COVID. “Hamsters treated with COV89-22 showed a reduced pathology score,” the team found. The results are promising. “These findings identify a class of… antibodies that broadly neutralize [coronaviruses] by targeting the stem helix,” the researchers wrote. Don’t break out the champagne quite yet. “Although these data are useful for vaccine design, we have not performed vaccination experiments in this study and thus cannot draw any definitive conclusions with regard to the efficacy of stem helix-based vaccines,” the NIH team warned. It’s one thing to test a few antibodies on hamsters. It’s another to develop, run trials with and get approval for a whole new class of vaccine. “It is really hard and most things that start out as good ideas fail for one reason or another,” James Lawler, an infectious disease expert at the University of Nebraska Medical Center, told The Daily Beast. And while the spine-helix antibodies appear to be broadly effective, it’s unclear how they stack up against antibodies that are more specific. In other words, a spine-helix jab might work against a bunch of different but related viruses, but work less well against any one virus than a jab that’s tailored specifically for that virus. “Further experiments need to be done to evaluate if they will be sufficiently protective in humans,” Tan said of the spine-helix antibodies.

There’s a lot of work to do before a spine-helix vaccine might be available at the corner pharmacy. And there are a lot of things that could derail that work. Additional studies could contradict the NIH team’s results. The new vaccine design might not work as well on people as it does on hamsters. The new jab could also turn out to be unsafe, impractical to produce or too expensive for widespread distribution. Barton Haynes, a Duke University immunologist, told The Daily Beast he looked at spine-helix vaccine designs last year and concluded they’d be too costly to warrant major investment. The main problem, he said, is that the spine-helix antibodies are less potent and “tough to induce” from their parent B-cells. The harder the pharmaceutical industry has to work to produce a vaccine, and the more vaccine it has to pack into a single dose in order to compensate for lower potency, the less cost-effective a vaccine becomes for mass-production. Maybe a spine-helix jab is in our future. Or maybe not. Either way, it’s encouraging that scientists are making incremental progress toward a more universal coronavirus vaccine. One that could work for many years on a wide array of related viruses. COVID for one isn’t going anywhere. And with each mutation, it risks becoming unrecognizable to the current vaccines. What we need is a vaccine that’s mutation-proof.

Publication cited published in Cell Host and Microbe (Nov. 7, 2022):

https://doi.org/10.1016/j.chom.2022.10.010 

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has launched an early-stage clinical trial evaluating an investigational vaccine to prevent infection with Nipah virus. The experimental vaccine is manufactured by Moderna, Inc., Cambridge, Massachusetts, and was developed in collaboration with NIAID’s Vaccine Research Center. It is based on a messenger RNA (mRNA) platform—a technology used in several approved COVID-19 vaccines. NIAID is sponsoring the Phase 1 clinical study, which is being conducted at the NIH Clinical Center in Bethesda, Maryland. Nipah virus infection is a zoonotic disease, meaning that it is spread between animals and people. Fruit bats are the natural host for the virus. The first known Nipah outbreak occurred in 1998 in Malaysia and Singapore and resulted in 265 human cases and 105 deaths, and caused significant economic damage to the swine industry there. Since 1999, outbreaks have occurred annually in Asia, primarily in Bangladesh and India. The virus can cause mild-to-severe disease rapidly progressing from respiratory infection symptoms to encephalitis (brain swelling) leading to coma or death. An estimated 40% to 75% of people infected with Nipah virus die. Although most cases are transmitted via animals, person-to-person transmission can occur. Currently, there is no licensed vaccine or treatment for Nipah virus infection.

“Nipah virus poses a considerable pandemic threat because it mutates relatively easily, causes disease in a wide range of mammals, can transmit from person-to-person, and kills a large percentage of the people it infects,” said NIAID Director Anthony S. Fauci, M.D. “The need for a preventive Nipah virus vaccine is significant.” NIAID’s Pandemic Preparedness Plan, published earlier this year, established a framework to study viruses of pandemic potential and prioritize research on prototype pathogens, such as Nipah virus. This is the first clinical trial using the prototype pathogen approach since the plan’s publication. The experimental mRNA-1215 Nipah virus vaccine will be tested in a dose-escalation clinical trial to evaluate its safety, tolerability, and ability to generate an immune response in 40 healthy adults ages 18 to 60 years. Specifically, four groups of 10 participants each will receive two doses of the investigational vaccine via injection in the shoulder muscle four or 12 weeks apart. Group one (10 participants) will receive two 25-microgram (mcg) injections; group two will receive two 50-mcg injections; and group three will receive two 100-mcg injections, each four weeks apart. The vaccine dose for the fourth group of participants will be determined based on an interim analysis of the results from the three previous groups. The fourth group will receive two injections 12 weeks apart. Study participants will be evaluated through clinical observation and blood collection at specified times throughout the study and will be followed by clinical study staff through 52 weeks following their final vaccination. For more information about the clinical trial, visit ClinicalTrials.gov using the study identifier NCT05398796. NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing, and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

Compound targets essential viral enzyme and prevents replication in cells.  The experimental drug TEMPOL may be a promising oral antiviral treatment for COVID-19, suggests a study of cell cultures by researchers at the National Institutes of Health. TEMPOL can limit SARS-CoV-2 infection by impairing the activity of a viral enzyme called RNA replicase. The work was led by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study appears in Science. “We urgently need additional effective, accessible treatments for COVID-19,” said Diana W. Bianchi, M.D., NICHD Director. “An oral drug that prevents SARS-CoV-2 from replicating would be an important tool for reducing the severity of the disease.” The study team was led by Tracey A. Rouault, M.D., head of the NICHD Section on Human Iron Metabolism. It discovered TEMPOL’s effectiveness by evaluating a more basic question on how the virus uses its RNA replicase, an enzyme that allows SARS-CoV-2 to replicate its genome and make copies of itself once inside a cell. Researchers tested whether the RNA replicase (specifically the enzyme’s nsp12 subunit) requires iron-sulfur clusters for structural support. Their findings indicate that the SARS-CoV-2 RNA replicase requires two iron-sulfur clusters to function optimally. Earlier studies had mistakenly identified these iron-sulfur cluster binding sites for zinc-binding sites, likely because iron-sulfur clusters degrade easily under standard experimental conditions.

Identifying this characteristic of the RNA replicase also enables researchers to exploit a weakness in the virus. TEMPOL can degrade iron-sulfur clusters, and previous research from the Rouault Lab has shown the drug may be effective in other diseases that involve iron-sulfur clusters. In cell culture experiments with live SARS-CoV-2 virus, the study team found that the drug can inhibit viral replication. Based on previous animal studies of TEMPOL in other diseases, the study authors noted that the TEMPOL doses used in their antiviral experiments could likely be achieved in tissues that are primary targets for the virus, such as the salivary glands and the lungs. “Given TEMPOL’s safety profile and the dosage considered therapeutic in our study, we are hopeful,” said Dr. Rouault. “However, clinical studies are needed to determine if the drug is effective in patients, particularly early in the disease course when the virus begins to replicate.” The study team plans on conducting additional animal studies and will seek opportunities to evaluate TEMPOL in a clinical study of COVID-19. NIH authors on the study include researchers from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. Authors from the Pennsylvania State University are funded by NIH’s National Institute of General Medical Sciences.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Findings published in Science (June 3, 2021):

https://doi.org/10.1126/science.abi5224

The National Institute of Allergy and Infectious Diseases awarded $2.5 million in grants to 12 institutions to study using bacteriophage therapy to combat antimicrobial-resistant bacteria. Bacteriophages, or phages, are viruses that target and consume bacteria. They are being used in some cases as a last resort to treat resistant bacterial infections that have not responded to traditional antibiotics.  “In recent decades, multidrug-resistant bacteria, particularly those that cause potentially deadly diseases like tuberculosis, have become a serious and growing global public health concern,” NIAID Director Anthony S. Fauci, MD, said in a press release. “With these awards, NIAID is supporting research needed to determine if phage therapy might be used in combination with antibiotics — or replace them altogether — in treating evolving antibiotic-resistant bacterial diseases.” The NIH said the funding will address knowledge gaps related to phages, including a study characterizing various types of phages, research investigating how phages combat biofilms, and research to determine how to identify new phages. Grant recipients include researchers from the Albert Einstein College of Medicine, University of Alabama at Birmingham, University of Connecticut, Georgia Institute of Technology, Harvard School of Public Health, University of Pittsburgh, Queens College, Texas A&M Agrilife Research, University of Wisconsin-Madison, Geneve Foundation, Guild Associates, and PhagePro.

The NIH plans to independently explore whether a Gilead compound — which some academics say is highly similar to remdesivir — might combat Covid-19. The National Institutes of Health plans to independently explore whether a Gilead Sciences (GILD) compound, which some academics maintain is highly similar to remdesivir, but which the company has deemphasized in its efforts, may be useful in combating Covid-19. The compound, called GS-441524, works in the same way as remdesivir to inhibit viruses, according to research that was conducted partly by the company (more here). But the compound has not been tested in humans and, for the past few months, a pair of researchers at the University of Texas MD Anderson Cancer Center has argued publicly that Gilead ought to run tests. Now, the NIH’s National Center for Advancing Translational Sciences is curious. Scientists at the institute have “reviewed the literature and agree that this compound merits further exploration,” according to an Aug. 20 letter sent to MD Anderson researchers and the advocacy group Public Citizen, which recently wrote to the NIH and the Food and Drug Administration in hopes of pressuring Gilead to conduct studies.

“We are planning to independently test the therapeutic hypothesis for GS-441524 in treating SARS-CoV-2, [which causes Covid-19], and have informed our colleagues at [the National Institute of Allergy and Infectious Diseases] about our plans for preclinical studies. We expect to conduct these studies quickly and make the results available to the research community for further consideration,” the agency said in the letter. The compound actually made headlines for a different reason earlier this year. GS-441524 has been sold on black markets to repel feline infectious peritonitis, a disease in cats caused by a different coronavirus than the virus that causes Covid-19. Lab tests have suggested GS-441524 is active against SARS-CoV-2, and it is apparently similar or superior to the effects of remdesivir at levels that do not cause much toxicity, according to the Anderson researchers, who want to run their own tests. They also maintain the compound is more easily synthesized than remdesivir, so it should be easier to create oral versions and make higher doses. Earlier this month, the drug maker explained there were several reasons for pursuing remdesivir instead. These include evidence indicating remdesivir is more effective in test tubes and animal models than GS-441524 in blocking viral replication, and was also more active in lab tests against multiple coronaviruses, include SARS-CoV-2.

The company and the researchers sparred over such issues as toxicology findings in both remdesivir and GS-441524. So far, though, the drug maker has not offered to cooperate in their research. A Gilead spokesman recently noted that additional preclinical studies to further compare remdesivir and GS-441524 have begun. [UPDATE: The following day, the spokesman wrote us to say the company has shared available preclinical data with the NIH.] One of the Anderson researchers, Victoria Yan, a graduate research assistant specializing in phosphate chemistry, wrote us that she is “really excited” by the NCATS decision. But she added the researchers are still seeking permission from Gilead to use data on the compound that is on file with the FDA. She is hopeful any data generated by NCATS can support their own investigational drug application to the FDA.

Initial trial to determine if monoclonal antibodies can shorten severity of COVID-19 in outpatients. Study aims to determine safety and efficacy of experimental monoclonal antibodies. A Phase 2 clinical trial will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease. Researchers sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are working with clinical sites to identify potential patient volunteers currently infected with SARS-CoV-2, the virus which causes COVID-19, who have mild to moderate disease not requiring hospitalization. They will be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial. The trial, which is known as ACTIV-2, also may investigate other experimental therapeutics later under the same trial protocol. If the investigational mAbs show promise, the study would expand from a Phase 2 to a Phase 3 trial to gather additional critical data from a larger pool of volunteers without delay. The trial will be led by the NIAID-funded AIDS Clinical Trials Group (ACTG) and will enroll participants at sites around the world.

ACTIV-2 was established as part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program instituted to speed development of the most promising treatments and vaccines. This study is also receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19. The design of the study is adaptive to enable maximum flexibility in the shortest time frame. If the experimental treatment appears effective in the first stage, the treatment can be advanced rapidly to testing in larger groups of volunteers. The study also can be adapted to test additional therapeutics. “We have seen encouraging, rapid results from other adaptive treatment trials for COVID-19,” said NIH Director Francis S. Collins, M.D., Ph.D. “Under ACTIV, specific therapeutics are being prioritized based on their likelihood for success. Prioritized therapeutics under ACTIV will use a master protocol that emphasizes flexibility, which enables these critical trials to be conducted without incurring delays when a treatment shows promise.”

The first therapeutic to be tested in this trial will be LY-CoV555, an investigational monoclonal antibody made by Eli Lilly and Company (Indianapolis, Indiana). LY-CoV555 emerged from Lilly’s collaboration with AbCellera Biologics (Vancouver, British Columbia). Antibodies are infection-fighting proteins produced by immune cells. So-called neutralizing antibodies target specific viruses or other pathogens. This antibody, which was discovered by AbCellera in collaboration with NIAID’s Vaccine Research Center, was isolated from a blood sample from a recovered COVID-19 patient. Copies of this antibody were then synthesized in a lab—the term “monoclonal” refers to these laboratory-manufactured antibodies. “Using an antibody generated by the immune system of a recovered COVID-19 patient gives us a jump start on finding a safe and effective therapeutic,” said NIAID Director Anthony S. Fauci, M.D. “Investigating a variety of different therapeutics, including monoclonal antibodies, will help ensure that we advance towards an effective treatment for people suffering from COVID-19 disease as quickly as possible.”...

One of the nation's top health experts recommends continuing avoiding large crowds and social interactions as the best defense against the pandemic.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has initiated the Collaborative Influenza Vaccine Innovation Centers (CIVICs) program, a new network of research centers that will work together in a coordinated, multidisciplinary effort to develop more durable, broadly protective and longer-lasting influenza vaccines. NIAID will provide up to approximately $51 million in total first-year funding for the program, which is designed to support the CIVICs program centers over seven years.

“To more effectively fight influenza on a global scale, we need better influenza vaccines that are more broadly protective,” said NIAID Director Anthony S. Fauci, M.D. “With the CIVICs program we hope to encourage an exchange of ideas, technology and scientific results across multiple institutions to facilitate a more efficient and coordinated approach to novel influenza vaccine development.” Seasonal influenza causes hundreds of thousands of hospitalizations and tens of thousands of deaths in the United States each year, according to the Centers for Disease Control and Prevention. While current seasonal influenza vaccines are widely available and provide important public health benefit, they could be improved. Notably, they do not always protect against all strains of circulating influenza viruses. Each year, months ahead of the flu season, scientists must make their best prediction as to which circulating viruses will be dominant. New seasonal influenza vaccines must be manufactured, distributed and administered to keep up with constantly evolving influenza viruses. This process can be slow, and if a drifted seasonal influenza virus emerges, that can impact the effectiveness of the vaccine against that virus. The relatively long timeline for vaccine production and the rapidly changing nature of influenza viruses poses a unique and difficult public health challenge for these reasons.

The CIVICs network will develop so-called universal influenza vaccines, which could provide longer-lasting protection than current vaccines and against a wider variety of influenza viruses. The CIVICs centers will conduct multidisciplinary research that supports the development of vaccine candidates through testing in preclinical studies, clinical trials and human challenge studies. The CIVICs network also will explore approaches to improve seasonal influenza vaccines, such as by testing alternative vaccine platforms or incorporating new adjuvants (substances added to vaccines to boost immunity). These advances could substantially reduce influenza hospitalizations and deaths in the future.

The CIVICs program will include three Vaccine Centers, one Vaccine Manufacturing and Toxicology Core, two Clinical Cores, and one Statistical, Data Management, and Coordination Center (SDMCC).

The Vaccine Centers will focus on designing novel vaccine candidates and delivery platforms with an emphasis on cross-protective vaccine strategies that could be used in healthy adults as well as populations at high risk for the most serious outcomes of influenza, such as children, older adults, and pregnant women. The Vaccine Centers also will focus on new ways to study influenza viruses and the human immune response to them through computer modeling, animal models and human challenge trials. The most promising candidate vaccines will advance to clinical trials conducted by the Clinical Cores. Vaccine candidates will first be evaluated for safety and immunogenicity in small Phase 1 clinical trials conducted among healthy adult participants. Successful vaccine candidates may eventually be advanced to larger Phase 2 clinical trials in healthy adults, or in specific age groups or at-risk populations. The Vaccine Manufacturing and Toxicology Core will work with the Vaccine Centers to develop and manufacture the vaccine candidates for clinical testing.....