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.
To better understand the role of bacteria in health and disease, National Institutes of Health researchers fed fruit flies antibiotics and monitored the lifetime activity of hundreds of genes that scientists have traditionally thought control aging. To their surprise, the antibiotics not only extended the lives of the flies but also dramatically changed the activity of many of these genes. Their results suggested that only about 30% of the genes traditionally associated with aging set an animal’s internal clock while the rest reflect the body’s response to bacteria.
“For decades scientists have been developing a hit list of common aging genes. These genes are thought to control the aging process throughout the animal kingdom, from worms to mice to humans,” said Edward Giniger, Ph.D., senior investigator, at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in iScience. “We were shocked to find that only about 30% of these genes may be directly involved in the aging process. We hope that these results will help medical researchers better understand the forces that underlie several age-related disorders.”
The results happened by accident. Dr. Giniger’s team studies the genetics of aging in a type of fruit fly called Drosophila. Previously, the team showed how a hyperactive immune system may play a critical role in the neural damage that underlies several aging brain disorders. However, that study did not examine the role that bacteria may have in this process.
To test this idea, they raised newborn male flies on antibiotics to prevent bacteria growth. At first, they thought that the antibiotics would have little or no effect. But, when they looked at the results, they saw something interesting. The antibiotics lengthened the fly’s lives by about six days, from 57 days for control flies to 63 for the treated ones.
“This is a big jump in age for flies. In humans, it would be the equivalent of gaining about 20 years of life,” said Arvind Kumar Shukla, Ph.D., a post-doctoral fellow on Dr. Giniger’s team and the lead author of the study. “We were totally caught off guard and it made us wonder why these flies took so long to die.”
Dr. Shukla and his colleagues looked for clues in the genes of the flies. Specially, they used advanced genetic techniques to monitor gene activity in the heads of 10, 30, and 45-day old flies. In a previous study, the team discovered links between the age of a fly and the activity of several genes. In this study, they found that raising the flies on antibiotics broke many of these links.
Overall, the gene activity of the flies fed antibiotics changed very little with age. Regardless of their actual age, the treated flies genetically looked like 30-day old control flies. This appeared to be due to a flat line in the activity of about 70% of the genes the researchers surveyed, many of which are thought to control aging.
“At first, we had a hard time believing the results. Many of these genes are classical hallmarks of aging and yet our results suggested that their activity is more a function of the presence of bacteria rather than the aging process,” said Dr. Shukla.
Notably, this included genes that control stress and immunity. The researchers tested the impact that the antibiotics had on these genes by starving some flies or infecting others with harmful bacteria and found no clear trend. At some ages, the antibiotics helped flies survive starvation or infection longer than normal whereas at other ages the drugs either had no effect or reduced the chances of survival.
Further experiments supported the results. For instance, the researchers saw similar results on gene activity when they prevented the growth of bacteria by raising the flies in a completely sterile environment without the antibiotics. They also saw a similar trend when they reanalyzed the data from another study that had raised flies on antibiotics. Again, the antibiotics severed many of the links between aging and hallmark gene activity.
Finally, the team found an explanation for why antibiotics extended the lives of flies in the remaining 30% of the genes they analyzed. In short, the rate at which the activity of these genes changed with age was slower than normal in flies that were fed antibiotics.
Interestingly, many of these genes are known to control sleep-wake cycles, the detection of odorants, and the maintenance of exoskeletons, or the crunchy shells that encase flies. Experiments on sleep-wake cycles supported the link between these genes and aging. The activity of awake flies decreased with age and this trend was enhanced by treating the flies with antibiotics.
“We found that there are some genes that are in fact setting the body’s internal clock,” said Dr. Giniger. “In the future, we plan to locate which genes are truly linked to the aging process. If we want to combat aging, then we need to know precisely which genes are setting the clock.”
This study was supported by the NIH Intramural Research Program at the NINDS.
A new study funded by the National Institutes of Health will evaluate the effects of remdesivir in pregnant women who have been prescribed the drug to treat COVID-19. The study, which will be conducted at 17 sites in the continental United States and Puerto Rico, aims to determine how pregnant women metabolize the drug and whether there are any potential side effects.
“Pregnant women with COVID-19 are at high risk for hospitalization, for intensive care admission and for needing ventilator support,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “There is an urgent need to identify effective treatments for this population and to determine whether drugs prescribed for other adults are appropriate for use in pregnancy.”
The study is funded by NICHD, the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Mental Health, all part of NIH. Called IMPAACT 2032, the study will be conducted by the NIH-funded International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network.
Originally developed to treat Ebola and Marburg virus infections, remdesivir was shown in a NIAID-funded clinical trial to accelerate recovery in patients with advanced COVID-19 disease. Remdesivir has since been approved by the U.S. Food and Drug Administration for the treatment(link is external) of COVID-19 in adults and children over age 12 years.
Although it has not been approved specifically for use in pregnancy, remdesivir can be prescribed to pregnant women if their physicians believe the drug may benefit them. However, physicians currently lack scientific evidence for the safety and efficacy of remdesivir for treating pregnant women with COVID-19. Because pregnancy may influence a drug’s effects, IMPAACT 2032 will compare remdesivir use in pregnant and non-pregnant women of reproductive age who are hospitalized with COVID-19.
The study will evaluate remdesivir’s pharmacokinetics—how a drug is absorbed, moves through the body and is broken down and eliminated in pregnant women and nonpregnant women of childbearing potential who receive it as part of clinical care. For women who received the drug within five days of delivery, samples from the plasma and umbilical cord will be analyzed for insight into remdesivir’s pharmacokinetics in the placenta. Breast milk will also be tested for remdesivir among women who are lactating. Researchers will also document potential side effects and adverse events that could occur with use of the drug.
The National Institutes of Health, working in collaboration with the Biomedical Advanced Research and Development Authority (BARDA), today announced a third round of contract awards for scale-up and manufacturing of new COVID-19 testing technologies.
Ellume/Luminostics
The six new Rapid Acceleration of Diagnostics (RADx) initiative contracts total $98.35 million for point-of-care and other novel test approaches that provide new modes of sample collection, processing and return of results. Innovations in these new technologies include integration with smart devices, mobile-lab processing that can be deployed to COVID-19 hot spots, and test results available within minutes.
These awards are part of the RADx Tech program, focused on rapidly advancing early testing technologies. RADx Tech and the RADx Advanced Technology Platforms (RADx-ATP) —the latter for late-stage scale-up projects— are now supporting a combined portfolio of 22 companies for a total of $476.4 million in manufacturing expansion contracts. These six additional technologies are expected to add as many as 500,000 tests per day to the U.S. capacity by the end of 2020 and 1 million tests per day by early 2021. Combined with previous contracts announced in July and September, RADx Tech and RADx-ATP contracts are expected to increase test capacity by 2.7 million tests per day by the end of 2020.
“Since launching in April, the NIH RADx initiative has moved swiftly to facilitate critical expansion of early and late-stage testing technologies as well as research to remove barriers to testing for underserved and vulnerable populations,” said NIH Director Francis S. Collins, M.D., Ph.D. “Each of the technologies emerging from the RADx initiative will play a critical role in extending accessibility to testing in diverse settings.”
The latest group of testing technologies have been optimized and assessed within the NIH RADx Tech development pipeline and have met the rigorous criteria for advancement. Factors such as speed, accuracy, cost and accessibility are key considerations for RADx support. The RADx initiative provides financial support and expertise to help companies reach milestones for U.S. Food and Drug Administration authorization, scale-up and commercialization.
“The current round of awards support five technologies that can be delivered to the point of care and a powerful laboratory test,” said Bruce J. Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and lead for RADx Tech, one of four programs of the NIH RADx initiative. “The technologies include an antigen test that provides results in 15 minutes, a viral RNA test deployed in mobile vans that can travel to COVID hotspots and tests that require only saliva, nasal swabs or blood from a finger prick.”
BARDA, part of the Office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services, provided the funding for these RADx Tech contracts from emergency supplemental appropriations to the Public Health and Social Services Emergency Fund.
BARDA has contributed substantially to the nation’s COVID testing capacity with development support of 30 SARS-COV-2 diagnostic tests since March, 15 of which have achieved FDA emergency use authorization (EUA). Five of the 30 tests can distinguish between influenza and SARS-COV-2, the virus that causes COVID-19, from the same sample, and two of those have achieved EUA. To date, BARDA’s industry partners have shipped more than 45 million tests to healthcare providers across the country.
“Through the RADx initiative, we are expanding on our long-standing partnership with NIH to bring essential technology to the American people in the fight against COVID-19,” said BARDA Acting Director Gary L. Disbrow, Ph.D. “Our staff at BARDA is lending our expertise and experience in advanced development, manufacturing and scale up to help make as many accurate, fast tests available as we can as quickly as possible.”
Statement of B.F. (Lee) Hall, M.D., Ph.D., and Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases.
Eliminating malaria — one of the world’s oldest and deadliest diseases — remains a critically important public health and biomedical research challenge. Despite remarkable advances in reducing malaria incidence and deaths since 2000, recent progress has become stagnant and has even reversed in some regions.
Malaria sporozoites, the infectious form of the malaria parasite that is injected into people by mosquitoes.
The World Health Organization(link is external) (WHO) estimates that in 2017 about 219 million cases of malaria occurred worldwide and approximately 435,000 people died of the disease. Unfortunately, malaria cases increased from 2016 to 2017 in the 10 highest-burden countries in Africa, and the number of cases per 1,000 in populations at risk remained at 59 from 2015 to 2017.
Today, the National Institutes of Health recognizes World Malaria Day and commits to a reinvigorated malaria research program. This year’s World Malaria Day theme, “Zero malaria starts with me,” encourages governments, companies, academic institutions, philanthropies, and others to prioritize malaria, mobilize resources, and empower communities affected by malaria to lead and coordinate response activities. The National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, is working toward “zero malaria” with coordinated global research projects to better understand the disease, improve diagnostics, treatments, and mosquito control interventions, and develop safe and effective vaccines.
NIAID works directly with scientists in malaria-endemic regions to build specialized local clinical research capacity. The NIAID-supported International Centers of Excellence for Malaria Research (ICEMR) program has more than 50 field sites in 17 endemic countries dedicated to multidisciplinary research on the complex interactions between the human host, mosquito vectors, and malaria parasites. ICEMR investigators share genomic and epidemiological data for parasites, mosquitoes, and human hosts through public databases such as PlasmoDB(link is external), VectorBase(link is external), and ClinEpiDB(link is external) to assist researchers in developing drugs, vaccines and diagnostics, and in improving public health programs.
ICEMR researchers are studying how the malaria-causing parasite adapts to antimalarial drug pressure and how that translates to the emergence and spread of drug resistance. Resistance to artemisinin drugs, used in most endemic areas, is emerging in Southeast Asia and appears to be spreading west. The ICEMRs are evaluating how asymptomatic malaria infections may contribute to persistent disease transmission and risk. Investigators also are studying how the behavior of malaria-transmitting mosquitoes is changing in response to insecticide use and environmental and ecosystem changes.
Another international research team supported by NIAID created mutated versions of nearly all of the 5,400 Plasmodium falciparum(P. falciparum) parasite genes to determine which of the organism’s genes are essential to growth and survival. The information will help investigators prioritize targets for future antimalarial drug development. One investigational drug being evaluated, DM1157, is a modified form of the antimalarial drug chloroquine. Similar to chloroquine, it interferes with the malaria parasite’s metabolism; however, it inhibits the parasite’s ability to expel the drug, thereby avoiding the drug resistance seen with chloroquine. A Phase 1 clinical trial to evaluate the drug’s safety began in September 2018.
Cerebral malaria — a severe form of illness that can lead to brain damage, long-term neurological deficits, and death — remains a significant problem in sub-Saharan Africa. ICEMR investigators and their collaborators identified brain swelling as a potential contributor to the high mortality rate among children in Malawi with cerebral malaria. A clinical trial is underway to assess whether measures to reduce brain swelling can improve treatment outcomes. ICEMR investigators in India are studying whether the same findings are seen in adults with cerebral malaria, while NIAID researchers are working to develop novel adjunctive cerebral malaria treatments.
NIAID also supports the development of various investigational malaria vaccines. The Institute has conducted and supported multiple early-stage clinical trials of PfSPZ, a candidate malaria vaccine made of weakened immature malaria parasites. It is designed to prevent malaria infection and is now being evaluated in multiple clinical trials in malaria endemic regions, including in infants and children. Another candidate vaccine based on a recombinant protein is currently in a Phase 1 clinical trial.
NIAID researchers also are working on a vaccine designed to block transmission of the malaria parasite from infected humans to mosquitoes. Although a transmission-blocking vaccine would not prevent malaria infection, by limiting further spread it could reduce new malaria infections over time. Results from a clinical trial in Mali indicate that the investigational vaccine, when formulated with an immunity-boosting adjuvant, shows promise. Plans are underway to evaluate the efficacy of the vaccine in a Phase 2 clinical trial in Mali.
NIAID scientists recently developed a monoclonal antibody from a person vaccinated with PfSPZ that potentially could be used for seasonal control and elimination efforts as well as by tourists, health care workers, and military personnel to prevent malaria infection. A trial evaluating the antibody’s safety and efficacy against a controlled human malaria infection (human challenge study) is planned for early 2020. NIAID experts also are collaborating with Malian scientists to discover additional broadly protective monoclonal antibodies.
Although recent data indicate that malaria control efforts may have stalled, numerous historical examples indicate that with enough commitment and ingenuity malaria elimination can be achieved, even after significant setbacks. NIAID-supported investigators, researchers and their collaborators are accelerating progress toward malaria elimination every day. On this World Malaria Day, we reaffirm our commitment to advancing the best research to reach our goal of “zero malaria.”
Lee Hall, M.D., Ph.D., is chief of the Parasitology and International Programs Branch in the NIAID Division of Microbiology and Infectious Diseases. Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, Maryland.
A research team led by scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has determined how several antibodies induced by Epstein-Barr virus (EBV), a herpesvirus that causes infectious mononucleosis and is associated with certain cancers, block infection of cells grown in the laboratory.
A cryo-EM image of the gH/gL/gp45 candidate vaccine constructNIAID
They then used this information to develop novel vaccine candidates that, in animals, elicited potent anti-EBV antibody responses that blocked infection of cell types involved in EBV-associated cancers.
Currently, there is no licensed vaccine for EBV. The virus is associated with certain cancers (nasopharyngeal and gastric) of epithelial cells, which form the lining of the body’s surfaces, as well as Burkitt and Hodgkin lymphomas, which are cancers of the immune system’s B cells. Worldwide, about 200,000 cases of EBV-associated cancers occur annually, resulting in 140,000 deaths.
Jeffrey I. Cohen, M.D., and Wei Bu, Ph.D., both of NIAID, led the investigation. Prior efforts to develop an EBV vaccine focused on a viral surface protein, gp350, that the virus uses to enter B cells. However, EBV infects not only B cells, but also epithelial cells that line the mouth and upper throat. These cells are usually infected after contact with saliva from an EBV-infected individual. The new research helps define the contributions of virus-neutralizing antibodies other than those directed at gp350 on B cells. Among other findings, the team determined that antibodies to viral proteins called the gH/gL complex play a major role in inhibiting EBV fusion with epithelial cells.
The scientists developed two vaccine candidates, one designed to elicit antibodies to gH/gL on epithelial cells and another that included gH/gL and another viral protein, gp42. The team tested the vaccines in a series of experiments in mice and monkeys. In both animal models, each of the experimental vaccines induced antibodies that potently inhibited epithelial cell fusion. The vaccine containing gp42 induced stronger B cell fusion inhibitory antibodies than the one containing gH/gL alone.
Unlike the gp350 candidate EBV vaccine, which protects only B cells from infection, the candidate vaccines described in the new paper elicited antibodies that could prevent EBV from fusing with both epithelial cells and B cells and thus may provide protection independent of cell type, the authors note. The team is planning to further develop one of the vaccine constructs with an eye toward human trials.
Ebola virus can infect the reproductive organs of male and female macaques, according to a study published in The American Journal of Pathology, suggesting that humans could be similarly infected.
Colorized transmission electron micrograph of the ovary from a nonhuman primate infected with Ebola virus. Characteristic filamentous Ebola virus particles are present between cells (bright red). Intracytoplasmic Ebola virus inclusion bodies forming crystalline arrays can be seen within ovarian stromal cells (darker red). NIAID
Prior studies of survivors of the 2014-2016 Ebola outbreak in West Africa have revealed sexual transmission of Ebola virus, and that viral RNA (Ebola virus genetic material) can persist in semen following recovery. While little is known about viral persistence in female reproductive tissues, pregnant women with Ebola virus disease have a maternal death rate of more than 80 percent and a fetal death rate of nearly 100 percent.
In this study, investigators from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and from Thomas Jefferson University infected four female and eight male macaques with the Makona variant of Ebola virus, the variant responsible for the recent West Africa outbreak. All the macaques succumbed to Ebola virus disease and were euthanized six to nine days after infection. The scientists then took reproductive tissue samples from each macaque and analyzed the samples for signs of Ebola virus infection, organ and tissue damage, and immune responses. They found widespread Ebola virus infection of reproductive organs with minimal tissue immune response or signs of disease.
Based on the findings, the authors hypothesize that Ebola virus can persist in these tissues in human survivors, and that the virus may reach seminal fluid in men by infecting immune cells called tissue macrophages. However, it is unclear if the detection of Ebola virus RNA in semen documented in human studies means that infectious virus is present.
The authors note that additional research is needed to learn how Ebola virus persists in these sites, to determine if drugs and vaccines can cure or prevent such infections, and to understand the mechanisms of sexual transmission, including why it appears to occur only rarely in people. To do this, NIAID scientists are developing a new nonhuman primate model of Ebola virus disease in which monkeys survive infection. Few macaques survive in the current model, making it difficult to study virus persistence and its long-term impacts.
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.
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