July 24, 2020 | The NIAID recently established the COVID-19 Prevention Network with the goal to register millions of volunteers for large-scale clinical testing of vaccines and monoclonal antibodies intended to protect people from COVID-19. This, plus more, is included in this week’s announcements and updates from the clinical research industry.

Literature Updates

A study by scientists from Duke-NUS Medical School, in collaboration with the National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore General Hospital and National Centre for Infectious Diseases suggests that infection and exposure to coronaviruses induces long-lasting memory T cells, which could help in the management of the current pandemic and in vaccine development against COVID-19. The team tested patients recovered from COVID-19 and found the presence of SARS-CoV-2-specific T cells in all of them. They also showed that patients who recovered from SARS 17 years ago, after the 2003 outbreak, still possess virus-specific memory T cells and displayed cross-immunity to SARS-CoV-2. Additionally, more than 50% of uninfected healthy individuals harbored SARS-CoV-2-specific T cells, possibly due to cross-reactive immunity obtained from exposure to other coronaviruses, such as those causing the common cold, or presently unknown animal coronaviruses. Follow-up studies have been initiated on the COVID-19 recovered patients to determine if their immunity as shown in their T cells persists over an extended period. The study published in Nature. DOI: 10.1038/s41586-020-2550-z

The Korea Brain Research Institute has discovered the elevation of ACE2 as a SARS-CoV-2 entry receptor gene expression in elderly patients with Alzheimer's disease, making them more vulnerable to COVID-19 infection. For the study, which published in the online version of the Journal of Infection, researchers assessed the risk of SARS-CoV-2 infection in patients with Alzheimer's dementia using a micro array dataset and total RNA sequencing. The team also confirmed elevated expression of the ACE2 gene in the brain tissue of the Alzheimer's disease model mice. Based on genome analysis of Alzheimer's patient groups with early-stage, mild, and severe disease, ACE2 gene expression elevates with disease progression. Study results are expected to be used as a new diagnostic method for the elderly with underlying degenerative brain diseases. DOI: 10.1016/j.jinf.2020.06.072

COVID-19 is associated with life-threatening blood clots in the arteries of the legs, according to another study published in Radiology. Researchers at Montefiore Medical Center say COVID-19 patients with symptoms of inadequate blood supply to the lower extremities tend to have larger clots and a significantly higher rate of amputation (25%) and death (38%) than uninfected people with the same condition. In March and April 2020, they identified 16 COVID-19-positive patients, average age 70, who underwent CT angiography of the lower extremities for symptoms of leg ischemia and they were compared with 32 COVID-19-negative patients, average age 71, who underwent CT angiography with similar symptoms in previous years and who were well matched with COVID-19 cohort for demographic and clinical characteristics. The rate of both amputation and death was only 3% among controls. DOI: 10.1148/radiol.2020202348

A phase II trial of an adenovirus type-5-vectored COVID-19 vaccine candidate has been found safe and to induce an immune response in a randomized controlled trial involving more than 500 people in China. The study, which published in The Lancet, included a small sub-group of participants ages 55 and older. The primary objective was to determine the most suitable dose for phase III trials that are needed to confirm whether the vaccine candidate effectively protects against SARS-CoV-2 infection. Currently, about 250 candidate vaccines against SARS-CoV-2 are in development worldwide. The authors note that pre-existing immunity to the human adenovirus which was used as the vector for this vaccine and increasing age could partially hamper the specific immune responses to vaccination, particularly for the antibody responses. DOI: 10.1016/S0140-6736(20)31605-6

The Lancet has also just published promising early stage results from a phase 1/2 clinical trial of the U.K.'s vaccine candidate against SARS-CoV-2. A phase 1/2 trial involving 1,077 healthy adults found that the vaccine induced strong antibody and T cell immune responses up to day 56. These responses may be even greater after a second dose, according to a sub-group study of 10 participants. The vaccine caused no serious events; minor side effects occurred more frequently than in the control group (given a meningitis vaccine) but some of these could be reduced by taking paracetamol. The authors, from the University of Oxford, say further clinical studies (including in older adults) should be done with this vaccine. DOI: 10.1016/S0140-6736(20)31604-4

Based on a review of data from a national registry in Iran, researchers from Tehran University of Medical Sciences have found that nearly 25% of 62,955 patients hospitalized and testing positive for COVID-19 between Feb. 20 and April 20, 2020 died within 30 days. Older patients and those with coexisting diseases were more likely to die in the hospital. The most prevalent symptom among patients who perished was shortness of breath. Results published in the Annals of Internal Medicine. DOI: 10.7326/M20-2911

In an extensive review of the latest findings on COVID-19's effect on organ systems outside the lungs published in Nature Medicine, researcher-clinicians at Beth Israel Deaconess Medical Center and Columbia University Irving Medical Center note that the virus may increase patients' risk of heart attack, kidney failure and clotting disorders. Neurological symptoms may occur in about a third of patients. Patients with severe cases of COVID-19 are also at risk for strokes caused by blood clots and delirium. Their review summarizes proposed mechanisms behind these wide-ranging systemic effects and provide clinical guidance for physicians. DOI: 10.1038/s41591-020-0968-3

A study led by Albert Einstein College of Medicine and Montefiore Health System that published in the Journal of Hospital Medicine confirms the findings of the large-scale U.K. RECOVERY trial that the steroid dexamethasone reduces deaths by about one-third in COVID-19 patients on ventilators and by about one-fifth among people who need oxygen but are not on ventilators. It additionally found the same life-saving benefits with other steroid formulations—and that a common blood test (to measure levels of C-reactive protein) may identify the best candidates for steroid treatment. DOI: 10.12788/jhm.3497

Researchers at The Rockefeller University in New York have developed new tools to rapidly test the ability of antibodies to neutralize SARS-CoV-2. The approach, described in the Journal of Experimental Medicine, will help scientists understand whether patients are susceptible to reinfection by SARS-CoV-2 and assess the effectiveness of experimental vaccines, as well as develop antibody-based therapies against the disease. Efforts are underway to treat and prevent COVID-19 using either purified antibodies or whole blood plasma collected from convalescent patients who produce large amounts of neutralizing antibodies. Successful vaccines against SARS-CoV-2 will also have to induce the production of neutralizing antibodies. The researchers developed surrogate viruses—versions of either the human immunodeficiency virus type-1 or vesicular stomatitis virus that produce the SARS-CoV-2 spike protein instead of their own surface proteins—which can be used in place of SARS-CoV-2 to test the neutralizing activity of antibodies targeting the coronavirus spike protein. The surrogate virus-based assays have already been used to determine the neutralizing potencies of hundreds of plasma samples and monoclonal antibodies in a biosafety level 2 laboratory. DOI: 10.1084/jem.20201181

Nitric oxide treatment could be pivotal in the world's fight against SARS-CoV-2, according to a review from the George Washington University and Albert Einstein College of Medicine that published in the journal Nitric Oxide. It plays key roles in maintaining normal vascular function and regulating inflammatory cascades that contribute to acute lung injury and acute respiratory distress syndrome and is one of several potential COVID-19 treatments included in the FDA’s emergency expanded access program. The review looked at data between 1993 and 2020 on the pathogenesis of coronaviruses and the use of nitric oxide as a treatment for respiratory illness and highlights its potential to improve clinical outcomes and alleviate the pandemic’s rapidly rising strain on healthcare capacity. DOI: 10.1016/j.niox.2020.07.003

Despite the political tensions between the United States and China, scientists in the two countries are working together more than ever to study the COVID-19 virus, suggests a study in PLOS ONE. The nations were world leaders in the topic area before COVID-19 and they remain so now. Collaborations between U.S. and Chinese scientists have intensified to the exclusion of most other countries, except the U.K., the authors report. DOI: 10.1371/journal.pone.0236307

According to a preliminary report from researchers at Columbia University Irving Medical Center and NewYork-Presbyterian, race and ethnicity did not affect pregnancy and birth outcomes in women with SARS-CoV-2 infection who gave birth at two hospitals in northern Manhattan during the height of the pandemic in New York City. The study, which published online in Obstetrics & Gynecology, looked at 673 women who gave birth between March 13 and April 23, 2020 at NewYork-Presbyterian Morgan Stanley Children's Hospital or NewYork-Presbyterian Allen Hospital. Among the first 100 women, 18% of Hispanic women tested positive for SARS-CoV-2 versus about 13% of black women and 9% who were white. But birth outcomes were similar across all ethnic groups, including those from economically disadvantaged neighborhoods, a finding that may be related to the fact that the hospitals implement universal SARS-CoV-2 testing among women admitted for delivery and provide more frequent follow-up care for women and newborns with COVID-19. DOI: 10.1097/AOG.0000000000004088

A series of autopsies conducted by Louisiana State University Health New Orleans pathologists shows the damage to the heart of COVID-19 patients is not the expected typical inflammation associated with myocarditis but a unique pattern of cell death in scattered individual heart muscle cells. Findings come from a detailed study of hearts from 22 deaths confirmed due to COVID-19 and are published in Circulation. The research team found that, unlike the first SARS coronavirus, SARS-CoV-2 was not present in heart muscle cells. Nor were there occluding blood clots in the coronary arteries. Autopsied patients all died of COVID-19 at University Medical Center in New Orleans; the majority were African American, and they ranged in age from 44-79. The majority had high blood pressure, half had insulin-treated type 2 diabetes, and about 41% had obesity. Viral infection found in some of the cells in the endothelium could potentially have caused dysfunction leading to individual cell death, the authors say, and cytokine storm may also play a role. DOI: 10.1161/CIRCULATIONAHA.120.049465

In a cohort study of 627 long-term care facilities, the incidence rate ratio for COVID-19-related death among residents was 13 times higher than that among community-living adults older than 69 years, report Canadian researchers in JAMA Open Network. Findings highlight the need for improved infection control, widespread testing, access to personal protective equipment, and other supports to protect this vulnerable population. DOI: 10.1001/jamanetworkopen.2020.15957

Interleukin 7 (IL-7) can be safely administered to critically ill patients with COVID-19 without exacerbating inflammation or pulmonary injury, conclude an international team of investigators in another study published in JAMA Network Open. IL-7 is currently in multiple randomized clinical trials for oncologic and infectious disorders, and a trial in the U.K. is evaluating its use among patients with severe COVID-19; IL-7 also has documented efficacy as an antiviral agent. In this case series, IL-7 was allowed for compassionate use in 12 critically ill patients with COVID-19 and severe lymphopenia in Belgium. IL-7 was well tolerated with no observed treatment-associated adverse effects noted and was associated with lymphocytes returning to a reference level, appearing to reverse a pathologic hallmark of COVID-19. Administration of IL-7 alone or in combination with other therapies warrants serious consideration for patients with COVID-19 and evidence of immunosuppression, the authors say. DOI: 10.1001/jamanetworkopen.2020.16485

Newly released data on treatment outcomes of people with cancer diagnosed with COVID-19 reveal a racial disparity in access to remdesivir, an antiviral drug that has been shown to shorten hospital stays, and increased mortality associated with dexamethasone, a steroid that has had the opposite effect in the general patient population. The data on 2,186 adults in the U.S. by the COVID-19 and Cancer Consortium (CCC19), published in Cancer Discovery, is the largest cancer-specific observational study to date of treatments purported to improve COVID-19 outcomes. The consortium's researchers confirm and expand upon earlier observations that there has been broad use of unproven COVID-19 therapies, almost all of them outside of clinical trials. Remdesivir is an exception but black patients are underrepresented in those trials, likely due to reasons other than purely clinical factors. In the first study of 928 patients by CCC19, the mortality rate among cancer patients affected by COVID-19 was found to be 13%; the latest study puts the rate at 16%. DOI: 10.1158/2159-8290.CD-20-0941

In a letter published in JAMA Otolaryngology - Head & Neck Surgery, Johns Hopkins researchers have presented confirmation of SARS-CoV-2 colonization of the middle ear and mastoid in two of three COVID-19 patients via autopsy, which has significant implications for otolaryngology procedures. Droplet precautions during ear surgery are warranted for patients with COVID-19 owing to risk of infection to healthcare personnel. DOI: 10.1001/jamaoto.2020.1922

In a review of the role smoking and vaping plays in the cerebrovascular and neurological dysfunction of those who contract COVID-19, researchers at Texas Tech University Health Sciences Center have found case studies demonstrating stroke occurrences in COVID-19 patients and the rates appear to be increasing every day. In one study, 36.45% of COVID patients had neurological symptoms. This is triggered by 13 blood coagulation factors that can be increased due to hypoxia, as occurs with smoking. COVID-19 appears to also raise some blood procoagulant, especially the von Wellebrand Factor that promotes platelet adhesion at the site of wounds. Because COVID-19 and smoking or vaping each increase blood coagulation factors that may eventually affect the cerebral vascular system, stroke risk may be higher still for COVID-19 patients who smoke. Recent clinical study data additionally shows some of the damage to the respiratory system caused by COVID-19 is permanent and that even after recovery patients still have an elevated risk for stroke unrelated to age and physical activity. Some of those with the highest risk factors for long-term problems are young adults in their 20s and 30s who were active and considered to be in their physical prime. Results published in the International Journal of Molecular Sciences. DOI: 10.3390/ijms21113916

Cancer patients diagnosed more than two years ago are more likely to have a severe COVID-19 infection, according to a study by researchers at King's College London and Guy's and St Thomas' Foundation Trust that published in Frontiers in Oncology. An additional finding was that cancer patients of Asian ethnicity or who were receiving palliative treatment for cancer were also at a higher risk of death from COVID-19. The study analyzed the outcomes of 156 cancer patients with confirmed COVID-19 diagnosis between Feb. 29 and May 12, 2020, 82% of whom presented with mild or moderate COVID-19 infection and the remainder having severe disease. Advanced statistical methods were employed to identify demographic and clinical characteristics associated with disease severity or death. At follow up 37 days later, 22% of the patients had died and the risk was higher for patients with Asian ethnicity, palliative treatment, or a diagnosis of cancer more than 24 months before onset of COVID-19 symptoms. Patients who presented with shortness of breath or high CRP levels (a common blood marker of inflammation) were also at higher risk of dying from COVID-19. DOI: 10.3389/fonc.2020.01279/full

A study by researchers at the University of California – Los Angeles Health Sciences shows that in people with mild cases of COVID-19 the antibodies against SARS-CoV-2 drop sharply over the first three months after infection, decreasing by roughly half every 36 days on average. If sustained at that rate, the antibodies would disappear within about a year. An incorrect rate of 73 days was previously reported due to a math miscalculation in the study, published in the New England Journal of Medicine. The researchers studied 20 women and 14 men and antibody tests were conducted at an average of 36 days and 82 days after the initial symptoms of infection. The findings raise concerns about antibody-based "immunity passports," and may have implications for the durability of antibody-based vaccines.

Industry Updates

Medidata is collaborating with Moderna to support clinical trials of mRNA-1273, Moderna’s COVID-19 vaccine candidate. Medidata’s suite of technologies is supporting the advancement of Moderna’s mRNA-1273 clinical trials, including the Phase 3 trial, which is expected to enroll 30,000 participants. The Medidata and Moderna teams are moving forward with the speed and urgency necessitated by the global pandemic, using Medidata’s innovative and scalable cloud platform for clinical development. This clinical trial is one of the largest ever to incorporate data capture directly from participants, decreasing the need for office visits. The “virtualization” of the study allows participants to use their own devices if they so choose, easing the burden of having to carry around a separate, provisioned device. Press release.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), recently established the COVID-19 Prevention Network (CoVPN). Its goal is to register millions of volunteers for large-scale clinical testing of vaccines and monoclonal antibodies intended to protect people from COVID-19. As part of this initiative, Oracle has developed a Cloud System called the CoVPN Volunteer Screening Registry to identify and screen volunteers who want to participate in COVID-19 clinical trials. Even though the system has been live only since mid-July, more than 100,000 people have already registered. This program is expected to support hundreds of clinical trial sites across the United States and internationally by the end of the year. The trials are inclusive of absolutely everyone from all communities, with a focus on those who are at higher risk for COVID-19. Press release.

In a presentation at the recent American Association for Cancer Research Virtual Meeting, it was reported that researchers at the University of Cincinnati (UC) Cancer Center have found that, contrary to their expectations, immunotherapy doesn't necessarily worsen complications for patients with both COVID-19 and cancer. Their study, which is ongoing, uses blood samples from patients with cancer taken from the UC COVID-19 biorepository. One promising initial finding is that the anti-diabetic drug, metformin, can reduce production of cytokines by immune cells of COVID-19 patients. Press release.

UC Davis Health has announced it is testing a new antibody cocktail (REGN-COV2) as a prevention and treatment for COVID-19. The clinical trial, sponsored by Regeneron Pharmaceuticals, is an adaptive phase I, II and III randomized, double-blinded, placebo-controlled study. It seeks to evaluate the efficacy and safety of REGN-COV2 (a combination of REGN10933+REGN10987 antibodies) in hospitalized adult patients with COVID-19. It builds on encouraging findings from a set of studies that showed the neutralizing impact of REGN10933 and REGN10987. Press release.

Messenger RNA medicines company Arcturus Therapeutics Holdings Inc. and Duke-NUS Medical School (Singapore) have announced that the vaccine candidate LUNAR-COV19 has been authorized to proceed to clinical trials. Arcturus and Duke-NUS partnered to develop a coronavirus vaccine using Arcturus' STARR technology and a unique platform developed at Duke-NUS allowing rapid screening of vaccines for potential effectiveness and safety. The healthy volunteer study will evaluate several dose levels of LUNAR-COV19 in up to 108 adults. Follow-up will be conducted to evaluate safety, tolerability and the extent and duration of the humoral and cellular immune response. New preclinical data demonstrate that neutralizing antibody levels in response to a single administration of LUNAR-COV19 (0.2, 2.0, 10.0 μg) continue to increase over 50 days, which is attributed to the self-replicating mRNA of the vaccine. Press release.