Research | Mount Sinai Today

Esteemed Vaccinologist Weighs in on New Vaccines and the ‘Beginning of the End of the Pandemic’

Nov 17, 2020 | COVID-19, Featured, Research, Vaccines

Florian Krammer, PhD, right, filled out the paperwork needed to participate in Pfizer’s COVID-19 clinical trial and discussed the trial with Judith A. Aberg, MD, left, the Dr. George Baehr Professor of Clinical Medicine, and Chief of the Division of Infectious Diseases for the Mount Sinai Health System.

“Dear world, we have a vaccine!”

Florian Krammer, PhD, Professor of Vaccinology at the Icahn School of Medicine at Mount Sinai recently tweeted this in response to news of the interim results to Pfizer Inc.’s COVID-19 vaccine clinical trial, which showed high efficacy in the final, phase 3 round of human testing. “This is the best news since January 10,” Dr. Krammer added. On that date, China released the genome of SARS-CoV-2, the virus that causes COVID-19. Dr. Krammer’s laboratory at Mount Sinai immediately moved from developing a universal flu vaccine to creating the first test to detect the presence of antibodies to SARS-CoV-2 and the first to measure the amount of antibodies.

By November 17, Pfizer had updated its phase 3 results to report that its vaccine was 95 percent effective against COVID-19, across age, gender, race, and ethnicity demographics. Only one day earlier, Moderna Inc. confirmed that its COVID-19 vaccine candidate had a very high efficacy rate in its first interim analysis of its phase 3 study, prompting Dr. Krammer to tweet, “Dear world, we have a second vaccine.”

Both the Pfizer and Moderna vaccines are based on new RNA technology. Rather than containing pieces of an actual virus, as traditional vaccines do, these vaccines contain molecular instructions in the form of messenger RNA (mRNA) that tell human cells to make the virus’s spike protein, the immune system’s key target for the virus. If all goes well, the patient’s immune system will react by making antibodies to the spike protein—and these antibodies will also latch on to the spike protein of the real virus and disable the virus.

“This is the beginning of the end of the pandemic,” says Dr. Krammer. But important questions concerning COVID-19 vaccines still remain. This fall, he volunteered to take part in the Pfizer COVID-19 vaccine clinical trial under way at Mount Sinai and other locations in the United States and abroad. Like the other 43,538 trial participants, Dr. Krammer does not know whether he received a placebo or the real vaccine, which is how the placebo-controlled, randomized, observer-blinded vaccine trial is designed.

Mount Sinai Today recently asked Dr. Krammer to explain Pfizer’s phase 3 vaccine results.

Why are you enthusiastic about the Pfizer vaccine?

The results from the phase 3 trial have to be seen in the context of preclinical data, phase 1 and phase 2 trials, where Pfizer showed the vaccine worked in nonhuman primates. Also, in early clinical trials the vaccine induced good neutralizing antibody responses. Now, in addition to that, we get efficacy results—reduction of the incidence of disease in the vaccinated group—that are in the 95 percent range. Ninety-five percent is pretty good. Even a vaccine that affords 50 percent protection against severe disease would be positive news.

What questions do you have concerning the Pfizer vaccine?

Right now, Pfizer is reporting that the vaccine has 95 percent efficacy against symptomatic disease. That will likely protect at-risk individuals from severe disease outcomes. But we still don’t know if the vaccine can protect from asymptomatic infection. If it doesn’t, would it stop vaccinated individuals from spreading the virus to others? It will be difficult to determine if the Pfizer vaccine can achieve this, because it would involve routinely testing trial participants for the presence of virus, and you can’t do that with almost 45,000 people. Also, how long-lasting will the protection be? In other words, will the vaccine’s efficacy decrease over time, requiring people to get revaccinated?

Do Pfizer’s interim results bode well for other COVID-19 vaccines in the pipeline?

This is looking good for many of the other vaccine candidates. The fact that Pfizer’s vaccine is based on inducing neutralizing antibodies that protect from symptomatic infection might mean that many other vaccines are likely to work as well. Moderna’s vaccine is almost identical in terms of the immune response. Others are similar too.

What are Pfizer’s next steps?

Now that Pfizer has filed an Emergency Use Authorization application with the U.S. Food and Drug Administration (FDA) and the FDA has authorized the emergency use of the vaccine, it is likely that the vaccine will only be available for high-risk groups and front-line workers at first. Over time more people will get vaccinated but this will take months. Now, while we wait for the vaccine, we must keep the virus circulation down. Mask up, physically distance, and stick to guidelines and regulations.

Do any of these concerns dampen your enthusiasm for the vaccine?

No. From my point of view there is a light at the end of the tunnel. Right now, we need a vaccine that works, even if it would only protect for a few months or doesn’t completely stop transmission. That’s what we need to get halfway back to normal. We’ve been in this for 10 months. We can do it for a few more. We have to be patient.

New England Journal of Medicine Study of Marine Recruits Provides Lessons in Controlling the Spread of COVID-19

Nov 12, 2020 | COVID-19, Featured, Research

To effectively control the spread of SARS-CoV-2, the virus that causes COVID-19, public health measures such as wearing face masks, social distancing, and handwashing must be combined with repeated and widespread testing. That is the conclusion of a new study in The New England Journal of Medicine by researchers from the Icahn School of Medicine at Mount Sinai and the Naval Medical Research Center, who looked at disease transmission among 1848 Marine recruits between May and July 2020.

The researchers studied the Marine recruits, the majority of whom were male and between the ages of 18 and 20, while they were in a two-week supervised quarantine. The study results, published on November 11, showed that few infected recruits had symptoms before diagnosis of SARS-CoV-2 infection, that transmission occurred despite implementing many best-practice public health measures, and that diagnoses were made only by scheduled tests, not by tests performed in response to the daily temperature checks and symptom screening of the recruits.

“If you rely only on testing you are going to miss cases and the virus will escape, and if you just use public health measures it’s not going to be sufficient,” says the study’s senior author, Stuart Sealfon, MD, the Sara B. and Seth M. Glickenhaus Professor of Neurology at the Icahn School of Medicine at Mount Sinai. “If you do both of them together you should be able to control this highly infectious virus. We hope this information helps in developing more effective measures to keep military installations and schools safe.”

The study data revealed asymptomatic spread of the virus even under strict military orders for quarantine and public health measures that most likely experienced better compliance than would be possible in other youth settings like college campuses. The researchers noted that the virus was largely transmitted within a given platoon group which trained and ate together while maintaining social distancing, handwashing, and other methods of infection control.

The study enrolled participants from nine different Marine recruit classes, each containing 350 to 450 recruits, between May 15 and the end of July. The participants were offered enrollment in a prospective, longitudinal study after self-quarantining at home for two weeks prior to arrival at basic training. Once they arrived, they were required to follow strict group quarantine measures with two-person rooms for two weeks—the duration of the study period—before the start of the actual training. The supervised group quarantine took place at a college used only for this purpose. Each recruit class was housed in different buildings and had different dining times and training schedules, so the classes did not interact.

Each weekly class was further divided into platoons of 50-60. During the study period, all recruits wore cloth masks, practiced social distancing of at least six feet, and regularly washed their hands. Most of their instruction, including exercising and learning military customs and traditions, was done outdoors. After each class finished quarantine, a deep cleaning, using bleach on surfaces, occurred in all rooms and common areas of the dormitories before the arrival of the next class.

To determine asymptomatic and symptomatic SARS-CoV-2 prevalence and transmission during supervised quarantine, participants were tested within 2 days of arrival, at 7 days, and at 14 days using a nasal swab (PCR) test authorized for emergency use by the U.S. Food and Drug Administration. Analysis of viral genomes from infected recruits identified multiple clusters that were temporally, spatially, and epidemiologically linked, revealing multiple local transmission events during quarantine.

“The identification of six independent transmission clusters defined by distinct mutations indicates that there were multiple independent SARS-CoV-2 introductions and outbreaks during the supervised quarantine,” says the study’s co-senior author, Harm van Bakel, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “The data from this large study indicates that in order to curtail coronavirus transmission in group settings and prevent spill-over to the wider community, we need to establish widespread initial and repeated surveillance testing of all individuals regardless of symptoms.”

Insight into COVID-19 characteristics and SARS-CoV-2 transmission in military personnel has relevance to developing safer approaches for related settings composed primarily of young adults such as schools, sports, and camps.

This work was supported by the Defense Health Agency through the Naval Medical Research Center and the Defense Advanced Research Projects Agency.

Overwhelming Majority of People Mount a Strong Immune Response to COVID-19: A Good Sign for Future Vaccines

Nov 11, 2020 | COVID-19, Featured, Research, Vaccines

Patient samples to be tested for SARS-CoV-2 antibodies. Credit: Centers for Disease Control and Prevention/James Gathany

More than 90 percent of people who recovered at home from mild and moderate cases of COVID-19 produced a robust and possibly protective level of antibodies that remained relatively stable for at least five months, according to a new study by researchers at the Icahn School of Medicine at Mount Sinai.

The study, published in the latest issue of Science, was one of the largest of its kind ever conducted. It included 30,082 individuals who were screened at the Mount Sinai Health System. The patients, of diverse ages and ethnic and socioeconomic backgrounds, presented with a range of symptoms—from those who had almost none to those who spent several weeks in bed.

The findings are important because they provide irrefutable evidence that the body, in most cases, responds to COVID-19 by producing neutralizing antibodies that characterize a protective immune response, which does not quickly fade. Also significant, the findings apply to the majority of people who actually get COVID-19—those with mild to moderate cases.

This latest data confirms the strength and reliability of Mount Sinai’s ELISA antibody test, which was the first to detect the presence of antibodies to SARS-CoV-2, the virus that causes COVID-19 and the first to measure the amount of antibodies present in the blood.

“We will continue to follow a subset of these individuals over time to see how long these antibodies last, but so far the data are encouraging in terms of possible protection and the potential of vaccines working,” says the study’s first author, Ania Wajnberg, MD, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai. “You can see that at five months the antibodies declined slightly, which is expected in a virus like this. But they certainly did not rapidly decline to zero, as had been reported in some press articles. That is not what we’re finding.”

Dr. Wajnberg says Mount Sinai’s leading microbiologists are working toward a better understanding of the precise level of antibody titers that would actually prevent an individual from getting sick from COVID-19 again. “That is going to take time,” she says. “We don’t want people with antibodies to think they can ignore guidelines around social distancing, masks, etc. But this is encouraging data.” Dr. Wajnberg says the team did not delve into the reasons why a very small segment of the patients did not mount a robust immune response, though this is seen in different viruses and may be an area of future research.

The study authors wrote that “Although we cannot provide conclusive evidence that these antibody responses protect from reinfection, we believe it is very likely that they will decrease the odds of getting reinfected and may attenuate the disease in the case of a breakthrough infection.”

“Vaccines generally work by eliciting an antibody response, and ongoing vaccine trials may also contribute to our understanding about the protective effects and duration of SARS CoV 2 antibodies,” says the study’s corresponding author Carlos Cordon-Cardo, MD, PhD, the Irene Heinz Given and John LaPorte Given Professor and Chair in Pathology, at the Icahn School of Medicine at Mount Sinai.

Mount Sinai Physicians Create an Effective Road Map for Treating COVID-19

Nov 5, 2020 | COVID-19, Featured, Research

Carlos Cordon-Cardo, MD, PhD

Experts at the Mount Sinai Health System have created a road map for clinicians to follow when providing care to COVID-19 patients, which characterizes four distinct stages of the COVID-19 disease cycle and outlines specific testing and treatment protocols for them. The new approach—called staging—is featured in the latest issue of Cancer Cell and is modeled after the way in which cancer and other complex diseases, such as chronic renal disease, are managed.

“COVID-19 parallels other very difficult diseases in that it manifests specific clinical phases of progression,” says the study’s corresponding author, Carlos Cordon-Cardo, MD, PhD, the Irene Heinz Given and John LaPorte Given Professor and Chair in Pathology, at the Icahn School of Medicine at Mount Sinai. “In the absence of clear guidance we thought staging this disease could help physicians navigate better by linking the right tests to the most appropriate interventions. We want to give patients a better chance of being cured based on objective laboratory data and clinical information that is appropriate at different stages of the disease.”

The study lists stage 1 as viral entry; stage 2 as viral dissemination; stage 3 as multi-system inflammation (severe); and stage 4 as endothelial damage, thrombosis, and multi-organ dysfunction (critical), which affects a minority of patients. The study authors draw comparisons between the spread of the SARS-CoV2 virus, which causes COVID-19, within the body, and the spread of cancer, which metastasizes throughout the body—both resulting from disease-producing agents that create a cascade of dysfunction.

Staging requires knowing more about the patient than simply whether they tested positive or negative for COVID-19. Physicians, and the community at large, would benefit from tests that would also offer an indication of the level of viral particles affecting the patient, either high or low; since a patient with a high viral load and comorbidities such as advanced age, hypertension, diabetes, and coronary artery disease would be at higher risk for a poor prognosis.

Visual Summary of COVID-19 Stages

Since the beginning of the pandemic, physicians have learned important lessons about giving treatments early in the disease cycle, when they are most effective. One example is convalescent plasma therapy, which is best given before the patient develops their own antibodies to COVID-19.

“Analogous to the way we treat cancer, COVID-19 treatments have to be adapted to the evolution of the disease,” says study author, Luis Isola, MD, Professor of Medicine (Hematology and Medical Oncology), and Pediatrics, at the Icahn School of Medicine at Mount Sinai. “Treatments that may be effective early on no longer impact late disease. Conversely, treatments that help patients with advanced disease may not help or be justifiable when they present with it.”

The study’s authors say it is important to have a systematic approach to COVID-19 diagnostics and treatments that would keep the disease from progressing in those who might develop severe cases. “The idea is for us to provide guidelines for people to understand that this is not a simple disease, but one that is more complex,” says Dr. Cordon-Cardo.

In May, Mount Sinai released an autopsy study of 67 individuals with COVID-19 who had been admitted to one of the Health System’s eight hospitals from March 20 to April 29. The study showed the degree to which COVID-19 can lead to excessive blood clots and multi-organ failure.

David Reich, MD, President and Chief Operating Officer of The Mount Sinai Hospital, and one the study’s authors, says, “We learned a huge amount from the autopsy and innovative laboratory data collected from the very large number of COVID-19 patients cared for in the Mount Sinai Health System. Synthesizing all of these data led to this staging concept that has the potential to help clinicians worldwide in their understanding of the stages of this disease and in guiding the appropriate use of emerging therapies.”

Mount Sinai’s road map would also help COVID-19 patients understand the state of their own health during the disease cycle. Cancer patients at stage 2, for example, understand the course of their disease will be easier than it would be at stage 3 or 4, when they would require more aggressive treatments. The same holds true for COVID-19.

Mount Sinai Researchers Streamline Patient Data to Find Patterns in COVID-19 Patients

Oct 29, 2020 | Artificial Intelligence, Featured, Research

Girish Nadkarni, MD

With the influx of patient data resulting from the SARS-CoV-2 pandemic, the Mount Sinai COVID Informatics Center is collaborating with London-based software company Clinithink to uncover key findings that can enable better treatment methods for COVID-19 patients.

Clinithink’s artificial intelligence platform, CLiX, processes large volumes of data from physician notes and documents within electronic health records, allowing providers to save time and effectively determine key information on patient conditions.

“We are currently using the platform to mine clinical documents in order to extract information to further our understanding of COVID-19 and its complexities, so we can determine the best course of action for individual patients,” said Girish Nadkarni, MD, Assistant Professor, Department of Medicine (Nephrology), Clinical Director of the Hasso Plattner Institute for Digital Health, and Co-Director of the Mount Sinai COVID Informatics Center.

Through the use of Clinithink’s platform “CLiX^TM unlock,” the COVID Informatics Center is creating risk scores for COVID-19 patient symptoms, sifting through data that has been stripped of any personal information to find patterns that can ultimately lead to new discoveries in COVID-19 treatment.

“Clinithink is enabling us to identify and distinguish the symptoms in hospitalized COVID-19 patients during admission, in order to determine if and when new symptoms are appearing during their hospitalization,” Dr. Nadkarni said.

The Icahn School of Medicine at Mount Sinai was the first academic institution in the nation to partner with Clinithink in 2016, its original use to accelerate the prescreening process to identify eligible candidates for clinical trials.

“The collaboration between Clinithink and Mount Sinai represents how novel research can be translated into clinical practice,” Chris Tackaberry, CEO of Clinithink, said. “We are delighted to see Mount Sinai extend the use of our platform as they continue to make breakthrough discoveries in COVID-19.”

The collaboration was facilitated by Mount Sinai Innovation Partners (MSIP), the technology commercialization engine at Mount Sinai.

“Collaborating with Clinithink improves the way we understand and serve our patients,” said Erik Lium, PhD, President of MSIP and Executive Vice President and Chief Commercial Innovation Officer at the Mount Sinai Health System. “We look forward to seeing how Dr. Nadkarni’s team leverages Clinithink to extend our knowledge about COVID-19, and potentially improve treatment and patient outcomes.”

Mount Sinai Gets $2.5 Million NIH Grant to Open New Avenues for Diabetes Treatment

Oct 8, 2020 | Diabetes, Featured, Research

Principal investigator Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine, right, and Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease).

About 420 million people in the world have Type 1 or Type 2 diabetes, including 30 million in the United States, and all suffer from reduced numbers of beta cells, says Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai. “There are 30 to 40 drugs on the market for diabetes, and none of them make beta cells regenerate,” he says. “Developing such a drug, and a precise way to deliver it, is our aim.”

A project led by Dr. Stewart recently received a $2.5 million, four-year grant from the National Institute of Diabetes Digestive and Kidney Disease, to support Mount Sinai researchers’ innovative efforts to regenerate insulin-producing beta cells that could lead to novel drugs for patients with diabetes.

Dr. Stewart’s team in 2015 identified the first potent human beta cell regenerative drug, harmine, which is in a class of drugs called DYRK1A inhibitors. They identified additional drugs that enhance the regenerative capabilities of harmine—TGF beta inhibitors in 2019, and GLP-1 receptor agonists in 2020. The new grant will support new efforts to develop a means to deliver these drugs precisely.

Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute, and Chalada Suebsuwong, PhD.

“These drugs clearly are effective but also have the potential to cause unwanted effects outside the beta cell, so we now need a way to target the beta cell regenerative drugs to the beta cell,” says Dr. Stewart, principal investigator of the grant. “In lay terms, we have a UPS package to make your beta cells better, but we do not yet know the address to deliver the package.” There are potential strategies for delivering these “packages” by attaching them to a GLP-1 receptor agonist or a monoclonal antibody, each a widely used type of drug.

The current project is a collaboration among Dr. Stewart; Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute; and Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.

The research has four aims: First, Dr. DeVita and his team are making TGF beta inhibitors that can be linked to other molecules targeting beta cells. Second, Dr. Moran is focused on making one such molecule, a monoclonal antibody, which can deliver the drugs to beta cells. Third, Dr. Stewart and Dr. DeVita will “conjugate” the drugs with the delivery methods to investigate which combinations work the best. And fourth, Dr. García-Ocaña will test the therapies on human beta cells in mice.

Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.

“We are excited about these collaborative and translational studies that link basic laboratory research with ultimate goal of treating patients. For the first time, we have a series of new molecules that could be effective for both major forms of diabetes,” Dr. DeVita says. “If successful, a new targeted molecule could be scaled up in the future for further drug development, with the potential to treat millions of people around the world.”

Dr. Stewart is the site principal investigator for another grant for the study of diabetes, obesity, and other metabolic disorders, which was recently renewed by the National Institutes of Health. That five-year, $9.5 million grant was awarded to support the Einstein-Mount Sinai Diabetes Research Center, a regional collaborative led by Jeffrey Pessin, PhD, the Judy R. and Alfred A. Rosenberg Professorial Chair in Diabetes Research at the Albert Einstein College of Medicine and principal investigator on the grant.

The Center was founded in 1976 and has long focused its efforts on minority and other underserved populations in the region. Five years ago, it expanded into a regional collaborative, partnering with Mount Sinai to increase its capacity to support research studies and services. “The idea of these center grants is to have a series of cores that allow us to help people who are doing research, to do it faster, better, and more cost-efficiently,” Dr. Stewart says. For example, at Mount Sinai a core providing expertise in immune technology is led by Dirk Homann, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); and a human islet adenovirus core is led by Dr. García-Ocaña.

“The Center has provided a major boost to basic science and clinical diabetes and obesity research and training efforts at both Mount Sinai, Albert Einstein College of Medicine, and multiple other medical schools in the greater New York region,” Dr. Stewart says. “The Einstein team has been an extraordinary scientific partner.”

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