A single-shot vaccine for COVID-19 being developed by a group of scientists, led by Beth Israel Deaconess Medical Center (BIDMC) immunologist Dan H. Barouch, has proven successful in tests on primates and could begin phase 3 trials as early as September.

The results of the tests on the vaccine, developed at BIDMC in collaboration with Johnson & Johnson, showed that it promoted creation of protective antibodies and built on the team’s previous results. It is published in the journal Nature.

“This vaccine led to robust protection against SARS-CoV-2 in rhesus macaques and is now being evaluated in humans,” said Barouch, who is director of BIDMC’s Center for Virology and Vaccine Research as well as the William Bosworth Castle Professor of Medicine at Harvard Medical School (HMS) and a member of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard.

Beth Israel Deaconess Medical Center immunologist Dan Barouch and his team have been working on the development of a COVID-19 vaccine since January. Rose Lincoln/Harvard file photo

The vaccine uses a common cold virus, called adenovirus serotype 26 (Ad26), to deliver the SARS-CoV-2 spike protein into host cells, where it stimulates the body to raise immune responses against the coronavirus.

Barouch has been working on the development of a COVID-19 vaccine since January, when Chinese scientists released the SARS-CoV-2 genome. The team developed a series of vaccine candidates designed to express different variants of the SARS-CoV-2 spike protein, the major target for neutralizing antibodies.

The researchers then conducted a study with 52 adult rhesus macaques, immunizing 32 with a single dose of one of seven different versions of the Ad26-based vaccine, and giving 20 animals placebo doses as controls. All vaccinated animals developed antibodies.

The work was done by Barouch’s lab and collaborators from BIDMC; the Ragon Institute; Janssen Vaccines & Prevention, a research arm of Johnson & Johnson; Massachusetts Institute of Technology; the University of North Carolina; and Boston Children’s Hospital.

Six weeks after immunization, all animals were exposed to SARS-CoV-2. All 20 animals that received the placebos became infected and showed high levels of virus in their lungs and nasal swabs. Of the six animals that received the optimal vaccine candidate, Ad26.COV2.S, none showed virus in their lungs, and only one animal showed low levels of virus in nasal swabs.

“Our data show that a single immunization with Ad26.COV2.S robustly protected rhesus macaques against SARS-CoV-2 challenge,” said Barouch, who is also a co-leader of the vaccine working group of the Massachusetts Consortium on Pathogen Readiness. “A single-shot immunization has practical and logistical advantages over a two-shot regimen for global deployment and pandemic control, but a two-shot vaccine will likely be more immunogenic, and thus both regimens are being evaluated in clinical trials. We look forward to the results of the clinical trials that will determine the safety and immunogenicity, and ultimately the efficacy, of the Ad26.COV2.S vaccine in humans.”

Investigators at BIDMC and other institutions have initiated a first-in-human phase 1/2 clinical trial of the vaccine in healthy volunteers. Kathryn E. Stephenson, assistant professor of medicine at HMS and associate member of the Ragon Institute, is the principal investigator for the trial at BIDMC, which is funded by Janssen Vaccines & Prevention.

Pending clinical trial outcomes, the vaccine is on track to start a phase 3 efficacy trial in 30,000 participants in September.

Funding for the project came, in part, from the Department of Health and Human Services Biomedical Advanced Research and Development Authority. Additional support was supplied by Janssen Vaccines & Prevention BV, the Ragon Institute of MGH, MIT, and Harvard, the Mark and Lisa Schwartz Foundation, Massachusetts Consortium on Pathogen Readiness, and the National Institutes of Health.

When it comes to traumatic injuries, it’s a race against time. A person with major hemorrhage can die from blood loss within minutes. Bleeding from the extremities can be slowed with compression but what about internal bleeding? In a hospital, internal bleeding can be controlled with the transfusion of clotting agents, such as platelets, but they require careful storage and refrigeration and can’t be carried by first responders. As a result, the majority of people who succumb to traumatic injuries outside a hospital die from treatable hemorrhages.

Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), in collaboration with Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Case Western Reserve University, report an injectable clotting agent that reduced blood loss by 97 percent in mice models. The freeze-dried agent, which has a physical consistency of cotton candy, can be stored at room temperature for several months and reconstituted in saline before injection.

The research is published in Science Advances.

“Our goal was to give first responders a tool to stop internal bleeding that could be easily carried in a backpack or stored in an ambulance and, once injected intravenously in hemorrhagic patients, stop internal bleeding for a period long enough to get the patient to a hospital,” said Samir Mitragotri, Hiller Professor of Bioengineering and Hansjorg Wyss Professor of Biologically Inspired Engineering at SEAS and senior author of the study.

Mitragotri is also a core faculty member at Harvard’s Wyss Institute for Biologically Inspired Engineering.

Mitragotri and his team developed a polymer-peptide conjugate called HAPPI (Hemostatic Agents via Polymer Peptide Interfusion) that can selectively bind to damaged blood vessels and activated platelets at the bleeding site. Circulating platelets are like the body’s EMTs — they are constantly surveying the body for wounds. When there is an injury to a blood vessel, the platelets get activated and attach themselves to the damaged vessel, causing a blood clot.

HAPPI binds to these activated platelets and enhances their accumulation at a bleeding site. It can be injected anywhere in the body and still make its way to the wound.

In mice models, HAPPI significantly lowered the bleeding time and bleeding volume of injuries. The researchers observed about a 99 percent reduction in bleeding time and a 97 percent reduction in blood loss. The researchers also found that for traumatic injuries, the injection of HAPPI increased the median survival rate beyond one hour — a critical goal for trauma care.

“A lot of trauma-related deaths happen within the first hour when blood loss is happening profusely and there is no intervention,” said Yongsheng Gao, a postdoctoral research associate at SEAS and the co-first author of the paper. “A key objective for first responders is to keep trauma patients alive during this so-called golden hour and in that time bring them to a hospital because once they get to the hospital, it’s a different game altogether.”

“With HAPPI, we sought to develop a safe and effective internal bandage,” said Apoorva Sarode, a former graduate student at SEAS and the co-first author of the study. “We think that the simple design and scalable synthesis process of HAPPI will facilitate its seamless scale-up and translation to larger animal models, and eventually to the patients.”

Funding from Harvard’s Blavatnik Biomedical Accelerator enabled the lab to advance and validate the technology in animal models. Going forward, the team aims to scale up the production of the materials and test it in larger animal models.

Harvard’s Office of Technology Development has protected the intellectual property associated with this project and is exploring commercialization opportunities.

The paper was co-authored by Anvay Ukidve and Zongmin Zhao from Harvard SEAS, Shihui Guo and Robert Flaumenhaft from Beth Israel Deaconess Medical Center, Anirban Sen Gupta from Case Western Reserve University, and Nikolaos Kokoroskos and Noelle Saillant from Massachusetts General Hospital. The research was supported by the National Institutes of Health under grant R01HL129179.

Scientists have created candidate vaccines, which eventually could protect billions of people from COVID-19, with astonishing speed, compressing scientific efforts that usually take years into months. But the leader of a key drug trial said Tuesday that the blistering research pace has nonetheless been too slow to catch the coronavirus.

“We are now five months into it, and a large-scale phase 3 trial launched yesterday, which is remarkable,” said Lindsey Baden, associate professor of medicine at Harvard Medical School (HMS). He also is a principal investigator of the first U.S. vaccine to enter such trials, some of which will happen at Harvard-affiliated Brigham and Women’s Hospital. “It is fast, but we need to be as fast as this virus is. … With four million infections, 150,000 deaths in this country alone, we have to move faster.”

Baden is a principal investigator for the Brigham’s trial of a messenger RNA-based vaccine, whose promising early results in 45 volunteers prompted federal officials to approve it for large-scale trials. The trials of the vaccine from Moderna Inc. and the National Institute of Allergy and Infectious Diseases will involve 30,000 people at 89 locations around the country. Early results showed that the vaccine was well-tolerated by subjects receiving it — though there were passing side effects such as chills, headaches, and injection-site pain — and it induced an immune response in volunteers.

The new trial will test that immune response on many more healthy subjects, seeing whether the vaccine protects from infection, and, as secondary goals, lessens severity of illness and reduces chances of death. The study will also probe the duration of any protection the vaccine provides.

Baden and others involved in developing and testing other vaccine candidates said getting one approved for wide use is unlikely before early next year. Dan Barouch, the William Bosworth Castle Professor of Medicine and professor of immunology at HMS and Beth Israel Deaconess Medical Center, said a candidate vaccine could be ready for emergency authorization by late fall, but only if everything goes as well as possible between now and then. Barouch’s adenovirus-based vaccine is being developed and tested in conjunction with Johnson & Johnson.

Trials of other promising vaccines are underway at the University of Oxford and in China.

Baden and Barouch spoke at an online public briefing on vaccine progress by the Massachusetts Consortium on Pathogen Readiness, or MassCPR, an HMS-led, multi-institution collaboration aimed at better understanding the SARS-CoV-2 virus and developing treatments and vaccines to protect against COVID-19.

The briefing included a discussion of how the human immune response works, of the challenges faced by high-risk communities, and of three major vaccine development efforts, along with a Q&A session.

HMS Dean George Daley, who hosted the briefing, said the rapid development of several vaccine candidates — a process that typically takes three to nine years — was made possible by “countless unglamorous hours in the lab” over earlier years and was evidence of the importance of supporting basic research. Despite the speed at which progress has been made toward a COVID-19 vaccine, he pointed out that globally in just seven months, some 15 million people have been infected and 600,000 have died.

“As the pandemic has caused grave human suffering, scientists have been working tirelessly to crack the biology and the behavior of the virus and develop treatments and vaccines,” Daley said. “They’ve done so with unprecedented speed and a true spirit of international cooperation and collaboration.”

Bisola Ojikutu, assistant professor of medicine and of global health and social medicine at HMS, said trials should include significant numbers of members of minority groups and, whenever a vaccine is ready, distribution efforts should ensure that the communities most at risk aren’t in the background. Ojikutu said that hospitalizations, a measure of severe COVID-19, are 4.6 times higher among Latinx Americans than among whites, while those among Blacks and Indigenous people are 4.7 times and 5.3 times higher, respectively.

Ojikutu said that efforts to tend to high-risk communities have hurdles to clear that include historical incidents of abuse, such as the Tuskegee syphilis study, in which 600 Black men with latent disease were observed without informed consent and never offered treatment when the disease became active. Other concerns include a vaccine’s safety, cost, and side effects.

Ojikutu said a lack of trust is reflected in a recent Associated Press study that asked respondents whether they would agree to get a COVID vaccine. While 56 percent of white respondents said yes, only 37 percent of Latinx respondents did, and just 25 percent of Blacks. Ojikutu said experts are looking to successful public health campaigns for other conditions, such as the HIV Vaccine Trials Network, which increased minority participation in trials from 17 percent between 1988 and 2002 to 33 percent between 2002 and 2016.

Strategies for recruiting minorities into trials include first acknowledging there is a trust problem, Ojikutu said, but also actively engaging the community, partnering with community health centers, holding virtual town halls and other informational outreach, and increasing the diversity of those working on the effort.

“Quite honestly, diversity in clinical trials is both scientific common sense and promotes social justice,” Ojikutu said.

The experts also discussed Barouch’s adenovirus vaccine, which uses an altered cold virus to present the immune system with SARS-CoV-2’s characteristic spike protein and generate an immune response. They also discussed another effort, supported by the Gates Foundation, that seeks to generate an immune response using a protein from part of the spike. That protein-based vaccine, according to Nicole Frahm of the Bill & Melinda Gates Medical Research Institute, would be cheaper to produce and distribute and so better able to reach disadvantaged countries and populations.

Though much has been learned in the months since SARS-CoV-2 exploded globally, many important questions remain, participants said. One key question is how durable immunity is. Barouch said that trials in nonhuman primates showed that the immune response can be both robust and lasting, but evidence also has emerged in humans to cast doubt onto how lasting the immunity gained from infection will be. Questions remain about how long any immunity received from a vaccine will last, which is something the trials, coupled with the passage of time, should illuminate.

“We believe that vaccines should proceed in parallel, since it is not yet clear which vaccine will be most protective and most deployable,” Barouch said. “There are 7 billion people in this world. Therefore we need multiple vaccines to be successful.”

The initial surge of COVID-19 patients in Boston-area hospitals has passed, but the memories of caring for them will forever remain with physicians involved in that care. We asked seven physician-scientists from the Broad Institute, who are also Harvard Medical School instructors, to talk about what they learned from their time helping COVID-19 patients, and how their experiences have informed their research.

Deb Hung

Core faculty member, co-director of the Infectious Disease and Microbiome Program at Broad, infectious disease physician and attending critical care physician at Brigham and Women’s Hospital, professor of genetics and associate professor at Harvard Medical School

Photo by Maria Nemchuk

The thing that struck me the most, from the experience of treating COVID-19 patients, was how heartbreakingly dehumanizing it was. Patients weren’t allowed to have visitors, and those intubated and sedated in the ICUs couldn’t talk to you. As a physician, I only knew a name and the medical parameters associated with the individual. During usual times, we get to know a little more about the patient — the personal and human side, with families and friends visiting. But with COVID, it was heartbreaking to see people dying alone, and their families couldn’t come in.

On top of that, we, as physicians and healthcare workers wearing protective equipment and face masks, feel like there is another kind of barrier between our patients and us. Quite frankly, because everyone is wearing a mask in the hospital, even that’s dehumanizing among the people you know and your colleagues — you can’t even exchange a smile.

What was challenging, from the scientific side, is that everyone was so desperate to do something, to try anything to help the patients. It was crazy and frustrating, but everyone felt this acute sense of desperation.

As things have calmed down a bit, there is now more time to evaluate a lot of data that has been collected to better assess what interventions are actually effective. But there is still a lot of work to do and we still have a lot to learn.

Michael Gillette

Senior group leader in the Proteomics Platform at Broad, attending physician in pulmonary and critical care medicine at Massachusetts General Hospital (MGH), assistant professor at Harvard Medical School

Photo courtesy of MGH

One thing that was striking during the first surge of the pandemic was the number of critically ill patients relative to hospital capacity. At MGH, we got up to about 180 patients requiring ICU-level care. To put that number into perspective, our main medical intensive care unit, where I spent most of my time during the last couple of months, is an 18-bed unit.

To accommodate the influx, our medical-surgical intensive care, surgical intensive care, cardiac intensive care, neurointensive care, pediatric intensive care, and burn units all were converted to adult COVID-19 intensive care units. There were two general medicine floors in one of our buildings that had the necessary physical infrastructure and also got turned into COVID-19 intensive care units.

Our conventional ICU ventilators were in short supply, and other equipment was pressed into service: travel ventilators, operating room ventilators, and the like. Dialysis machines used for renal replacement had to be circulated between patients. Even ECMO (extracorporeal membrane oxygenation) circuits that oxygenate and scrub CO2 from the blood outside the body to allow the lungs to rest were in full utilization.

With that sort of patient census, we didn’t have the number of pulmonary or anaesthesia critical care doctors we needed. It was extraordinary to watch all kinds of care providers stepping forward to provide care for COVID-19 patients outside their usual roles. The number of people who worked extraordinary hours under very stressful circumstances, dealing with a disease that nobody understood very well, in many cases operating outside of their area of domain expertise, and did it with a positive attitude, was remarkable and heartwarming.

The biggest takeaway was probably the degree to which the pandemic highlighted all sorts of fundamental inequities in our healthcare system and our social structure. Not that one isn’t aware of them, but there hasn’t ever been anything in my lifetime that has made it this impossible to ignore.

After working 90- or 100-hour weeks in the hospital, it wasn’t easy to focus on research, which during other times of the year is my principal occupation. My proteomics group at the Broad has a translational research focus where I help scientists understand the ramifications of their work for clinical applications. We make sure that we are focusing our questions in the most meaningful way and serve the patients that the research ultimately is intended to serve.

Pradeep Natarajan

Associate member of the Program in Medical and Population Genetics at Broad, director of preventive cardiology at MGH, clinical cardiologist at the MGH Cardiovascular Disease Prevention Center, assistant professor at Harvard Medical School

Photo courtesy of MGH

During the first COVID-19 surge in Massachusetts, we converted one of our inpatient cardiology units at MGH to a COVID-19-specific cardiology unit. During this time, I was on clinical service, supervising that unit during this first surge of COVID-19.

The overwhelmingly large knowledge gap that physicians were dealing with in the face of this public health emergency was immediately apparent as I began treating patients with COVID-19. We don’t have multiple high-quality randomized controlled trials to go back and immediately reference in order to figure what’s the right thing to do for our patients. We are depending a lot on clinical intuition from experience with other acute respiratory processes, rapidly gaining experience, synthesizing and vetting scientific literature in real-time, and then immediately applying it to patients with COVID-19. None of us learned about COVID-19 in medical school. There are commonalities with other respiratory illnesses, but there are a lot of unique features as well.

It has been remarkable to see the resiliency and the adaptability of our local health systems to deal with this once-in-a-century pandemic. I certainly can’t be prouder of my colleagues — the nurses, physicians, technicians, and administrative staff — rallying together to address these needs.

Marcia Goldberg

Associate member of the Infectious Disease and Microbiome Program at Broad, infectious disease physician and professor of medicine and of microbiology at MGH and Harvard Medical School

Photo courtesy of Harvard Medical School

I participate in remote analysis of hospitalized patients in two capacities: First, I provide advice to the primary caretakers caring for COVID-19 infected patients. In essence, I respond to specific questions from primary caretakers that may relate to the management, diagnosis, and/or treatment of these patients. Second, I am part of an infectious diseases team that interprets the testing of inpatients who could be infected with COVID-19, including whether an individual is infected and, for infected individuals, when it is safe for them to come out of isolation.

What struck me the most with the patients was the rapidity with which they might go from having relatively mild illness to severe and life-threatening illness.

There are two things that stay with me from this experience: when we work together, we can transform healthcare in response to any threat; and how unpredictable and fragile life is.

My indirect interactions with patients have afforded me a small window into the enormity of their suffering and isolation, which highlight the importance of identifying new therapeutics. I believe the best way to achieve this goal is to improve our understanding of the underlying mechanisms of the disease. This is what drives me to work harder and harder on our research into the immune response to COVID-19.

Anna Greka

Institute member at Broad, director of the Broad’s Kidney Disease Initiative, associate physician in the Renal Division in the Department of Medicine at Brigham and Women’s Hospital, associate professor at Harvard Medical School

Photo courtesy of the Broad Center

I was not scheduled to be on service during the time of COVID-19, but I decided to volunteer in case they needed my help, as either a general physician or kidney expert. It turns out I was needed as a kidney specialist because, in addition to the obviously horrific lung disease, we started seeing an influx in COVID-19 patients facing kidney failure and in need of dialysis machines.

The most difficult thing in caring for patients with COVID-19 was the inability to spend a lot of time with them. It was really strange not to be able to touch and communicate with them. I would say the real unsung heroes in this case are the nurses, and in particular, the dialysis nurses, who had to be in the room in full PPE for the entire time that the dialysis procedure is taking place. Anybody who’s been in PPE knows, it’s extremely hot and very uncomfortable to be in that for hours. Because there were no guests allowed, the nurses were the only source of comfort for many patients. The nurses really went above and beyond, and I think it’s important that they’re recognized for their sacrifices.

The other thing that was very poignant from my time on service was having to think about what I might bring home to my family, which isn’t something that I’ve had to think about often in my career. But so many things were unknown at the time. We were all doing these elaborate decontamination procedures when we got home, every single day, to make sure that we didn’t expose our family to anything. I think that also added to people’s stress.

On a more positive side, there was an immense sense of camaraderie among physicians and nurses and respiratory technicians and other hospital staff, like our valet staff and the service staff who were manning the stations for dispensing the masks and the shields. People were really trying to be there for each other, and that helped everybody push through and feel not alone.

My time on service also stimulated me to think outside the box about ways that I could help as a scientist. I think the main thing that we learned from this is that science is the only way forward. We can overcome any difficulty that humanity faces using science and technology, and I think there’s a renewed understanding that that’s humanity’s best hope.

Benjamin Gewurz

Associate member of the Genetic Perturbation Platform at Broad, infectious disease physician at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, assistant professor and associate director, virology program, Harvard Medical School

Photo by Carly Gillis Photography

During the March through April peak, I volunteered for 10 very busy daytime and overnight shifts on the hospital COVID-19 beeper.

These were interesting and challenging shifts, with as many as 80 calls per day coming in from worried nurses, residents, and attending physicians. As testing capabilities and policies on testing and PPE were rapidly developing, many questions came in from all areas of the hospital. For instance, how many tests need to be done and how far apart should they be to clear a patient for surgery that requires general anaesthesia? What to do with a patient admitted from a rehab facility whose roommate was rumored to have COVID-19?

Early on, a major role was to work with physicians to decide how to deploy limited COVID-19 RT-PCR testing resources, ration precious PPE, and interpret test results as assays were still being optimized. We also had to help decide how best to allocate negative pressure rooms and whom to triage to rapidly expanding COVID-19 wards.

We need to be more prepared for the next pandemic. With increased air travel, population growth, climate change, and high-risk agricultural practices, we are clearly susceptible to another pandemic in the near future, perhaps even with another type of coronavirus. Not only do we need to be better prepared to test and trace earlier the next time, but also to have adequate PPE stockpiles. We should also be thinking about developing compounds against host and viral targets that can be rapidly deployed.

My experience with patient care has highlighted things that we can do to be better prepared for the next pandemic, in terms of staying ahead of the curve to develop diagnostics, small molecule and antibody therapeutics, and vaccines that can be more rapidly deployed. Seeing how frightening, dangerous and disruptive to society a pandemic virus is — and realizing how helpless we were early on, without evidence to guide treatment strategies or resources to adequately test—has been quite motivating for me in my research on the virus.

Roby Bhattacharyya

Associated scientist in the Infectious Disease and Microbiome Program at Broad, attending infectious disease physician at MGH, and instructor in medicine, Harvard Medical School

Photo courtesy of the Broad Center

During the two weeks in April that I was on service, the surge was really building in Massachusetts, and by the end, half of our thousand-bed hospital was COVID-19 patients. Which is crazy — that this thing that had infected its first human less than six months earlier was suddenly the majority of what we were caring for.

At MGH, we had to create five new ICUs from floors that were normally regular medical wards or perioperative care areas. This was incredible. I don’t think anybody at MGH had seen the need for surge capacity like this before. The hospital had spent months planning for it, and it went off without a hitch from my perspective as a consultant, thanks to the hard work and planning of a lot of people.

The other thing I remember about the time leading up to my two weeks on service in April was how eerie it was to hear from doctors in Italy and Spain, then Washington, then New York City about how slammed they were, when our hospital was actually quieter than usual because we had cancelled elective surgeries in anticipation of the surge. People were using the analogy of when the ocean is sucked out away from the beach before a tsunami hits — eerie calm in the moment with a strong sense of foreboding. And sure enough, the surge came. Fortunately, with the preparation measures the Boston area and MGH took, it stretched us to the limits of our capacity but not past.

I’ve reflected since being on service about how much we’ve benefitted from real-time science compared to the original SARS in 2003. I was in grad school when SARS hit, and had forgotten that we didn’t even learn that it was a virus until after it had been controlled. (There was speculation at the time that it was caused by a specific kind of intracellular, unculturable bacteria.) Which meant that there was no diagnostic test possible in real-time, so diagnoses had to be phenomenological.

There have been many challenges with the real-time science around COVID playing out in the news and public sphere, and diagnostics were initially delayed and remain more limited than anyone would like, but there has been a lot of progress too. It’s easy to lose sight of how different this pandemic would have been if it had hit 15 to 20 years ago.

Temporary loss of smell, or anosmia, is the main neurological symptom and one of the earliest and most commonly reported indicators of COVID-19. Studies suggest it better predicts the disease than other well-known symptoms such as fever and cough, but the underlying mechanisms for loss of smell in patients with COVID-19 have been unclear.

Now, an international team of researchers led by neuroscientists at Harvard Medical School has identified the olfactory cell types in the upper nasal cavity most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19.

Surprisingly, sensory neurons that detect and transmit the sense of smell to the brain are not among the vulnerable cell types.

Reporting in Science Advances on July 24, the research team found that olfactory sensory neurons do not express the gene that encodes the ACE2 receptor protein, which SARS-CoV-2 uses to enter human cells. Instead, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons, as well as certain populations of stem cells and blood vessel cells.

The findings suggest that infection of nonneuronal cell types may be responsible for anosmia in COVID-19 patients and help inform efforts to better understand the progression of the disease.

“Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells,” said senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at HMS.

This implies that in most cases, SARS-CoV-2 infection is unlikely to permanently damage olfactory neural circuits and lead to persistent anosmia, Datta added, a condition that is associated with a variety of mental and social health issues, particularly depression and anxiety.

“I think it’s good news, because once the infection clears, olfactory neurons don’t appear to need to be replaced or rebuilt from scratch,” he said. “But we need more data and a better understanding of the underlying mechanisms to confirm this conclusion.”

A majority of COVID-19 patients experience some level of anosmia, most often temporary, according to emerging data. Analyses of electronic health records indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have fever, cough or respiratory difficulty, compared to patients without COVID-19.

Some studies have hinted that anosmia in COVID-19 differs from anosmia caused by other viral infections, including by other coronaviruses.

For example, COVID-19 patients typically recover their sense of smell over the course of weeks — much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as stuffy nose. Some COVID-19 patients, however, experience anosmia without any nasal obstruction.

Pinpointing vulnerability

In the current study, Datta and colleagues set out to better understand how sense of smell is altered in COVID-19 patients by pinpointing cell types most vulnerable to SARS-CoV-2 infection.

They began by analyzing existing single-cell sequencing datasets that in total catalogued the genes expressed by hundreds of thousands of individual cells in the upper nasal cavities of humans, mice and nonhuman primates.

The team focused on the gene ACE2, widely found in cells of the human respiratory tract, which encodes the main receptor protein that SARS-CoV-2 targets to gain entry into human cells. They also looked at another gene, TMPRSS2, which encodes an enzyme thought to be important for SARS-CoV-2 entry into the cell.

The analyses revealed that both ACE2 and TMPRSS2 are expressed by cells in the olfactory epithelium — a specialized tissue in the roof of the nasal cavity responsible for odor detection that houses olfactory sensory neurons and a variety of supporting cells.

Neither gene, however, was expressed by olfactory sensory neurons. By contrast, these neurons did express genes associated with the ability of other coronaviruses to enter cells.

The researchers found that two specific cell types in the olfactory epithelium expressed ACE2 at similar levels to what has been observed in cells of the lower respiratory tract, the most common targets of SARS-CoV-2, suggesting a vulnerability to infection.

These included sustentacular cells, which wrap around sensory neurons and are thought to provide structural and metabolic support, and basal cells, which act as stem cells that regenerate the olfactory epithelium after damage. The presence of proteins encoded by both genes in these cells was confirmed by immunostaining.

In additional experiments, the researchers found that olfactory epithelium stem cells expressed ACE2 protein at higher levels after artificially induced damage, compared with resting stem cells. This may suggest additional SARS-CoV-2 vulnerability, but it remains unclear whether or how this is important to the clinical course of anosmia in patients with COVID-19, the authors said.

Datta and colleagues also analyzed gene expression in nearly 50,000 individual cells in the mouse olfactory bulb, the structure in the forebrain that receives signals from olfactory sensory neurons and is responsible for initial odor processing.

Neurons in the olfactory bulb did not express ACE2. The gene and associated protein were present only in blood vessel cells, particularly pericytes, which are involved in blood pressure regulation, blood-brain barrier maintenance and inflammatory responses. No cell types in the olfactory bulb expressed the TMPRSS2gene.

Smell loss clue

Together, these data suggest that COVID-19-related anosmia may arise from a temporary loss of function of supporting cells in the olfactory epithelium, which indirectly causes changes to olfactory sensory neurons, the authors said.

“We don’t fully understand what those changes are yet, however,” Datta said. “Sustentacular cells have largely been ignored, and it looks like we need to pay attention to them, similar to how we have a growing appreciation of the critical role that glial cells play in the brain.”

The findings also offer intriguing clues into COVID-19-associated neurological issues. The observations are consistent with hypotheses that SARS-CoV-2 does not directly infect neurons but may instead interfere with brain function by affecting vascular cells in the nervous system, the authors said. This requires further investigation to verify, they added.

The study results now help accelerate efforts to better understand smell loss in patients with COVID-19, which could in turn lead to treatments for anosmia and the development of improved smell-based diagnostics for the disease.

“Anosmia seems like a curious phenomenon, but it can be devastating for the small fraction of people in whom it’s persistent,” Datta said. “It can have serious psychological consequences and could be a major public health problem if we have a growing population with permanent loss of smell.”

The team also hope the data can help pave inroads for questions on disease progression such as whether the nose acts as a reservoir for SARS-CoV-2. Such efforts will require studies in facilities that allow experiments with live coronavirus and analyses of human autopsy data, the authors said, which are still difficult to come by. However, the collaborative spirit of pandemic-era scientific research calls for optimism.

“We initiated this work because my lab had a couple of datasets ready to analyze when the pandemic hit, and we published an initial preprint,” Datta said. “What happened after that was amazing, researchers across the globe offered to share and merge their data with us in a kind of impromptu global consortium. This was a real collaborative achievement.”

Co-first authors on the study are David Brann, Tatsuya Tsukahara and Caleb Weinreb. Additional authors include Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren Logan, Bradley Goldstein, Matthew Grubb and John Ngai.

The study was supported by grants from the National Institutes of Health (grants RO11DC016222 and U19 NS112953) and the Simons Collaboration on the Global Brain. Additional funding information can be found in the full text of the paper. DOI: 10.1126/sciadv.abc1564.