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.

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.”

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.

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.

Experiencing adversity early in life has a direct effect on a person’s mental and physical health as they grow, and certain kinds of trauma can affect the pace of aging, according to new Harvard research.

In addition to being risk factors for anxiety, depression, and stress, early life experiences like poverty, neglect, and violence are powerful predictors of physical health outcomes like cardiovascular disease, diabetes, cancer, and even early mortality, said Katie McLaughlin, associate professor of psychology and senior author of “Biological Aging in Childhood and Adolescence Following Experiences of Threat and Deprivation: A Systematic Review and Meta-Analysis,” in a new paper in the Aug. 3 Psychological Bulletin.

In their research, McLaughlin and three colleagues investigated two different forms of childhood adversity and their connection to alterations in the pace of biological aging, including the onset of puberty, the rate of cellular aging, and the maturation of regions in the brain underlying emotional responses.

They found that violent or traumatic experiences led to accelerations in pubertal development, brain development, and cellular aging, while neglect and chronic poverty did not, though they can affect physical and cognitive development in other ways. For example, children exposed to deprivation often experience delays in cognitive development and difficulties with learning and memory that can contribute to poor school performance.

“The question we were really interested in is whether all negative experiences early in life are the same in terms of how they might impact the aging process, and one of the most interesting findings of the paper is that the answer is a very clear ‘no,’” said McLaughlin.

The group reviewed 83 ELA studies, focusing on participants under age 18 and separating the experiences into two categories: threat-based (experiencing or witnessing violence) and deprivation-based (neglect by families or institutions). They investigated the associations between each using a variety of biological aging metrics: pubertal development, brain development, and cellular aging.

In their analysis of pubertal development, the researchers found that children who experienced violence reached puberty at an earlier age than those who did not, but this was not true for children exposed to deprivation or poverty. In this case, researchers postulate, earlier sexual maturation may act as the body’s way to prepare for earlier reproduction, based on the presence of threats that could contribute to imminent mortality.

“We now have these very early markers of biological aging that we can use as potential flags for kids who could be in trouble down the road,” said Natalie Colich, a postdoctoral researcher at the University of Washington and first author on the paper. “If you have a kid who comes into a pediatrician’s office and is showing precocious pubertal onset, you can first start to [ask] questions about the experiences this child had in early childhood and also know that this child is probably at risk for mental and physical health problems down the road. So [biological aging] is a good marker for these two things that we should watch out for in order to promote a healthier trajectory of development.”

To measure cellular aging, researchers examined existing findings on the connection between early adversity and the length of telomeres, nucleopeptide complexes that protect chromosomes from degradation. Shortened telomere length is often associated with chronic stress and other health issues in adults, and they found that children exposed to violence had shorter telomeres.

Another area was epigenetic aging metrics, in which patterns of methylation across the genome can be used to estimate a person’s chronological age. Again, children who experienced violence showed accelerated epigenetic aging markers compared with their chronological age, indicating that their cells aged more quickly than expected. No such acceleration was found for children who experienced deprivation or poverty in the absence of violence.

The paper also looked at the effect of threat-based early adversity on brain development, for which the researchers examined cerebral cortex thickness. That outer layer of the brain becomes thinner in a linear fashion over time, indicating advances in development that track with the chronological age of a child. In their review of research, the group found that children exposed to violence showed accelerated thinning, particularly in regions of the brain that process social and emotional information — a change that can affect the brain’s ability to process and manage social situations and emotions.

“If you’re growing up in an environment where there are constant threats around you, the network of brain regions that are involved in social and emotional processing becomes more efficient at processing threat-related information, which could accelerate processes like synaptic pruning where that network is getting rid of connections that it doesn’t need and becomes efficient more quickly for kids who are growing up in dangerous contexts,” said McLaughlin.

“We know from other work we’ve done in the lab that for a kid who’s been chronically exposed to violence, [there] are stronger emotional reactions to things in their environment, particularly to things that might be negative. Typically, those kids may also have difficulty modulating those responses. So you might see more intense emotions and emotions that last for a longer time or that are more difficult for kids to regulate after exposure to violence,” she added.

McLaughlin and her colleagues see myriad applications for their analysis, noting that how “you were raised early in life can place you on a trajectory towards greater risk for health problems in adulthood,” she said. The study also prompts important questions about “whether the kinds of psychosocial interventions that we’ve developed for kids who have experienced trauma and violence, which we know lead to improved mental health outcomes, might actually be able to slow down this acceleration of biological aging.

“Identifying intervention strategies that can alter the pace of aging may ultimately be able to prevent the emergence of health problems later for children who have experienced adversity,” she said.

Children who receive sustained treatment against common parasitic infections grow up to achieve a higher standard of living, with long-lasting health and economic benefits that extend to their communities, according to new findings from an international research team.

The pioneering 20-year study of Kenyan schoolchildren led by Edward Miguel, an economist at UC Berkeley, and co-authored by Michael Kremer, the Gates Professor of Developing Societies and winner of the 2019 Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel, found that youngsters who received a few extra years of deworming treatment — costing as little as 50 cents a child per year — eventually achieved better jobs and attained higher incomes than those who got less treatment.

“We found that, in Kenya, this modest investment led to significant improvements in the lives of infected individuals and for whole communities, and the benefits are long-lasting,” said Miguel, a development economist. “But parasitic infections remain prevalent in many low-income countries, and there’s a resurgence in some poor, rural low-income areas of the United States. Clearly, this research can serve as a guide to policymakers in much of the world.”

Kremer, whose Nobel Prize recognized his development of novel ways to study poverty, said the research also provides an unanticipated warning in light of the COVID-19 pandemic: Students who lose a year or more of school — and school-based social services — may likewise risk suffering lasting negative impact on their work and earning power.

There may be new trouble ahead for states that had gotten COVID-19 under control after the March and April surges but are now seeing case numbers drift up.

The movement may be an early signal that governors and other local officials need to take modest steps to head off the need for more drastic measures in several weeks’ time, according to Ashish Jha, K.T. Li Professor of Global Health at the Harvard T.H. Chan School of Public Health and director of the Harvard Global Health Institute.

Officials should be mindful of just how quickly a trickle of new cases can become a steady stream and then a deadly flood, Jha said in a Monday conference call with reporters. That change, he said, can occur in just a few weeks’ time and could, in some states, threaten plans to reopen schools and colleges next month.

“The problem with this disease is it lulls you,” Jha said. “When numbers start increasing, you’re down at 20 or 30 or 50 cases and it goes to, like, 70, then 120, then 180, and it still looks really small but it’s actually starting to get into exponential growth. What happens is by the time it hits you … that you have a problem … you’re starting to replicate from a much higher number and the cases really start spiking. This is what happened with Arizona, Texas, Florida.”

In the Northeast, states like Maine and Vermont have managed to keep their case counts low while in Massachusetts and New Hampshire they have begun creeping up in recent weeks. In his regular COVID-19 updates, Massachusetts Gov. Charlie Baker has repeatedly warned residents to wear masks, practice social distancing, and avoid large gatherings, particularly indoors, like the house parties that recently resulted in isolated case spikes.

“The governors were careful in opening up, but when I look around at what’s happening — I live in Eastern Massachusetts … People are starting to let their guard down. We’re starting to get gatherings, and people are hosting house parties,” said Jha. “If you actually care about schools, then you probably need to tolerate a much, much lower level of indoor gatherings. That’s indoor restaurants, bars, gyms…. What you do about house parties, I have no idea.”

In Massachusetts, both new cases and deaths have fallen dramatically since the pandemic’s early peak in April, when new cases were well over 1,000 a day. Though the daily death rate has continued to slowly drop, new cases have begun to climb. In early July, the state was logging around 200 daily cases — the exact number fluctuated — and on Sunday, the state reported 353. In addition, the seven-day average of positive test results has increased since early July from 1.8 percent to 2.2 percent of every 100 tests given, a sign that more people are testing positive.

States that want to reopen schools for in-person classes should focus on getting community transmission numbers as low as possible, Jha said, so the likely spikes that will result from children going back to classrooms will be more manageable.

Jha said he has been fielding calls from local government and school leaders because of the uncertainty around school reopening plans, how much in-person instruction should happen, and what kinds of safeguards should be in place. A major complicating factor involves the numerous scientific unknowns around COVID and children. There is very limited data available, but Jha suspects that children 10 and under are not only less at risk to get seriously ill, they’re probably also less of a risk for spreading it. High schoolers and to a certain extent middle-schoolers are probably more like adults in their physical reactions to the virus, in their risk of both getting sick and passing it on.

That argues, he said, for sending young children to school in communities where transmission is under control, so they can benefit from in-person instruction. Educators say that social relationships with teachers and peers are essential for learning for younger students. But Jha also notes that the cost-benefit ratio may tilt the other way in neighborhoods where case numbers are high.

The months to come will be a challenge for school officials, he said. They can increase chances for success by layering protective policies and practices, such as wearing masks, holding classes outside early in the fall, and conducting regular testing as resources and test technology allow. Regardless of the structure established at a school, however, flexibility will be a needed asset, as adjustments to the constantly shifting ground of this pandemic will be critical.

“The key is flexibility,” Jha said. “When we get to September, I can tell you what October looks like.”

New treatment regimens for multidrug-resistant tuberculosis (MDR-TB) have shown early effectiveness in 85 percent of patients in a cohort that included many people with serious comorbidities that would have excluded them from clinical trials, according to the results of a new international study.

The results, based on observational data from a diverse cohort of patients in 17 countries, underscore the need for expanded access to the recently developed TB medicines bedaquiline and delamanid. By contrast, the historical standard of care, still in use in much of the world, has approximately 60 percent treatment efficacy globally.

The study was published July 24 in the American Journal of Respiratory and Critical Care Medicine.

“This is important evidence that these new regimens will work well for the true population suffering from this disease,” said lead study author Molly Franke, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School.

Global collaboration

The research was conducted as part of endTB, an international partnership with leaders from HMS, Partners In Health, Médecins Sans Frontières, Interactive Research & Development, the Institute of Tropical Medicine in Antwerp, and Epicentre.

“Our findings underscore the need for urgent expanded access to these drugs,” said Carole Mitnick, associate professor of global health and social medicine in the Blavatnik Institute at HMS and a co-author of the study. While recent announcements of a price reduction for bedaquiline and an expected reduction for delamanid are welcome, the researchers said, more must be done to improve treatment guidelines worldwide and to scale up treatment with these new regimens.

The need for better treatments for MDR-TB is dire. The WHO estimates that there are nearly 500,000 new cases of MDR-TB per year and that nearly 200,000 people die of the disease each year . In 2018, only one out of three patients were given an effective treatment, and only half of these were cured.

New hope

In the early 2010s, regulatory agencies approved the first new TB drugs in 50 years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. With the historical standard of care and some newer regimens, certain subgroups of patients, including those with HIV or hepatitis C or diabetes experience worse treatment outcomes than patients without these conditions. In addition, these conditions preclude patients from participating in clinical trials for these drugs.

It’s important to examine whether these subgroups experience any benefit from the new regimens that might be observed in healthier study participants, the researchers said. They noted that only a large cohort study has the statistical power to explore these differences.

The endTB study showed that for the new regimens, early treatment response was similar for patients without serious comorbidities or other complicating factors and for those with diabetes, hepatitis C and severe drug resistance.

Patients with severe TB disease when they started treatment had worse outcomes than patients with less severe disease. Sixty-eight percent of people with severe disease had early favorable responses to the new regimen, compared to 89 percent without severe disease. Among patients with HIV coinfection, early outcomes on the new regimens were favorable in 73 percent, compared to 84 percent in those without HIV.

The results are based on an analysis of early treatment results from more than 1,000 MDR-TB patients who were enrolled in the study between April 2015 and March 2018. The study examines outcomes after six months in a treatment that lasts 15 months or longer. Long-term effectiveness will be measured at the end of treatment and during follow-up.

For this study, the researchers counted how many of those patients, within the first six months of treatment with regimens containing bedaquiline, delamanid, or both, experienced culture conversion, a state in which the bacteria that cause TB can no longer be found on a sample. Previous studies have shown this to be a strong predictor of successful treatment outcomes.

Confirmation with end-of-treatment outcomes will be important and more work needs to be done to ensure successful treatment in these populations, the researchers said.

“The early results from these studies offer convincing evidence that these new regimens offer a very promising alternative to the historical regimens that achieve approximately 60 percent success at end of treatment, and to other new treatments that are becoming available,” said Mitnick, who is a senior researcher at Partners In Health and co-principal investigator of the clinical trials being conducted by endTB.

“We’re eager to follow these patients as they progress through treatment in order to verify the effectiveness of these new regimens,” she added.

Complex challenges

Observational research makes so many important contributions to improving treatment outcomes for complex illnesses in complicated populations that it is critical to continue research efforts past the stage of clinical trials in illnesses like tuberculosis, the researchers said.

While tuberculosis has nearly disappeared in wealthier populations, it remains a critical threat in communities with fewer resources. A big part of the challenge of treating MDR-TB is finding regimens that will work in low-resource settings with complex populations that often include great diversity and many people who might be undernourished or sick with other illnesses.

The partnership is also studying the safety of the new regimens. Preliminary results suggest that side effects from the new regimen may be much less severe than those seen with the historical treatment, which has been known to cause deafness and psychosis.

“TB is well-controlled where control is easy,” Mitnick said. “We need to find better ways to treat it where it’s difficult.”

The global reach of endTB has now provided clinicians with invaluable hands-on experience with bedaquiline and delamanid and helped change country guidelines, getting the new drugs registered for use in more than half of the17 endTB countries, the researchers said. The endTB observational study has contrinuted to changing global guidelines, including new recommendations for concomitant use of bedaquiline and delamanid and extended use of each drug.

Moving forward

The endTB partnership is using the same model for promoting innovation to prepare for what researchers hope will be the next change on the horizon in care for MDR-TB: all-oral, shortened regimens, which are being studied in the current phase of endTB’s clinical trial. While the implementation program continues to roll out and reaches new patients, the endTB trial has enrolled 465 patients with MDR-TB in new all-oral regimens that could transform care for MDR-TB.

The all-oral regimens used in the endTB observational study and the all-oral, shortened regimens studied in the trials would be particularly helpful during international health crises like the coronavirus pandemic, the researchers noted. These all-oral regimens are much easier to deliver in routine times and especially so in times of extreme crisis that burden health systems.

“If the ongoing trials demonstrate reduced toxicity of the all-oral, shortened regimens, this is another huge benefit for their delivery in good times and bad,” Mitnick said.

The project also transformed the landscape for TB trials by running in six countries (Georgia, Kazakhstan, Lesotho, Pakistan, Peru, South Africa) on four continents. This is the first time a clinical trial has taken place in some of these sites, the researchers said.

“In global health we see many vicious cycles, where poverty and lack of access to care combine to make diseases worse,” Franke said. “On the other hand, bringing care delivery, training and research together the way we are in the endTB project can be a kind of virtuous cycle, where each turn of the wheel brings better care, improved health and greater well-being.”

The endTB project is funded by Unitaid.

Just five steps are enough to gain control of the nation’s COVID-19 outbreak and head off a return to the complete lockdowns many states declared in March and April, according to Anthony Fauci, one of the federal government’s top voices on pandemic response.

Fauci, director of the National Institute of Allergy and Infectious Diseases, said Wednesday afternoon at a Harvard online event that wearing masks, keeping distances between people, washing hands often, pushing activities outdoors rather than indoors, and avoiding or closing bars have already proven effective in bringing down cases in Arizona, where cases surged in July before falling again in recent weeks.

If those steps were fully implemented, he said, even Sun Belt states with surging case numbers would return to a manageable level within as little as six weeks. The big stumbling block is a lack of unified response across the nation, fueled in part by hostility to science shown by some and directed at public health officials, including himself, even though the evidence for the recommendations is clear, he said.

“What Arizona did is … finally say, ‘We’re in trouble. We’re going to implement those fundamental principles’ and they came right down in a nice curve, which is really good,” Fauci said.

Fauci responded to questions from Harvard faculty members and from CNN correspondent Sanjay Gupta during the discussion “When Public Health Means Business,” hosted by Harvard T.H. Chan School of Public Health Dean Michelle Williams and co-sponsored by the New England Journal of Medicine.

Fauci was introduced by Williams and Harvard President Larry Bacow. Bacow, who was sick with COVID-19 in March, said many Americans have lost someone or know someone who lost someone to the virus. The pandemic, he said, has not only sickened the nation, it’s exposed deep inequities in the health care system and the criminal justice system, particularly in regard to communities of color, which both contract COVID-19 and die of it at higher rates.