Dissecting a Disease

By KEVIN JIANG May 18, 2020 Research HMS Community

Click to watch the opening remarks of the MassCPR public briefing

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

In late December of 2019, patients with an unusual pneumonia began presenting at emergency rooms in central China, representing the first documented cases of the COVID-19 pandemic, a public health crisis that has today transformed lives and communities across the globe.

In response to the crisis, Harvard Medical School convened the Massachusetts Consortium on Pathogen Readiness (MassCPR), a broad multi-institutional initiative that aims to turn the tide of the current pandemic and establish rapid response systems to help deal with future outbreaks.

Get more HMS news here. Learn more about the consortium and its work here.

On May 15, MassCPR held its first public briefing to provide an overview of the progress of the efforts of the hundreds of scientists, clinicians and public health experts that encompass the consortium.

“What I’ve witnessed over these last three months has been truly humbling. By bringing us together, this tragedy brings out the best in us,” said George Q. Daley, dean of Harvard Medical School in his opening remarks at the briefing.

Formed during a historic meeting at HMS on March 2nd, MassCPR was initiated under a collaborative research agreement between Harvard University and the Guangzhou Institute of Respiratory Diseases in China with catalytic funding from the China Evergrande Group, which will provide support to researchers based in Massachusetts and China to combat COVID-19.

An initial group of projects and key resources were awarded over $16.5 million in funding support on May 13.

“We cannot deal with a global threat by going it alone or by being isolationist. We must work together, across labs, across institutions, across geographic borders,” Daley said. “We are doing this through MassCPR.”

At the briefing, renowned pulmonologist and respiratory health expert Zhong Nanshan of the Guangzhou Institute, echoed Daley’s message of cooperation and collaboration.

“I am sure the scientists and clinicians from both sides may offer a great contribution in combatting the COVID19 pandemic. The substantial cooperation between us will be of great success,” said Zhong, who led the Chinese response to the SARS epidemic in 2003.

Celebrating the collaborative and transnational efforts of the consortium, China Evergrande CEO James Xia made remarks, as did the MassCPR’s governing committee, which in addition to Daley includes David Golan, HMS dean for research operations and global programs, and faculty co-leaders Arlene Sharpe, chair of the Department of Immunology at HMS, and Bruce Walker, director of the Ragon Institute of MGH, MIT and Harvard.

Consortium working group leaders then presented overviews of the work, challenges, overarching goals and key projects under way in each of MassCPR’s six primary focus areas: clinical disease management, pathogenesis, diagnostics, epidemiology, therapeutics and vaccine design.

Clinical disease management

Clinical disease management working group co-lead Lindsey Baden, HMS associate professor of medicine at Brigham and Women’s Hospital, discussed efforts to address the urgent need to define best practices for treatment and prevention of COVID-19, including the creation of guidance for patient care that informed national guidelines.

Within the span of weeks, members of the working group have launched over a dozen collaborative clinical trials across MassCPR institutions, with over 400 patients enrolled, to study the efficacy of drugs that show promise as treatments for COVID-19.

Trials under way include drugs that disable the virus such as remdesivir and favipiravir; medications that combat the inflammatory response that marks severe disease, and therapies that address other complications of the disease such as the development of blood clots.

“We rapidly engaged our broad Boston and Massachusetts medical community to design high quality trials that could be deployed immediately and to develop knowledge that could inform us as to what works, what doesn’t work and what could be used not only locally but globally,” said Baden, who is director of clinical research in infectious diseases at Brigham and Women’s, director of infectious diseases at Dana-Farber Cancer Institute and deputy editor of The New England Journal of Medicine.

Pathogenesis: How the virus causes disease

Pathogenesis working group co-lead Galit Alter, HMS professor of medicine at Massachusetts General Hospital and group leader at the Ragon Institute, outlined efforts to understand how the SARS-CoV-2 virus affects cells, tissues and organs to cause disease and how the body responds to the infection.

The group’s research targets a broad range of fundamental questions, including how the virus infects, how it spreads, how it is sensed by the body, why age and other factors influence outcomes, whether viral genetic variation affects disease severity, and how to identify and harness protective immune responses to guide the development of vaccines and treatments.

The pathogenesis working group is composed of experts representing nearly every facet of biomedicine, from critical care and infectious disease physicians to virologists and geneticists to mathematicians and chemical engineers—most of whom were not working on infectious diseases just a few weeks ago.

“Most inspiring is the remarkable redeployment of the scientific community across Massachusetts,” Alter said. “Scientists from multiple institutions took a stand in early March, applying their remarkably diverse expertise to tackle this global problem, to dissect this disease and to contribute new knowledge to the globe to help bring an end to this pandemic.”

Diagnostics

Diagnostics working group co-lead David Walt, the Hansjörg Wyss Professor of Biologically Inspired Engineering at HMS, discussed efforts to accelerate the development of timely and reliable diagnostic tools for COVID-19.

The group’s projects include rapid point-of-care tests that can be used at doctor’s offices and hospitals; the design of direct-to-consumer technologies that allow individuals to test at home; large-scale diagnostic platforms to test tens of thousands of samples at a time; , technologies to reveal if individuals have been exposed to SARS-CoV-2 and much more. To achieve this, working group members are applying or developing advanced technologies, including CRISPR-based approaches, nanomaterials and next-generation genomic sequencing.

MassCPR is supporting the diagnostics accelerator program at the Mass General/Brigham Center for COVID Innovation to validate the efficacy of new technologies and platforms, and established the MassCPR sample bank to facilitate the sharing of precious clinical samples between hospitals and research institutions.

“We need more testing and continued innovation. But we also need to use this testing to solve problems that are broader,” said Walt, HMS professor of pathology at Brigham and Women’s and a core faculty at the Wyss Institute for Biologically Inspired Engineering at Harvard University. “We are focused on the ultimate implementation of these diagnostics and testing technologies to help our city, state, country and the world safely get back to work, school and our new normal.”

Epidemiology

Epidemiology working group co-lead Megan Murray, the Ronda Stryker and William Johnston Professor of Global Health at HMS, discussed their efforts to understand the disease’s movement and behavior across populations, its local and global distribution, and its impact.

The group’s efforts range from tracking how many people have been or are currently affected by COVID-19 in Massachusetts, the U.S. and countries around the world to modeling the impact of prevention measures such as social distancing to searching for determinants of disease that may explain why some people have a severe response while others have only mild or undetectable disease.

Their projects also include real-time tracking of infection in communities, including sampling coronavirus presence in wastewater and collecting antibody samples at carefully chosen sites across the country. Researchers are also using advanced genomic technologies, such as repurposing DNA analysis methods that have been used to track migrations of ancient peoples in order to monitor the disease as it evolves over time and space.

The epidemiology working group is also looking at other outcomes of the pandemic, including impacts on economic health, overall societal health and the pandemic’s effect on mental health.

“This conglomeration of very different projects has really blossomed under the organization of the MassCPR, bringing together lots of different people who can think through how best to approach these problems and use the resources available in this amazing community to address them,” said Murray, who is professor of epidemiology at the Harvard T.H. Chan School of Public Health.

Therapeutics

Therapeutics working group co-lead Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS, discussed how they are working to meet the urgent need for drugs and therapies that prevent or treat COVID-19.

The group is working on rapidly testing thousands of existing drugs, many already used to treat other diseases, to search for ones that may be effective against COVID-19. This rapid repurposing of existing drugs could offer the fastest way to impact the pandemic, Abraham said.

Researchers in this group are searching for small-molecule drugs that can target and inactivate key viral proteins. To accelerate discovery, the team is harnessing the power of supercomputers in partnership with Google, to virtually screen billions of small molecules in weeks, rather than years.

Members of the working group have also identified numerous antibody candidates, including from recovered patients, to develop therapies that could neutralize SARS-CoV-2. These approaches target the interaction between the spike protein, the characteristic crown of thorns that the virus uses to enter cells and the ACE2 receptor on human cells that the spike protein attacks.

The group’s goal is to identify drugs, compounds and antibodies that can eventually be tested against the live virus at the National Emerging Infectious Diseases Laboratories at Boston University (NEIDL), a member of the MassCPR, Abraham said.

“Ultimately, our goal is to rapidly put molecules to the test,” Abraham said. “The partnership with NEIDL has been critical to our ability to rapidly move therapeutics to human use. The next step they’re getting ready for now is preclinical efficacy testing, which we’re quite excited about.”

Vaccines

Vaccines working group co-lead Dan Barouch, HMS professor of medicine at Beth Israel Deaconess Medical Center, discussed their efforts to develop vaccines that are critical to ultimately ending the pandemic and protecting against future outbreaks.

The working group has numerous vaccine programs under way, including an RNA vaccine from the Cambridge biotech company Moderna, spearheaded by MassCPR group co-lead Andrea Carfi, head of infectious disease research at Moderna, which recently became the first vaccine to reach clinical trials; and a vaccine candidate developed in partnership with Johnson & Johnson, led by Barouch.

To accelerate vaccine development against this new disease, members of the working group are leveraging their expertise and experience in vaccine science against a host of other infectious pathogens including HIV, hepatitis-C, SARS and MERS.

They are also working to ensure that the enormous manufacturing and distribution needs can be met to help populations around the world achieve herd immunity. This requires that multiple vaccines be developed in parallel, in order to determine which are the safest, most effective and most distributable.

“Vaccine development for COVID-19 is proceeding faster than for any other pathogen in history,” said Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess and member of the Ragon Institute.

“There are 7 billion people in this world. There has never been a vaccine program that has achieved that number of doses of a vaccine,” he added. “It would be wonderful if not one vaccine is successful, but actually if multiple vaccines are successful and reach the finish line.”

Resources and community

In addition to the six MassCPR working groups, consortium members representing NEIDL and member hospital institutions presented overviews of their facilities and highly collaborative resource-sharing programs that support the consortium’s efforts.

At the biosafety level 4-rated NEIDL, researchers are able to safely work with live viruses, which is critical for the consortium’s efforts to understand SARS-CoV-2, and to develop diagnostics, therapeutics and vaccines.

And the MassCPR Sample Biobank has helped member hospitals to come together to communicate on how best to recruit patients for studies, how to gather data and how to collect specimens to share with each other and with researchers throughout the consortium.

In addition to the core funding provided by the China Evergrande Group, MassCPR was enabled by critical support from philanthropists and supporters, including the Massachusetts Life Sciences Center, the state’s economic development and investment agency dedicated to supporting the growth of life sciences, Mark and Lisa Schwartz, the Bertarelli Foundation and many others.

“We’re blown away by what’s been accomplished in just the last 10 weeks,” said Mark Schwartz at the public briefing. “It’s been especially encouraging to see how much sharing of ideas and data and results there’s been between U.S. and Chinese scientists. At a time when there’s been little collaboration between our governments, there’s been a huge amount of trust and confidence at a personal level, at a lab level.”

A Q&A session with reporters representing national and intentional media outlets concluded the briefing.