In mid-March, two of the nation’s leading authorities on SARS-CoV2, Susan R. Weiss, PhD, and Frederic Bushman, PhD, were invited to participate in a virtual event reviewing the topic of “the next pandemic”. Together, Drs. Weiss and Bushman are Co-Directors of the Penn Center of Research for Coronaviruses and Other Emerging Pathogens. The Center is at the hub of a group of research laboratories and institutions, including the Perelman School of Medicine, the Wistar Institute and the Children’s Hospital of Philadelphia, devoted to the morphology, pathology and genetics of SARS-CoV2 and other infectious diseases.
Hosted by Perry World House at the University of Pennsylvania, the event was moderated by infectious disease specialist, Harvey Rubin, MD, PhD, Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania. The Perry World House is a center for scholarly inquiry, teaching, research, international exchange, policy engagement, and public outreach on pressing global issues at the University of Pennsylvania.
About the Experts: Susan R. Weiss, PhD, and Frederic D. Bushman, PhD
Susan R. Weiss, PhD
In a career spanning four decades, Dr. Weiss has emerged as a leading virologist for the study of coronaviruses (CoVs). Early in the 1970s, her introduction to the coronaviruses was fortuitous: She found a reference to the coronaviruses while reading the journal of Virology, and discovered that they had not been well elucidated.
During her postdoctoral research, Dr. Weiss began studying the coronaviruses, and continued this research at the Medical School of the University of Pennsylvania in 1980. In addition to her role directing the Penn Center of Research for Coronaviruses and Other Emerging Pathogens, she serves as Vice Chair of the Department of Microbiology at the University of Pennsylvania.
Frederic D. Bushman, PhD
Dr. Bushman leads a laboratory that investigates host-microbe interactions in health and disease, with particular focus on the human microbiome, HIV pathogenesis, and DNA integration in human gene therapy. Dr. Bushman is the William Maul Measey Professor in Microbiology at the Perelman School of Medicine at the University of Pennsylvania. Known for its expertise in deep genome sequencing, the Bushman laboratory recently verified the UK variant B117 of SARS-CoV2 when it arrived in Philadelphia.
On the Next Pandemic
The following key points, with background information, are derived from the Next Pandemic webinar, and reflect the perspective of the Penn Physician Blog and its editors only. Excerpts have been lightly edited for clarity.
The approaching pandemic will likely have a non-human source.
According to Dr. Bushman, the next pandemic will arrive from an animal reservoir. The capacity of a virus to leap from one species to another (cross-species host switching, or simply spillover) occurs naturally as a consequence of environmental and pathogenic factors, and is not a new phenomenon. It is believed, for example, that measles originated with the domestication of cattle 1400 years ago. More recently, swine flu passed from pigs to humans and the highly pathogenic avian influenza virus A(H5N1) leaped from chickens to humans.
In addition to an animal source, the infecting agent will require efficient human-to-human spread, something like a respiratory virus, Dr. Bushman says, though he doesn’t discount biting insects as a source of transmission.
“Asymptomatic spread is a feature that seems to be consistent with efficient spread between humans,” he said. “With SARS-CoV2, we see that there’s asymptomatic spread, and that’s probably a big feature of why it spread so efficiently.” In addition to the coronaviruses, Dr. Bushman lists influenza, monkey pox (a disease similar—but unrelated—to smallpox, carried by rats and monkeys), and the mosquito-borne flaviviruses, including West Nile, dengue and Zika.
“There’s a host of others,” Dr. Bushman concludes. “Ebola, Marburg. We can debate the features of each, but these are the ones people are worried about.”
Animal-to-human coronavirus transmission was not an expected event.
Prior to the emergence of SARS in 2002, cross-species transmission of the coronaviruses was known within animal species, but no animal-to-human transmission had been recorded. That the coronaviruses could cross to humans from an animal source was unexpected, Dr. Weiss, says, even among researchers who had devoted decades to their study.
“When the first SARS emerged in southern China… the small group of researchers that work on these viruses were absolutely shocked,” Dr. Weiss recounts. “Because until that day, we had never heard of any kind of really pathogenic human [corona]viruses.” With the arrival of MERS and SARS-CoV2, she observes, the researchers amazement was replaced by concern that more hadn’t been done to prepare for them.
Much of the groundwork for the COVID vaccines was established before the millennium.
The CoVs have been the source of vaccine research and development for domestic animals for decades, and some of the first warnings about the potential for a coronavirus pandemic in humans had their origin in veterinary science. The research that contributed to these early vaccines proved useful in defining the pathology of the CoVs, according to Dr Weiss, with identification of the S protein occurring in the late 1970s, followed by apprehension of its furin protein cleavage. Cleaving the S protein yields the receptor binding (S1) and transmembrane fusion (S2) subunits, the objects of vaccine and therapeutic intervention.
By the time SARS arrived, Dr. Weiss recounts, the viruses had been sequenced and cloned, and their replication and structure?including the 16 proteins that are conserved among all coronaviruses—was understood. This information was critical to the identification of both SARS and SARS-CoV2 when they appeared.
SARS and MERS might have prepared us for COVID, but the opportunity was lost.
Like its descendent, SARS-associated coronavirus (SARS-CoV, or SARS) is thought to have originated in raccoon dogs and civets sold in live markets in southern China. According to the CDC, SARS disappeared only six months after spreading to more than two dozen countries. Much of the credit for its eradication has been attributed to effective containment. In the United States, only eight SARS infections were documented by laboratory testing and an additional 19 probable SARS infections were reported during the outbreak.
Middle Eastern Respiratory Syndrome (MERS) appeared in 2012 with a vector in dromedary camels, and has never disappeared. Although the mortality rate for MERS is exceptional (35.5%), the disease doesn’t appear to be particularly infectious, and has not spread beyond the Arabian peninsula.
A month after its emergence, the genetic sequence of SARS was published by the CDC, and that of MERS was available within a year of its appearance. Soon thereafter, vaccines were in development for both CoV strains (including protein subunit vaccines, virus-like particle vaccines, DNA vaccines, viral vector vaccines, whole-inactivated vaccines and live-attenuated vaccines). However, these vaccines encountered immunopathological complications and safety concerns that were unaddressed at the time of SARS’ containment, and had not been resolved when MERS arrived in its limited geographical sphere a decade later.
Reflecting on lost opportunities, Dr. Weiss noted as well the dearth of antiviral development to address the CoVs in the years after SARS and MERS appeared, a statement that echoes that found in the World Bank’s third edition (2017) of Major Infectious Diseases: Key Messages from Disease Control Priorities:
“Compared with antibiotics to treat bacterial infections, relatively few antiviral drugs have been developed to treat these emerging viral infections [SARS, MERS, Ebola, Zika]. Therefore, the most important intervention is to break the chain of transmission.”
There will be new viral emergences, and antivirals will be needed as they arise.
“Antivirals are really important for these viruses because they all have a very similar genetic material and they make very similar proteins,” Dr. Weiss says. The importance of antivirals in the years ahead will be to serve as safeguards until vaccines can be developed to address specific outbreaks.
“I think it’s important that we keep developing antivirals because if another coronavirus emerges from animals again we will likely not be protected by the current vaccines.” [Note: Here, Dr. Weiss is not referring to variants of the current SARS-CoV2, for which the present vaccines seem to offer protection, but to a new, genetically distinct, disease. There is to date no universal vaccine for the coronaviruses.]
“We will need these antiviral therapies as a quick response to whatever new virus should emerge,” she says. “An antiviral directed against one of the coronaviruses would very likely work against all of them.”
Dr. Weiss and investigator Sara Cherry have been investigating avenues to advance the development and use of antivirals against SARS-CoV2 since early 2020.