Covid-19 - Are We in Truly Deep Sh*t or Not?

In 2020, we find ourselves in the midst of a global pandemic due to the coronavirus named Covid-19. There is an enormous amount of information - both validated scientific information and outright fake information -- circulating rapidly through social media and other channels. The challenge is in determining what is trustworthy versus what is not. The key question is whether the current pandemic is really a big deal, or not -- i.e. just a politically motivated “hoax” as some believe. 

What follows is a brief look back at the research on the 1918 Spanish Flu. It is a Cliff’s Notes version (quotes and paraphrases) of the pandemic research detailed on the following section of the CDC website: https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virus.html. It recounts the history of the research on the virus that caused the 1918 pandemic that killed an estimated 50 million people, and infected 500 million, worldwide. The extraordinary virulence of the 1918 H1N1 flu, often referred to as the “spanish flu,” puzzled researchers for decades. 

Recovery of the 1918 virus that was lost to history for decades

In 1951, Johan Hultin, a 25-year-old Swedish microbiologist and Ph.D. student at the University of Iowa, decided to search for the 1918 virus that was lost to history for decades. Hultin led an expedition to a small ocean-side village in Alaska called Brevig Mission. Brevig Mission was home to around 80 adults, mostly Inuit Natives, in 1918. “During the five-day period from November 15-20, the 1918 pandemic claimed the lives of 72 of the villages’ 80 adult inhabitants.” Hultin hoped to find traces of the 1918 virus itself, frozen in time within the tissues of the villagers who died from the disease and were buried in a mass grave in the permafrost. If he could find the virus, sequence its genome, and recreate the virus in a highly safe and regulated laboratory setting, he could study its secrets and better prepare for future pandemics. 

During the 1951 expedition, Hultin was able to uncover the body of a little girl who died from the disease. He successfully obtained lung tissue to study. But, despite his efforts, the lengthy travel time and the lack of refrigeration meant that he failed to get viable samples back to his lab. It wasn’t until 46 years later, in 1997 that Hultin got another chance to pursue the 1918 virus. 

That year, Hultin came across an article in the journal Science authored by Jeffery Taubenberger entitled, “Initial Genetic Characterization of the 1918 “Spanish” Influenza Virus.” Taubenberger was studying fragments of RNA obtained from lung tissue of a U.S. service member who died from the virus, in 1918 in South Carolina. Taubenberger’s genetic sequencing work did not represent a complete sequence of the 1918 virus’ genome, but it enabled him to identify the 1918 virus as a novel influenza A (H1N1) virus that belonged to a subgroup of viruses that came from humans and pigs. 

In 1997, Hultin invited Taubenberger to join him in an expedition back to Brevig Mission, a second attempt to obtain lung tissue samples to isolate the virus. The team found the body of an Inuit woman that Hultin named “Lucy” whose lungs were perfectly frozen and preserved in the permafrost. This time, the tissue samples were successfully transported back to the Armed Forces Institute of Pathology, to Taubenberger and his fellow researchers, including Dr. Ann Reid, who confirmed that viable1918 virus genetic material had indeed been recovered from Lucy’s lung tissue.

Sequencing and studying the genes of the 1918 virus

With this genetic material, the next step was to sequence the genes of the 1918 virus. Dr. Ann Reid initially focused on sequencing the virus’ hemagglutinin (HA) gene, which determines the virus’ surface proteins that allow it to enter and infect respiratory cells -- i.e. its ability to infect cells, or infectiousness. New data from this sequencing work suggested that the 1918 virus’ ancestors were influenza viruses known to infect mammals, but the HA itself may have been obtained from avian viruses. The 1918 virus’ HA had only four glycosylation sites, while modern human HA’s had five; so the virus did not appear to have come from, or evolved in, human hosts. Further, the 1918 virus’ HA also did not contain a “cleavage site” mutation, a recognized genetic marketer for virulence - i.e. the severity or harmfulness of a disease. So what was responsible for the 1918 virus’ exceptional virulence?

A subsequent study focused on the 1918 virus’ neuraminidase (NA) gene. An influenza virus’ NA surface proteins allow an influenza virus to break out of an infected cell and infect other cells - i.e. its ability to spread within the host. The researchers found that the NA gene of the 1918 virus shared many sequence and structural characteristics with both mammalian and avian influenza virus strains, suggesting that it likely was introduced from birds into mammals shortly before the 1918 pandemic. But again, the researchers could not find any single feature of the 1918 virus’ NA that could explain its virulence. 

Over the course of the following decade, other researchers completed the sequencing of the 1918 virus’ remaining genes - flu viruses have 8 genes in total. With the entire genome of the 1918 virus now sequenced, the necessary information was in place to reconstruct a live version of the 1918 virus.

Reconstructing the 1918 virus in the laboratory for pathogenicity studies

Dr. Terrence Tumpey was selected by the CDC to undertake the task of reconstructing the deadly virus in a CDC laboratory that was certified to the highest levels of biosecurity. In the summer of 2005, Dr. Tumpey successfully brought the 1918 virus back from extinction, in the laboratory. The next step was to study the 1918 virus’ pathogenicity (i.e., the ability of the virus to cause disease and harm a host), with laboratory studies. 

Controlled studies that measured various morbidities (i.e., weight loss, virus replication, and 50% lethal dose titers) were conducted on laboratory mice. Some mice were infected with the 1918 virus; other mice were infected with different influenza viruses that were designed via reverse genetics to have varying combinations of genes from the 1918 virus and contemporary human seasonal influenza A(H1N1) viruses. These other viruses were called “recombinant viruses.”

The fully reconstructed 1918 virus was striking in terms of its ability to quickly replicate, i.e., make copies of itself and spread infection in the lungs of infected mice. For example, four days after infection, the amount of 1918 virus found in the lung tissue of infected mice was 39,000 times higher than that produced by any one of the recombinant flu viruses used for comparison. Furthermore, the 1918 virus was at least 100 times more lethal than the other recombinant viruses tested. However, the 1918 virus did not cause systemic infection in its victims - i.e. it did not spread to other vital organs of mice — such as the brain, heart, liver and spleen. The research showed that the unique combination of all of the 1918 virus’ genes together made it so dangerous, not any single component. The researchers wrote “the constellation of all eight genes together make an exceptionally virulent virus.”

1918 compared to today

In 1918, the world was still engaged in World War I. Movement and mobilization of troops placed large numbers of people in close contact and living spaces were overcrowded. Health services were limited, and up to 30% of U.S. physicians were deployed to military service. In addition, medical technology and countermeasures at the time were limited or non-existent. No diagnostic tests existed at the time that could test for influenza infection. In fact, at that time doctors didn’t know influenza viruses existed.

Since 1918, the world has experienced three additional pandemics, in 1957, 1968, and most recently in 2009. These subsequent pandemics were less severe and caused considerably lower mortality rates than the 1918 pandemic. The 1957 H2N2 pandemic and the 1968 H3N2 pandemic each resulted in an estimated 1 million global deaths, while the 2009 H1N1 pandemic resulted in fewer than 0.3 million deaths in its first year. In 2013, the avian influenza A(H7N9) virus from China caused 1,568 human infections with a very high case-fatality proportion of about 39%. However, it had NOT gained the capability to spread quickly and efficiently between people. If it did, experts believe it could result in a pandemic with severity comparable to the 1918 pandemic.

"The 2013 avian influenza A (H7N9) virus caused 1,568 human infections with a high case-fatality proportion of about 39%. However, it HAD NOT gained the capability to spread quickly and efficiently between people."

“If a severe pandemic, such as occurred in 1918 happened today, it would still likely overwhelm health care infrastructure, both in the United States and across the world. Hospitals and doctors’ offices would struggle to meet demand from the number of patients requiring care. Such an event would require significant increases in the manufacture, distribution and supply of medications, products and life-saving medical equipment, such as mechanical ventilators. Businesses and schools would struggle to function, and even basic services like trash pickup and waste removal could be impacted.” 

The Worst Case Scenario

These predictions are playing out across the globe, exactly as feared. The first cases of the global pandemic caused by Covid-19 were reported in Wuhan, a province in China, in December 2019. Now 3 months in, in March 2020, over 700,000 confirmed cases of the covid-19 virus have been reported in 199 countries around the world - and continued exponential growth in case numbers, despite inadequate and low rates of testing in some countries (in other words, if there were more testing, the case numbers would be even higher than reported now). There is evidence that this respiratory virus HAS gained the ability to spread efficiently between people, the worst case scenario. 

"The current evidence suggests that this respiratory virus - Covid-19 - HAS GAINED the ability to spread efficiently between people, the worst case scenario."

Some countries have thus enacted lockdowns and “social distancing” measures designed to reduce the continued human-to-human spread of the Covid-19 virus. But tools like quarantine and isolation—which were key to controlling SARS—are unlikely stop spread of a virus that can transmit during the period from infection to symptoms, experts say. With some diseases, like influenza and measles, people who are infected but who are not yet feeling sick—people who are still going to work or school, taking public transit, shopping in malls, or going to movies—can pass the viruses to others.

The world population has grown to 7.6 billion people (compared to 1.8 billion in 1918) and so have swine and poultry populations as a means to feed them. This expanded number of hosts provides increased opportunities for novel influenza viruses from birds and pigs to spread, evolve and infect people. Global movement of people and goods has also increased, allowing the latest disease threat to be an international plane flight away. Due to the mobility and expansion of human populations, even once exotic pathogens, like Ebola, which previously affected only people living in remote villages of the African jungle, now have been documented to find their way into urban areas, causing large outbreaks.

Even the best defense against the flu -- a flu vaccine -- may not be available soon enough. Generally, it has taken about 20 weeks to select and manufacture a new vaccine. When it eventually becomes available, flu vaccines are often only moderately effective, even when well matched to circulating viruses. And finally, there remains an inadequate global capacity for mass producing flu vaccines, to make enough doses and get them to those most in need. An finally "herd immunity," which many are talking about now, does not apply until enough people have been vaccinated or have gotten the disease and recovered from it. And even then it assumes that humans' natural immune response is enough to slow or prevent the infection or the spread of the virus. For more background on herd immunity, see https://www.sciencealert.com/why-herd-immunity-will-not-save-us-from-the-covid-19-pandemic.

So “Are We in Truly Deep Sh*t with Covid-19?” Yeah. We are. And that’s just from the scientific point of view.

For more scientific detail, please refer to the original source material on the CDC website: https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virus.html.

For some good news, please see this very calm, rational explanation from an ICU doctor at Cornell, in NYC, on the front lines of seeing Covid-19 patients. It's not actually 47 mins (he took a whole bunch of questions at the end)