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My basement is overrun by sports cards from the 1980s and 1990s, all of which aren't worth the cardboard they're printed on. And they've never been more priceless.

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One of the most photographed British women of the 1980s talks about feminism, her abusive father and how she battled her fears to come out as gay

In a small, unloved hotel, the receptionist greets me and Samantha Fox with pursed lips: “There will be no interview here,” she says. I feel as if I’ve wandered into the pages of Fox’s new autobiography, Forever, which is littered with bizarre anecdotes of best-laid plans going awry. From her ill-fated presenting partnership with a spaced-out Mick Fleetwood at the 1989 Brit awards, to a secret naked horseback photo shoot in Antigua – during which her steed galloped off with her to a busy tourist beach – not much has gone as expected in Fox’s life. Not least the day she worked with her childhood idol David Cassidy, who died earlier this month, which she says culminated in being sexually assaulted by him. Despite these, and many other setbacks, she says she is a “lucky girl”.

Fox was just 16 when her mother entered her for the Sunday People’s Face and Shape of 1983 competition – her wholesome, girl-next-door image made her the most popular Page 3 girl ever, and one of the most photographed women of the 1980s, alongside Princess Diana and Margaret Thatcher. By 21, she had made her first pop record and retired from modelling, going on to break the US and sell 30m records worldwide.

We’re interacting less with the outside world – and the societal pressures that come with it. Are some women still wearing makeup every day?

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System treats maternity allowance as unpaid income, skewing the amount of universal credit paid out

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Prime Minister Justin Trudeau says that an agreement has been reached with all provinces and territories to top up the wages of some essential front-line workers including those in long-term care facilities where COVID-19 has spread among both residents and staff, with deadly impact. This comes as the military deployment to long-term care homes is being expanded.

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Early in the morning on April 5, 2020, an article appeared on the website Medium with the title “Covid-19 had us all fooled, but now we might have finally found its secret.” The article claimed that the pathology of COVID-19 was completely different from what public health authorities, such as the World Health Organization, had previously described. According to the author, COVID-19 strips the body’s hemoglobin of iron, preventing red blood cells from delivering oxygen and damaging the lungs in the process. It also claimed to explain why hydroxychloroquine, an experimental treatment often hyped by President Trump, should be effective.

The article was published under a pseudonym—libertymavenstock—but the associated account was linked to a Chicagoland man working in finance, with no medical expertise. (His father is a retired M.D., and in a follow-up note posted on a blog called “Small Dead Animals,” the author claimed that the original article was a collaboration between the two of them.) Although it was not cited, the claims were apparently based on a single scientific article that has not yet undergone peer-review or been accepted for publication, along with “anecdotal evidence” scraped from social media.1

While Medium allows anyone to post on their site and does not attempt to fact-check content, this article remained up for less than 24 hours before it was removed for violating Medium’s COVID-19 content policy. Removing the article, though, has not stopped it from making a splash. The original text continues to circulate widely on social media, with users tweeting or sharing versions archived by the Wayback Machine and re-published by a right-wing blog. As of April 12, the article had been tweeted thousands of times.

There is a pandemic of misinformation about COVID-19 spreading on social media sites. Some of this misinformation takes well-understood forms: baseless rumors, intentional disinformation, and conspiracy theories. But much of it seems to have a different character. In recent months, claims with some scientific legitimacy have spread so far, so fast, that even if it later becomes clear they are false or unfounded, they cannot be laid to rest. Instead, they become information zombies, continuing to shamble on long after they should be dead.

It is not uncommon for media sources like Medium to retract articles or claims that turn out to be false or misleading. Neither are retractions limited to the popular press. In fact, they are common in the sciences, including the medical sciences. Every year, hundreds of papers are retracted, sometimes because of fraud, but more often due to genuine errors that invalidate study findings.2 (The blog Retraction Watch does an admirable job of tracking these.)

Reversing mistakes is a key part of the scientific process. Science proceeds in stops and starts. Given the inherent uncertainty in creating new knowledge, errors will be made, and have to be corrected. Even in cases where findings are not officially retracted, they are sometimes reversed— definitively shown to be false, and thus no longer valid pieces of scientific information.3

Researchers have found, however, that the process of retraction or reversal does not always work the way it should. Retracted papers are often cited long after problems are identified,4 sometimes at a rate comparable to that before retraction. And in the vast majority of these cases, the authors citing retracted findings treat them as valid.5 (It seems that many of these authors pull information directly from colleagues’ papers, and trust that it is current without actually checking.) Likewise, medical researchers have bemoaned the fact that reversals in practice sometimes move at a glacial pace, with doctors continuing to use contraindicated therapies even though better practices are available.6

For example, in 2010, the anesthesiologist Scott Reuben was convicted of health care fraud for fabricating data and publishing it without having performed the reported research. Twenty-one of Reuben’s articles were ultimately retracted. And yet, an investigation four years later found half of these articles were still consistently cited, and that only one-fourth of these citations mentioned that the original work was fraudulent.7 Given that Reuben’s work focused on the use of anesthetics, this failure of retraction is seriously disturbing.

Claims with some scientific legitimacy continue to shamble on long after they should be dead.

But why don’t scientific retractions always work? At the heart of the matter lies the fact that information takes on a life of its own. Facts, beliefs, and ideas are transmitted socially, from person to person to person. This means that the originator of an idea soon loses control over it. In an age of instant reporting and social media, this can happen at lightning speed.

The first models of the social spread of information were actually epidemiological models, developed to track the spread of disease. (Yes, these are the very same models now being used to predict the spread of COVID-19.) These models treat individuals as nodes in a network and suppose that information (or disease) can propagate between connected nodes.

Recently, one of us, along with co-authors Travis LaCroix and Anders Geil, repurposed these models to think specifically about failures of retraction and reversal.8 A general feature of retracted information, understood broadly, is that it is less catchy than novel information in the following way. People tend to care about reversals or retractions only when they have already heard the original, false claim. And they tend to share retractions only when those around them are continuing to spread the false claim. This means that retractions actually depend on the spread of false information.

We built a contagion model where novel ideas and retractions can spread from person to person, but where retractions only “infect” those who have already heard something false. Across many versions of this model, we find that while a false belief spreads quickly and indiscriminately, its retraction can only follow in the path of its spread, and typically fails to reach many individuals. To quote Mark Twain, “A lie can travel halfway around the world while the truth is putting on its shoes.” In these cases it’s because the truth can’t go anywhere until the lie has gotten there first.

Another problem for retractions and reversals is that it can be embarrassing to admit one was wrong, especially where false claims can have life or death consequences. While scientists are expected to regularly update their views under normal circumstances, under the heat of media and political scrutiny during a pandemic they too may be less willing to publicize reversals of opinion.

The COVID-19 pandemic has changed lives around the world at a startling speed—and scientists have raced to keep up. Academic journals, accustomed to a comparatively glacial pace of operations, have faced a torrent of new papers to evaluate and process, threatening to overwhelm a peer-review system built largely on volunteer work and the honor system.9 Meanwhile, an army of journalists and amateur epidemiologists scour preprint archives and university press releases for any whiff of the next big development in our understanding of the virus. This has created a perfect storm for information zombies—and although it also means erroneous work is quickly scrutinized and refuted, this often makes little difference to how those ideas spread.

Many examples of COVID-19 information zombies look like standard cases of retraction in science, only on steroids. They originate with journal articles written by credentialed scientists that are later retracted, or withdrawn after being refuted by colleagues. For instance, in a now-retracted paper, a team of biologists based in New Delhi, India, suggested that novel coronavirus shared some features with HIV and was likely engineered.10 It appeared on an online preprint archive, where scientists post articles before they have undergone peer review, on January 31; it was withdrawn only two days later, following intense critique of the methods employed and the interpretation of the results by scientists from around the world. Days later, a detailed analysis refuting the article was published in the peer-reviewed journal Emerging Microbes & Infections.11 But a month afterward, the retracted paper was still so widely discussed on social media and elsewhere that it had that highest Altmetric score—a measure of general engagement with scientific research—of any scientific article published or written in the previous eight years. Despite a thorough rejection of the research by the scientific community, the dead information keeps walking.

Other cases are more subtle. One major question with far-reaching implications for the future development of the pandemic is to what extent asymptomatic carriers are able to transmit the virus. The first article reporting on asymptomatic transmission was a letter published in the prestigious New England Journal of Medicine claiming that a traveler from China to Germany transmitted the disease to four Germans before her symptoms appeared.12 Within four days, Science reported that the article was flawed because the authors of the letter had not actually spoken with the Chinese traveler, and a follow-up phone call by public health authorities confirmed that she had had mild symptoms while visiting Germany after all.13 Even so, the article has subsequently been cited nearly 500 times according to Google Scholar, and has been tweeted nearly 10,000 times, according to Altmetric.

Media reporting on COVID-19 should be linked to authoritative sources that are updated as information changes.

Despite the follow-up reporting on this article’s questionable methods, the New England Journal of Medicine did not officially retract it. Instead, a week after publishing the letter, the journal added a supplemental appendix describing the progression of the patient’s symptoms while in Germany, leaving it to the reader to determine whether the patient’s mild early symptoms should truly count. Meanwhile, subsequent research14, 15 involving different cases has suggested that asymptomatic transmission may be possible after all—though as of April 13, the World Health Organization considers the risk of infection from asymptomatic carriers to be “very low.” It may turn out that transmission of the virus can occur before any symptoms appear, or while only mild symptoms are present, or even in patients who will never go on to present symptoms. Even untangling these questions is difficult, and the jury is still out on their answers. But the original basis for claims of confirmed asymptomatic transmission was invalid, and those sharing them are not typically aware of the fact.

Another widely discussed article, which claims that the antiviral drug hydroxychloroquine and the antibiotic azithromycin, when administered together, are effective treatments for COVID-19 has drawn enormous amounts of attention to these particular treatments, fueled in part by President Trump.16 These claims, too, may or may not turn out to be true—but the article with which they apparently originated has since received a statement of concern from its publisher, noting that its methodology was problematic. Again, we have a claim that rests on shoddy footing, but which is spreading much farther than the objections can.17 And in the meantime, the increased demand for these medications has led to dangerous shortages for patients who have an established need for them.18

The fast-paced and highly uncertain nature of research on COVID-19 has also created the possibility for different kinds of information zombies, which follow a similar pattern as retracted or refuted articles, but with different origins. There have been a number of widely discussed arguments to the effect that the true fatality rate associated with COVID-19 may be ten or even a hundred times lower than early estimates from the World Health Organization, which pegged the so-called “case fatality rate” (CFR)—the number of fatalities per detected case of COVID-19—at 3.4 percent.19-21

Some of these arguments have noted that the case fatality rate in certain countries with extensive testing, such as Iceland, Germany, and Norway, is substantially lower. References to the low CFR in these countries have continued to circulate on social media, even though the CFR in all of these locations has crept up over time. In the academic realm, John Ioannidis, a Stanford professor and epidemiologist, noted in an editorial, “The harms of exaggerated information and non‐evidence‐based measures,” published on March 19 in the European Journal of Clinical Investigation, that Germany’s CFR in early March was only 0.2 percent.21 But by mid-April it had climbed to 2.45 percent, far closer to the original WHO estimate. (Ioannidis has not updated the editorial to reflect the changing numbers.) Even Iceland, which has tested more extensively than any other nation, had a CFR of 0.47 percent on April 13, more than 4 times higher than it was a month ago. None of this means that the WHO figure was correct—but it does mean some arguments that it is wildly incorrect must be revisited.

What do we do about false claims that refuse to die? Especially when these claims have serious implications for decision-making in light of a global pandemic? To some degree, we have to accept that in a world with rapid information sharing on social media, information zombies will appear. Still, we must combat them. Science journals and science journalists rightly recognize that there is intense interest in COVID-19 and that the science is evolving rapidly. But that does not obviate the risks of spreading information that is not properly vetted or failing to emphasize when arguments depend on data that is very much in flux.

Wherever possible, media reporting on COVID-19 developments should be linked to authoritative sources of information that are updated as the information changes. The Oxford-based Centre for Evidence-Based Medicine maintains several pages that review the current evidence on rapidly evolving questions connected to COVID-19—including whether current data supports the use of hydroxychloroquine and the current best estimates for COVID-19 fatality rates. Authors and platforms seeking to keep the record straight should not just remove or revise now-false information, but should clearly state what has changed and why. Platforms such as Twitter should provide authors, especially scientists and members of the media, the ability to explain why Tweets that may be referenced elsewhere have been deleted. Scientific preprint archives should encourage authors to provide an overview of major changes when articles are revised.

And we should all become more active sharers of retraction. It may be embarrassing to shout one’s errors from the rooftops, but that is what scientists, journals, and responsible individuals must do to slay the information zombies haunting our social networks.

Cailin O’Connor and James Owen Weatherall are an associate professor and professor of logic and philosophy at the University of California, Irvine. They are coauthors of The Misinformation Age: How False Beliefs Spread.

Lead image: nazareno / Shutterstock

References

1. Liu, W. & Li, H. COVID-19 attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv (2020).

2. Wager, E. & Williams, P. Why and how do journals retract articles? An analysis of Medline retractions 1988-2008. Journal of Medical Ethics 37, 567-570 (2011).

3. Prasad, V., Gall, V., & Cifu, A. The frequency of medical reversal. Archives of Internal Medicine 171, 1675-1676 (2011).

4. Budd, J.M., Sievert, M., & Schultz, T.R. Phenomena of retraction: Reasons for retraction and citations to the publications. The Journal of the American Medical Association 280, 296-297 (1998).

5. Madlock-Brown, C.R. & Eichmann, D. The (lack of) impact of retraction on citation networks. Science and Engineering Ethics 21, 127-137 (2015).

6. Prasad, V. & Cifu, A. Medical reversal: Why we must raise the bar before adopting new technologies. Yale Journal of Biology and Medicine 84, 471-478 (2011).

7. Bornemann-Cimenti, H., Szilagyi, I.S., & Sandner-Kiesling, A. Perpetuation of retracted publications using the example of the Scott S. Reuben case: Incidences, reasons and possible improvements. Science and Engineering Ethics 22, 1063-1072 (2016).

8. LaCroix, T., Geil, A., & O’Connor, C. The dynamics of retraction in epistemic networks. Preprint. (2019).

9. Jarvis, C. Journals, peer reviewers cope with surge in COVID-19 publications. The Scientist (2020).

10. Pradhan, P., et al. Uncanny similarity of unique inserts in the 2019-nCoV spike protein to HIV-1 gp120 and Gag. bioRxiv (2020).

11. Xiao, C. HIV-1 did not contribute to the 2019-nCoV genome. Journal of Emerging Microbes and Infections 9, 378-381 (2020).

12. Rothe, C., et al. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. New England Journal of Medicine 382, 970-971 (2020).

13. Kupferschmidt, K. Study claiming new coronavirus can be transmitted by people without symptoms was flawed. Science (2020).

14. Hu, Z., et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Science China Life Sciences (2020). Retrieved from doi: 10.1007/s11427-020-1661-4.

15. Bai, R., et al. Presumed asymptomatic carrier transmission of COVID-19. The Journal of the American Medical Association 323, 1406-1407 (2020).

16. Gautret, P., et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents (2020).

17. Ferner, R.E. & Aronson, J.K. Hydroxychloroquine for COVID-19: What do the clinical trials tell us? The Centre for Evidence-Based Medicine (2020).

18. The Arthritis Foundation. Hydroxychloroquine (Plaquenil) shortage causing concern. Arthritis.org (2020).

19. Oke, J. & Heneghan, C. Global COVID-19 case fatality rates. The Centre for Evidence-Based Medicine (2020).

20. Bendavid, E. & Bhattacharya, J. Is the coronavirus as deadly as they say? The Wall Street Journal (2020).

21. Ionnidis, J.P.A. Coronavirus disease 2019: The harms of exaggerated information and non-evidence-based measures. European Journal of Clinical Investigation 50, e13222 (2020).

It seems like people who get infected with SARS-CoV-2 retain immunity, but we can’t be sure how long that immunity will last. We still lack the testing capabilities to be certain.eamesBot / Shutterstock

This story was updated post-publication to include information from a study published on the preprint server medRxiv on April 17, 2020.

With more than half a million cases of COVID-19 in the United States1 and the number of deaths increasing daily, it remains unclear when and how we might return to some semblance of pre-pandemic life. This leaves many grappling with an important question: Do you become immune after SARS-CoV-2 infection? And, if so, how long might that immunity last?

In 2019, the virus SARS-CoV-2 jumped to a human host for the first time, causing the disease COVID-19. When you become infected with a new virus, your body does not possess the antibodies necessary to mount a targeted immune response. Antibodies, proteins belonging to the immunoglobulin family, consist of four chains of amino acids that form a characteristic Y-shaped structure. Antibodies are manufactured by the immune system to bind to antigens (viral proteins) to neutralize viral infectivity.

When you inhale an aerosolized droplet containing SARS-CoV-2, the virus encounters the cells of the mucous membrane lining the respiratory tract. If effective contact is made, the virus binds to a particular receptor on these cells called ACE-2. After binding ACE-2, a host enzyme is co-opted to cleave the virus’ surface protein, called the spike protein, allowing the virus to enter the cell.

It appears that individuals with COVID-19 do create neutralizing antibodies—the basis of immunity.

Within the first few hours of infection, the body’s first line of defense—the innate immune response—is activated. The innate immune response is non-specific. When a “foreign” molecule is detected, innate immune cells signal to other cells to alter their response or prepare to combat infection.

In the following days, the adaptive immune response is activated, which is more specific. The adaptive immune response will peak one to two weeks post-infection and consists of antibodies and specialized immune cells. It is called the “adaptive” immune response because of its ability to tailor the response to a specific pathogen. Antibodies can neutralize viral infectivity by preventing virus from binding to receptors, blocking cell entry, or causing virus particles to aggregate.2 Once an infection has resolved, some of these antibodies remain in the body as immunological memory to be recruited for protection in the case of reinfection. To be immune to a virus is to possess this immunological memory.

Many vaccines work by activating the adaptive immune response. Inactivated virus, viral protein, or some other construct specific to a particular virus are introduced into the body as vaccines to initiate an immune response. Ideally, the body creates antibodies against the viral construct so that it can mount a succinct response when infected by the virus. However, in order to work effectively, a vaccine must provoke an immune response that is sufficiently robust. If the body only produces low concentrations of neutralizing antibodies, adequate immunological memory may not be sustained.

While there is still much that we have to learn about SARS-CoV-2, it appears that individuals with COVID-19 do create neutralizing antibodies—the basis of immunity. However, we don’t know for certain how long that immunity might offer protection. On the question of COVID-19 re-infection, Matt Frieman, a coronavirus researcher at the University of Maryland School of Medicine, commented in a recent interview with NPR: “We don’t know very much … I think there’s a very likely scenario where the virus comes through this year, and everyone gets some level of immunity to it, and if it comes back again, we will be protected from it—either completely or if you do get reinfected later, a year from now, then you have much less disease. That’s the hope, but there is no way to know that.”3

Immunity to a virus is measured by serological testing—patient blood is collected and analyzed for the presence of antibodies against a particular virus. Serological data is most informative when collected long-term, so the data we have been able to obtain on SARS-CoV-2 is limited. However, data on other coronaviruses that we’ve had the opportunity to study in more depth can inform our estimations on how this outbreak may evolve.

First, we can look to the coronaviruses that are known to cause the common cold. Following infection with one of these coronaviruses, disease is often mild; therefore, the concentration of antibodies detected in the blood is low. This is because mild disease often indicates a less robust immune response. Interestingly, it is not the virus itself that causes us to feel sick, but, rather, our body’s response to it. Typically, the sicker we feel, the stronger the immune response; therefore, after a cold, we are often only protected for a year or two against the same virus.4 While SARS-CoV-2 wouldn’t necessarily act like these common coronaviruses, the body’s response to these coronaviruses serves as a point of reference upon which to make predictions in the absence of virus-specific data.

We can also look to coronaviruses that are known to cause severe disease, such as SARS-CoV, which caused the 2002-2003 outbreak of SARS in China. One study discovered that antibodies against SARS-CoV remained in the blood of healthcare workers for 12 years after infection.5 While it is not certain that SARS-CoV-2 will provoke a response similar to that of SARS-CoV, this study provides us with information that can inform our estimates on immunity following COVID-19 and provide hope that immunity will provide long-term protection.

If immunity to SARS-CoV-2 diminishes as it does for common cold coronaviruses, it is likely that wintertime outbreaks will recur.

Scientists have also been working to analyze antibodies in samples from individuals infected with SARS-CoV-2. A research group in Finland recently published a study detailing the serological data collected from a COVID-19 patient over the course of their illness.6 Antibodies specific to SARS-CoV-2 were present within two weeks from the onset of symptoms. Similarly, another recent report analyzing patients with confirmed COVID-19 indicated that it took approximately 11-14 days for neutralizing antibodies to be detected in blood.7 Both of these studies, while preliminary, suggest that the basis for immunity is present in patients infected with SARS-CoV-2.

Another report looked at the possibility for recurrence of COVID-19 following re-infection with SARS-CoV-2.8 In this study, rhesus macaques were infected with SARS-CoV and allowed to recover after developing mild illness. Once blood samples were collected and confirmed to test positive for neutralizing antibodies, half of the infected macaques were re-challenged with the same dose of SARS-CoV-2. The re-infected macaques showed no significant viral replication or recurrence of COVID-19. While macaques “model” human immunity, not predict it, these data further support the possibility that antibodies manufactured in response to SARS-CoV-2 are protective against short-term re-infection.

We can also analyze a virus’ structure, and the information gained from sequencing the viral genome, when trying to predict its behavior. All viruses continually undergo mutation in the process of rapid replication. They lack the necessary machinery to repair changes incurred to the genetic sequence (we as humans also incur mutations to our genetic sequence daily, but we have more sophisticated genetic repair mechanisms in place). The occurrence of significant genetic changes to the viral genome that result in viable genetic changes to a virus is termed antigenic variation. We see a lot of antigenic variation in influenza viruses (thus the need to create new vaccines each year); but the coronaviruses seem to be relatively stable antigenically.4 This is because most coronaviruses have an enzyme that allows them to correct genetic errors sustained during replication. The more stable a virus remains over time, the more likely that antibodies manufactured in response to infection or vaccination will remain effective at neutralizing viral infectivity.

All this considered, it appears that immunity is retained following SARS-CoV-2 infection. So too, that immunity might persist long enough to warrant the implementation of vaccination. However, we still have much to learn about this virus, and whether there may be some cross-immunity between SARS-CoV-2 and other coronaviruses. The widespread variation in patient immune responses adds an additional layer of complexity. We still don’t have a good understanding of why people have different responses to viral infection—some of this variation is owed to genetic variation, but how and why some people have more robust immune responses and more severe disease is still unknown.4 In some cases, individuals show a high immune response because the concentration of virus is high. In other cases, individuals show a high immune response because they differ in some aspect of immune regulation or efficiency. However, as levels of immunity increase generally across a population, the population approaches what is called “herd immunity”—when the percentage of a population immune to a particular virus is sufficiently high that viral load drops below the threshold required to sustain the infection in that population.9

How the pandemic will evolve in the coming months is uncertain. Outcomes depend on a myriad of factors—the duration of immunity, the dynamics of transmission and how we mitigate those dynamics through social distancing, the development of therapeutics and or vaccines, and the ability of healthcare systems to handle COVID-19 caseloads. If immunity to SARS-CoV-2 diminishes as it does for common cold coronaviruses, it is likely that wintertime outbreaks will recur in coming years.10 Whether immunity to other coronaviruses might offer some cross protective immunity to SARS-CoV-2 will also play a role, albeit to a lesser extent. Widespread serological testing to assess the duration of immunity to SARS-CoV-2 is imperative, but many countries still lack this capability.

A recent study looking at serological data from 3,300 symptomatic and asymptomatic individuals in California estimates that there may be as many as 48,000-81,000 people who have been infected with SARS-Cov-2 in Santa Clara County, which is 50- to 85-fold more cases than we previously thought.11 This small-scale survey emphasizes the importance of serological testing in determining the true extent of infection.

The continuation of rigid social distance also hangs in a balance—one-time social distancing measures may drive the SARS-CoV-2 epidemic peak into the fall and winter months, especially if there is increased wintertime transmissibility.10 New therapeutics, vaccines, or measures such as contact tracing and quarantine—once caseloads have been reduced and testing capacity increased—might reduce the need for rigid social distancing. However, if such measures are not put in place, mathematical models predict that surveillance and recurrent social distancing may be required through 2022.10 Only time will tell.

Helen Stillwell is a research associate in immunobiology at Yale University.

References

1. The COVID Tracking Project https://covidtracking.com/data/us-daily (2020).

2. Virology Blog: About Viruses and Viral Disease. Virus neutralization by antibodies. virology.ws (2009).

3. GreenfieldBoyce, N. Do you get immunity after recovering from a case of coronavirus? NPR (2020).

4. Racaniello, V., Langel, S., Leifer, C., & Barker, B. Immune 29: Immunology of COVID-19. Immune Podcast. microbe.tv (2020).

5. Guo, X., et al. Long-Term persistence of IgG antibodies in SARS-CoV infected healthcare workers. bioRxiv (2020). Retrieved from doi: 10.1101/20202/02/12/20021386

6. Haveri, A., et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveillance 25, (2020).

7. Zhao, J., et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clinical Infectious Diseases (2020). Retrieved from doi: 10.1093/cid/ciaa344

8. Bao, L., et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv (2020). Retrieved from doi: 10.1101/20202.03.13.990226

9. Virology Blog: About Viruses and Viral Disease. Herd immunity. virology.ws (2008).

10. Kissler, S.M. Tedijanto, C., Goldstein, E., Grad, Y.H., & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the post-pandemic period. Science eabb5793 (2020).

11. Bendavid, E., et al. COVID-19 antibody seroprevalence in Santa Clara County, California. medRxiv (2020). Retrieved from doi: 10.1101/2020.04.14.20062463

There are many challenges to developing a vaccine that will be successful against COVID-19.eamesBot / Shutterstock

Wayne Koff is one of the world’s experts on vaccine development, the president and CEO of the Human Vaccines Project. He possesses a deep understanding of the opportunities and challenges along the road to a safe and effective vaccine against COVID-19. He has won prestigious awards, published dozens of scientific papers, held major positions in academia, government, industry, and nonprofit organizations. But Koff, 67, has never produced a successful vaccine.

“I have been an abject failure,” he says. He smiles with a charming, self-deprecating sense of humor. “That’s what the message is.”

The real reason for Koff’s lack of success is that he spent most of his career searching for a vaccine against HIV, the virus that causes AIDS. It remains, as he and many others put it, “the perfect storm” of a viral infection resistant to a vaccine development. Almost 40 years after doctors first recognized the disease in five men in Los Angeles—and 70 million people have been infected worldwide—there are no adequate animal models. Neutralizing antibodies, the backbone of many vaccines, do not stop it, and most importantly, HIV begins its assault on the body by attacking CD4 T cells, which serve as the command center of much of the immune system.

As for COVID-19, “We’re all hoping this one is going to be easier,” says Koff, a slight, bearded man with thick, curly salt-and-pepper hair. “There are research issues that still have to be addressed on a COVID vaccine. But they are a lot more straightforward than what we were dealing with in HIV.”

Let’s say we have a vaccine in 18 months. How do you make 1 billion doses or 4 billion doses or whatever it’s going to take to immunize everybody?

Koff and others started the Human Vaccines Project in 2016, modeled on the Human Genome Project. The project works with industry and academia to study the human immune system and develop vaccines, incorporating every modern-day tool, including artificial intelligence, computational biology, and big data sets. Today it is partnered with the Harvard T.H. Chan School of Public Health.

With COVID-19, Koff says, scientists “know the target is the spike protein binding site.” This is where the proteins sticking out from the virus attach to the cells in the human respiratory system. “If you can elicit antibodies against those proteins, they should be neutralizing.” He puts a strong emphasis on should. To prove antibodies will prevent infection, scientists must watch a population of people who’ve been infected for months or longer. It’s a good bet, based on similar viruses, that antibodies will appear and protect—although no one right now can predict how long and how well.

Depending on which count you use, more than 70 companies, universities, and other institutions are offering candidate vaccines. Koff says the real number of companies is lower. During the AIDS crisis, he says, “a lot of people claimed they had an experimental HIV vaccine in development. Some of those were a one-person lab who had created a paper company to attract investors.”

But even with a lower number, almost everyone involved in the search for a vaccine agrees that several different approaches from different research organizations need to proceed in parallel. The world does not have the time to bet on one horse. The race will be neither simple nor cheap.

“The probability of success, depending on whose metric is used in vaccines, is somewhere between 6 and 10 percent of candidate vaccines that make it from the animal model through licensure,” Koff says. “That process costs $1 billion or more. So you can do the math.”

Koff sees big potential problems at the outset. “In the best of all worlds, let’s say we have a vaccine in 18 months. Who knows where the epidemic is going to be then and what its impact is going to be? How do you make 1 billion doses or 4 billion doses or whatever it’s going to take to immunize everybody? Will we need one dose or two or three? These are issues people just haven’t faced before.”

COVID-19 also presents some unique dangers for vaccine safety. Based on how the virus behaves when it infects some people, there’s a chance a vaccine could dangerously overstimulate the immune system, a reaction called immune enhancement. “I’m hoping it’s more theoretical than real,” Koff says. “But that has to be addressed and it may slow down the entire process.” To ensure safety, he says, “It may mean we have to test the vaccine in a larger number of people. It’s one thing to do a 50-person trial in healthy adults as a safety signal. It’s another thing to run a trial of 4,000 or 5000 or more individuals.”

The world does not have the time to bet on one horse. The race will be neither simple nor cheap.

A virus also sometimes causes mysterious, potentially deadly blood clots. This means an experimental vaccine could hypothetically induce the same damage. “This is a bad bug,” Koff says. “We’re just starting to understand that pathogenesis.”

A big question is who should be the first volunteers for widespread vaccine testing. “Who are the high-risk groups?” asks Koff. “Is it nursing-home residents and staff, health-care workers and people on the front lines, or people someplace else like grocery stores? We must also make sure a vaccine is effective for the elderly and people in the developing world.”

Many vaccines work well in young and healthy people but not in older adults because immunity declines with age. Influenza vaccine is a prime example. Rotavirus vaccine, which protects against the deadliest killer—diarrheal disease in children—works better in the developed world. In the developing world, the virus often circulates year-round. Infants get antibodies from breast milk but not enough to prevent disease. Worse, those antibodies can make the vaccine less effective.

Another hypothetical obstacle is that a mutation in the COVID-19 virus could render a vaccine designed today less effective in the future. While the virus mutates frequently, so far there has been little change in the critical part of the spike that binds to human cells.

Of course, neither Koff nor all the others working for a COVID-19 vaccine focus solely on the potential obstacles. At one time, all vaccines against viruses either killed viruses, such as the Salk polio vaccine, or rendered them harmless, such as the Sabin polio vaccine. Now there is a multiplicity of ways to stimulate an immune response to prevent infection or reduce the consequences. These include genetically engineered protein subunits (peptides) or virus-like particles. Such approaches have led to successful vaccines against hepatitis B and human papilloma virus, which causes cervical cancer. Researchers now use “vectors”—harmless viruses attached to the protein subunits and virus particles to transmit them into the body. There are also many new adjuvants, chemicals that boost immune response to a vaccine.

Newer platforms include direct injection of messenger-RNA. M-RNA is the chemical used to translate the information in DNA into proteins in all cells. The Moderna Company, which received a $483 million grant from the U.S. government, and has begun early clinical trials, uses m-RNA to try to make the body produce proteins to protect against the COVID-19 virus. INOVIO Pharmaceuticals uses pieces of DNA called plasmids to achieve the same objective. It has also begun phase 1 studies.

“There are about eight platforms, and it would be good to see a couple vaccines in each of those advance,” Koff says. Predicting which of these most likely to succeed or fail he says would be “simply foolish.”

Many groups, including the Human Vaccines Initiative, are plotting routes to test any possible vaccine more quickly than tradition dictates with an “adaptive trial design.” Usually trials begin with a phase 1 study of some 50 healthy people to search for any immediate signs of toxicity, then moves onto about 200 people in a phase 2, still looking for hazards and a signal of immunity, and then to phase 3 in thousands of people. But the plan here is to start phases 2 and 3 even before its predecessors are finished, and keep recruiting additional volunteers so long as no danger signals arise.

Good animal models are appearing almost daily. Macaque monkeys, hamsters, and genetically engineered mice have all been infected in the laboratory and could determine whether potential vaccines exhibit various types of immunity. Members of Congress from both sides of the aisle have suggested that healthy human volunteers should be allowed to agree to be test subjects, allowing themselves to be infected. Stanley Plotkin, a vaccine researcher at the University of Pennsylvania, was among the first to suggest the idea.

Arthur Caplan, a bioethicist at New York University, says that “deliberately causing disease in humans is normally abhorrent.” But COVID-19 is anything but a normal circumstance. In this case, Caplan says, “asking volunteers to take risks without pressure or coercion is not exploitation but benefitting from altruism.” At least 1,500 people have already volunteered to be such human guinea pigs, although none of the experimental vaccines is far enough along to try such challenging experiments.

Koff says the key to a successful vaccine is a cooperative effort. “It’s going to take a whole different way of thinking to move this onto the expedited train,” he says. “The old dog-eat-dog, ‘I’m going to beat you to the end of the game,’ isn’t going to help us with this.” Seth Berkley, who worked with Koff at the International AIDS Vaccine Initiative, and now heads GAVI, an international vaccine organization, agrees that a COVID-19 vaccine needs a Manhattan Project approach. “An initiative of this scale won’t be easy,” Berkley says. “Extraordinary sharing of information and resources will be critical, including data on the virus, the various vaccine candidates, vaccine adjuvants, cell lines, and manufacturing advances.”

Koff has no regrets about spending so many years on an AIDS vaccine without results. He learned a great deal, he says, which he’s putting to work in the COVID-19 crisis. “The reason COVID-19 vaccines should be a lot easier is because most of the platforms, the novel approaches, and the clinical infrastructure for the testing of vaccines, came out of HIV.” He pauses. “We’re far better prepared.”

Robert Bazell is an adjunct professor of molecular, cellular, and developmental biology at Yale. For 38 years, he was chief science correspondent for NBC News.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line.Castleski / Shutterstock

On January 5, six days after China officially announced a spate of unusual pneumonia cases, a team of researchers at Shanghai’s Fudan University deposited the full genome sequence of the causal virus, SARS-CoV-2, into Genbank. A little more than three months later, 4,528 genomes of SARS-CoV-2 have been sequenced,1 and more than 883 COVID-related clinical trials2 for treatments and vaccines have been established. The speed with which these trials will deliver results is unknown—the delicate bаlance of efficacy and safety can only be pushed so far before the risks outweigh the benefits. For this reason, a long-term solution like vaccination may take years to come to market.3

The good news is that a lack of treatment doesn’t preclude an end to the ordeal. Viral outbreaks of Ebola and SARS, neither of which had readily available vaccines, petered out through the application of consistent public health strategies—testing, containment, and long-term behavioral adaptations. Today countries that have previously battled the 2002 SARS epidemic, like Taiwan, Hong Kong, and Singapore, have shown exemplary recovery rates from COVID. Tomorrow, countries with high fatality rates like Sweden, Belgium, and the United Kingdom will have the opportunity to demonstrate what they’ve learned when the next outbreak comes to their shores. And so will we.

The first Ebola case was identified in 1976,4 when a patient with hemorrhagic symptoms arrived at the Yambuku Mission Hospital, located in what is now the Democratic Republic of Congo (DRC). Patient samples were collected and sent to several European laboratories that specialized in rare viruses. Scientists, without sequencing technology, took about five weeks to identify the agent responsible for the illness as a new member of the highly pathogenic Filoviridae family.

The first Ebola outbreak sickened 686 individuals across the DRC and neighboring Sudan. 453 of the patients died, with a final case fatality rate (CFR)—the number of dead out of number of sickened—of 66 percent. Despite the lethality of the virus, sociocultural interventions, including lockdowns, contact-tracing, campaigns to change funeral rites, and restrictions on consumption of game meat all proved effective interventions in the long run.

That is, until 2014, when there was an exception to the pattern. Ebola appeared in Guinea, a small country in West Africa, whose population had never before been exposed to the virus. The closest epidemic had been in Gabon, 13 years before and 2,500 miles away. Over the course of two years, the infection spread from Guinea into Liberia and Sierra Leone, sickening more than 24,000 people and killing more than 10,000.

Countries that have previously battled the 2002 SARS epidemic, like Taiwan and Hong Kong, have shown exemplary recovery rates.

During the initial phase of the 2014 Ebola outbreak, rural communities were reluctant to cooperate with government directives for how to care for the sick and the dead. To help incentivize behavioral changes, sociocultural anthropologists like Mariane Ferme of the University of California, Berkeley, were brought in to advise the government. In a recent interview with Nautilus, Ferme indicated that strategies that allowed rural communities to remain involved with their loved ones increased cooperation. Villages located far from the capital, she said, were encouraged to “deputize someone to come to the hospital, to come to the burial, so they could come back to the community and tell the story of the body.” For communities that couldn’t afford to send someone to the capital, she saw public health officials adopt a savvy technological solution—tablets to record video messages that were carried between convalescent patients and their families.

However, there were also systemic failures that, in Ferme’s opinion, contributed to the severity of the 2014 West African epidemic. In Sierra Leone, she said, “the big mistake early on was to distribute [weakly causal] information about zoonotic transmission, even when it was obviously community transmission.” In other words, although there had been an instance of zoonotic transmission—the virus jumping from a bat to a human—that initiated the epidemic, the principle danger was other contagious individuals, not game meat. Eventually, under pressure from relief groups, the government changed its messaging to reflect scientific consensus.

But the retraction shook public faith in the government and bred resentment. The mismatch between messaging and reality mirrors the current pandemic. Since the COVID outbreak began, international and government health officials have issued mixed messages. Doubts initially surfaced about the certainty of the virus being capable of spreading from person to person, and the debate over the effectiveness of masks in preventing infection continues.

Despite the confused messaging, there has been general compliance with stay-at-home orders that has helped flatten the curve. Had the public been less trusting of government directives, the outcome could have been disastrous, as it was in Libera in 2014. After a two-week lockdown was announced, the Liberian army conducted house-to-house sweeps to check for the sick and collect the dead. “It was a draconian method that made people hide the sick and dead in their houses,” Ferme said. People feared their loved ones would be buried without the proper rites. A direct consequence was a staggering number of active cases, and an unknown extent of community transmission. But in the end, the benchmark for the end of Ebola and SARS was the same. The WHO declared victory when the rate of new cases slowed, then stopped. By the same measure, when an entire 14-day quarantine period passes with no new cases of COVID-19, it can be declared over.

It remains possible that even if we manage to end the epidemic, it will return again. Driven by novel zoonotic transmissions, Ebola has flared up every few years. Given the extent of COVID-19’s spread, and the potential for the kind of mutations that allow for re-infection, it may simply become endemic.

Two factors will play into the final outcome of COVID-19 are pathogenicity and virulence. Pathogenicity is the ability of an infectious agent to cause disease in the host, and is measured by R0—the number of new infections each patient can generate. Virulence, on the other hand, is the amount of harm the infectious agent can cause, and is best measured by CFR. While the pathogenicity of Ebola, SARS, and SARS-CoV-2 is on the same order—somewhere between 1 to 3 new infections for each patient, virulence differs greatly between the two SARS viruses and Ebola.

The case fatality rate for an Ebola infection is between 60 to 90 percent. The spread in CFR is due to differences in infection dynamics between strains. The underlying cause of the divergent virulence of Ebola and SARS is largely due to the tropism of the virus, meaning the cells that it attacks. The mechanism by which the Ebola virus gains entry into cells is not fully understood, but it has been shown the virus preferentially targets immune and epithelial cells.5 In other words, the virus first destroys the body’s ability to mount a defense, and then destroys the delicate tissues that line the vascular system. Patients bleed freely and most often succumb to low blood pressure that results from severe fluid loss. However, neither SARS nor SARS-CoV-2 attack the immune system directly. Instead, they enter lung epithelial cells through the ACE2 receptor, which ensures a lower CFR. What is interesting about these coronaviruses is that despite their similar modes of infection, they demonstrate a range of virulence: SARS had a final CFR of 10 percent, while SARS-CoV-2 has a pending CFR of 1.4 percent. Differences in virulence between the 2002 and 2019 SARS outbreaks could be attributed to varying levels of care between countries.

The chart above displays WHO data of the relationship between the total number of cases in a country and the CFR during the 2002-2003 SARS-CoV epidemic. South Africa, on the far right, had only a single case. The patient died, which resulted in a 100 percent CFR. China, on the other hand, had 5,327 cases and 349 deaths, giving a 7 percent CFR. The chart below zooms to the bottom left corner of the graph, so as to better resolve critically affected countries, those with a caseload of less than 1,000, but with a high CFR.

Here is Hong Kong, with 1,755 cases and a 17 percent CFR. There is also Taiwan, with 346 cases and an 11 percent CFR. Finally, nearly tied with Canada is Singapore with 238 cases and a 14 percent CFR.

With COVID-19, it’s apparent that outcome reflects experience. China has 82,747 cases of COVID, but has lowered their CFR to 4 percent. Hong Kong has 1,026 cases and a 0.4 percent CFR. Taiwan has 422 cases at 1.5 percent CFR, and Singapore with 8,014 cases, has a 0.13 percent CFR.

It was the novel coronavirus identification program established in China in the wake of the 2002 SARS epidemic that alerted authorities to SARS-CoV-2 back in November of 2019. The successful responses by Taiwan, Hong Kong, and Singapore can also be attributed to a residual familiarity with the dangers of an unknown virus, and the sorts of interventions that are necessary to prevent a crisis from spiraling out of control.

In West Africa, too, they seem to have learned the value of being prepared. When Ferme returned to Liberia on March 7, she encountered airport staff fully protected with gowns, head covers, face screens, masks, and gloves. By the time she left the country, 10 days later, she said, “Airline personnel were setting up social distancing lines, and [rural vendors] hawking face masks. Motorcycle taxis drivers, the people most at risk after healthcare workers—all had goggles and face masks.”

The sheer number of COVID-19 cases indicates the road to recovery will take some time. Each must be identified, quarantined, and all contacts traced and tested. Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars. Northwestern University economists Martin Eichenbaum et al. modeled6 the cost of a yearlong shutdown to be $4.2 trillion, a cost that proactive countries will not face. A recent Harvard study7 published in Science suggests the virus will likely make seasonal appearances going forward, potentially requiring new waves of social distancing. In other words, initial hesitancy will have repercussions for years. In the future, smart containment principles,6 where restrictions are applied on the basis of health status, may temper the impact of these measures.

Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars.

Inaction was initially framed as promoting herd immunity, where spread of the virus is interrupted once everyone has fallen sick with it. This is because getting the virus results in the same antibody production process as getting vaccinated—but doesn’t require the development of a vaccine. The Johns Hopkins Bloomberg School of Public Health estimates that 70 percent of the population will need to be infected with or vaccinated against the virus8 for herd immunity to work. Progress toward it has been slow, and can only be achieved through direct infection with the virus, meaning many will die. A Stanford University study in Santa Clara County9 suggests only 2.5 percent to 4.2 percent of the population have had the virus. Another COVID hotspot in Gangelt, Germany, suggests 15 percent10—higher, but still nowhere near the 70 percent necessary for herd immunity. Given the dangers inherent in waiting on herd immunity, our best hope is a vaccine.

A key concern for effective vaccine development is viral mutation. This is because vaccines train the immune system to recognize specific shapes on the surface of the virus—a composite structure called the antigen. Mutations threaten vaccine development because they can change the shape of the relevant antigen, effectively allowing the pathogen to evade immune surveillance. But, so far, SARS-CoV-2 has been mutating slowly, with only one mutation found in the section most accessible to the immune system, the spike protein. What this suggests is that the viral genome may be sufficiently stable for vaccine development.

What we know, though, is that Ebola was extinguished due to cooperation between public health officials and community leaders. SARS-CoV ended when all cases were identified and quarantined. The Spanish Flu in 1918 vanished after two long, deadly seasons.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line. With 26 million unemployed and protests erupting around the country, it seems there are many who would prefer to risk life and limb rather than face financial insolvency. Applying smart containment principles in the aftermath of the shutdown might be the best way to get the economy moving again, while maintaining the safety of those at greatest risk. Going forward, vigilance and preparedness will be the watchwords of the day, and the most efficient way to prevent social and economic ruin.

Anastasia Bendebury and Michael Shilo DeLay did their PhDs at Columbia University. Together they created Demystifying Science, a science literacy organization devoted to providing clear, mechanistic explanations for natural phenomena. Find them on Twitter @DemystifySci.

References

1. Genomic epidemiology of novel coronavirus - Global subsampling. Nextstrain www.nextstrain.org.

2. Covid-19 TrialsTracker. TrialsTracker www.trialstracker.net.

3. Struck, M. Vaccine R&D success rates and development times. Nature Biotechnology 14, 591-593 (1996).

4. Breman, J. & Johnson, K. Ebola then and now. The New England Journal of Medicine 371 1663-1666 (2014).

5. Baseler, L., Chertow, D.S., Johnson, K.M., Feldmann, H., & Morens, D.M. THe pathogenesis of Ebola virus disease. The Annual Review of Pathology 12, 387-418 (2017).

6. Eichenbaum, M., Rebell, S., & Trabandt, M. The macroeconomics of epidemics. The National Bureau of Economic Research Working Paper: 26882 (2020).

7. Kissler, S., Tedijanto, C., Goldstein, E., Grad, Y., & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science eabb5793 (2020).

8. D’ Souza, G. & Dowdy, D. What is herd immunity and how can we achieve it with COVID-19? Johns Hopkins COVID-19 School of Public Health Insights www.jhsph.edu (2020).

9. Digitale, E. Test for antibodies against novel coronavirus developed at Stanford Medicine. Stanford Medicine News Center Med.Stanford.edu (2020).

10. Winkler, M. Blood tests show 14%of people are now immune to COVID-19 in one town in Germany. MIT Technology Review (2020).

On January 5, six days after China officially announced a spate of unusual pneumonia cases, a team of researchers at Shanghai’s Fudan University deposited the full genome sequence of the causal virus, SARS-CoV-2, into Genbank. A little more than three months later, 4,528 genomes of SARS-CoV-2 have been sequenced,1 and more than 883 COVID-related clinical trials2 for treatments and vaccines have been established. The speed with which these trials will deliver results is unknown—the delicate bаlance of efficacy and safety can only be pushed so far before the risks outweigh the benefits. For this reason, a long-term solution like vaccination may take years to come to market.3

The good news is that a lack of treatment doesn’t preclude an end to the ordeal. Viral outbreaks of Ebola and SARS, neither of which had readily available vaccines, petered out through the application of consistent public health strategies—testing, containment, and long-term behavioral adaptations. Today countries that have previously battled the 2002 SARS epidemic, like Taiwan, Hong Kong, and Singapore, have shown exemplary recovery rates from COVID. Tomorrow, countries with high fatality rates like Sweden, Belgium, and the United Kingdom will have the opportunity to demonstrate what they’ve learned when the next outbreak comes to their shores. And so will we.

The first Ebola case was identified in 1976,4 when a patient with hemorrhagic symptoms arrived at the Yambuku Mission Hospital, located in what is now the Democratic Republic of Congo (DRC). Patient samples were collected and sent to several European laboratories that specialized in rare viruses. Scientists, without sequencing technology, took about five weeks to identify the agent responsible for the illness as a new member of the highly pathogenic Filoviridae family.

The first Ebola outbreak sickened 686 individuals across the DRC and neighboring Sudan. 453 of the patients died, with a final case fatality rate (CFR)—the number of dead out of number of sickened—of 66 percent. Despite the lethality of the virus, sociocultural interventions, including lockdowns, contact-tracing, campaigns to change funeral rites, and restrictions on consumption of game meat all proved effective interventions in the long run.

That is, until 2014, when there was an exception to the pattern. Ebola appeared in Guinea, a small country in West Africa, whose population had never before been exposed to the virus. The closest epidemic had been in Gabon, 13 years before and 2,500 miles away. Over the course of two years, the infection spread from Guinea into Liberia and Sierra Leone, sickening more than 24,000 people and killing more than 10,000.

Countries that have previously battled the 2002 SARS epidemic, like Taiwan and Hong Kong, have shown exemplary recovery rates.

During the initial phase of the 2014 Ebola outbreak, rural communities were reluctant to cooperate with government directives for how to care for the sick and the dead. To help incentivize behavioral changes, sociocultural anthropologists like Mariane Ferme of the University of California, Berkeley, were brought in to advise the government. In a recent interview with Nautilus, Ferme indicated that strategies that allowed rural communities to remain involved with their loved ones increased cooperation. Villages located far from the capital, she said, were encouraged to “deputize someone to come to the hospital, to come to the burial, so they could come back to the community and tell the story of the body.” For communities that couldn’t afford to send someone to the capital, she saw public health officials adopt a savvy technological solution—tablets to record video messages that were carried between convalescent patients and their families.

However, there were also systemic failures that, in Ferme’s opinion, contributed to the severity of the 2014 West African epidemic. In Sierra Leone, she said, “the big mistake early on was to distribute [weakly causal] information about zoonotic transmission, even when it was obviously community transmission.” In other words, although there had been an instance of zoonotic transmission—the virus jumping from a bat to a human—that initiated the epidemic, the principle danger was other contagious individuals, not game meat. Eventually, under pressure from relief groups, the government changed its messaging to reflect scientific consensus.

But the retraction shook public faith in the government and bred resentment. The mismatch between messaging and reality mirrors the current pandemic. Since the COVID outbreak began, international and government health officials have issued mixed messages. Doubts initially surfaced about the certainty of the virus being capable of spreading from person to person, and the debate over the effectiveness of masks in preventing infection continues.

Despite the confused messaging, there has been general compliance with stay-at-home orders that has helped flatten the curve. Had the public been less trusting of government directives, the outcome could have been disastrous, as it was in Libera in 2014. After a two-week lockdown was announced, the Liberian army conducted house-to-house sweeps to check for the sick and collect the dead. “It was a draconian method that made people hide the sick and dead in their houses,” Ferme said. People feared their loved ones would be buried without the proper rites. A direct consequence was a staggering number of active cases, and an unknown extent of community transmission. But in the end, the benchmark for the end of Ebola and SARS was the same. The WHO declared victory when the rate of new cases slowed, then stopped. By the same measure, when an entire 14-day quarantine period passes with no new cases of COVID-19, it can be declared over.

It remains possible that even if we manage to end the epidemic, it will return again. Driven by novel zoonotic transmissions, Ebola has flared up every few years. Given the extent of COVID-19’s spread, and the potential for the kind of mutations that allow for re-infection, it may simply become endemic.

Two factors will play into the final outcome of COVID-19 are pathogenicity and virulence. Pathogenicity is the ability of an infectious agent to cause disease in the host, and is measured by R0—the number of new infections each patient can generate. Virulence, on the other hand, is the amount of harm the infectious agent can cause, and is best measured by CFR. While the pathogenicity of Ebola, SARS, and SARS-CoV-2 is on the same order—somewhere between 1 to 3 new infections for each patient, virulence differs greatly between the two SARS viruses and Ebola.

The case fatality rate for an Ebola infection is between 60 to 90 percent. The spread in CFR is due to differences in infection dynamics between strains. The underlying cause of the divergent virulence of Ebola and SARS is largely due to the tropism of the virus, meaning the cells that it attacks. The mechanism by which the Ebola virus gains entry into cells is not fully understood, but it has been shown the virus preferentially targets immune and epithelial cells.5 In other words, the virus first destroys the body’s ability to mount a defense, and then destroys the delicate tissues that line the vascular system. Patients bleed freely and most often succumb to low blood pressure that results from severe fluid loss. However, neither SARS nor SARS-CoV-2 attack the immune system directly. Instead, they enter lung epithelial cells through the ACE2 receptor, which ensures a lower CFR. What is interesting about these coronaviruses is that despite their similar modes of infection, they demonstrate a range of virulence: SARS had a final CFR of 10 percent, while SARS-CoV-2 has a pending CFR of 1.4 percent. Differences in virulence between the 2002 and 2019 SARS outbreaks could be attributed to varying levels of care between countries.

The chart above displays WHO data of the relationship between the total number of cases in a country and the CFR during the 2002-2003 SARS-CoV epidemic. South Africa, on the far right, had only a single case. The patient died, which resulted in a 100 percent CFR. China, on the other hand, had 5,327 cases and 349 deaths, giving a 7 percent CFR. The chart below zooms to the bottom left corner of the graph, so as to better resolve critically affected countries, those with a caseload of less than 1,000, but with a high CFR.

Here is Hong Kong, with 1,755 cases and a 17 percent CFR. There is also Taiwan, with 346 cases and an 11 percent CFR. Finally, nearly tied with Canada is Singapore with 238 cases and a 14 percent CFR.

With COVID-19, it’s apparent that outcome reflects experience. China has 82,747 cases of COVID, but has lowered their CFR to 4 percent. Hong Kong has 1,026 cases and a 0.4 percent CFR. Taiwan has 422 cases at 1.5 percent CFR, and Singapore with 8,014 cases, has a 0.13 percent CFR.

It was the novel coronavirus identification program established in China in the wake of the 2002 SARS epidemic that alerted authorities to SARS-CoV-2 back in November of 2019. The successful responses by Taiwan, Hong Kong, and Singapore can also be attributed to a residual familiarity with the dangers of an unknown virus, and the sorts of interventions that are necessary to prevent a crisis from spiraling out of control.

In West Africa, too, they seem to have learned the value of being prepared. When Ferme returned to Liberia on March 7, she encountered airport staff fully protected with gowns, head covers, face screens, masks, and gloves. By the time she left the country, 10 days later, she said, “Airline personnel were setting up social distancing lines, and [rural vendors] hawking face masks. Motorcycle taxis drivers, the people most at risk after healthcare workers—all had goggles and face masks.”

The sheer number of COVID-19 cases indicates the road to recovery will take some time. Each must be identified, quarantined, and all contacts traced and tested. Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars. Northwestern University economists Martin Eichenbaum et al. modeled6 the cost of a yearlong shutdown to be $4.2 trillion, a cost that proactive countries will not face. A recent Harvard study7 published in Science suggests the virus will likely make seasonal appearances going forward, potentially requiring new waves of social distancing. In other words, initial hesitancy will have repercussions for years. In the future, smart containment principles,6 where restrictions are applied on the basis of health status, may temper the impact of these measures.

Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars.

Inaction was initially framed as promoting herd immunity, where spread of the virus is interrupted once everyone has fallen sick with it. This is because getting the virus results in the same antibody production process as getting vaccinated—but doesn’t require the development of a vaccine. The Johns Hopkins Bloomberg School of Public Health estimates that 70 percent of the population will need to be infected with or vaccinated against the virus8 for herd immunity to work. Progress toward it has been slow, and can only be achieved through direct infection with the virus, meaning many will die. A Stanford University study in Santa Clara County9 suggests only 2.5 percent to 4.2 percent of the population have had the virus. Another COVID hotspot in Gangelt, Germany, suggests 15 percent10—higher, but still nowhere near the 70 percent necessary for herd immunity. Given the dangers inherent in waiting on herd immunity, our best hope is a vaccine.

A key concern for effective vaccine development is viral mutation. This is because vaccines train the immune system to recognize specific shapes on the surface of the virus—a composite structure called the antigen. Mutations threaten vaccine development because they can change the shape of the relevant antigen, effectively allowing the pathogen to evade immune surveillance. But, so far, SARS-CoV-2 has been mutating slowly, with only one mutation found in the section most accessible to the immune system, the spike protein. What this suggests is that the viral genome may be sufficiently stable for vaccine development.

What we know, though, is that Ebola was extinguished due to cooperation between public health officials and community leaders. SARS-CoV ended when all cases were identified and quarantined. The Spanish Flu in 1918 vanished after two long, deadly seasons.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line. With 26 million unemployed and protests erupting around the country, it seems there are many who would prefer to risk life and limb rather than face financial insolvency. Applying smart containment principles in the aftermath of the shutdown might be the best way to get the economy moving again, while maintaining the safety of those at greatest risk. Going forward, vigilance and preparedness will be the watchwords of the day, and the most efficient way to prevent social and economic ruin.

Anastasia Bendebury and Michael Shilo DeLay did their PhDs at Columbia University. Together they created Demystifying Science, a science literacy organization devoted to providing clear, mechanistic explanations for natural phenomena. Find them on Twitter @DemystifySci.

References

1. Genomic epidemiology of novel coronavirus - Global subsampling. Nextstrain www.nextstrain.org.

2. Covid-19 TrialsTracker. TrialsTracker www.trialstracker.net.

3. Struck, M. Vaccine R&D success rates and development times. Nature Biotechnology 14, 591-593 (1996).

4. Breman, J. & Johnson, K. Ebola then and now. The New England Journal of Medicine 371 1663-1666 (2014).

5. Baseler, L., Chertow, D.S., Johnson, K.M., Feldmann, H., & Morens, D.M. THe pathogenesis of Ebola virus disease. The Annual Review of Pathology 12, 387-418 (2017).

6. Eichenbaum, M., Rebell, S., & Trabandt, M. The macroeconomics of epidemics. The National Bureau of Economic Research Working Paper: 26882 (2020).

7. Kissler, S., Tedijanto, C., Goldstein, E., Grad, Y., & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science eabb5793 (2020).

8. D’ Souza, G. & Dowdy, D. What is herd immunity and how can we achieve it with COVID-19? Johns Hopkins COVID-19 School of Public Health Insights www.jhsph.edu (2020).

9. Digitale, E. Test for antibodies against novel coronavirus developed at Stanford Medicine. Stanford Medicine News Center Med.Stanford.edu (2020).

10. Winkler, M. Blood tests show 14%of people are now immune to COVID-19 in one town in Germany. MIT Technology Review (2020).

Lead image: Castleski / Shutterstock

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