It’s amazing how many pandemic books there are, and how thoroughly the idea of a global pandemic had crept into our popular culture well before the current situation. My daughter and I watched the Tom Hanks movie Inferno over the weekend, mostly because we wanted to gaze at the city of Florence. It’s not a great movie, but it is visually stunning in several ways. The plot is not something I gave much attention to when I first saw the film a couple of years ago: a rich Ted-talking eccentric decides to kill off most of the people of the world to save the Earth from over-population and the ravages 16 billion people would mean for other species and the health of the biosphere.
When I first saw the film in 2016, I regarded the plotline (will the vial of lethal germs be released or not?) as nothing but the usual “James Bond” setup for whatever else happened in the film. This time I watched it with greater alertness.
The fact is, of course, that COVID-19 is a serious global nuisance that has disrupted the lives of all Americans in a way that almost nobody could have predicted (well, there is Bill Gates, of course), but it is not the Black Plague, which swept away somewhere between one-fourth and one-half of all Europeans between 1348-1352, or the Yellow Fever epidemic in Philadelphia, which killed one in 10 inhabitants of America’s largest city in 1793, or the Spanish Flu, which killed somewhere between 57 and 100 million people worldwide in 1918.
If the coronavirus eventually kills 5 million people worldwide, and a couple of hundred thousand Americans before the vaccines gallop in to save the day a year or 18 months hence, it will have been a comparatively minor event in the history of global pandemics. The moment when it appeared that the hospital and medical infrastructure of New York might collapse has now passed. And though the death toll continues to climb towards perhaps 150,000 American dead by Aug. 1, 2020, the national dread that created a sustained will-we-survive and how-will-we-cope conversation in virtually every household in the United States is mostly over. The question now is when and how (and if) the country can return to what the late John McCain called regular order.
In the past two months I have read more than a dozen pandemic books, from Daniel Defoe’s A Journal of the Plague Year (1721), to Stephen King’s endless The Stand (1978). They are all interesting. If you outline the takeaway insights from these books, written over the span of many hundreds of years, they all make essentially the same points:
The great scourge of Thomas Jefferson’s era (1743-1826) was smallpox. Historians have estimated that perhaps as many as 2 billion people have died of smallpox in recorded history. That’s a pretty arbitrary figure, but it certainly indicates how serious the problem was. Modern epidemiology has not only eliminated smallpox as a threat to civilization but has been engaged in a protracted debate about whether to snuff it out altogether once and for all, or to keep a tiny bit of it alive in a handful of tightly secured vials in case we need to study it in the face of other disease epidemics. It was officially declared eradicated in 1980.
For most of human history, you either got it or you didn’t and then you either survived it or you didn’t. George Washington was infected by smallpox in Barbados in 1751. He survived, and though he was slightly disfigured, he was thereafter immune to the disease. It is possible that this early brush with smallpox saved the American Revolution 20 years later. In 18th-century Europe, 400,000 people died annually of smallpox.
By the time Jefferson was born in 1743, there was an experimental inoculation procedure, but it was quite dangerous and therefore highly controversial. The idea was to give healthy individuals a very tiny amount of actual smallpox under quarantine and very carefully controlled conditions and simply hope that the person’s immune system would be able to fight it off. Survival would immunize that individual for life. The procedure required many weeks of quarantine, fasting, puking, and rest, followed by a very light diet through convalescence. John Adams wrote a fascinating account of his own inoculation in 1764. He was 28 years old.
Young Thomas Jefferson’s first journey out of his native Virginia was to Philadelphia in 1766 to be inoculated. He would have undertaken the procedure in Williamsburg or Norfolk had it been available. He made the long journey (eight to 10 days in either direction) because he wanted to protect himself from the disease and study the procedure at the same time for possible incorporation into his own community at Monticello. With his characteristic taciturnity about personal things, Jefferson did not leave us a detailed account of the medical procedure, which required prolonged isolation, personal discipline and a great deal of patience.
Inoculation was first introduced in Europe 40 years earlier. Lady Mary Wortley Montague (1689-1762) had spent time in Turkey as the wife of the British ambassador to the Ottoman Empire. There she had witnessed inoculation in the zenanas (segregated women’s quarters) she visited. She called the procedure “engrafting,” which she described in an important “Letter to a Friend” on April 1, 1717. Mrs. Montagu’s brother had died of smallpox four years earlier and she herself had survived a bout of smallpox in 1715, but with her famous beauty disfigured. She had her five-year-old son Edward inoculated in the British Embassy in Turkey.
When she returned with her family to Britain, she became an outspoken advocate for the procedure. The English medical establishment decried inoculation and denounced Mary Montagu. Still, in 1721 when a smallpox epidemic broke out in England, she had her daughter inoculated in London. This was the first recorded use of the procedure in England. The medical establishment was slow to accept the efficacy of inoculation, which it regarded as an “oriental folk remedy.” It seemed counter-intuitive and just wrong-headed to give a healthy person a dose of smallpox to try to prevent her or him from getting it by accident.
New England Puritan minister Cotton Mather (1663-1728) first promoted inoculation in America. In 1706, Reverend Mather purchased a black slave he named Onesimus (from the Epistle to Philemon). Ten years later, Onesimus told Mather he had been made immune to smallpox in Africa by having the pus of an infected person rubbed on an open wound on his arm. This is known as the variolation method. Mather interrogated other slaves to learn more, confirmed the story, and became an advocate for inoculation. He was subjected to the usual criticism and pushback. An explosive device was thrown through the window of his home. In this instance, racism joined fear as a means of discrediting the medical procedure. What possible wisdom could come from a slave?
The smallpox plague that disturbed Britain in 1721 found its way that same year to Boston. Now Mather and Dr. Zabdiel Boylston, the only physician in Boston who supported the technique, offered their inoculation services to anyone who would trust them. Of the 242 people Boylston inoculated, only six died, or one in 40. Of those who did not undergo the procedure, one in seven died.
America’s greatest exemplar of the Enlightenment, Benjamin Franklin, became a passionate advocate of the procedure after his first son Franky died of smallpox on Nov. 21, 1736, at the age of four. Because Franklin was known to be a friend to inoculation, rumors spread in Philadelphia that Franky had died from the procedure. To set the record straight, the grieving father wrote an article in the Pennsylvania Gazette on Dec. 30, 1736: He had “intended to get [Francis] inoculated as soon as he should have recovered sufficient strength from a flux with which he had been long afflicted.” Franklin assured the public that his son “received the distemper in the common way of infection.”
In 1774, Franklin, who was an indefatigable creator of associations, societies, clubs and public institutions, including volunteer fire departments and lending libraries, established the Society for Inoculating the Poor Gratis to help the poor people of Philadelphia have access to inoculation. In his famous autobiography, Franklin wrote: “In 1736 I lost one of my sons, a fine boy of four years old, by the smallpox taken in the common way. I long regretted bitterly and still regret that I had not given it to him by inoculation. This I mention for the sake of the parents who omit that operation, on the supposition that they should never forgive themselves if a child died under it.”
As a young man, the future English physician Edward Jenner (1749-1823) overheard an English milkmaid say, “I shall never have smallpox for I have had cowpox. I shall never have an ugly pockmarked face.” Many years later, remembering the incident, Jenner, now a doctor, interrogated other milkmaids and then experienced one of the most important “eureka” moments in history. Without understanding how germs work, with no knowledge of anything called a virus, Dr. Jenner realized that cowpox (also known as kinepox) must be closely related to smallpox, and that surviving it seemed to make individuals immune to the more deadly disease. He reckoned that cowpox and smallpox must share some essential epidemiological element and since cowpox was neither lethal nor usually disfiguring, careful use of cowpox material would represent a superior protection against smallpox than variolation, which was a more dangerous procedure.
On May 14, 1796, Jenner inoculated an eight-year-old boy named James Phipps with kinepox pus. Phipps developed mild fever and discomfort. Ten days later he felt fine. Two months after that, Dr. Jenner inoculated the boy again, but this time with serum from a fresh smallpox sore. No disease developed. The smallpox vaccine had been born. Our term “vaccination” dates from this episode. Vaccination comes from the Latin word for cow, “vacca.” Jenner called the cowpox serum “vaccinia.” The terminology reminds us that all western vaccination stems from this moment in 1796.
No good deed goes unpunished, apparently, not even one that changes the history of the planet. In Britain, Edward Jenner was subjected to the usual harassment and ridicule. The paper he submitted to the Royal Society of England was rejected by none other than Sir Joseph Banks, one of Britain’s premier naturalists, botanists, and patrons of science. It took many years and the vaccination experiments of other physicians and scientists before Jenner’s work was vindicated.
Eventually, Jenner received worldwide recognition for his discovery. Devoted like Jefferson to the philanthropic principles of the Enlightenment, Dr. Jenner not only made no effort to enrich himself but devoted so much of his time and energy to promoting vaccination that he endured periods of real poverty. Finally, in 1802, the British Parliament voted him a reward of £10,000. Five years later he received £20,000 more from Parliament.
The true vaccine found its way to America thanks to Dr. John Haygarth of Bath. He sent some of Jenner’s material to Benjamin Waterhouse, a professor of physics at Harvard University. Waterhouse, in turn sent serum and reports of the vaccine’s efficacy to Thomas Jefferson, now the third president of the United States.
Dr. Edward Jenner discovered the true smallpox vaccine in 1796.
In the new world, inoculation had a very rough reception. When John Dalgleish and Archibald Campbell began inoculating individuals in Norfolk, Virginia, an angry mob burned down Campbell’s house. Similar incidents occurred in Salem and Marblehead, Mass. In Charleston, S.C., an inoculation control law of 1738 imposed a fine of £500 on anyone providing or receiving inoculation within two miles of the city. A similar law was passed in New York City in 1747.
The measures in New England were so draconian that Benjamin Waterhouse noted the paradox: “New England, the most democratical region on the face of the earth voluntarily submitted to more restrictions and abridgements of liberty, to secure themselves against that terrific scourge, than any absolute monarch could have enforced.” (This, strangely prescient, anticipates the current debate about liberty versus public health). It was in the middle colonies — Maryland, Pennsylvania, New Jersey — that inoculation was most tolerated in the second half of the 18th century. That’s why Jefferson made the long journey to Philadelphia to be inoculated in 1766.
Jefferson first became aware of the discovery of a true smallpox vaccine from the newspapers he read in Philadelphia and the new capitol in Washington, D.C. Then, on Dec. 1, 1800, just after Jefferson’s election to the presidency, Benjamin Waterhouse sent him his pamphlet on the vaccine with a lovely cover letter saying that he regarded Jefferson as “one of our most distinguished patriots and philosophers.” Jefferson responded immediately, thanking Waterhouse for the publication and declaring, with his usual grace, that “every friend of humanity must look with pleasure on this discovery, by which one evil the [more] is withdrawn from the condition of man: and contemplating the possibility that future improvements & discoveries, may still more & more lessen the catalogue of evils. in this line of proceeding you deserve well of your [country?] and I pray you to accept my portion of the tribute due you.”
The following June, Waterhouse sent Jefferson a long letter explaining how the vaccine must be administered, how the serum could be preserved over time, and how much the controversial procedure needed the public support of a man of Jefferson’s stature in the “republic of letters.” President Jefferson became known as a defender and promoter of vaccination. In fact, he even arranged for his protégé Meriwether Lewis to carry some of the serum with him up the Missouri River in 1804-05, instructing him to “carry with you some matter of the kine pox, inform those of them with whom you may be, of its efficacy as a preservative from the small pox; and instruct & encourage them in the use of it. This may be especially done wherever you may winter.” Unfortunately, by the time the Lewis and Clark Expedition reached their winter encampment in today’s North Dakota, the serum had become inert. Thus Jefferson’s philanthropic initiative to vaccinate the Native Americans of the American West was stillborn.
Then, on May 14, 1806, now in his second term, Jefferson wrote perhaps the greatest presidential fan letter of all time. He took time from his duties as president to write the following letter to Edward Jenner. I quote it in its entirety:
SIR,— I have received a copy of the evidence at large respecting the discovery of the vaccine inoculation which you have been pleased to send me, and for which I return you my thanks. Having been among the early converts, in this part of the globe, to its efficiency, I took an early part in recommending it to my countrymen. I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility. Harvey’s discovery of the circulation of the blood was a beautiful addition to our knowledge of the animal economy, but on a review of the practice of medicine before and since that epoch, I do not see any great amelioration which has been derived from that discovery. You have erased from the calendar of human afflictions one of its greatest. Yours is the comfortable reflection that mankind can never forget that you have lived. Future nations will know by history only that the loathsome small-pox has existed and by you has been extirpated. Accept my fervent wishes for your health and happiness and assurances of the greatest respect and consideration.
Who would not have wished to receive this magnificent, selfless, public-spirited, and enlightened letter? Unfortunately, we do not know how or even if Dr. Jenner responded. Except in medical circles, Edward Jenner has been largely forgotten.
Heavy hearts soared Monday with news that Moderna’s Covid-19 vaccine candidate — the frontrunner in the American market — seemed to be generating an immune response in Phase 1 trial subjects. The company’s stock valuation also surged, hitting $29 billion, an astonishing feat for a company that currently sells zero products.
But was there good reason for so much enthusiasm? Several vaccine experts asked by STAT concluded that, based on the information made available by the Cambridge, Mass.-based company, there’s really no way to know how impressive — or not — the vaccine may be.
While Moderna blitzed the media, it revealed very little information — and most of what it did disclose were words, not data. That’s important: If you ask scientists to read a journal article, they will scour data tables, not corporate statements. With science, numbers speak much louder than words.
Even the figures the company did release don’t mean much on their own, because critical information — effectively the key to interpreting them — was withheld.
Experts suggest we ought to take the early readout with a big grain of salt. Here are a few reasons why.
The National Institute for Allergy and Infectious Diseases has partnered with Moderna on this vaccine. Scientists at NIAID made the vaccine’s construct, or prototype, and the agency is running the Phase 1 trial. This week’s Moderna readout came from the earliest of data from the NIAID-led Phase 1.
NIAID doesn’t hide its light under a bushel. The institute generally trumpets its findings, often offering director Anthony Fauci — who, fair enough, is pretty busy these days — or other senior personnel for interviews.
But NIAID did not put out a press release Monday and declined to provide comment on Moderna’s announcement.
The company’s statement led with the fact that all 45 subjects (in this analysis) who received doses of 25 micrograms (two doses each), 100 micrograms (two doses each), or a 250 micrograms (one dose) developed binding antibodies.
Later, the statement indicated that eight volunteers — four each from the 25-microgram and 100-microgram arms — developed neutralizing antibodies. Of the two types, these are the ones you’d really want to see.
We don’t know results from the other 37 trial participants. This doesn’t mean that they didn’t develop neutralizing antibodies. Testing for neutralizing antibodies is more time-consuming than other antibody tests and must be done in a biosecurity level 3 laboratory. Moderna disclosed the findings from eight subjects because that’s all it had at that point. Still, it’s a reason for caution.
Separately, while the Phase 1 trial included healthy volunteers ages 18 to 55 years, the exact ages of these eight people are unknown. If, by chance, they mostly clustered around the younger end of the age spectrum, you might expect a better response to the vaccine than if they were mostly from the senior end of it. And given who is at highest risk from the SARS-CoV-2 coronavirus, protecting older adults is what Covid-19 vaccines need to do.
The report of neutralizing antibodies in subjects who were vaccinated comes from blood drawn two weeks after they received their second dose of vaccine.
“That’s very early. We don’t know if those antibodies are durable,” said Anna Durbin, a vaccine researcher at Johns Hopkins University.
Moderna stated that the antibody levels seen were on a par with — or greater than, in the case of the 100-microgram dose — those seen in people who have recovered from Covid-19 infection.
But studies have shown antibody levels among people who have recovered from the illness vary enormously; the range that may be influenced by the severity of a person’s disease. John “Jack” Rose, a vaccine researcher from Yale University, pointed STAT to a study from China that showed that, among 175 recovered Covid-19 patients studied, 10 had no detectable neutralizing antibodies. Recovered patients at the other end of the spectrum had really high antibody levels.
So though the company said the antibody levels induced by vaccine were as good as those generated by infection, there’s no real way to know what that comparison means.
STAT asked Moderna for information on the antibody levels it used as a comparator. The response: That will be disclosed in an eventual journal article from NIAID, which is part of the National Institutes of Health.
“The convalescent sera levels are not being detailed in our data readout, but would be expected in a downstream full data exposition with NIH and its academic collaborators,” Colleen Hussey, the company’s senior manager for corporate communications, said in an email.
Durbin was struck by the wording of the company’s statement, pointing to this sentence: “The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.”
“I thought: Generally? What does that mean?” Durbin said. Her question, for the time being, can’t be answered.
Rose said the company should disclose the information. “When a company like Moderna with such incredibly vast resources says they have generated SARS-2 neutralizing antibodies in a human trial, I would really like to see numbers from whatever assay they are using,” he said.
The company has not yet brought a vaccine to market, but it has a variety of vaccines for infectious diseases in its pipeline. It doesn’t publish on its work in scientific journals. What is known has been disclosed through press releases. That’s not enough to generate confidence within the scientific community.
“My guess is that their numbers are marginal or they would say more,” Rose said about the company’s SARS-2 vaccine, echoing a suspicion that others have about some of the company’s other work.
“I do think it’s a bit of a concern that they haven’t published the results of any of their ongoing trials that they mention in their press release. They have not published any of that,” Durbin noted.
Still, she characterized herself as “cautiously optimistic” based on what the company has said so far.
“I would like to see the data to make my own interpretation of the data. But I think it is at least encouraging that we’ve seen immune responses with this RNA vaccine that we haven’t seen with previous RNA vaccines for other pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.
Moderna has been more forthcoming with data on at least one of its other vaccine candidates. In a statement issued in January about a Phase 1 trial for its cytomegalovirus (CMV) vaccine, it quantified how far over baseline measures antibody levels rose in vaccines.
A vaccine manufacturer is reporting preliminary data suggesting its COVID-19 vaccine is safe, and appears to be eliciting in test subjects the kind of immune response capable of preventing disease.
Moderna, Inc., of Cambridge, Mass., developed the vaccine in collaboration with the National Institute of Allergy and Infectious Diseases. The results reported Monday come from an initial analysis of a Phase I study primarily designed to see if the vaccine is safe.
The company reports no serious side-effects; however, modest side-effects included redness at the injection site, headache, fever and flu-like symptoms, although none of these lasted more than a day.
The first 45 volunteers for the vaccine trial were divided into three groups, with each group getting a different dose of the vaccine. All groups got an initial shot, followed by a booster shot a month later.
In addition to safety, the company also looked at the vaccine’s ability to induce antibodies to the coronavirus — what’s known as its immunogenicity. It did, for all subjects at all dose levels. In addition, eight of the subjects were tested for the presence of neutralizing antibodies that prevent the virus from infecting cells in the laboratory. All eight did.
The Food and Drug Administration has given Moderna the green light to begin a Phase II study expected to enroll an additional 600 volunteers — half older than 55 — to provide additional immunogenicity data. The company hopes by July to begin a Phase III study, aimed at showing that the vaccine can actually prevent disease.
The Moderna vaccine is made using messenger RNA, or mRNA, a molecule containing the genetic instructions to make a protein on the coronavirus surface that is recognized by our immune systems. Although mRNA vaccines have been studied for several years, so far none has been licensed by the FDA.
The advantage of mRNA vaccines over more traditional vaccines is they can be made quickly. The company says it was just 63 days from the time Chinese scientists revealed the genetic sequence to the time a vaccine was injected into the first volunteer.
Moderna’s is one of about a dozen COVID-19 vaccine candidates that have begun studies in humans.
Fed chair says economy may not fully bounce back until virus vaccine is available.
Federal Reserve chair Jay Powell has warned that a full US economic recovery may take until the end of next year and require the development of a Covid-19 vaccine.
“For the economy to fully recover, people will have to be fully confident. And that may have to await the arrival of a vaccine,” Mr Powell told CBS News on Sunday. A full revival would happen, he said, but “it may take a while . . . it could stretch through the end of next year, we really don’t know”.
He added: “Assuming there is not a second wave of the coronavirus, I think you will see the economy recover steadily through the second half of this year.”
Mr Powell told CBS it was likely there would be a “couple more months” of net job losses, with the unemployment rate climbing to as high as 20-25 per cent. But he said it was “good news” that the “overwhelming” majority of those claiming unemployment benefits report themselves as having been laid off temporarily, meaning they are expecting to go back to their old jobs.
Oil prices and stocks in Asia rose on Monday despite the gloomy outlook. West Texas Intermediate, the US crude benchmark, climbed 4.4 per cent to take it above $30 a barrel for the first time in two months. Brent crude, the international benchmark, rose 3.6 per cent to $33.67 a barrel. Japan’s Topix was up 0.4 per cent and China’s CSI 300 index of Shanghai- and Shenzhen-listed stocks added 0.6 per cent.
Donald Trump, US president, said last week that he hoped to have a vaccine ready by the end of 2020. But public health experts, including Anthony Fauci, the head of the US National Institute of Allergy and Infectious Diseases, and Rick Bright, the recently ousted head of the US Biomedical Advanced Research and Development Authority, have warned that the process is likely to take longer.
Dr Fauci, a high-profile member of Mr Trump’s coronavirus task force, has said he expects the search for a vaccine to take at least a year to 18 months. But Dr Bright has said that was too optimistic.
Some world leaders have also raised doubts about the immediate prospects for a vaccine. Giuseppe Conte, prime minister of Italy, said at the weekend that his country could “not afford” to wait for a vaccine, while Boris Johnson, UK prime minister, warned that a vaccine “might not come to fruition” at all.
Mr Powell said that while lawmakers had “done a great deal and done it very quickly”, Congress and the Fed may need to do more “to avoid longer-run damage to the economy”.
The Fed chair said fiscal policies that “help businesses avoid avoidable insolvencies and that do the same for individuals” would position the US economy for a strong recovery post-crisis.
Mr Powell also reiterated his position against using negative interest rates, something Mr Trump has called for. The Fed chair told CBS that the Federal Open Market Committee had eschewed negative interest rates after the last financial crisis in favour of “other tools” such as forward guidance and quantitative easing.
The US Congress has already approved nearly $3tn of economic relief measures intended to support struggling businesses and individuals, but there is growing consensus in Washington that more fiscal stimulus will be needed — even if Democrats and Republicans are divided over how to dole out federal funds.
Late on Friday, the Democrat-controlled House of Representatives passed Nancy Pelosi’s plan for $3tn in new stimulus spending.
Mr Trump has repeatedly called for the next stimulus to include a cut to payroll taxes — deductions for entitlements such as social security and Medicare. Last week, Larry Kudlow, the top White House economic adviser, suggested that lower corporate taxes and looser business regulation should be part of any future relief package.
The Trump administration has taken a more bullish stance on the US economic recovery than Mr Powell, with White House officials repeatedly insisting that the economy will bounce back before the end of the year.
Mr Powell told CBS it was a “reasonable expectation that there will be growth in the second half of the year” but “we won’t get back to where we were by the end of the year”.
Rick Bright, the ousted director of a crucial federal office charged with developing countermeasures to infectious diseases, testified before Congress on Thursday that the US will face an even worse crisis without additional preparations to curb the coronavirus pandemic.