Today, the U.S. military requires troops to be immunized against multiples diseases, including tetanus, diphtheria, hepatitis A, and polio. Several states require workers at healthcare facilities to be vaccinated against diseases such as pertussis, chickenpox, measles, mumps, and rubella. Hospital systems often require additional vaccinations as a condition of employment. And legally, all employers, in any industry, can compel their employees to get vaccinated.

The mandates can be directed toward customers, as well. Just as business owners can bar shoeless and shirtless clients from entering their restaurants, salons, arenas, and stores, they can legally keep people out for any number of reasons, “as long as they’re not running afoul of any antidiscrimination laws,” says Dorit Rubinstein Reiss, a professor of health and vaccine law at the University of California, Hastings College of the Law.

When a COVID-19 vaccine becomes available, some experts think states will require targeted industries to enforce vaccine mandates for their employees, especially those we’ve come to know as “essential workers.”

“Grocery store workers get exposed to a lot of people, but also have the chance to infect a lot of people because of the nature of their work and the fact that virtually everybody needs to buy food,” says Carmel Shachar, executive director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School. Hospitality industry workers – those who work in restaurants, bars, and coffee shops, for example – could also see similar mandates.

“It’s in an employer’s interest to make sure that their workplace is protected and that you can’t infect your colleagues,” Shachar says. “Having a widely accessible vaccine gets a lot of employers out of having to control their clients’ behavior.” And with a vaccinated workforce, “you don’t need to worry if the people you’re serving at the restaurant have COVID-19.”

Even the general public could be incentivized to get vaccinated. “Oddly enough, the best way to impose a mandate is to reward people with more freedom if they follow that mandate,” Caplan says. For example, with proof of inoculation, you would be able to attend a sporting event “as a reward for doing the right thing,” he says. “And I can imagine people saying, If you want to go to my restaurant, my bowling alley, or my tattoo parlor, then I want to see a vaccine certificate, too.”

Booster shots could also be required, depending on the efficacy of future vaccines. Flu vaccines are effective about 70 percent of the time, says Lauren Grossman, professor of emergency medicine at the University of Colorado Denver, and new shots are needed each year. Yvonne Maldonado, a health policy professor at Stanford University, warns that any COVID-19 vaccine may not elicit lasting immunity and could require frequent boosters. If that’s the case, mandates would likely also include proof of booster shots.

CERTIFIED VACCINATED

While the enforcement of such mandates wouldn’t be without its challenges, it would hardly be impossible or without precedent. To board an Emirates flight to Dubai today, for example, all passengers must present a negative COVID-19 test certificate. Once a vaccine is available, airlines could put in place sweeping regulations requiring COVID-19 vaccination certificates.

Reiss says federal laws could require proof of a COVID-19 vaccine to get a passport – which would then display an emblem showing your vaccination status. Driver’s licenses could be updated in a similar fashion, Caplan says. At work, employee badges could carry vaccination stickers, and a paper certificate from your doctor could serve as vaccine proof for public events.

“Perhaps we’ll get to a point where we need to sign proof of immunity to book an appointment,” Grossman says.

More than 150 COVID-19 vaccines are currently in development. Prices for various vaccines have begun to emerge, with some front-runners saying shots could cost as little as four dollars or as much as $37 per dose – which is about what a flu shot costs. Employers who mandate COVID-19 vaccines may help cover the costs, provide time off to obtain the vaccine, or offer on-site vaccinations, says Amber Clayton, director of the Society for Human Resource Management HR Knowledge Center. To help people without insurance or who are low-income or unemployed, some officials have suggested that the federal government could provide shots for free, but details of such a program have not been released.

If such mandates are put into place, not everyone will welcome them: a recent Gallup poll shows that as many as 35 percent of Americans wouldn’t get a COVID-19 vaccine even if it were free. And while anti-vaccine sentiment across the country remains low overall, vaccine hesitancy is growing, with some studies indicating childhood vaccine rates are dropping across the country.

Those with anti-vaccine sentiments are what Caplan describes as a loud minority: They often use compelling campaigns to spread fear about vaccines. For instance, some purport that the measles, mumps, and rubella (MMR) vaccine – required for all school-age children – causes autism. This assertion has been proven false, but it has also caused a decline in MMR vaccination.

Similar anti-vaccine campaigns directed at the vaccines under development for COVID-19 have started to spread, even before a vaccine has been approved for the public. Vaccine mandates, experts say, could be the target of aggressive campaigns from groups that say they are concerned with the safety and efficacy of a vaccine developed at record speed.

People who express hesitancy about a potential COVID-19 vaccine often say their top worry is safety, which raises concerns that some Americans could shy away from inoculation. But if a COVID-19 vaccine is proven safe, “I think the majority of people will want it,” Caplan says. “And if the majority of people want it, you won’t have to mandate it – they’ll be looking for it.”

DOZENS OF COVID-19 VACCINES ARE IN DEVELOPMENT. HERE ARE THE ONES TO FOLLOW

Dozens of COVID-19 vaccines are in development. Here are the ones to follow.
Here are the COVID-19 vaccine prospects that have made it to phase three trials and beyond.
National Geographic magazine
August 21, 2020

https://www.nationalgeographic.com/science/health-and-human-body/human-diseases/coronavirus-vaccine-tracker-how-they-work-latest-developments-cvd

More than 150 coronavirus vaccines are in development across the world – and hopes are high to bring one to market in record time to ease the global crisis. Several efforts are underway to help make that possible, including the U.S. government’s Operation Warp Speed initiative, which has pledged $10 billion and aims to develop and deliver 300 million doses of a safe, effective coronavirus vaccine by January 2021. The World Health Organization is also coordinating global efforts to develop a vaccine, with an eye toward delivering two billion doses by the end of 2021.

The candidates, like all vaccines, essentially aim to instruct the immune system to mount a defense, which is sometimes stronger than what would be provided through natural infection and comes with fewer health consequences.

To do so, some vaccines use the whole coronavirus, but in a killed or weakened state. Others use only part of the virus – whether a protein or a fragment. Some transfer the coronavirus proteins into a different virus that is unlikely to cause disease or even incapable of it. Finally, some vaccines under development rely on deploying pieces of the coronavirus’s genetic material, so our cells can temporarily make the coronavirus proteins needed to stimulate our immune systems. (Here’s what vaccines are and how they work.)

It can typically take 10 to 15 years to bring a vaccine to market; the fastest-ever – the vaccine for mumps – required four years in the 1960s. Vaccines go through a multi-stage clinical trial process, which starts by checking their safety and whether they trigger an immune response in a small group of healthy humans. The second phase widens the testing pool to include groups of people who may have the disease or be more likely to catch it, to gauge the vaccine’s effectiveness. The third phase expands the pool up to the thousands to make sure the vaccine is safe and effective among a wider array of people, given that immune response can vary by age, ethnicity, or by underlying health conditions. It then goes to regulatory agencies for approval – which can be a lengthy process itself.

Even after a vaccine is approved, it faces potential roadblocks when it comes to manufacturing and distribution, from scaling up the production to meet demands to deciding which populations should get it first – and at what cost. Many vaccines also stay in what’s called phase four, a perpetual stage of regular study. (Here’s how we’ll know when a COVID-19 vaccine is ready.) But vaccine developers are attempting to compress that process for SARS-CoV-2 by running clinical trial phases simultaneously, and the U.S. Food and Drug Administration has promised to fast-track the approval process.

Though it’s too soon to say which candidates will ultimately be successful, here’s a look at the vaccine prospects that have made it to phase three and beyond – including a quick primer on how they work and where they stand.

MODERNA THERAPEUTICS

Name: mRNA-1273

Who: A Massachusetts-based biotech company, in collaboration with the National Institutes of Health.

What: This vaccine candidate relies on injecting snippets of a virus’s genetic material, in this case mRNA, into human cells. They create viral proteins that mimic the coronavirus, training the immune system to recognize its presence. This technology has never been licensed for any disease. If successful, it would be the first mRNA vaccine approved for human use. (Here’s how mRNA vaccines work.)

Status: On July 27, Moderna announced it had started the third phase of its clinical trials, even as it continues to monitor phase two results. Preliminary findings from phase one have shown that healthy subjects produced coronavirus antibodies and a reaction from T-cells, another arm of the human immune response. Phase three will test the vaccine in 30,000 U.S. participants. Moderna says it is on track to deliver at least 500 million doses per year beginning in 2021, thanks in part to the deal it has struck with Swiss manufacturer Lonza that will allow it to manufacture up to one billion doses a year.

PFIZER

Name: BNT162b2

Who: One of the world’s largest pharmaceutical companies, based in New York, in collaboration with German biotech company BioNTech.

What: Pfizer and BioNTech are also developing an mRNA vaccine based on the German company’s earlier efforts to use the technology in experimental cancer vaccines. Pfizer has signed a nearly $2 billion contract with the U.S. government to provide 100 million doses by December 2020 – an agreement that goes into effect when and if the drug is approved and delivered.

Status: On July 27, Pfizer and BioNTech launched a trial that combines phase two and three by enrolling a diverse population in areas with significant SARS-CoV-2 transmission. It will examine the vaccine’s effect in 30,000 people from 39 U.S. states and from Brazil, Argentina, and Germany. The project is aiming to seek regulatory review as early as October 2020 to meet the December deadline – and hopes to supply 1.3 billion doses by the end of 2021. Preliminary results of phase one/two data show the vaccine produces antibodies and T-cell responses specific to the SARS-CoV-2 protein.

UNIVERSITY OF OXFORD

Name: ChAdOx1 nCoV-19

Who: The U.K. university, in collaboration with the biopharmaceutical company AstraZeneca.

What: Oxford’s candidate is what’s known as a viral vector vaccine, essentially a “Trojan horse” presented to the immune system. Oxford’s research team has transferred the SARS-CoV-2 spike protein – which helps the coronavirus invade cells – into a weakened version of an adenovirus, which typically causes the common cold. When this adenovirus is injected into humans, the hope is that the spike protein will trigger an immune response. AstraZeneca and Oxford plan to produce a billion doses of vaccine that they’ve agreed to sell at cost.

Status: Preliminary results from this candidate’s first two clinical trial phases revealed that the vaccine had triggered a strong immune response – including increased antibodies and responses from T-cells – with only minor side effects such as fatigue and headache. It has now moved into phase three of clinical trials, aiming to recruit up to 50,000 volunteers in Brazil, the United Kingdom, the United States, and South Africa.

SINOVAC

Name: CoronaVac

Who: A Chinese biopharmaceutical company, in collaboration with Brazilian research center Butantan.

What: CoronaVac is an inactivated vaccine, meaning it uses a non-infectious version of the coronavirus. While inactivated pathogens can no longer produce disease, they can still provoke an immune response, such as with the annual influenza vaccine.

Status: On July 3, Brazil’s regulatory agency granted this vaccine candidate approval to move ahead to phase three, as it continues to monitor the results of the phase two clinical trials. Preliminary results in macaque monkeys, published in Science, revealed that the vaccine produced antibodies that neutralized 10 strains of SARS-CoV-2. Sinovac has also released preprint results of its phase two human trial that likewise showed the vaccine produced antibodies with no severe adverse reactions. Phase three will recruit nearly 9,000 healthcare professionals in Brazil. Sinovac will also conduct phase three trials in Indonesia and Bangladesh.

SINOPHARM

Who: China’s state-run pharmaceutical company, in collaboration with the Wuhan Institute of Biological Products.

What: Sinopharm is also using an inactivated SARS-CoV-2 vaccine that it hopes will reach the public by the end of 2020. Preliminary findings from two randomized trials, published in JAMA, have shown the vaccine can trigger an antibody response with no serious adverse effects. The study did not measure T cell-mediated immune responses. These results are significant, though, as they are the first published data from human clinical trials for a COVID-19 vaccine that uses a whole, inactivated virus.

Status: In mid-July, Sinopharm launched its first phase three trial among 15,000 volunteers – aged 18 to 60, with no serious underlying conditions – in the United Arab Emirates. The company selected the UAE because it has a diverse population made up of approximately 200 nationalities, making it an ideal testing ground. Sinopharm will also undertake phase three trials in locations such as Peru and Bahrain.

MURDOCH CHILDREN’S RESEARCH INSTITUTE

Name: Bacillus Calmette-Guerin BRACE trial

Who: The largest child health research institute in Australia, in collaboration with the University of Melbourne.

What: For nearly a hundred years, the Bacillus Calmette-Guerin (BCG) vaccine has been used to prevent tuberculosis by exposing patients to a small dose of live bacteria. Evidence has emerged over the years that this vaccine may boost the immune system and help the body fight off other diseases as well. Researchers are investigating whether these benefits may also extend to SARS-CoV-2, and this trial has reached phase three in Australia. Though as of April 12, the World Health Organization says there is no evidence that the BCG vaccine protects people against infection with the coronavirus.

Status: In April, researchers from the Murdoch Children’s Research Institute began a series of randomized controlled trials that will test whether BCG might work on the coronavirus as well. They aim to recruit 10,000 healthcare workers in the study.

CANSINO BIOLOGICS

Name: Ad5-nCoV

Who: A Chinese biopharmaceutical company.

What: CanSino has also developed a viral vector vaccine, using a weakened version of the adenovirus as a vehicle for introducing the SARS-CoV-2 spike protein to the body. Preliminary results from phase two trials, published in The Lancet, have shown that the vaccine produces “significant immune responses in the majority of recipients after a single immunisation.” There were no serious adverse reactions documented.

Status: Though the company was still technically in phase two of its trial, on June 25, CanSino became the first company to receive limited approval to use its vaccine in people. The Chinese government has approved the vaccine for military use only, for a period of one year. On August 15, Russian biopharmaceutical company Petrovax announced it had launched the first phase three clinical trial of Ad5-nCoV.

THE GAMALEYA NATIONAL CENTER OF EPIDEMIOLOGY AND MICROBIOLOGY

Name: Sputnik V

Who: A Russian research institution, in partnership with the state-run Russian Direct Investment Fund.

What: Gamaleya has developed a viral vector vaccine that also uses a weakened version of the common cold-causing adenovirus to introduce the SARS-CoV-2 spike protein to the body. This vaccine uses two strains of adenovirus, and it requires a second injection after 21 days to boost the immune response. Russia has not published any data from its clinical trials, but officials with the institute state that they have completed phases one and two. The researchers also claim the vaccine produced strong antibody and cellular immune responses.

Status: Despite the lack of published evidence, Russia has cleared the Sputnik V vaccine for widespread use and claimed it as the first registered COVID-19 vaccine on the market. Russia reports that it will start phase three clinical trials on August 12; the World Health Organization, however, lists the Sputnik V vaccine as being in phase one of clinical trials.

SCIENTISTS SEE SIGNS OF LASTING IMMUNITY TO COVID-19, EVEN AFTER MILD INFECTIONS

Scientists See Signs of Lasting Immunity to Covid-19, Even After Mild Infections

New research indicates that human immune system cells are storing information about the coronavirus so they can fight it off again.

By Katherine J. Wu
New York Times
Aug. 17, 2020

https://www.nytimes.com/2020/08/16/health/coronavirus-immunity-antibodies.html?

“This is exactly what you would hope for,” said Marion Pepper, an immunologist at the University of Washington and an author on another of the new studies, which is currently under review at the journal Nature. “All the pieces are there to have a totally protective immune response.”

Protection against reinfection cannot be fully confirmed until there is proof that most people who encounter the virus a second time are actually able to keep it at bay, Dr. Pepper said. But the findings could help quell recent concerns over the virus’s ability to dupe the immune system into amnesia, leaving people vulnerable to repeat bouts of disease.

Researchers have yet to find unambiguous evidence that coronavirus reinfections are occurring, especially within the few months that the virus has been rippling through the human population. The prospect of immune memory “helps to explain that,” Dr. Pepper said.

In discussions about immune responses to the coronavirus, much of the conversation has focused on antibodies – Y-shaped proteins that can latch onto the surfaces of pathogens and block them from infecting cells. But antibodies represent just one wing of a complex and coordinated squadron of immune soldiers, each with their own unique modes of attack. Viruses that have already invaded cells, for instance, are cloaked from antibodies, but are still vulnerable to killer T cells, which force infected cells to self-destruct. Another set of T cells, nicknamed “helpers,” can coax B cells to mature into antibody-making machines.

(Yet another sector of the immune system assails pathogens within minutes of their arrival, while sending out signals called cytokines to mobilize forces from elsewhere in the body. Some evidence suggests that severe cases of Covid-19 may stem from this early process going awry.)

Notably, several of the new studies are finding these powerful responses in people who did not develop severe cases of Covid-19, Dr. Iyer added. Some researchers have worried that infections that take a smaller toll on the body are less memorable to the immune system’s studious cells, which may prefer to invest their resources in more serious assaults. In some cases, the body could even jettison the viruses so quickly that it fails to catalog them. “This paper suggests this is not true,” Dr. Iyer said. “You can still get durable immunity without suffering the consequences of infection.”

THE TREATMENT THAT COULD CRUSH COVID

The Treatment That Could Crush Covid

Early trials show signaling cells eliminate the virus, calm the immune response and repair tissue damage.

By Kevin Kimberlin
Wall Street Journal
Aug. 14, 2020

https://www.wsj.com/articles/the-treatment-that-could-crush-covid-11597360709

More than 500 clinical trials are under way world-wide in the race to find an effective treatment for Covid-19. Everybody wants it; nobody has it – yet. But one of the most promising therapies for Covid-19 patients uses “medicinal signaling cells,” or MSCs, which are found on blood vessels throughout the body.

In preliminary studies, these cells cut the death rate significantly, particularly in the sickest patients. With a powerful 1-2-3 punch, these cells eliminate the virus, calm the immune overreaction known as a cytokine storm, and repair damaged lung tissue – a combination offered by no other drug. This type of regenerative medicine could be as revolutionary as Jonas Salk’s polio vaccine.

In one pilot study in March, doctors at Mount Sinai Hospital in New York treated a dozen severely ill Covid-19 patients on ventilators with MSCs. Two infusions modulated their hyperactive immune systems, and 83% of those patients survived. With such promising results, the team at Mount Sinai and the supplier of the cells, Mesoblast Ltd., won Food and Drug Administration clearance and National Institutes of Health funding to conduct a randomized trial on 300 patients. The first patients in the trial received the treatment in early May.

A July 10 article in the Lancet reported on 13 critically ill Covid-19 patients also treated with MSCs. Eleven of the 13 patients lived – an 85% survival rate, which mirrors the results from Mount Sinai. The number of virus-fighting T-cells rose even as inflammation fell, suggesting that these cells can control the immune response as needed. In addition, chest X-rays showed that the drug repaired lung tissue, in some cases within 48 hours.

Healing tissue is essential because the cytokine battle with the Covid-19 virus is so vicious that it punches holes in the delicate lung membranes, allowing the virus to flood into the bloodstream and body cavities. These holes must be repaired, as virus leaks create some of the complications not usually associated with respiratory infections – blood clotting, heart attacks, stroke and multiple organ failure, which cause about 40% of Covid-19-related deaths. Blood-vessel density, and thereby the number of MSCs, decreases as we age, gain weight or develop diseases, which may explain why the elderly and those with chronic health conditions are faring worst.

In other words, this disease appears to be both a respiratory and a vascular infection. That is why the ability to fight infection, control the immune response and repair damaged tissue is such a valuable combination.

How can one drug do all this? MSCs were first identified and named by Prof. Arnold Caplan and colleagues at Case Western Reserve University in Ohio nearly 30 years ago. To translate this discovery into therapies, Mr. Caplan and I in 1993 launched Osiris Therapeutics, Inc. which developed this MSC into the world’s first approved systemically delivered cell therapy. During early years of scientific inquiry, Mr. Caplan and colleagues discovered that MSCs monitor and protect virtually every vessel in our bodies – the 60,000 miles of vessels that transport oxygen, nutrition and waste to and from every one of our cells.

When a MSC detects an infection or an injury to those vessels, it transforms into a factory to recruit and pump out immune-modulating and vessel-repair agents. These cells ameliorate crippling and deadly conditions when traditional chemical or biochemical drugs fail. The number of potential uses is enormous. MSCs are being tested on more than 900 different human ailments. Mr. Caplan describes these cells not as a “wonder drug,” but as a wonder drugstore.

Consider the results from trials conducted by Mesoblast on graft-versus-host Disease. Children with this horrible affliction suffer such a violent immune reaction that the skin and the lining of their intestines peel off. Up to 80% of children die if steroids don’t stop the inflammation. But in one trial, 160 of 239 patients (67%) who didn’t respond to steroids and other treatments survived after infusion with MSCs. Their cytokine storm disappeared. Injured tissues normalized. Based on these results, the FDA agreed to expedite its review and grant a decision by Sept. 30.

This is exactly the type of cell being tested for Covid-19 in the May trial. If the cells perform as they did at Mount Sinai in March and elsewhere, the results should be available before the end of September. A positive finding could help those most at risk of the disease’s worst effects. But the medical community and wider public are largely unaware of the potential for using MSCs to treat Covid.

Amid so much darkness, MSCs are a ray of hope – not only for the most desperate coronavirus patients, but all of us ready to end the pandemic and discover new ways to fix the body’s broken systems.

NEW RESEARCH SUGGESTS THAT SOME OF US MAY BE PARTIALLY PROTECTED DUE TO PAST ENCOUNTERS WITH COMMON COLD CORONAVIRUSES

New research suggests that some of us may be partially protected due to past encounters with common cold coronaviruses

Forty percent of people with coronavirus infections have no symptoms. Might they be the key to ending the pandemic?

By Ariana Eunjung Cha
Washington Post
August 15, 2020

https://www.washingtonpost.com/health/2020/08/08/asymptomatic-coronavirus-covid/

During its seven-month global rampage, the coronavirus has claimed more than 700,000 lives. But Gandhi began to think the bigger mystery might be why it has left so many more practically unscathed.

What was it about these asymptomatic people, who lived or worked so closely to others who fell severely ill, she wondered, that protected them? Did the “dose” of their viral exposure make a difference? Was it genetics? Or might some people already have partial resistance to the virus, contrary to our initial understanding?

Efforts to understand the diversity in the illness are finally beginning to yield results, raising hope the knowledge will help accelerate development of vaccines and therapies – or possibly even create new pathways toward herd immunity in which enough of the population develops a mild version of the virus that they block further spread and the pandemic ends.

“A high rate of asymptomatic infection is a good thing,” said Gandhi, an infectious-disease specialist at the University of California at San Francisco. “It’s a good thing for the individual and a good thing for society.”

The coronavirus has left numerous clues – the uneven transmission in different parts of the world, the mostly mild impact on children. Perhaps most tantalizing is the unusually large proportion of infected people with no symptoms. The Centers for Disease Control and Prevention last month estimated that rate at about 40 percent.

Those clues have sent scientists off in different directions: Some are looking into the role of the receptor cells, which the virus uses to infiltrate the body, to better understand the role that age and genetics might play. Others are delving into face masks and whether they may filter just enough of the virus so that those wearing them had mild cases or no symptoms at all.

The theory that has generated the most excitement in recent weeks is that some people walking among us might already have partial immunity.

When SARS-CoV-2 was first identified on Dec. 31, 2019, public health officials deemed it a “novel” virus because it was the first time it had been seen in humans who presumably had no immunity from it whatsoever. There’s now some very early, tentative evidence suggesting that assumption might have been wrong.

One mind-blowing hypothesis – bolstered by a flurry of recent studies – is that a segment of the world’s population may have partial protection thanks to “memory” T cells, the part of our immune system trained to recognize specific invaders. This could originate from cross protection derived from standard childhood vaccinations. Or, as a paper published Tuesday in Science suggested, it could trace back to previous encounters with other coronaviruses, such as those that cause the common cold.

“This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill,” National Institutes of Health Director Francis Collins remarked in a blog post this past week.

On a population level, such findings, if validated, could be far-reaching.

Hans-Gustaf Ljunggren, a researcher at Sweden’s Karolinska Institute, and others have suggested that public immunity to the coronavirus could be significantly higher than what has been suggested by serology studies. In communities in Boston, Barcelona, Wuhan and other major cities, the proportion of people estimated to have antibodies and therefore presumably be immune has mostly been in the single digits. But if others had partial protection from T cells, that would raise a community’s immunity level much higher.

This, Ljunggren said, would be “very good news from a public health perspective.”

Some experts have gone so far as to speculate whether some surprising recent trends in the epidemiology of the coronavirus – the drop in infection rates in Sweden where there have been no widespread lockdowns or mask requirements, or the high rates of infection in Mumbai’s poor areas but little serious disease – might be due to preexisting immunity.

Others say it’s far too early to draw such conclusions. Anthony S. Fauci, the United States’ top infectious-disease expert, said in an interview that while these ideas are being intensely studied, such theories are premature. He agreed that at least some partial preexisting immunity in some individuals seems a possibility.

And he said the amount of virus someone is exposed to – called the inoculum – “is almost certainly an important and likely factor” based on what we know about other viruses.

But Fauci cautioned there are multiple likely reasons – including youth and general health – that determine whether a particular individual shrugs off the disease or dies of it. He also emphasized that even those with mild illness may have lingering medical issues.

That reinforces the need, in his view, for continued vigilance in social distancing, masking and other precautions.

“There are so many other unknown factors that maybe determine why someone gets an asymptomatic infection,” Fauci said. “It’s a very difficult problem to pinpoint one thing.”

MEMORY MACHINE

News headlines have touted the idea based on blood tests that 20 percent of some New York communities might be immune, 7.3 percent in Stockholm, 7.1 percent in Barcelona. Those numbers come from looking at antibodies in people’s blood that typically develop after they are exposed to a virus. But scientists believe another part of our immune system – T cells, a type of white blood cell that orchestrates the entire immune system – could be even more important in fighting against the coronavirus.

Recent studies have suggested that antibodies from the coronavirus seem to stick around for only two to three months in some people. While work on T cells and the coronavirus is only getting started – testing T cells is much more laborious than antibody testing – previous research has shown that, in general, T cells tend to last years longer.

One of the first peer-reviewed studies on the coronavirus and T cells was published in mid-May in the journal Cell by Alessandro Sette, Shane Crotty and others at the La Jolla Institute for Immunology near San Diego.

The group was researching blood from people who were recovering from coronavirus infections and wanted to compare that to samples from uninfected controls who were donors to a blood bank from 2015 to 2018. The researchers were floored to find that in 40 to 60 percent of the old samples, the T cells seemed to recognize SARS-CoV-2.

“The virus didn’t even exist back then, so to have this immune response was remarkable,” Sette said.

Research teams from five other locations reported similar findings. In a study from the Netherlands, T cells reacted to the virus in 20 percent of the samples. In Germany, 34 percent. In Singapore, 50 percent.

The different teams hypothesized this could be due to previous exposure to similar pathogens. Perhaps fortuitously, SARS-CoV-2 is part of a large family of viruses. Two of them – SARS and MERS – are deadly and led to relatively brief and contained outbreaks. Four other coronavirus variants, which cause the common cold, circulate widely each year but typically result in only mild symptoms. Sette calls them the “less-evil cousins of SARS-CoV-2.”

This week, Sette and others from the team reported new research in Science providing evidence the T cell responses may derive in part from memory of “common cold” coronaviruses.

“The immune system is basically a memory machine,” he said. “It remembers and fights back stronger.”

Interestingly, the researchers noted in their paper, the strongest reaction they saw was against the spike proteins that the virus uses to gain access to cells – suggesting that fewer viral copies get past these defenses.

“The current model assumes you are either protected or you are not – that it’s a yes or no thing,” Sette added. “But if some people have some level of preexisting immunity, that may suggest it’s not a switch but more continuous.”

CHILDHOOD VACCINES

Nearly 2,000 miles away, at the Mayo Clinic in Rochester, Minn., Andrew Badley was zeroing in the possible protective effects of vaccines.

Teaming up with data experts from nference, a company that manages their clinical data, he and other scientists looked at records from 137,037 patients treated at the health system to look for relationships between vaccinations and coronavirus infection.

They knew that the vaccine for smallpox, for example, had been shown to protect against measles and whooping cough. Today, a number of existing vaccines are being studied to see if any might offer cross-protection against SARS-CoV-2.

The results were intriguing: Seven types of vaccines given one, two or five years in the past were associated with having a lower rate of infection with the new coronavirus. Two vaccines in particular seemed to show stronger links: People who got a pneumonia vaccine in the recent past appeared to have a 28 percent reduction in coronavirus risk. Those who got polio vaccines had a 43 percent reduction in risk.

Venky Soundararajan, chief scientific officer of nference, remembers when he first saw how large the reduction appeared to be, he immediately picked up his phone and called Badley: “I said, ‘Is this even possible?’”

The team looked at dozens of other possible explanations for the difference. They adjusted for geographic incidence of the coronavirus, demographics, comorbidities, even whether people had had mammograms or colonoscopies under the assumption that people who got preventive care might be more apt to social distance. But the risk reduction still remained large.

“This surprised us completely,” Soundararajan recalled. “Going in we didn’t expect anything or maybe one or two vaccines showing modest levels of protection.”

The study is only observational and cannot show a causal link by design, but Mayo researchers are looking at a way to quantify the activity of these vaccines on the coronavirus to serve as a benchmark to the new vaccines being created by companies such as Moderna. If existing vaccines appear as protective as new ones under development, he said, they could change the world’s whole vaccine strategy.

GENETICS AND BIOLOGY

At NIH headquarters in Bethesda, Md., meanwhile, Alkis Togias has been laser-focused on one group of the mildly impacted: children. He wondered if it might have something to do with the receptor known as ACE2, through which the virus hitchhikes into the body.

In healthy people, the ACE2 receptors perform the important function of keeping blood pressure stable. The novel coronavirus latches itself to ACE2, where it replicates. Pharmaceutical companies are trying to figure out how to minimize the receptors or to trick the virus into attaching itself to a drug so it doesn’t replicate and travel throughout the body.

Was it possible, Togias asked, that children naturally expressed the receptor in a way that makes them less vulnerable to infection?

He said recent papers have produced counterintuitive findings about one subgroup of children – those with a lot of allergies and asthma. The ACE2 receptors in those children were diminished, and when they were exposed to an allergen such as cat hair, the receptors were further reduced. Those findings, combined with data from hospitals showing that asthma did not seem to be a risk factor for the respiratory virus, as expected, have intrigued researchers.

“We are thinking allergic reactions may protect you by down-regulating the receptor,” he said. “It’s only a theory of course.”

Togias, who is in charge of airway biology for the National Institute of Allergy and Infectious Diseases, is looking at how those receptors seem to be expressed differently as people age, as part of a study of 2,000 U.S. families. By comparing those differences and immune responses within families, they hope to be able to better understand the receptors’ role.

Separately, a number of genetic studies show variations in genes associated with ACE2 with people from certain geographic areas, such as Italy and parts of Asia, having distinct mutations. No one knows what significance, if any, these differences have on infection, but it’s an active area of discussion in the scientific community.

MASKS

Before the pandemic, Gandhi, the University of California researcher, specialized in HIV. But like other infectious-disease experts these days, she has spent many of her waking hours thinking about the coronavirus. And in scrutinizing the data on outbreaks one day, she noticed what might be a pattern: People were wearing masks in the settings with the highest percentage of asymptomatic cases.

The numbers on two cruise ships were especially striking. In the Diamond Princess, where masks weren’t used and the virus was likely to have roamed free, 47 percent of those tested were asymptomatic. But in the Antarctic-bound Argentine cruise ship, where an outbreak hit in mid-March and surgical masks were given to all passengers and N95 masks to the crew, 81 percent were asymptomatic.

Similarly high rates of asymptomatic infection were documented at a pediatric dialysis unit in Indiana, a seafood plant in Oregon and a hair salon in Missouri, all of which used masks. Gandhi was also intrigued by countries such as Singapore, Vietnam and the Czech Republic that had population-level masking.

“They got cases,” she noted, “but fewer deaths.”

The scientific literature on viral dose goes back to around 1938 when scientists began to find evidence that being exposed to one copy of a virus is more easily overcome than being exposed to a billion copies. Researchers refer to the infectious dose as ID50 – or the dose at which 50 percent of the population would become infected.

While we don’t know what that level might be for the coronavirus (it would be unethical to expose humans in this way), previous work on other nonlethal viruses showed that people tend to get less sick with lower doses and more sick with higher doses. A study published in late May involving hamsters, masks and SARS-CoV-2 found those given coverings had milder cases than those who did not get them.

In an article published this month in the Journal of General Internal Medicine, Gandhi noted that in some outbreaks early in the pandemic in which most people did not wear masks, 15 percent of the infected were asymptomatic. But later on, when people began wearing masks, the rate of asymptomatic people was 40 to 45 percent.

She said the evidence points to masks not just protecting others – as U.S. health officials emphasize – but protecting the wearer as well. Gandhi makes the controversial argument that while we’ve mostly talked about asymptomatic infections as terrifying due to how people can spread the virus unwittingly, it could end up being a good thing.

“It is an intriguing hypothesis that asymptomatic infection triggering immunity may lead us to get more population-level immunity,” Gandhi said. “That itself will limit spread.”

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