A New Theory Asks: Could a Mask Be a Crude ‘Vaccine’?

Scientists float a provocative — and unproven — idea: that masks expose the wearer to just enough of the virus to spark a protective immune response.

A new scientific paper explores the concept of variolation, the deliberate exposure to a pathogen to generate a protective immune response.

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Daniel Acker for The New York Times

By Katherine J. Wu

Sept. 8, 2020

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As the world awaits the arrival of a safe and effective coronavirus vaccine, a team of researchers has come forward with a provocative new theory: that masks might help to crudely immunize some people against the virus.

The unproven idea, described in a commentary published Tuesday in the New England Journal of Medicine, is inspired by the age-old concept of variolation, the deliberate exposure to a pathogen to generate a protective immune response. First tried against smallpox, the risky practice eventually fell out of favor, but paved the way for the rise of modern vaccines.

Masked exposures are no substitute for a bona fide vaccine. But data from animals infected with the coronavirus, as well as insights gleaned from other diseases, suggest that masks, by cutting down on the number of viruses that encounter a person’s airway, might reduce the wearer’s chances of getting sick. And if a small number of pathogens still slip through, the researchers argue, these might prompt the body to produce immune cells that can remember the virus and stick around to fight it off again.

“You can have this virus but be asymptomatic,” said Dr. Monica Gandhi, an infectious disease physician at the University of California, San Francisco, and one of the commentary’s authors. “So if you can drive up rates of asymptomatic infection with masks, maybe that becomes a way to variolate the population.”

That does not mean people should don a mask to intentionally inoculate themselves with the virus. “This is not the recommendation at all,” Dr. Gandhi said. “Neither are pox parties,” she added, referring to social gatherings that mingle the healthy and the sick.

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The theory cannot be directly proven without clinical trials that compare the outcomes of people who are masked in the presence of the coronavirus with those who are unmasked — an unethical experimental setup. And while outside experts were intrigued by the theory, they were reluctant to embrace it without more data, and advised careful interpretation.

“It seems like a leap,” said Saskia Popescu, an infectious disease epidemiologist based in Arizona who was not involved in the commentary. “We don’t have a lot to support it.”

Taken the wrong way, the idea could lull the masked into a false sense of complacency, potentially putting them at higher risk than before, or perhaps even bolster the incorrect notion that face coverings are entirely useless against the coronavirus, since they cannot render the wearer impervious to infection.

“We still want people to follow all the other prevention strategies,” Dr. Popescu said. That means staying vigilant about avoiding crowds, physical distancing and hand hygiene — behaviors that overlap in their effects, but can’t replace one another.

The coronavirus variolation theory hinges on two assumptions that are difficult to prove: that lower doses of the virus lead to less severe disease, and that mild or asymptomatic infections can spur long-term protection against subsequent bouts of sickness. Although other pathogens offer some precedent for both concepts, the evidence for the coronavirus remains sparse, in part because scientists have only had the opportunity to study the virus for a few months.

Experiments in hamsters have hinted at a connection between dose and disease. Earlier this year, a team of researchers in China found that hamsters housed behind a barrier made of surgical masks were less likely to get infected by the coronavirus. And those who did contract the virus became less sick than other animals without masks to protect them.

A few observations in humans seem to support this trend as well. In crowded settings where masks are in widespread use, infection rates seem to plummet. And although face coverings cannot block all inbound virus particles for all people, they do seem to be linked to less illness. Researchers have uncovered largely silent, symptomless outbreaks in venues from cruise ships to food processing plants, all full of mostly masked people.

Data linking dose to symptoms have been gathered for other microbes that attack the human airway, including influenza viruses and the bacteria that cause tuberculosis.

But despite decades of research, the mechanics of airborne transmission largely remain “a black box,” said Jyothi Rengarajan, an expert in vaccines and infectious disease at Emory University who was not involved in the commentary.

That is partly because it is difficult to pin down the infectious dose required to sicken a person, Dr. Rengarajan said. Even if researchers eventually settle on an average dose, the outcome will vary from person to person, since factors like genetics, a person’s immune status and the architecture of their nasal passages can all influence how much virus can colonize the respiratory tract.

And confirming the second half of the variolation theory — that masks allow entry to just enough virus to prime the immune system — might be even trickier. Although several recent studies have pointed to the possibility that mild cases of Covid-19 can provoke a strong immune response to the coronavirus, durable protection cannot be proven until researchers gather data on infections for months or years after these have resolved.

On the whole, the theory “has some merits,” said Angela Rasmussen, a virologist at Columbia University who was not involved in the commentary. “But I’m still pretty skeptical.”

It is important to remember, she said, that vaccines are inherently less dangerous than actual infections, which is why practices like variolation (sometimes called inoculation) eventually became obsolete. Before vaccines were discovered, doctors made do by rubbing bits of smallpox scabs or pus into the skin of healthy people. The resulting infections were usually less severe than smallpox cases caught the typical way, but “people definitely got smallpox and died from variolation,” Dr. Rasmussen said. And variolation, unlike vaccines, can make people contagious to others.

Dr. Gandhi acknowledged these limitations, noting that the theory should not be construed as anything other than that — a theory. Still, she said, “Why not drive up the possibility of not getting sick and having some immunity while we’re waiting for the vaccine?”

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By E.J. Mundell

HealthDay Reporter

WEDNESDAY, Sept. 9, 2020 (HealthDay News) — The world is still waiting for a safe, effective coronavirus vaccine. But new research now suggests that billions of people may already be using a crude vaccine of sorts: face masks.

The theory — and it remains largely a theory — is that by filtering out airborne coronavirus droplets and thereby lowering the dose of SARS-CoV-2 a person inhales, infections have much less chance of producing symptoms.

Much in the way vaccination works, an immune response would be triggered in the mask-wearer upon contact with a small amount of virus, but at a level that’s not likely to cause serious illness.

“If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence, might contribute to increasing the proportion of SARS-CoV-2 infections that are asymptomatic,” said Dr. Monica Gandhi and Dr. George Rutherford in a commentary published Sept. 8 in the New England Journal of Medicine. Both authors are from the University of California, San Francisco.

There’s some good evidence that masks could be working in this way, according to the two experts. They pointed out that animal studies conducted since the 1930s have borne out the notion of a “lethal dose,” or how many viral particles are needed to cause severe disease.

More recently, studies conducted in hamsters seem to show that “higher doses of administered virus led to more severe manifestations of COVID-19,” Gandhi and Rutherford wrote. And when the hamsters were protected with simulated masking, they “were less likely to get infected, and if they did get infected, they either were asymptomatic or had milder symptoms than unmasked hamsters,” the experts noted.

For ethical reasons, similar trials in humans haven’t been conducted. But population studies seem to support the “mask as vaccine” theory. For example, the U.S. Centers for Disease Control and Prevention reported that by mid-July about 40% of coronavirus infections were asymptomatic, but in areas of the United States where mask wearing was very prevalent, that number rose to 80%.

In early outbreaks of SARS-CoV-2 infections on cruise ships, before the widespread use of face masks, the rate of cases with no symptoms was about 20%, Gandhi and Rutherford noted. But in an outbreak on one Argentinian cruise ship where face masks were mandated for passengers and crew, the rate of asymptomatic cases rose sharply, to 81%.

Finally, in two recent outbreaks in U.S. food-processing plants where workers were told to wear masks, 95% of cases of coronavirus infections were asymptomatic, and the remaining 5% experienced only mild-to-moderate symptoms, the two experts said.

Dr. Amesh Adalja is an infectious disease expert and senior scholar at the Johns Hopkins Center for Health Security in Baltimore. Reading over the NEJM essay, he agreed that “if facial coverings decrease the amount of virus a person is infected with, they can provide a way of tilting towards infections that result in minimal or no symptoms, yet induce some degree of immunity.”

But experts caution that in no way should masks be viewed as a substitute for a safe, effective vaccine.

Speaking to the New York Times, Emory University vaccines expert Jyothi Rengarajan noted that inhaled exposure to even small amount of live virus is a much riskier proposition than the more controlled effects of a vaccine. That’s because there are variations between individuals in immune responses, genetics, and even the structure of the nasal passages, she said. So even when wearing a mask, it’s still possible that inhalation of SARS-CoV-2 could still make some people very ill.

However, masks certainly may cut down on that risk. And as the world waits for a vaccine, “any public health measure that could increase the proportion of asymptomatic SARS-CoV-2 infections may both make the infection less deadly and increase population-wide immunity without severe illnesses and deaths,” Gandhi and Rutherford concluded.

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As SARS-CoV-2 continues its global spread, it’s possible that one of the pillars of Covid-19 pandemic control — universal facial masking — might help reduce the severity of disease and ensure that a greater proportion of new infections are asymptomatic. If this hypothesis is borne out, universal masking could become a form of “variolation” that would generate immunity and thereby slow the spread of the virus in the United States and elsewhere, as we await a vaccine.

One important reason for population-wide facial masking became apparent in March, when reports started to circulate describing the high rates of SARS-CoV-2 viral shedding from the noses and mouths of patients who were presymptomatic or asymptomatic — shedding rates equivalent to those among symptomatic patients.1 Universal facial masking seemed to be a possible way to prevent transmission from asymptomatic infected people. The Centers for Disease Control and Prevention (CDC) therefore recommended on April 3 that the public wear cloth face coverings in areas with high rates of community transmission — a recommendation that has been unevenly followed across the United States.

Past evidence related to other respiratory viruses indicates that facial masking can also protect the wearer from becoming infected, by blocking viral particles from entering the nose and mouth.2 Epidemiologic investigations conducted around the world — especially in Asian countries that became accustomed to population-wide masking during the 2003 SARS pandemic — have suggested that there is a strong relationship between public masking and pandemic control. Recent data from Boston demonstrate that SARS-CoV-2 infections decreased among health care workers after universal masking was implemented in municipal hospitals in late March.

SARS-CoV-2 has the protean ability to cause myriad clinical manifestations, ranging from a complete lack of symptoms to pneumonia, acute respiratory distress syndrome, and death. Recent virologic, epidemiologic, and ecologic data have led to the hypothesis that facial masking may also reduce the severity of disease among people who do become infected.3 This possibility is consistent with a long-standing theory of viral pathogenesis, which holds that the severity of disease is proportionate to the viral inoculum received. Since 1938, researchers have explored, primarily in animal models, the concept of the lethal dose of a virus — or the dose at which 50% of exposed hosts die (LD50). With viral infections in which host immune responses play a predominant role in viral pathogenesis, such as SARS-CoV-2, high doses of viral inoculum can overwhelm and dysregulate innate immune defenses, increasing the severity of disease. Indeed, down-regulating immunopathology is one mechanism by which dexamethasone improves outcomes in severe Covid-19 infection. As proof of concept of viral inocula influencing disease manifestations, higher doses of administered virus led to more severe manifestations of Covid-19 in a Syrian hamster model of SARS-CoV-2 infection.4

If the viral inoculum matters in determining the severity of SARS-CoV-2 infection, an additional hypothesized reason for wearing facial masks would be to reduce the viral inoculum to which the wearer is exposed and the subsequent clinical impact of the disease. Since masks can filter out some virus-containing droplets (with filtering capacity determined by mask type),2 masking might reduce the inoculum that an exposed person inhales. If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence,2 might contribute to increasing the proportion of SARS-CoV-2 infections that are asymptomatic. The typical rate of asymptomatic infection with SARS-CoV-2 was estimated to be 40% by the CDC in mid-July, but asymptomatic infection rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evidence for this hypothesis. Countries that have adopted population-wide masking have fared better in terms of rates of severe Covid-related illnesses and death, which, in environments with limited testing, suggests a shift from symptomatic to asymptomatic infections. Another experiment in the Syrian hamster model simulated surgical masking of the animals and showed that with simulated masking, hamsters were less likely to get infected, and if they did get infected, they either were asymptomatic or had milder symptoms than unmasked hamsters.

The most obvious way to spare society the devastating effects of Covid-19 is to promote measures to reduce both transmission and severity of illness. But SARS-CoV-2 is highly transmissible, cannot be contained by syndromic-based surveillance alone,1 and is proving difficult to eradicate, even in regions that implemented strict initial control measures. Efforts to increase testing and containment in the United States have been ongoing and variably successful, owing in part to the recent increase in demand for testing.

The hopes for vaccines are pinned not just on infection prevention: most vaccine trials include a secondary outcome of decreasing the severity of illness, since increasing the proportion of cases in which disease is mild or asymptomatic would be a public health victory. Universal masking seems to reduce the rate of new infections; we hypothesize that by reducing the viral inoculum, it would also increase the proportion of infected people who remain asymptomatic.3

In an outbreak on a closed Argentinian cruise ship, for example, where passengers were provided with surgical masks and staff with N95 masks, the rate of asymptomatic infection was 81% (as compared with 20% in earlier cruise ship outbreaks without universal masking). In two recent outbreaks in U.S. food-processing plants, where all workers were issued masks each day and were required to wear them, the proportion of asymptomatic infections among the more than 500 people who became infected was 95%, with only 5% in each outbreak experiencing mild-to-moderate symptoms.3 Case-fatality rates in countries with mandatory or enforced population-wide masking have remained low, even with resurgences of cases after lockdowns were lifted.

Variolation was a process whereby people who were susceptible to smallpox were inoculated with material taken from a vesicle of a person with smallpox, with the intent of causing a mild infection and subsequent immunity. Variolation was practiced only until the introduction of the variola vaccine, which ultimately eradicated smallpox. Despite concerns regarding safety, worldwide distribution, and eventual uptake, the world has high hopes for a highly effective SARS-CoV-2 vaccine, and as of early September, 34 vaccine candidates were in clinical evaluation, with hundreds more in development.

While we await the results of vaccine trials, however, any public health measure that could increase the proportion of asymptomatic SARS-CoV-2 infections may both make the infection less deadly and increase population-wide immunity without severe illnesses and deaths. Reinfection with SARS-CoV-2 seems to be rare, despite more than 8 months of circulation worldwide and as suggested by a macaque model. The scientific community has been clarifying for some time the humoral and cell-mediated components of the adaptive immune response to SARS-CoV-2 and the inadequacy of antibody-based seroprevalence studies to estimate the level of more durable T-cell and memory B-cell immunity to SARS-CoV-2. Promising data have been emerging in recent weeks suggesting that strong cell-mediated immunity results from even mild or asymptomatic SARS-CoV-2 infection,5 so any public health strategy that could reduce the severity of disease should increase population-wide immunity as well.

To test our hypothesis that population-wide masking is one of those strategies, we need further studies comparing the rate of asymptomatic infection in areas with and areas without universal masking. To test the variolation hypothesis, we will need more studies comparing the strength and durability of SARS-CoV-2–specific T-cell immunity between people with asymptomatic infection and those with symptomatic infection, as well as a demonstration of the natural slowing of SARS-CoV-2 spread in areas with a high proportion of asymptomatic infections.

Ultimately, combating the pandemic will involve driving down both transmission rates and severity of disease. Increasing evidence suggests that population-wide facial masking might benefit both components of the response.