September, researchers from the University of California at San Francisco published a perspective piece in the New England Journal of Medicine espousing a compelling theory about how masks can act as a crude vaccine. Their theory is that masking reduces the “viral inoculum,” or the dose of virus that one inhales, and when one gets this low dose of virus, it is more likely that they will get either a mildly symptomatic or even asymptomatic infection. And if one then develops immunity, then this acts as a crude vaccine.

It is indeed a compelling theory, and I commented on this research when it was released before being peer-reviewed. That piece generated a lot of buzz, and so did this article by Drs. Ghandi and Rutherford. In response, several scientists wrote to the New England Journal of Medicine to respond to the article, and the Journal published those correspondences along with Dr. Ghandi’s response.

In the first letter, scientists from Columbia, New York, and Virginia wrote,

There is insufficient evidence to support the claim that masks reduce the infectious dose of SARS-CoV-2 and the severity of Covid-19, much less that their use can induce protective immunity. Substantial knowledge gaps must be addressed before claims are made about the efficacy of face masks in reducing morbidity or eliciting immune responses.

Masks are used primarily to reduce SARS-CoV-2 transmission rather than reduce the dose of infectious particles or mitigate the severity of Covid-19. The suggestion that masks offer an alternative to vaccination without evidence that the benefits outweigh the great risks implicitly encourages reckless behavior.

The second letter was a lot longer, written by scientists from New Orleans and Minneapolis:

Gandhi and Rutherford’s theory regarding the potential for variolation by means of facial masking is not consistent with the emerging science of transmission of SARS-CoV-2. This virus does not appear to follow a classic dose–response relationship (i.e., the lower a viral inoculum exposure, the less severe the disease). Experimental infection studies involving healthy adult macaques have shown that severe clinical disease rarely occurs after respiratory infection in SARS-CoV-2, which would be the expected pathophysiological consequence if the dose–response assumption were valid (1). Viral replication is related to dose, but disease severity is not. The epidemiology indicates that the occurrence of severe Covid-19 is associated with preexisting conditions and other risk factors, such as age, sex, and pregnancy status (2).

They made good points, and so I was very interested in seeing what Drs. Ghandi and Rutherford had to say in response:

We agree that well-described host characteristics, including age and coexisting conditions, influence disease severity. However, more evidence is accruing to support the idea that the viral inoculum of SARS-CoV-2 (lowered by means of masking or social distancing) is associated with disease severity (1–4). Direct experimentation in humans to support this theory is not feasible, but studies in animals have shown the association; in addition to the hamster model, which we cited in our Perspective article, a new model in ferrets shows the same dose–response relationship (3). The association between viral inoculum and disease severity may be related to an overwhelmed innate immune response and has been seen in other viral infections in which the host immune response contributes prominently to viral pathogenesis, such as in SARS-CoV-2, measles, influenza, and dengue.

The use of the term “variolation” refers to the fact that strong T-cell immunity to SARS-CoV-2 appears to be generated with asymptomatic or mild infection, as shown in multiple recent studies; the duration of that immunity is unknown, and we stress the need for a safe and effective vaccine. We did not mean to imply in our Perspective article that people should be deliberately infected with SARS-CoV-2. In fact, as practicing infectious disease physicians, we counsel very strongly against deliberate infection, given the case fatality rate and the complicated interplay between host and pathogen. However, because vaccine trials are also examining strategies for reducing the severity of infection, we are interested in any public health strategy (including masking or social distancing) (4) that could reduce disease severity.

Although the evidence regarding reduced transmission and acquisition of infection with the wearing of cloth masks was originally mixed, there is increasing evidence both from physical sciences and from epidemiologic investigations that cloth masks (if worn properly) reduce both transmission and acquisition (5). The data have evolved on cloth and surgical masks, leading the state of California, for instance, to change its public health messaging to “masks protect you and others.” We hope our article encourages investigators to conduct further studies of the relationship between viral inoculum and disease severity with SARS-CoV-2. Although proving this hypothesis by means of experiments in humans will never be feasible, further studies in animals and observational studies will strengthen the evidence base.

These letters to the editor in medical journals are a great window into the discussions between scientists, and they don’t make the news headlines or press releases. That’s why I shared them in this piece.

Now, notice, none of the scientists — not one — claimed that masks should not be worn or that masks are not effective, unlike the “expert” the White House has enlisted. They simply took issue with the claims of Drs. Ghandi and Rutherford as lacking scientific evidence. And their response to the letters made me even more comfortable with the theory that masks can indeed act as crude vaccines.

Also notice that Drs. Ghandi and Rutherford did not say that masks are the be-all and end-all. They also agree that a vaccine is essential to ending this pandemic once and for all. While we await the trials to be completed to ensure the vaccines’ safety and efficacy, however, everyone needs to be wearing a mask. That’s what the science says. We need to listen to the science.