As many celebrate the rollout of the first COVID-19 vaccines, scientists are racing to find out whether these new shots not only protect individuals from disease, but also prevent them from transmitting the coronavirus to others.

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It turns out that vaccine protection is more complicated than it seems. Are the new vaccines merely symptom-reducing keeping those who receive it safe from getting ill but not necessarily preventing them from infecting other people or can they truly block transmission of the virus, which is often spread by infected people who show no signs of sickness?

Youd rather have a vaccine that completely blocks infection rather than preventing symptoms, said Dr. Joshua Schiffer, an infectious disease researcher at Fred Hutchinson Cancer Research Center. It could save the lives of many people who have yet to get the vaccine, by protecting them indirectly.

Yet here is the problem: The giant, successful studies that determined that both the Moderna and Pfizer vaccines were an astonishing 90%-95% effective in preventing disease cannot completely answer the question of how they worked. The trials designs only allow an imperfect estimate of whether the vaccines block infection or just symptoms. Until now, that question was less urgent than finding out if they worked at all.

It is a question that is now so important to the rollout of vaccines that Schiffer and key vaccine experts involved in the trials are considering different approaches to provide rapid answers.

One option is human challenge studies in which about 100 paid volunteers are deliberately exposed to the coronavirus. In a paper posted on Dec. 14 on the preprint server MedRxiv, Schiffer and his colleagues discuss how measuring levels of virus among participants in such studies might provide the information they need. Preprints are not peer-reviewed prior to publication but serve as a quick way to present new research for public critique by other scientists.

The teams proposed study would go like this: In the controlled environment of a human challenge trial, about 50 young adult volunteers would receive a vaccine, and the same number would get a placebo. Then, all the participants would be deliberately infected with a strain of the COVID-19 virus. Only young volunteers would be recruited for the study, because they are most likely to come down with just a mild case of COVID-19.

Isolated in a safe location for two weeks, participants would get regular swabs for a test that not only detects virus but can measure how much of it the viral load is in their specimens. The higher the viral load, the more likely a person is likely to transmit the virus to others.

If the scientists find the vaccinated group is shedding no or very little virus compared to the placebo group, it will be strong evidence that the vaccine not only stops disease, it prevents or reduces the chances the recipient would be contagious.

While I do think that a human challenge study would provide the answer, the ethics of this approach are complex and require significant debate among experts in the field, said Schiffer.

The study authors, who include Drs. Larry Corey and Myron Cohen, leading figures in the federal vaccine studies managed by the COVID-19 Prevention Network, also discuss an alternative to human challenge trials.

As outlined in the paper, this second proposed study would enroll university students, a cohort know to be at high risk for coronavirus infection but also less likely to suffer from severe disease. The idea would be to enroll a large number of students living in dormitories and assign half to a vaccine, half to a placebo.

No one would be deliberately infected. The virus would spread as it naturally does in these communities, but the participants would undergo regular and frequent viral load testing. Over the course of time, the study should be able to compare patterns of viral transmissibility between groups, in a more natural environment than the laboratory-based human challenge trial.

However, such a trial would have to be large and capable of handling massive amounts of testing and data.

Either of these studies are potentially critically important and would complement each other well, Schiffer said.

Much of Schiffers paper is devoted to complex computer modeling of different vaccine rollout scenarios that take into consideration assumptions of how effective the vaccine is in preventing symptomatic disease or transmission factors that are not well measured in the ongoing vaccine trials. The nature of protection afforded by new COVID-19 vaccines could have an impact on whether nor not they can prevent a fourth wave of infections and deaths this spring.

Using extensive data provided by King County, the large Puget Sound region that includes Seattle, Schiffer and his colleagues ran computer simulations of vaccine rollout. Their simulations show that if the Moderna and Pfizer vaccines offer complete protection against infections, then the anticipated fourth wave of infection in that region could be prevented if vaccine is rolled out quickly enough, with an estimated 60% reduction in cases and deaths.

If it turns out that the vaccines work primarily by reducing symptoms saving the lives of those vaccinated but not curbing ongoing viral transmission the model projects the region could experience a fourth wave of about 200,000 new infections and over 500 deaths in 2021.

Vaccines performing primarily as symptom reducers are also less likely to contribute as rapidly to herd immunity, in which enough people are protected by either previous infection or vaccines that the virus burns out for lack of sufficient new targets.

As 2020 draws to a close, the vaccine rollout is indeed a cause for celebration in a pandemic-weary nation where more than 300,000 have already died. With their proposed studies, Schiffer and colleagues hope to offer evidence-based guidance on how to get the most out of these breakthroughs in in the coming year.