What should define a SARS-CoV-2 breakthrough infection?
We need a more precise definition of what a true breakthrough case is (Figure 1). We suggest that breakthrough disease should be defined by a positive SARS-CoV-2 PCR test from the respiratory tract and documentation of lower respiratory tract disease (Figure 1). On the other hand, detection of the SARS-CoV-2 virus in the upper respiratory tract in a fully vaccinated individual with no symptoms or mild upper respiratory tract infection symptoms (loss of smell) would not meet the criteria for a breakthrough infection. This is not to say that these positive tests are not infections, as they do carry the risk of transmission, they are just not breakthrough infections. Perhaps they are best classified as post-vaccination upper respiratory tract infections. The formal criteria for a true breakthrough infection could include evidence of radiographic abnormalities, a widened alveolar-arterial (A-a) gradient, or hypoxemia defined by low oxygen saturations in the arterial blood by pulse oximetry. These criteria will be critical to determine which positive SARS-CoV-2 tests are true vaccine failures in the lower respiratory tract versus the upper respiratory tract. In the current environment of widespread vaccine hesitancy, these distinctions will be crucial to maintaining, and possibly increasing, the publics trust in vaccines as well as understanding the role of vaccination in ending the pandemic. Figure 1 Clinical scenarios and proposed classification of breakthrough infection based on disease in the lower respiratory tract. We propose that breakthrough infection after COVID-19 vaccination is defined by evidence of lower respiratory tract infection (LRI) and a positive PCR test for SARS-COV-2. Vaccinated individuals who are asymptomatic or have symptoms limited to an upper respiratory tract infection (URI) are not experiencing a breakthrough infection, although it is important to understand that these individuals may still be able to transmit virus. We also suggest that those individuals who do not mount an effective immune response to vaccination do not represent cases of breakthrough infection. *Transmission risk is likely proportionate to the viral copy number.