SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact

Abstract

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fully vaccinated individuals are receiving intense scrutiny because of their importance in determining how long restrictions to control virus transmission will need to remain in place in highly vaccinated populations as well as in determining the need for additional vaccine doses or changes to the vaccine formulations and/or dosing intervals. Measurement of breakthrough infections is challenging outside of randomized, placebo-controlled, double-blind field trials. However, laboratory and observational studies are necessary to understand the impact of waning immunity, viral variants and other determinants of changing vaccine effectiveness against various levels of coronavirus disease 2019 (COVID-19) severity. Here, we describe the approaches being used to measure vaccine effectiveness and provide a synthesis of the burgeoning literature on the determinants of vaccine effectiveness and breakthrough rates. We argue that, rather than trying to tease apart the contributions of factors such as age, viral variants and time since vaccination, the rates of breakthrough infection are best seen as a consequence of the level of immunity at any moment in an individual, the variant to which that individual is exposed and the severity of disease being considered. We also address key open questions concerning the transition to endemicity, the potential need for altered vaccine formulations to track viral variants, the need to identify immune correlates of protection, and the public health challenges of using various tools to counter breakthrough infections, including boosters in an era of global vaccine shortages.

Fig. 1. Conceptual model: levels of immunity determine susceptibility to breakthrough infections.

The figure illustrates how the interplay between the age of the vaccinated individual, immune competent or compromised state, the variant of SARS-CoV-2, and time since vaccination determine the susceptibility to breakthrough infection. The blue lines chart the levels of immune response that develop following a two-dose primary vaccine regimen, which peaks and wanes (first rapidly and the more slowly) and is then boosted by a third dose (booster) 6–7 months after the second. At the time of writing, insufficient data exist to define the kinetics of immunity following the third dose. The outcome of an exposure (protection or breakthrough) depends on the relative magnitude of (1) the current level of immunity of an individual and the level required to prevent infection (long dashed lines) or severe disease (short dashed lines) with a variant that is well matched to the vaccine, such as the Alpha variant (indicated in beige), or is a less well matched variant, such as the Delta variant (indicated in red). Increased age (and some other factors, such as an immunocompromised state) are associated with lower initial immune responses to primary vaccination and to booster (indicated by light blue line) compared with those of a healthy, younger individual (indicated by dark blue line).