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.

Effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes

“…Finally, a study from South Africa estimated VE against infection at 33% in the Omicron period compared to 77% in the pre-Omicron period. 19 Direct comparisons to other jurisdictions are challenging 20 due to differences in study methodology, outcome definitions (i.e., symptomatic infection vs. any infection), vaccination policies (i.e., homologous vs. heterologous vaccine schedules, third dose eligibility criteria, product-specific policies), population age structures, and public health measures that were in place during the study period (e.g., vaccine certificates, mask mandates 21 ). Despite this, the general trends across the studies are similar, demonstrating substantially lower VE against Omicron infection than for previous SARS-CoV-2 variants.…”

Managing waning vaccine protection against SARS-CoV-2 variants

“…Third, the estimates of vaccine effectiveness and the magnitude of waning protection (ie, RRs in this study) should be interpreted with caution owing to challenges in estimating risk of infection and severe outcomes among vaccinated and unvaccinated individuals in observational studies. 4,5 Notwithstanding these methodological limitations, the finding that protection with ChAdOx1 nCoV-19 wanes is crucial, because ChAdOx1 nCoV-19 is one of the most widely used vaccines and its effectiveness against the omicron variant has yet to be characterised. Preliminary data show that the antibodies from a three-dose course of mRNA vaccines neutralise omicron, although all the studies report a notable drop in neutralising antibody titres compared with earlier variants such as delta.…”

“…Third, the estimates of vaccine effectiveness and the magnitude of waning protection (ie, RRs in this study) should be interpreted with caution owing to challenges in estimating risk of infection and severe outcomes among vaccinated and unvaccinated individuals in observational studies. 4 , 5 …”

Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

“…This would enable comparisons of naive patients with vaccinated and previously infected patients. Lipsitch et al speculate that a higher viral inoculum might reduce vaccine efficacy [54]; future SIMCoV experiments can assess how the number of FOI impact T cell control of infection in vaccinated people. SIMCoV could also be used to study other respiratory diseases, such as influenza, or even be extended to model infection in other organs.…”