Severe breakthrough COVID-19 cases in the SARS-CoV-2 delta (B.1.617.2) variant era.

Despite compelling evidence that SARS-CoV-2 vaccines are highly effective in preventing COVID-19 infections, breakthrough cases have been emerging at an increasing rate. A retrospective cohort study by Tartof and colleagues found that vaccine effectiveness against COVID-19 decreased over time; however, its effectiveness against hospitalisation associated with COVID-19 remained robust, with no apparent reduction in vaccine effectiveness between 1 month (87%) and 5 months (88%) after vaccination with the BNT162b2 vaccine. Although most breakthrough COVID-19 cases are mild or moderate in severity, severe cases and deaths have been reported. In this Comment, we describe the shift in the landscape of severe COVID-19 requiring hospitalisation in a health system with high regional vaccination rates, whereby 90·9% of individuals aged 65–74 years and 85·6% of those aged 75 years and older are fully vaccinated as of Oct 17, 2021.

We conducted a systematic review of patients with SARS-CoV-2 infection confirmed by PCR test, who were hospitalised at the Yale New Haven Health System (New Haven, CT, USA) between Aug 4 and Oct 12, 2021, during which time the SARS-CoV-2 delta (B.1.617.2) variant accounted for over 95% of COVID-19 cases in the region. Among 371 patients admitted with a positive SARS-CoV-2 PCR test, 129 (35%) were fully vaccinated at the time of hospitalisation. 222 (60%) patients met the criteria for being severely or critically ill with COVID-19 during their hospitalisation, among whom 82 (37%) were fully vaccinated. Overall, a much larger proportion of patients hospitalised with a positive SARS-CoV-2 test had severe or critical breakthrough COVID-19 during this period (82 [22%] of 371 patients) than was reported in the same health-care system between March 23 to July 1, 2021 (14 [1%] of 969 patients), when the delta variant accounted for less than 20% of COVID-19 cases in the region.5, 6 Additionally, evaluation of time to COVID-19 from the date of final vaccine dose showed a marked rise in the frequency of severe breakthrough cases with an increasing number of days since completed vaccination (appendix p 1).

Among the patients with severe or critical COVID-19, the age distribution of patients with breakthrough infections was skewed towards older age groups (mean age 71·5 years) compared with those who were unvaccinated (55·2 years; appendix p 2). Furthermore, underlying comorbidities—including cardiovascular and lung disease, type 2 diabetes, history of malignancy, and baseline use of immunosuppressive medications—were more prevalent in patients with breakthrough infections than in those who were unvaccinated (appendix p 3). Despite these differences, which could potentially portend worse clinical outcomes for the patients with severe breakthrough COVID-19, we observed a shorter mean duration of hospitalisation (10·8 days vs 13·1 days), lower risk of advanced oxygen or ventilatory support (26 [32%] of 82 vs 72 [51%] of 140 patients), and lower in-hospital mortality (eight [10%] vs 17 [12%] patients) among patients with breakthrough COVID-19 than among those who were unvaccinated.

The shifting landscape of breakthrough COVID-19 cases is likely to involve multiple factors, including demonstrated waning of antibody response after full vaccination7, 8 and emergence of variant strains of SARS-CoV-2. The differences in the incidence of breakthrough cases based on vaccine type is of interest and will need further investigation. The accelerating trend of breakthrough COVID-19 cases with time since vaccination highlight the important need for booster vaccinations, especially given emerging data supporting their efficacy, in particular for older populations and for individuals with underlying comorbidities who face an increased risk of developing severe breakthrough infections.