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IntroductionCOVID-19 vaccines significantly reduce SARS-CoV-2 (SCoV2)-related hospitalization and mortality in randomized controlled clinical trials, as well as in real-world effectiveness against different circulating SCoV2-lineages. However, some vaccine recipients show breakthrough infection and it remains unknown, which host and viral factors contribute to this risk and how many resulted in severe outcomes. Our aim was to identify demographic and clinical risk factors for SCoV2 breakthrough infections and severe disease in fully vaccinated individuals and to compare patient characteristics in breakthrough infections caused by SCoV2 Alpha or Delta variant. MethodsWe conducted an exploratory retrospective case-control study from 28th of December to 25th of October 2021 dominated by the Delta SCoV2 variant. All cases of infection had to be reported by law to the local health authorities. Vaccine recipients data was anonymously available from the national Vaccination Monitoring Data Lake and the main local vaccine center. We compared anonymized patients characteristics of breakthrough infection (n=492) to two overlapping control groups including all vaccine recipients from the Canton of Basel-City (group 1 n=126586 and group 2 n=109382). We also compared patients with breakthrough infection caused by the Alpha to Delta variant. We used different multivariate generalized linear models (GLM). ResultsWe found only 492/126586 (0.39%) vaccine recipients with a breakthrough infection after vaccination during the 10 months observational period. Most cases were asymptomatic or mild (478/492 97.2%) and only very few required hospitalization (14/492, 2.8%). The time to a positive SCoV2 test shows that most breakthrough infections occurred between a few days to about 170 days after full vaccination, with a median of 78 days (interquartile range, IQR 47-124 days). Factors associated with a lower odds for breakthrough infection were: age (OR 0.987, 95%CI 0.983-0.992), previous COVID-19 infection prior to vaccination (OR 0.296, 95%CI 0.117-0.606), and (self-declared) serious side-effects from previous vaccines (OR 0.289, 95%CI 0.033-1.035). Factors associated with a higher odds for breakthrough infection were: vaccination with the Pfizer/BioNTech vaccine (OR 1.459, 95%CI 1.238-1.612), chronic disease as vaccine indication (OR 2.109, 95%CI 1.692-2.620), and healthcare workers (OR 1.404, 95%CI 1.042-1.860). We did not observe a significantly increased risk for immunosuppressed patients (OR 1.248, 95% CI 0.806-1.849). ConclusionsOur study shows that breakthrough infections are rare and show mild illness, but that it occurs early after vaccination with more than 50% of cases within 70 to 80 days post-full vaccination. This clearly implies that boost vaccination should be much earlier initiated compared to the currently communicated 180-day threshold. This has important implications especially for risk groups associated with more frequent breakthrough infections such as healthcare workers, and people in high-risk care facilities. Due to changes in the epidemiological dynamic with new variants emerging, continuous monitoring of breakthrough infections is helpful to provide evidence on booster vaccines and patient groups at risk for potential complications.
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BackgroundCoronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP). MethodsLPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. ResultsThe median age of study participants was 59 (range 24-85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4-10) and 8 days (IQR 5-10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 g/mL (IQR 18.9-31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values. ConclusionsHigh LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.
