ABSTRACT
ZF2001, a protein subunit vaccine against coronavirus disease 2019 (COVID-19), contains recombinant tandem repeat of dimeric receptor-binding domain (RBD) protein of the SARS-CoV-2 spike protein with an aluminium-based adjuvant. During the development of this vaccine, two nonclinical studies were conducted to evaluate female fertility, embryo-fetal development, and postnatal developmental toxicity in SpragueâDawley rats according to the ICH S5 (R3) guideline. In Study 1 (embryo-fetal developmental toxicity, EFD), 144 virgin female rats were randomly assigned into four groups and received three doses of vaccine (25 µg or 50 µg RBD protein/dose, containing the aluminium-based adjuvant), the aluminium-based adjuvant or a sodium chloride injection administered intramuscularly on days 21 and 7 prior to mating and on gestation day (GD) 6. In Study 2 (pre- and postnatal developmental toxicity, PPND), ZF2001 at a dose of 25 µg RBD protein/dose or sodium chloride injection was administered intramuscularly to female rats (n = 28 per group) 7 days prior to mating and on GD 6, GD 20 and postnatal day (PND) 10. There were no obvious adverse effects in dams, except for local injection site reactions related to the aluminium-based adjuvant (yellow nodular deposits in the interstitial muscle fibres). There were also no effects of ZF2001 on the mating performance, fertility or reproductive performance of parental females, embryo-fetal development, postnatal survival, growth, physical development, reflex ontogeny, behavioural and neurofunctional development, or reproductive performance of the offspring. The strong immune responses associated with binding and neutralising antibodies were both confirmed in dams and fetuses or offspring in these two studies. These results would support clinical trials or the use of ZF2001 in maternal immunisation campaigns, including those involving women with childbearing potential, regardless of pregnancy status.
ABSTRACT
While mechanical ventilation practices on venovenous extracorporeal membrane oxygenation (VV ECMO) are variable, most institutions utilize a lung rest strategy utilizing relatively low positive end-expiratory pressure (PEEP). The effect of PEEP titration using esophageal manometry during VV ECMO on pulmonary and cardiac function is unknown. This was a retrospective study of 69 patients initiated on VV ECMO between March 2020 through November 2021. Patients underwent standard PEEP (typically 10 cm H2O) or optimal PEEP (PEEP titrated to an end-expiratory transpulmonary pressure 0-3 cm H2O) throughout the ECMO run. The optimal PEEP strategy had higher levels of applied PEEP (17.9 vs. 10.8 cm H2O on day 2 of ECMO), decreased incidence of hemodynamically significant RV dysfunction (4.55% vs. 44.0%, p = 0.0001), and higher survival to decannulation (72.7% vs. 44.0%, p = 0.022). Survival to discharge did not reach statistical significance (61.4% vs. 44.0%, p = 0.211). In univariate logistic regression analysis, optimal PEEP was associated with less hemodynamically significant RV dysfunction with an odds ratio (OR) of 0.06 (95% confidence interval [CI] = 0.01-0.27, p = 0.0008) and increased survival to decannulation with an OR of 3.39 (95% CI 1.23-9.79), p = 0.02), though other confounding factors may have contributed.