Estimated Effectiveness of Postpartum Maternal Messenger RNA COVID-19 Vaccination Against Delta and Omicron SARS-CoV-2 Infection and Hospitalization in Infants Younger Than 6 Months.

This case-control study estimates the effectiveness of maternal postpartum messenger RNA (mRNA) COVID-19 vaccination against Delta and Omicron SARS-CoV-2 infection and hospitalization in infants younger than 6 months.

Maternal mRNA covid-19 vaccination during pregnancy and delta or omicron infection or hospital admission in infants: test negative design study.

OBJECTIVE: To estimate the effectiveness of maternal mRNA covid-19 vaccination during pregnancy against delta and omicron severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and hospital admission in infants. DESIGN: Test negative design study. SETTING: Community and hospital testing in Ontario, Canada. PARTICIPANTS: Infants younger than six months of age, born between 7 May 2021 and 31 March 2022, who were tested for SARS-CoV-2 between 7 May 2021 and 5 September 2022. INTERVENTION: Maternal mRNA covid-19 vaccination during pregnancy. MAIN OUTCOME MEASURES: Laboratory confirmed delta or omicron infection or hospital admission of the infant. Multivariable logistic regression estimated vaccine effectiveness, with adjustments for clinical and sociodemographic characteristics associated with vaccination and infection. RESULTS: 8809 infants met eligibility criteria, including 99 delta cases (4365 controls) and 1501 omicron cases (4847 controls). Infant vaccine effectiveness from two maternal doses was 95% (95% confidence interval 88% to 98%) against delta infection and 97% (73% to 100%) against infant hospital admission due to delta and 45% (37% to 53%) against omicron infection and 53% (39% to 64%) against hospital admission due to omicron. Vaccine effectiveness for three doses was 73% (61% to 80%) against omicron infection and 80% (64% to 89%) against hospital admission due to omicron. Vaccine effectiveness for two doses against infant omicron infection was highest with the second dose in the third trimester (53% (42% to 62%)) compared with the first (47% (31% to 59%)) or second (37% (24% to 47%)) trimesters. Vaccine effectiveness for two doses against infant omicron infection decreased from 57% (44% to 66%) between birth and eight weeks to 40% (21% to 54%) after 16 weeks of age. CONCLUSIONS: Maternal covid-19 vaccination with a second dose during pregnancy was highly effective against delta and moderately effective against omicron infection and hospital admission in infants during the first six months of life. A third vaccine dose bolstered protection against omicron. Effectiveness for two doses was highest with maternal vaccination in the third trimester, and effectiveness decreased in infants beyond eight weeks of age.

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review.

BACKGROUND: Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signalling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical coronavirus disease 2019 (COVID-19). Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. OBJECTIVES: To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab's use in these populations with COVID-19. SOURCES: PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. The US Food and Drug Administration and the European Medicines Agency guidance for the industry and regulatory approval documents were reviewed. CONTENT: Published data on tocilizumab in pregnancy include 610 cases (n = 20 with COVID-19) together with seven mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared with the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow up was limited. Tocilizumab appears to be compatible with breastfeeding. IMPLICATIONS: Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.

Pharmacokinetic/Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19.

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

Role of maternal COVID-19 vaccination in providing immunological protection to the newborn.

Pregnant and postpartum individuals are known to have an elevated risk of severe COVID-19 compared with their non-pregnant counterparts. Vaccination is the most important intervention to protect these populations from COVID-19-related morbidity and mortality. An added benefit of maternal COVID-19 vaccination is transfer of maternal immunity to newborns and infants, for whom a vaccine is not (yet) approved. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific binding and neutralizing antibodies are present in infant cord blood and breast milk following natural maternal infection and transfer of maternal immunity following COVID-19 vaccination is an area of active research. In this review, we synthesize the available research, discuss knowledge gaps, and outline factors that should be evaluated and reported when studying the transfer of maternal immunity following COVID-19 vaccination. The data reviewed herein suggest that maternal SARS-CoV-2-specific binding antibodies are efficiently transferred via the placenta and breast milk following maternal mRNA COVID-19 vaccination. Moreover, antibodies retain strong neutralizing capacity. Antibody concentrations appear to be at least as high in infant cord blood as in the maternal serum, but lower in breast milk. Breast milk IgA rises rapidly following maternal vaccination, whereas IgG rises later but may persist longer. At least two COVID-19 vaccine doses appear to be required to reach maximal antibody concentrations in cord blood and breast milk. There is no indication that infants consuming breast milk from vaccinated mothers experience serious adverse effects, although follow-up is limited. No clear pattern has emerged regarding changes in milk supply following maternal vaccination. The heterogeneity in important methodological aspects of reviewed studies underscores the need to establish standard best practices related to research on the transfer of maternal COVID-19 vaccine-induced immunity.

A review of remdesivir for COVID-19 in pregnancy and lactation.

Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts, underscoring the need for effective prevention and treatment strategies. However, despite progress in innovative and flexible trial designs during the COVID-19 pandemic, regressive policies excluding pregnant and breastfeeding people from biomedical research persist. Remdesivir, a broad-spectrum antiviral, was the first drug licensed for the treatment of COVID-19, based on data showing it reduced the time to recovery in hospitalized patients. Pregnant and breastfeeding people were specifically excluded from all clinical trials of remdesivir in COVID-19, but data are accumulating from post-marketing registries, compassionate use programmes and case series/reports. In this review we synthesize these data and highlight key knowledge gaps to help inform clinical decision-making about its use in pregnancy and lactation.

Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19.

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.

Remdesivir: Review of Pharmacology, Pre-clinical Data, and Emerging Clinical Experience for COVID-19.

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic ß-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.