Waning of the Humoral Response to SARS-CoV-2 in Pregnancy is Variant-Dependent

ImportanceThe SARS-CoV-2 alpha variant posed increased risk for COVID-19 complications in pregnant women. However, its impact on the maternal humoral response and placental IgG transport remains unclear. ObjectiveTo characterize the maternal humoral waning and neonate immunity acquired during the 3rd COVID-19 wave in Israel, dominated by the Alpha variant, as compared to earlier Wildtype infections and humoral response to vaccination across gestation. DesignMaternal and fetal blood serum were collected at delivery since April 2020 from parturients. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel supplemented with additional HA-coupled microspheres. SettingA nationwide multicenter cohort study on SARS-CoV-2 infections and vaccination during pregnancy. ParticipantsExpectant women presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 primary groups: SARS-CoV-2 positive (n = 157) and fully vaccinated during pregnancy (n = 125), and unvaccinated noninfected controls matched to the infected group by BMI, maternal age, comorbidities and gestational age (n = 212). Eligibility criteria included pregnant women without active COVID-19 disease, age [≥]18 years and willingness to provide informed consent. Main Outcome(s) and Measure(s)Pregnant womens humoral response is dependent on the SARS-CoV-2 strain. ResultsThe humoral response to infection as detected at birth, showed a gradual and significant decline as the interval between infection/vaccination and delivery increased. Significantly faster decay of antibody titers was found for infections occurring during the 3rd wave compared to earlier infections/vaccination. Cord blood IgG antigens levels correlated with maternal IgG. However, cord IgG-HA variance significantly differed in SARS-CoV2 infections as compared to the other groups. No sexual dimorphism in IgG transfer was observed. Lastly, high fetal IgM response to SARS-CoV-2 was detected in 17 neonates, all showing elevated IgM to N suggesting exposure to SARS-Cov-2 antigens. Conclusions and RelevanceInfections occurring during the 3rd wave induced a faster decline in humoral response when compared to Wildtype infections or mRNA BNT162b2 vaccination during pregnancy, consistent with a shift in disease etiology and severity induced by the Alpha variant. Vaccination policies in previously infected pregnant women should consider the timing of exposure along pregnancy as well as the risk of infection to specific variants of concern. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the difference in the maternal-fetal humoral response between Alpha variant and SARS-CoV-2 Wildtype infections? FindingsIn this nationwide multicenter study including 494 pregnant women, the maternal humoral response to Alpha variant infection was weaker and shorter when compared to Wildtype infections. Placental transport compensated for the maternal waning of immunity. Fetal sex did not affect humoral response. MeaningVaccination policies should be adjusted to account for the timing of infection and the SARS-CoV-2 variant.

Efficient Maternal to Neonatal transfer of SARS-CoV-2 and BNT162b2 antibodies

BackgroundThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection. MethodsA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to three study groups: vaccinated (n=86); PCR confirmed SARS-CoV-2 infected during pregnancy (n=65), and unvaccinated non-infected controls (n=62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD and N). ResultsBNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (Anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer rate was significantly lower for third-trimester as compared to second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group. ConclusionsAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.

COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor.

Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we present covalentizer, a computational pipeline for creating irreversible inhibitors based on complex structures of targets with known reversible binders. For each ligand, we create a custom-made focused library of covalent analogs. We use covalent docking, to dock these tailored covalent libraries and to find those that can bind covalently to a nearby cysteine while keeping some of the main interactions of the original molecule. We found ~11,000 cysteines in close proximity to a ligand across 8,386 protein-ligand complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In prospective evaluation against a panel of kinases, five out of nine predicted covalent inhibitors showed IC50 between 155 nM - 4.2 M. Application of the protocol to an existing SARS-CoV-1 Mpro reversible inhibitor led to a new acrylamide inhibitor series with low micromolar IC50 against SARS-CoV-2 Mpro. The docking prediction was validated by 11 co-crystal structures. This is a promising lead series for COVID-19 antivirals. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.