High rates of SARS-CoV-2 infection in pregnant Ugandan women and association with stunting in infancy (preprint)

Background: SARS-CoV-2 has been well studied in resource-rich areas but many questions remain about effects of infection in African populations, particularly in vulnerable groups such as pregnant women. Methods: We describe SARS-CoV-2 immunoglobulin (Ig) G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda. Results: From December 2020 to February 2022, among 400 unvaccinated pregnant women, serologic assessments revealed that 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected either prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time. No participants experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infection (-1.54 versus -0.37 and -0.51, p=0.009). Conclusion: Pregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with shorter stature in early infancy.

Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19 (preprint)

The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, mild to moderate infections are an important contributor to ongoing transmission. There remains a critical need to identify host immune biomarkers predictive of clinical and virologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial of Peginterferon Lambda for treatment of SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We define early immune signatures, including plasma levels of RIG-I and the CCR2 ligands (MCP1, MCP2 and MCP3), associated with control of oropharyngeal viral load, the degree of symptom severity, and immune memory (including SARS-CoV-2-specific T cell responses and spike (S) protein-binding IgG levels). We found that individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine had similar early immune trajectories to those observed in this natural infection cohort, including the induction of both inflammatory cytokines (e.g. MCP1) and negative immune regulators (e.g. TWEAK). Finally, we demonstrate that machine learning models using 8-10 plasma protein markers measured early within the course of infection are able to accurately predict symptom severity, T cell memory, and the antibody response post-infection.

Post-vaccination SARS-CoV-2 infections and incidence of the B.1.427/B.1.429 variant among healthcare personnel at a northern California academic medical center (preprint)

BackgroundDistribution of mRNA-based SARS-CoV-2 vaccines to healthcare personnel (HCP) in the United States began in December 2020, with efficacy > 90%. However, breakthrough infections in fully vaccinated individuals have been reported. Meanwhile, multiple SARS-CoV-2 variants of concern have emerged worldwide, including the B.1.427/B.1.429 variant first described in California. Little is known about the real-world effectiveness of the mRNA-based SARS-CoV-2 vaccines against novel variants including B.1.427/B.1.429. MethodsIn this quality improvement project, post-vaccine SARS-CoV-2 cases (PVSCs) were defined as individuals with positive SARS-CoV-2 nucleic acid amplification test (NAAT) after receiving at least one dose of a SARS-CoV-2 vaccine. Chart extraction of demographic and clinical information was performed, and available specimens meeting cycle threshold value criteria were tested for L452R, N501Y and E484K mutations by RT-PCR. ResultsFrom December 2020 to March 2021, 189 PVSCs were identified out of 22,729 healthcare personnel who received at least one dose of an mRNA-based SARS-CoV-2 vaccine. Of these, 114 (60.3%) occurred within 14 days of first vaccine dose (early post-vaccination), 49 (25.9%) within 14 days of the second vaccine dose (partially vaccinated), and 26 (13.8%) >14 days after the second dose (fully vaccinated). Of 115 samples available for mutation testing, 42 were positive for L452R alone, presumptive of B.1.427/B.1.429; three had N501Y mutation alone and none were found with E484K mutation. Though on univariate analysis partially- and fully-vaccinated PVSCs were more likely than early post-vaccination PVSCs to be infected with presumptive B.1.427/B.1.429, when adjusted for community prevalence of B.1.427/B.1.429 at the time of infection, partially- and fully-vaccinated PVSC did not have statistically significantly elevated risk ratios for infection with this variant (RR 1.40, 95% CI 0.81-2.43 and RR 1.13, 95% CI 0.59-2.16, respectively). ConclusionsThe great majority of PVSCs occurred prior to the expected onset of full, vaccine-derived immunity. Although the B.1.427/B.1.429 variant did not represent a significantly higher proportion of PVSCs than expected, numbers were small and there was a trend towards higher representation in the partially- and fully-vaccinated subset. Continued infection control measures in the workplace and in the community including social distancing and masking, particularly in the early days post-vaccination, as well as continued variant surveillance in PVSCs, is imperative in order to anticipate and control future surges of infection.

Inflammatory but not respiratory symptoms associated with ongoing upper airway viral replication in outpatients with uncomplicated COVID-19 (preprint)

BackgroundThe vast majority of SARS-CoV-2 infections are uncomplicated and do not require hospitalization, but contribute to ongoing transmission. Our understanding of the clinical course of uncomplicated COVID-19 remains limited. MethodsWe detailed the natural history of uncomplicated COVID-19 among 120 outpatients enrolled in a randomized clinical trial of Peginterferon Lambda. We characterized symptom trajectory and clusters using exploratory factor analysis, assessed predictors of symptom resolution and cessation of oropharyngeal viral shedding using Cox proportional hazard models, and evaluated associations between symptoms and viral shedding using mixed effects linear models. ResultsHeadache, myalgias and chills peaked at day 4 after symptom onset; cough peaked on day 9. Two distinct symptom cluster trajectories were identified; one with mild, upper respiratory symptoms, and the other with more severe and prolonged inflammatory symptoms. The median time to symptom resolution from earliest symptom onset was 17 days (95% CI 14-18). Neither enrollment SARS-CoV-2 IgG levels (Hazard ratio [HR] 1.88, 95% CI 0.84-4.20) nor oropharyngeal viral load at enrollment (HR 1.01, 95% CI 0.98-1.05) were significantly associated with the time to symptom resolution. The median time to cessation of viral shedding was 10 days (95% CI 8-12), with higher SARS-CoV-2 IgG levels at enrollment associated with hastened resolution of viral shedding (HR 3.12, 95% CI 1.4-6.9, p=0.005). Myalgia, joint pains, and chills were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection. ConclusionsIn this outpatient cohort, inflammatory symptoms peaked early and were associated with ongoing SARS-CoV-2 replication. SARS-CoV-2 antibody levels were associated with more rapid viral shedding cessation, but not with time to symptom resolution. These findings have important implications for COVID-19 screening approaches and clinical trial design.