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The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of spike, such as the S2 subdomain. Here, we present a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in S2, including regions outside of those commonly reported. One of the S2 mAbs, C20.119, which bound to a highly conserved epitope in the fusion peptide, was able to broadly neutralize across SARS-CoV-2 variants, SARS-CoV-1, and closely related zoonotic sarbecoviruses. The majority of the mAbs were non-neutralizing; however, many of them could mediate antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1-targeting mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Several of the mAbs with ADCC function also bound to spike trimers from other human coronaviruses (HCoVs), such as MERS-CoV and HCoV-HKU1. Our findings suggest S2 mAbs can target diverse epitopes in S2, including functional mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response. Author summary: The early successes of vaccines and antibody therapies against SARS-CoV-2, the virus responsible for the COVID-19 global pandemic, leveraged the considerable antibody response to the viral entry protein, spike, after vaccination or infection. These initial interventions were highly effective at protecting from infection and reducing severe disease or death. However, the rapid emergence of new SARS-CoV-2 variants has severely compromised the utility of COVID-19 vaccines and antibody-based treatments. SARS-CoV-2 shows no sign of abating, with the continued rise of new variants with distinct alterations most significantly in regions of the spike protein that elicit most of the anti-viral functional antibody response, which in turn facilitates viral escape from the immune response. These findings suggest a critical need to identify vaccine approaches and therapies that provide the broadest possible antibody responses, focused on regions of spike critical for SARS-CoV-2 infection and, therefore, do not undergo changes that could lead to immune evasion. Our study describes a panel of functional antibodies, from individuals after SARS-CoV-2 infection, that recognize regions of spike that appear conserved across SARS-CoV-2 variants and other closely related viruses, that could guide more effective vaccine design in the face of continued viral evolution. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to examine the incidence of rebound hypotension in patients with septic shock requiring both norepinephrine and vasopressin infusions once discontinuation of 1 of these agents is warranted. Methods: A multicenter, retrospective study was conducted in 3 hospitals within a single health system between January 1, 2016, and December 31, 2017. The study population included adults, 18 years and older, diagnosed with septic shock and requiring concurrent infusions of norepinephrine and vasopressin. The primary outcome evaluated the incidence of rebound hypotension within 24 hours after the first vasopressor was discontinued. Secondary outcomes included intensive care unit length of stay, hospital length of stay, total vasopressor duration, and the time to rebound hypotension after first vasopressor discontinuation. Results: A total of 69 patients were included in the study, 38 in the vasopressin discontinued first group and 31 in the norepinephrine discontinued first group. Rebound hypotension occurred in 82% of patients in the vasopressin discontinued first group compared with 48% in the norepinephrine discontinued first group (P =.004). No differences were observed in secondary outcomes, including intensive care unit or hospital length of stay, total vasopressor duration, or the time to rebound hypotension. Conclusions: Discontinuation of norepinephrine before vasopressin may lead to less incidence of rebound hypotension in patients with septic shock who require concurrent norepinephrine and vasopressin infusions. Similar to previous studies, this study found no difference in secondary outcomes. [ABSTRACT FROM AUTHOR]

Infants of HIV positive mothers can acquire HIV infection by various routes, but even in the absence of antiviral treatment, the majority of these infants do not become infected. There is evidence that maternal antibodies may provide some protection from infection, but gestational maternal antibodies have not yet been characterized in detail. One of the most studied vertically-infected infants is BG505, as the virus from this infant yielded an Envelope protein that was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time point just prior to vertical transmission. These nAbs belonged to 21 clonal families, employed a variety of VH genes, many were specific for the HIV-1 Env V3 loop, and this V3 specificity correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The isolated nAbs did not recapitulate the full breadth of heterologous nor autologous virus neutralization by contemporaneous plasma. Notably, we found that the V3-targeting nAb families neutralized one particular maternal Env variant even though all tested variants had low V3 sequence diversity and were measurably bound by these nAbs. None of the nAbs neutralized BG505 transmitted virus. Furthermore, the MG505 nAb families were found at relatively low frequencies within the maternal B cell repertoire: all less than 0.25% of total IgG sequences. Our findings illustrate an example of the diversity of HIV-1 nAbs within one mother, cumulatively resulting in a collection of antibody specificities that can contribute to the transmission bottleneck. [ABSTRACT FROM AUTHOR]