Faculty Bibliography

The Covid-19 pandemic has exposed the difficulty of the US public health system to respond effectively to vulnerable subpopulations, causing disproportionate rates of morbidity and mortality. New York Haredi-Orthodox Jewish communities represent a group that have been heavily impacted by Covid-19. Little research has examined their experience or perceptions toward Covid-19 and vaccines. We conducted a cross-sectional, observational study to explore the experience of Covid-19 among Haredim. Paper surveys were self-administered between December 2020 and January 2021 in Haredi neighborhood pediatricians' offices in Brooklyn, New York. Of 102 respondents, 43% reported either a positive SARS-CoV-2 viral or antibody test. Participants trusted their physicians, Orthodox medical organizations, and rabbinic leaders for medical information. Knowledge of Covid-19 transmission and risk was good (69% answered ≥ 4/6 questions correctly). Only 12% of respondents would accept a Covid-19 vaccine, 41% were undecided and 47% were strongly hesitant. Independent predictors of strong vaccine hesitancy included believing natural infection to be better than vaccination for developing immunity (adjusted odds ratio [aOR] 4.28; 95% confidence interval [CI] 1.23-14.86), agreement that prior infection provides a path toward resuming communal life (aOR 4.10; 95% CI 1.22-13.77), and pandemic-related loss of trust in physicians (aOR 5.01; 95% CI 1.05-23.96). The primary disseminators of health information for self-protective religious communities should be stakeholders who understand these groups' unique health needs. In communities with significant Covid-19 experience, vaccination messaging may need to be tailored toward protecting infection-naïve individuals and boosting natural immunity against emerging variants.

Therapeutics for patients hospitalized with coronavirus disease 2019 (COVID-19) are urgently needed during the pandemic. Bamlanivimab is a potent neutralizing monoclonal antibody that blocks severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) attachment and entry into human cells, which could potentially lead to therapeutic benefit. J2W-MC-PYAA was a randomized, double-blind, sponsor unblinded, placebo-controlled, single ascending dose first-in-human trial (NCT04411628) in hospitalized patients with COVID-19. A total of 24 patients received either placebo or a single dose of bamlanivimab (700 mg, 2,800 mg, or 7,000 mg). The primary objective was assessment of safety and tolerability, including adverse events and serious adverse events, with secondary objectives of pharmacokinetic (PK) and pharmacodynamic analyses. Treatment-emergent adverse event (TEAE) rates were identical in the placebo and pooled bamlanivimab groups (66.7%). There were no apparent dose-related increases in the number or severity of TEAEs. There were no serious adverse events or deaths during the study, and no discontinuations due to adverse events. PKs of bamlanivimab is linear and exposure increased proportionally with dose following single i.v. administration. The half-life was ~ 17 days. These results demonstrate the favorable safety profile of bamlanivimab, and provided the initial critical evaluation of safety, tolerability, and PKs in support of the development of bamlanivimab in several ongoing clinical trials.

BACKGROUND:While people who inject drugs (PWID) are vulnerable to the adverse outcomes of events like COVID-19, little is known regarding the impact of the current pandemic on PWID. We examine how COVID-19 has affected PWID in New York City across four domains: substance use, risk behaviors, mental health, and service utilization. METHODS:As part of a randomized trial to improve access to HCV treatment for PWID, we recruited 165 participants. Eligibility criteria included detectable HCV RNA and recent drug injection. The present cross-sectional analysis is based on a subsample of 106 participants. We compared responses between two separate samples: 60 participants interviewed prior to the pandemic (pre-COVID-19 sample) and 46 participants interviewed during the pandemic (COVID-19 sample). We also assessed differences by study group [accessible care (AC) and usual care (UC)]. RESULTS:Compared to the pre-COVID-19 sample, those interviewed during COVID-19 reported higher levels of mental health issues, syringe reuse, and alcohol consumption and greater reductions in syringe-service programs and buprenorphine utilization. In the analysis conducted by study group, the UC group reported significantly higher injection risk behaviors and lower access to buprenorphine treatment during COVID-19, while during the same period, the AC group reported lower levels of substance use and injection risk behaviors. CONCLUSION:The current study provides insight on how COVID-19 has negatively affected PWID. Placing dispensing machines of harm-reduction supplies in communities where PWID live and increasing secondary exchange, mobile services, and mail delivery of supplies may help maintain access to lifesaving supplies during big events, such as COVID-19. Trial registration ClinicalTrials.gov NCT03214679. Registered July 11 2017. https://clinicaltrials.gov/ct2/show/NCT03214679 .

Young age is a risk factor for respiratory and gastrointestinal infections. Here, we compared infant and adult mice to identify age-dependent mechanisms that drive susceptibility to mucosal infections during early life. Transcriptional profiling of the upper respiratory tract (URT) epithelium revealed significant dampening of early life innate mucosal defenses. Epithelial-mediated production of the most abundant antimicrobial molecules, lysozyme, and lactoferrin, and the polymeric immunoglobulin receptor (pIgR), responsible for IgA transcytosis, was expressed in an age-dependent manner. This was attributed to delayed functional development of serous cells. Absence of epithelial-derived lysozyme and the pIgR was also observed in the small intestine during early life. Infection of infant mice with lysozyme-susceptible strains of Streptococcus pneumoniae or Staphylococcus aureus in the URT or gastrointestinal tract, respectively, demonstrated an age-dependent regulation of lysozyme enzymatic activity. Lysozyme derived from maternal milk partially compensated for the reduction in URT lysozyme activity of infant mice. Similar to our observations in mice, expression of lysozyme and the pIgR in nasopharyngeal samples collected from healthy human infants during the first year of life followed an age-dependent regulation. Thus, a global pattern of reduced antimicrobial and IgA-mediated defenses may contribute to increased susceptibility of young children to mucosal infections.

Highly transmissible SARS-CoV-2 variants identified in India and designated B.1.617, Kappa (B.1.617.1), Delta (B.1.617.2), B.1.618 and B.1.36.29, contain spike mutations L452R, T478K, E484K, E484Q and N440K located within the spike receptor binding domain and thus could contribute to increased transmissibility and potentially allow re-infection or cause resistance to vaccine-elicited antibody. To address these issues, we used lentiviruses pseudotyped by variant spikes to measure their neutralization by convalescent sera, vaccine-elicited and Regeneron therapeutic antibodies and ACE2 affinity. Convalescent sera and vaccine-elicited antibodies neutralized viruses with Delta spike with 2-5-fold decrease in titer in different donors. Regeneron antibody cocktail neutralized virus with the Delta spike with a 2.6-fold decrease in titer. Neutralization resistance to serum antibodies and monoclonal antibodies was mediated by L452R mutation. These relatively modest decreases in antibody neutralization titer for viruses with variant spike proteins suggest that current vaccines will remain protective against the family of Delta variants.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.

BACKGROUND:The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2Â (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS:In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS:A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS:AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

The increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine efficacy. Here, neutralizing antibody titers elicited by mRNA-based and an adenoviral vector-based vaccine against variant pseudotyped viruses were compared. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals were of low neutralizing titer (IC ₅₀ <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest the benefit of a second immunization following Ad26.COV2.S to increase protection against the variants.