Faculty Bibliography

Background/UNASSIGNED:Effective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. Methods/UNASSIGNED:We conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14. Results/UNASSIGNED: = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay. Conclusions/UNASSIGNED:In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.

In March 2020, the World Health Organization (WHO) declared a pandemic of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)¹. With rapidly accumulating cases and deaths reported globally², a vaccine is urgently needed. We report the available safety, tolerability, and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose escalation study among 45 healthy adults, 18 to 55 years of age, randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD). Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 µg was not administered due to increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared to the 30 μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titers in sera increased with dose level and after a second dose. Geometric mean neutralizing titers reached 1.9- to 4.6-fold that of a panel of COVID-19 convalescent human sera at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate. (ClinicalTrials.gov identifier: NCT04368728).

BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally. Multiple vaccine candidates are under development, but no vaccine is currently available. METHODS:Healthy adults 18-55 and 65-85 years of age were randomized in an ongoing, placebo-controlled, observer-blinded dose-escalation study to receive 2 doses at 21-day intervals of placebo or either of 2 lipid nanoparticle-formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain, or BNT162b2, which encodes a prefusion stabilized membrane-anchored SARS-CoV-2 full-length spike. In each of 13 groups of 15 participants, 12 received vaccine and 3 received placebo. Groups were distinguished by vaccine candidate, age of participant, and vaccine dose level. Interim safety and immunogenicity data of BNT162b1 in younger adults have been reported previously from US and German trials. We now present additional safety and immunogenicity data from the US Phase 1 trial that supported selection of the vaccine candidate advanced to a pivotal Phase 2/3 safety and efficacy evaluation. RESULTS:In both younger and older adults, the 2 vaccine candidates elicited similar dose-dependent SARS-CoV-2-neutralizing geometric mean titers (GMTs), comparable to or higher than the GMT of a panel of SARS-CoV-2 convalescent sera. BNT162b2 was associated with less systemic reactogenicity, particularly in older adults. CONCLUSION/CONCLUSIONS:These results support selection of the BNT162b2 vaccine candidate for Phase 2/3 large-scale safety and efficacy evaluation, currently underway.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 236 SARS-CoV2 sequences from cases in the New York City metropolitan area during the initial stages of the 2020 COVID-19 outbreak. The majority of cases throughout the region had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that the majority were most related to cases from Europe. Our data are consistent with numerous seed transmissions from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of real-time genomic surveillance in addition to traditional epidemiological indicators.

OBJECTIVE:Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion. SETTING/METHODS:From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP. PARTICIPANTS/METHODS:All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible. RESULTS:No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens. CONCLUSIONS:Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.

Crimean-Congo hemorrhagic fever is the most geographically widespread tick-borne virus, with infection resulting in mortality in up to 30% of cases. Clinical diagnosis alone is difficult due to the nonspecific nature of symptoms; therefore, laboratory diagnostics should be utilized for patients with residence in or travel to regions of endemicity in whom the disease is suspected. This minireview provides an overview of laboratory tests available for Crimean-Congo hemorrhagic fever (CCHF) and their utility in diagnosis with a focus on diagnosing CCHF in humans.

During the 2014-16 W. Africa outbreak of Ebola virus disease, the US had no mechanism to study investigational treatments rapidly, and individual institutions provided investigational products as emergency investigational new drugs (eINDs). Consequently, determining the optimum care for the disease was not achieved. The Special Pathogens Research Network (SPRN) was established to create the infrastructure to conduct multi-center clinical research to improve outcomes for emerging special pathogens. This included establishing a central IRB at the University of Nebraska Medical Center and 10 collaborative sites across the US. As the COVID-19 outbreak began, the SPRN quickly executed three protocols. We share efficiencies and ideas for future improvements. At the onset of the COVID-19 outbreak, the network established three clinical protocols: 1) a "natural history" protocol for collecting discarded specimens and patient data; 2) a NIAID-sponsored randomized placebo controlled trial with the antiviral drug Remdesivir; and 3) a prospective data and sample collection protocol. We evaluated the IRB approval timeline centrally and at partner sites and the rapidity of first subject enrollment. We assessed aspects that facilitated or hindered the adoption of the different protocols across the network. Central and other site IRB approvals occurred expeditiously. Subjects were enrolled within one day of site approval in all three studies. UNMC enrolled the first US patient in the Remdesivir RCT. IRB approval occurred at all 10 sites within 32 days of central IRB approval; however, contracts for data use and material transfer agreements (DUAs and MTAs) lagged. Consequently, some sites developed their own natural history protocols, rather than adopt a network protocol. In conclusion, the SPRN pre-existing network of 10 sites was able to enroll subjects rapidly at the start of the outbreak, functioning as one unit in many respects. Contracting for specimen collection protocols has proved challenging and thus has impacted the ability to organize and deliver. This continues to be addressed