Crimean-Congo Hemorrhagic Fever Virus for Clinicians-Diagnosis, Clinical Management, and Therapeutics.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread tickborne viral infection worldwide and has a fatality rate of up to 62%. Despite its widespread range and high fatality rate, no vaccines or treatments are currently approved by regulatory agencies in the United States or Europe. Supportive treatment remains the standard of care, but the use of antiviral medications developed for other viral infections have been considered. We reviewed published literature to summarize the main aspects of CCHFV infection in humans. We provide an overview of diagnostic testing and management and medical countermeasures, including investigational vaccines and limited therapeutics. CCHFV continues to pose a public health threat because of its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, potential for severe and fatal illness, and limited medical countermeasures for prophylaxis and treatment. Clinicians should become familiar with available diagnostic and management tools for CCHFV infections in humans.

Crimean-Congo Hemorrhagic Fever Virus for Clinicians-Epidemiology, Clinical Manifestations, and Prevention.

Crimean-Congo hemorrhagic fever (CCHF) is a tickborne infection that can range from asymptomatic to fatal and has been described in >30 countries. Early identification and isolation of patients with suspected or confirmed CCHF and the use of appropriate prevention and control measures are essential for preventing human-to-human transmission. Here, we provide an overview of the epidemiology, clinical features, and prevention and control of CCHF. CCHF poses a continued public health threat given its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, and potential for severe and fatal illness, in addition to the limited medical countermeasures for prophylaxis and treatment. A high index of suspicion, comprehensive travel and epidemiologic history, and clinical evaluation are essential for prompt diagnosis. Infection control measures can be effective in reducing the risk for transmission but require correct and consistent application.

Crimean Congo Hemorrhagic Fever Virus for Clinicians-Virology, Pathogenesis, and Pathology.

Crimean-Congo hemorrhagic fever (CCHF), caused by CCHF virus, is a tickborne disease that can cause a range of illness outcomes, from asymptomatic infection to fatal viral hemorrhagic fever; the disease has been described in >30 countries. We conducted a literature review to provide an overview of the virology, pathogenesis, and pathology of CCHF for clinicians. The virus life cycle and molecular interactions are complex and not fully described. Although pathogenesis and immunobiology are not yet fully understood, it is clear that multiple processes contribute to viral entry, replication, and pathological damage. Limited autopsy reports describe multiorgan involvement with extravasation and hemorrhages. Advanced understanding of CCHF virus pathogenesis and immunology will improve patient care and accelerate the development of medical countermeasures for CCHF.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered with and without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China due to an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n=180), ages 19-50 years, were enrolled into this partially-blinded, randomized, multi-center Phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with two different boost intervals (21 versus 120 days) and two dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition (HAI) and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest HAI GMT (95%CI) observed against the 2017 A(H7N9) strain was 133.4 (83.6, 212.6) among participants who received homologous, adjuvanted 3.75 ug+AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. (NCT03589807).

A Pregnant Adolescent with COVID-19 and Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C), a new condition related to coronavirus disease 2019 (COVID-19) in the pediatric population, was recognized by physicians in the United Kingdom in April 2020. Given those up to the age of 21 years can be affected, pregnant adolescents and young adults are susceptible. However, there is scant information on how MIS-C may affect pregnancy and whether the presentation differs in the pregnant population. We report a case of a pregnant adolescent with COVID-19 and MIS-C with a favorable outcome. This case highlights the considerations in managing a critically ill pregnant patient with a novel illness and the importance of a multidisciplinary team in coordinating care.

Cellular and humoral immunity to Ebola Zaire glycoprotein and viral vector proteins following immunization with recombinant vesicular stomatitis virus-based Ebola vaccine (rVSVΔG-ZEBOV-GP).

While effective at preventing Zaire ebolavirus (ZEBOV) disease, cellular immunity to ZEBOV and vector-directed immunity elicited by the recombinant vesicular stomatitis virus expressing ZEBOV glycoprotein (rVSVΔG-ZEBOV-GP) vaccine remain poorly understood. Sera and peripheral blood mononuclear cells were collected from 32 participants enrolled in a prospective multicenter study [ClinicalTrials.gov NCT02788227] before vaccination and up to six months post-vaccination. IgM and IgG antibodies, IgG-producing memory B cells (MBCs), and T cell reactivity to ZEBOV glycoprotein (ZEBOV-GP), vesicular stomatitis virus-Indiana strain (VSV-I) matrix (M) protein, and VSV-I nucleoprotein (NP) were measured using ELISA, ELISpot, and flow cytometry, respectively. 11/32 (34.4%) participants previously received a different investigational ZEBOV vaccine prior to enrollment and 21/32 (65.6%) participants were ZEBOV vaccine naïve. Both ZEBOV vaccine naïve and experienced participants had increased ZEBOV-GP IgG optical densities (ODs) post-rVSVΔG-ZEBOV-GP vaccination while only ZEBOV vaccine naïve participants had increased ZEBOV-GP IgM ODs. Transient IgM and IgG antibody responses to VSV-I M protein and NP were observed in a minority of participants. All participants had detectable ZEBOV-GP specific IgG-producing MBCs by 6 months post-vaccination while no changes were observed in the median IgG-producing MBCs to VSV-I proteins. T cell responses to ZEBOV-GP differed between ZEBOV vaccine experienced and ZEBOV vaccine naïve participants. T cell responses to both VSV-I M protein and VSV-I NP were observed, but were of a low magnitude. The rVSVΔG-ZEBOV-GP vaccine elicits robust humoral and memory B cell responses to ZEBOV glycoprotein in both ZEBOV vaccine naïve and experienced individuals and can generate vector-directed T cell immunity. Further research is needed to understand the significance of pre-existing vector and target antigen immunity on responses to booster doses of rVSVΔG-ZEBOV-GP and other rVSV-vectored vaccines.

Lassa Virus Infection: a Summary for Clinicians.

OBJECTIVES: This summary on Lassa virus (LASV) infection and Lassa fever disease (LF) was developed from a clinical perspective to provide clinicians with a condensed, accessible understanding of the current literature. The information provided highlights pathogenesis, clinical features, and diagnostics emphasizing therapies and vaccines that have demonstrated potential value for use in clinical or research environments. METHODS: We conducted an integrative literature review on the clinical and pathological features, vaccines, and treatments for LASV infection, focusing on recent studies and in vivo evidence from humans and/or non-human primates (NHPs), when available. RESULTS: Two antiviral medications with potential benefit for the treatment of LASV infection and 1 for post-exposure prophylaxis were identified, although a larger number of therapeutic candidates are currently being evaluated. Multiple vaccine platforms are in pre-clinical development for LASV prevention, but data from human clinical trials are not yet available. CONCLUSION: We provide succinct summaries of medical countermeasures against LASV to give the busy clinician a rapid reference. Although there are no approved drugs or vaccines for LF, we provide condensed information from a literature review for measures that can be taken when faced with a suspected infection, including investigational treatment options and hospital engineering controls.

Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum.

BACKGROUND: Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge. METHODS: Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion). RESULTS: The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC. CONCLUSIONS: High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics. CLINICAL TRIALS REGISTRATION: NCT02473224.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Pediatric Osteoarticular Infections Caused by Mycobacteria Tuberculosis Complex: A 26-Year Review of Cases in San Diego, CA.

BACKGROUND: Osteoarticular infections (OAIs) account for 10%-20% of extrapulmonary Mycobacteria tuberculosis (MTB) complex infections in children and 1%-2% of all pediatric tuberculosis infections. Treatment regimens and durations typically mirror recommendations for other types of extrapulmonary MTB, but there are significant variations in practice, with some experts suggesting a treatment course of 12 months or longer. METHODS: We conducted a retrospective review of children diagnosed with MTB complex OAI and cared for between December 31, 1992, and December 31, 2018, at a tertiary care pediatric hospital near the United States-Mexico border. RESULTS: We identified 21 children with MTB complex OAI during the study period. Concurrent pulmonary disease (9.5%), meningitis (9.5%), and intra-abdominal involvement (14.3%) were all observed. MTB complex was identified by culture from operative samples in 15/21 children (71.4%); 8/15 (53.3%) cultures were positive for Mycobacterium bovis. Open bone biopsy was the most common procedure for procurement of a tissue sample and had the highest culture yield. The median duration of antimicrobial therapy was 52 weeks (interquartile range, 46-58). Successful completion of therapy was documented in 15 children (71.4%). Nine children (42.9%) experienced long-term sequelae related to their infection. CONCLUSION: Among the 21 children with MTB complex OAI assessed, 8 of 15 (53.3%) children with a positive tissue culture had M. bovis, representing a higher percentage than in previous reports and potentially reflecting its presence in unpasteurized dairy products in the California-Baja region. Bone biopsy produced the highest culture yield in this study. Given the rarity of this disease, multicenter collaborative studies are needed to improve our understanding of the presentation and management of pediatric MTB complex OAI.

SARS-CoV-2 Among Infants <90 Days of Age Admitted for Serious Bacterial Infection Evaluation.

OBJECTIVES: To determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants hospitalized for a serious bacterial infection (SBI) evaluation and clinically characterize young infants with SARS-CoV-2 infection. METHODS: A retrospective chart review was conducted on infants <90 days of age hospitalized for an SBI evaluation. The study was conducted at 4 inpatient facilities in New York City from March 15, 2020, to December 15, 2020. RESULTS: We identified 148 SBI evaluation infants who met inclusion criteria. A total of 22 infants (15%) tested positive for SARS-CoV-2 by nasopharyngeal reverse transcription polymerase chain reaction; 31% of infants admitted during periods of high community SARS-CoV-2 circulation tested positive for SARS-CoV-2, compared with 3% when community SARS-CoV-2 circulation was low (P < .001). The mean age of infants with SARS-CoV-2 was higher than that of SARS-CoV-2-negative infants (33 [SD: 17] days vs 23 [SD: 23] days, respectively; P = .03), although no age difference was observed when analysis was limited only to febrile infants. An isolated fever was the most common presentation of SARS-CoV-2 (n = 13; 59%). Admitted infants with SARS-CoV-2 were less likely to have positive urine culture results (n = 1 [5%] versus n = 25 [20%], respectively; P = .002), positive cerebrospinal culture results (n = 0 [0%] versus n = 5 [4%], respectively; P = .02), or be admitted to intensive care (n = 2 [9%] versus n = 47 [37%]; P < .001), compared with infants without SARS-CoV-2. CONCLUSIONS: SARS-CoV-2 was common among young infants hospitalized for an SBI evaluation during periods of high but not low community SARS-CoV-2 circulation in New York City, although most infants did not require intensive care admission.

South American Hemorrhagic Fevers: A summary for clinicians.

OBJECTIVES: This article is one of a series on acute, severe diseases of humans caused by emerging viruses for which there are no or limited licensed medical countermeasures. We approached this summary on South American Hemorrhagic Fevers (SAHF) from a clinical perspective that focuses on pathogenesis, clinical features, and diagnostics with an emphasis on therapies and vaccines that have demonstrated potential for use in an emergency situation through their evaluation in nonhuman primates (NHPs) and/or in humans. METHODS: A standardized literature review was conducted on the clinical, pathological, vaccine, and treatment factors for SAHF as a group and for each individual virus/disease. RESULTS: We identified 2 treatments and 1 vaccine platform that have demonstrated potential benefit for treating or preventing infection in humans and 4 other potential treatments currently under investigation. CONCLUSION: We provide succinct summaries of these countermeasures to give the busy clinician a head start in reviewing the literature if faced with a patient with South American Hemorrhagic Fever. We also provide links to other authoritative sources of information.

Characteristics of Hospitalized Children With SARS-CoV-2 in the New York City Metropolitan Area.

OBJECTIVES: To describe the characteristics of hospitalized children with severe acute respiratory syndrome coronavirus 2 in New York City metropolitan area. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study at 4 hospitals comprising 82 hospitalized children (0-21 years) who tested positive for severe acute respiratory syndrome coronavirus 2 after symptoms and risk screening between March 1 and May 10, 2020. We subdivided patients on the basis of their admission to acute or critical care units and by age groups. Further subanalyses were performed between patients requiring respiratory support or no respiratory support. RESULTS: Twenty-three (28%) patients required critical care. Twenty-nine (35%) patients requiring respiratory support, with 9% needing mechanical ventilation, and 1 required extracorporeal support. All patients survived to discharge. Children with any comorbidity were more likely to require critical care (70% vs 37%, P = .008), with obesity as the most common risk factor for critical care (63% vs 28%, P = .02). Children with asthma were more likely to receive respiratory support (28% vs 8%, P = .02), with no difference in need for critical care (P = .26). Children admitted to critical care had higher rates of renal dysfunction at presentation (43% vs 10%, P = .002). CONCLUSIONS: Children with comorbidities (obesity and asthma in particular) were at increased risk for critical care admission and/or need for respiratory support. Children with renal dysfunction at presentation were more likely to require critical care.

Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.

BACKGROUND: 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: 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: A total of 128 patients were included in the intention-to-treat analysis. Baseline demographic, clinical, and laboratory characteristics were similar between the HCQ (n = 67) and placebo (n = 61) arms. At day 14, 11 (16.4%) subjects assigned to HCQ and 6 (9.8%) subjects assigned to placebo met the severe disease progression end point, but this did not achieve statistical significance (P = .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: 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.

The Immune Response to Eastern Equine Encephalitis Virus Acquired Through Organ Transplantation.

The human immune response to eastern equine encephalitis virus (EEEV) infection is poorly characterized due to the rarity of infection. We examined the humoral and cellular immune response to EEEV acquired from an infected donor via liver transplantation. Both binding and highly neutralizing antibodies to EEEV as well as a robust EEEV-specific IgG memory B cell response were generated. Despite triple-drug immunosuppressive therapy, a virus-specific CD4+ T cell response, predominated by interferon-γ production, was generated. T cell epitopes on the E2 envelope protein were identified by interferon-γ ELISpot. Although these results are from a single person who acquired EEEV by a non-traditional mechanism, to our knowledge this work represents the first analysis of the human cellular immune response to EEEV.

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City region.

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 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates.

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 persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States. METHODS: In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two 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 membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 µg, 20 µg, 30 µg, and 100 µg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 µg of BNT162b1), participants received one dose. RESULTS: A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. CONCLUSIONS: The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Serosurvey on healthcare personnel caring for patients with Ebola virus disease and Lassa virus in the United States.

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: 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: 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.

RNA-Based COVID-19 Vaccine BNT162b2 Selected for a Pivotal Efficacy Study.

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: These results support selection of the BNT162b2 vaccine candidate for Phase 2/3 large-scale safety and efficacy evaluation, currently underway.