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The immunologic mechanisms underlying the improved serologic responses to heterologous prime-boost avian influenza vaccination are unclear. An exploratory analysis of the immune responses following 1 dose of influenza A/H7N9 inactivated vaccine in subjects who received an influenza A/H7N7 inactivated vaccine (N = 17) 8 years earlier or who were influenza A/H7-naïve (10) was performed. Plasma IL-6 and IL-21 concentrations by ELISA, the frequency of A/H7N7-specific memory B cells and antibody secreting cells by ELISpot, the frequency of circulating T follicular helper cells and the frequency of T cells expressing IL-6 and IL-21 by flow cytometry were assessed at baseline (D1), and 8 days (D9) and 28 days (D29) after vaccination. We assessed the correlation between these measurements and the D29 serologic responses to the boost vaccine. Plasma IL-6 concentration on D9 significantly correlated with the H7N7 and H7N9 hemagglutination inhibition (HAI) antibody levels (P = .03 and 0.02 respectively); and the percentage of T cells expressing IL-21 on D9 significantly correlated with H7N9 HAI antibody seroconversion (P

BackgroundWhile Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen.MethodsIn this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-μg, Janssen Ad26.COV2.S 5×1010 virus particles, or Pfizer-BioNTech BNT162b2 30-μg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29.Results458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations.ConclusionHomologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.(Funded by National Institute of Allergy and Infectious Diseases; Clinical Trials.gov number, NCT04889209)

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

This report updates the 2009 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding use of anthrax vaccine in the United States (Wright JG, Quinn CP, Shadomy S, Messonnier N. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP)], 2009. MMWR Recomm Rep 2010;59[No. RR-6]). The report 1) summarizes data on estimated efficacy in humans using a correlates of protection model and safety data published since the last ACIP review, 2) provides updated guidance for use of anthrax vaccine adsorbed (AVA) for preexposure prophylaxis (PrEP) and in conjunction with antimicrobials for postexposure prophylaxis (PEP), 3) provides updated guidance regarding PrEP vaccination of emergency and other responders, 4) summarizes the available data on an investigational anthrax vaccine (AV7909), and 5) discusses the use of anthrax antitoxins for PEP. Changes from previous guidance in this report include the following: 1) a booster dose of AVA for PrEP can be given every 3 years instead of annually to persons not at high risk for exposure to Bacillus anthracis who have previously received the initial AVA 3-dose priming and 2-dose booster series and want to maintain protection; 2) during a large-scale emergency response, AVA for PEP can be administered using an intramuscular route if the subcutaneous route of administration poses significant materiel, personnel, or clinical challenges that might delay or preclude vaccination; 3) recommendations on dose-sparing AVA PEP regimens if the anthrax vaccine supply is insufficient to vaccinate all potentially exposed persons; and 4) clarification on the duration of antimicrobial therapy when used in conjunction with vaccine for PEP. These updated recommendations can be used by health care providers and guide emergency preparedness officials and planners who are developing plans to provide anthrax vaccine, including preparations for a wide-area aerosol release of B. anthracis spores. The recommendations also provide guidance on dose-sparing options, if needed, to extend the supply of vaccine to increase the number of persons receiving PEP in a mass casualty event.

BACKGROUND: Schistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health. METHODS: The safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18–50 year olds were randomized to receive 3 doses~ 8 weeks apart of saline placebo, or 10 μg, 30 μg, or 100 μg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 μg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. RESULTS: Vaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 μg or 100 μg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 μg or 100 μg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 μg, 30 μg or 100 μg of Sm-TSP-2/Al with GLA-AF, suggesting a dose-response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). CONCLUSIONS: Sm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.

Recent studies have suggested that among those receiving seasonal influenza vaccine (SIV), reduced immunogenicity is observed in recently vaccinated (RV; within the past season or 2) persons when compared with those not recently vaccinated (NRV). We performed a meta-analysis to assess the effect of recent immunization with SIV on serum H5 hemagglutination inhibition (HAI) antibody responses after influenza A/H5N1 vaccination using data from a series of randomized controlled trials. The primary outcome was seroconversion measured by HAI assays following receipt of 2 doses of H5N1 vaccine. The geometric mean titer (GMT) of serum HAI antibody after vaccination was the secondary outcome. Analyses were performed using propensity score (PS) matching. The PS for each individual in the meta-analysis cohort was calculated using logistic regression and covariates included age, gender, race, antigen dose, adjuvant, statin use and vaccine manufacturer. 2015 subjects enrolled in 7 clinical trials were eligible for inclusion in the meta-analysis cohort; among these, 915 (45%) were RV. 901 RV subjects were matched (1:1) with replacement to a subject who was NRV. Subjects who received SIV within the previous season were significantly less likely to seroconvert following H5N1 vaccination (adjusted odds ratio 0.76; 95%CI 0.60–0.96; p = 0.024), and the GMT was 18% higher among NRV subjects (GM ratio of HAI antibody 1.18; 95%CI 1.04–1.33; p = 0.008). Further work is needed to better define the effects of, and mechanisms contributing to, reduced immune responses to H5N1 vaccine among RV subjects.

Objective In response to the emergence of influenza viruses with pandemic potential, we evaluated a swine-origin influenza A/H3N2 variant (H3N2v) vaccine in children. Study design This multicenter phase II open-label study assessed the safety and immunogenicity of two doses, 21 days apart, of investigational unadjuvanted subvirion monovalent inactivated H3N2v vaccine administered via intramuscular injection. Children 6–35 months of age received 7.5mcg or 15mcg of hemagglutinin (HA)/dose; children 3–17 years of age received 15mcg HA/dose. Safety and reactogenicity were assessed by measuring the occurrence of solicited injection site and systemic reactions in the 7 days after each vaccination; adverse events were assessed for 42 days and serious adverse events for 7 months after the first vaccination. Immunogenicity was evaluated by measuring hemagglutination inhibition (HAI) and neutralizing (Neut) antibodies to H3N2v prior to and 21 days after each vaccination. Cross-reactivity against seasonal H3N2 strains was evaluated. Results The H3N2v vaccine was well tolerated. Transient mild to moderate injection site tenderness, pain and erythema was observed, with the most commonly reported systemic reactogenicity being irritability in children 6–35 months, and headache and fatigue in children 9–17 years old. Children 6–35 months old, whether they received 7.5mcg or 15mcg/dose, had low HAI and Neut antibody responses after two doses compared to older children. Children under 9 years of age required two doses of vaccine to demonstrate a response, while 9–17 year olds responded well after one dose. Previous influenza vaccination and older age were associated with higher immune responses to H3N2v vaccine. Children 9–17 years of age also developed cross-reactive antibodies against recent seasonal H3N2 influenza viruses. Conclusion The H3N2v vaccine was safe and immunogenic in children and adolescents. Age-related increases in immunogenicity against H3N2v and seasonal H3N2 viruses were observed, suggesting prior priming via infection and/or immunization. Clinical trial registry: The trial is registered with clinicaltrial.gov: NCT02100436 .

This report updates the 2010 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding prevention of Japanese encephalitis (JE) among U.S. travelers and laboratory workers (Fischer M, Lindsey N, Staples JE, Hills S. Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59[No. RR-1]). The report summarizes the epidemiology of JE, describes the JE vaccine that is licensed and available in the United States, and provides recommendations for its use among travelers and laboratory workers.JE virus, a mosquitoborne flavivirus, is the most common vaccine-preventable cause of encephalitis in Asia. JE occurs throughout most of Asia and parts of the western Pacific. Approximately 20%-30% of patients die, and 30%-50% of survivors have neurologic, cognitive, or behavioral sequelae. No antiviral treatment is available.Inactivated Vero cell culture-derived JE vaccine (Ixiaro [JE-VC]) is the only JE vaccine that is licensed and available in the United States. In 2009, the U.S. Food and Drug Administration (FDA) licensed JE-VC for use in persons aged ≥17 years; in 2013, licensure was extended to include children aged ≥2 months.Most travelers to countries where the disease is endemic are at very low risk for JE. However, some travelers are at increased risk for infection on the basis of their travel plans. Factors that increase the risk for JE virus exposure include 1) traveling for a longer period; 2) travel during the JE virus transmission season; 3) spending time in rural areas; 4) participating in extensive outdoor activities; and 5) staying in accommodations without air conditioning, screens, or bed nets. All travelers to countries where JE is endemic should be advised to take precautions to avoid mosquito bites to reduce the risk for JE and other vectorborne diseases. For some persons who might be at increased risk for JE, the vaccine can further reduce the risk for infection. The decision about whether to vaccinate should be individualized and consider the 1) risks related to the specific travel itinerary, 2) likelihood of future travel to countries where JE is endemic, 3) high morbidity and mortality of JE, 4) availability of an effective vaccine, 5) possibility (but low probability) of serious adverse events after vaccination, and 6) the traveler's personal perception and tolerance of risk.JE vaccine is recommended for persons moving to a JE-endemic country to take up residence, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas. JE vaccine also should be considered for shorter-term (e.g.

In August 2017, Hurricane Harvey caused unprecedented flooding and devastation to the Houston metropolitan area (1). Mold exposure was a serious concern because investigations after Hurricanes Katrina and Rita (2005) had documented extensive mold growth in flood-damaged homes (2,3). Because mold exposure can cause serious illnesses known as invasive mold infections (4,5), and immunosuppressed persons are at high risk for these infections (6,7), several federal agencies recommend that immunosuppressed persons avoid mold-contaminated sites (8,9). To assess the extent of exposure to mold and flood-damaged areas among persons at high risk for invasive mold infections after Hurricane Harvey, CDC and Texas health officials conducted a survey among 103 immunosuppressed residents in Houston. Approximately half of the participants (50) engaged in cleanup of mold and water-damaged areas; these activities included heavy cleanup (23), such as removing furniture or removing drywall, or light cleanup (27), such as wiping down walls or retrieving personal items. Among immunosuppressed persons who performed heavy cleanup, 43% reported wearing a respirator, as did 8% who performed light cleanup. One participant reported wearing all personal protective equipment (PPE) recommended for otherwise healthy persons (i.e., respirator, boots, goggles, and gloves). Immunosuppressed residents who are at high risk for invasive mold infections were exposed to mold and flood-damaged areas after Hurricane Harvey; recommendations from health care providers to avoid exposure to mold and flood-damaged areas could mitigate the risk to immunosuppressed persons.

ObjectivesThe objective of our study was to evaluate the impact of a multifaceted stewardship intervention on adherence to the evidence-based practice guidelines on treatment of uncomplicated cystitis in primary care. We hypothesised that our intervention would increase guideline adherence in terms of antibiotic choice and duration of treatment.DesignA preintervention and postintervention comparison with a contemporaneous control group was performed. During the first two study periods, we obtained baseline data and performed interviews exploring provider prescribing decisions for cystitis at both clinics. During the third period in the intervention clinic only, the intervention included a didactic lecture, a decision algorithm and audit and feedback. We used a difference-in-differences analysis to determine the effects of our intervention on the outcome and guideline adherence to antibiotic choice and duration.SettingTwo family medicine clinics (one intervention and one control) were included.ParticipantsAll female patients with uncomplicated cystitis attending the study clinics between 2016 and 2019.ResultsOur sample included 932 visits representing 812 unique patients with uncomplicated cystitis. The proportion of guideline-adherent antibiotic regimens increased during the intervention period (from 33.2% (95% CI 26.9 to 39.9) to 66.9% (95% CI 58.4 to 74.6) in the intervention site and from 5.3% (95% CI 2.3 to 10.1) to 17.0% (95% CI 9.9 to 26.6) in the control site). The increase in guideline adherence was greater in the intervention site compared with the control site with a difference-in-differences of 22 percentage points, p=0.001.ConclusionA multifaceted intervention increased guideline adherence for antibiotic choice and duration in greater magnitude than similar trends at the control site. Future research is needed to facilitate scale-up and sustainability of case-based audit and feedback interventions in primary care.

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Norovirus (NoV) is the leading cause of viral-related diarrhea in cancer patients, in whom it can be chronic, contributing to decreased quality of life, interruption of cancer care, malnutrition, and altered mucosal barrier function. Immunosuppressed cancer patients shed NoV for longer periods of time than immunocompetent hosts, favoring quasispecies development and emergence of novel NoV variants. While nucleic acid amplification tests (NAATs) for NoV diagnosis have revolutionized our understanding of NoV burden of disease, not all NAATs provide information on viral load or infecting genotype. There is currently no effective antiviral or vaccine for chronic NoV infections. Screening for inhibitors of NoV replication in intestinal organoid culture models and creation of NoV-specific adoptive T cells are promising new strategies to develop treatments for chronic NoV in immunosuppressed patients. Herein we summarize data on the epidemiology, clinical manifestations, diagnostic challenges, and treatment of NoV infection in patients with cancer.

Background Safe, effective, and easy to deploy adjuvants are needed for influenza prepandemic preparedness. Based on recent reports, we hypothesized that preapplication of topical imiquimod followed by intradermal (ID) vaccination with monovalent inactivated influenza A/H5N1 vaccine (MIV A/H5N1) results in improved serologic responses. Methods We randomized 50 healthy adults in a 1:1 ratio to receive topical imiquimod (group 1) or control cream (group 2) followed by ID injection of 9 µg of the hemagglutinin MIV A/H5N1 in 2 doses, 21 days apart. Subjects were followed for safety and serologic responses as measured by the hemagglutination inhibition (HAI) and microneutralization (MN) assays. Results Solicited and unsolicited adverse events were comparable between groups 1 and 2, and were mostly mild to moderate in severity. At 21 days after dose 2, the geometric mean titers (GMTs) of HAI antibodies against the vaccine strain were 16.2 and 24.3 in groups 1 and 2, respectively. The MN antibody GMTs were 9.3 and 10.7 in groups 1 and 2, respectively. There were no significant differences in antibody levels between groups at study time points. Conclusions Topical imiquimod administration combined with ID MIV A/H5N1 was safe but did not result in improved serologic responses to the vaccine. Clinical Trials Registration. NCT03472976.

As the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines passed UK and US regulatory milestones in late 2020 and early 2021, multiple professional societies offered recommendations to assist pregnant and breastfeeding people as they choose whether to undergo vaccination. Despite such guidance, the lack of data describing vaccine safety, immunogenicity, and efficacy in pregnant and breastfeeding people has made this decision challenging for many. However, even considering the paucity of data, the known risks of coronavirus disease 2019 during pregnancy likely outweigh the not yet fully elucidated risks of SARS-CoV-2 vaccines, which have reassuring safety and efficacy profiles among nonpregnant people.

Summary This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the rVSVΔG-ZEBOV-GP Ebola vaccine (Ervebo) in the United States. The vaccine contains rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus (VSV) in which the gene encoding the glycoprotein of VSV was replaced with the gene encoding the glycoprotein of Ebola virus species Zaire ebolavirus. Persons with a history of severe allergic reaction (e.g., anaphylaxis) to rice protein should not receive Ervebo. This is the first and only vaccine currently licensed by the Food and Drug Administration for the prevention of Ebola virus disease (EVD). These guidelines will be updated based on availability of new data or as new vaccines are licensed to protect against EVD. ACIP recommends preexposure vaccination with Ervebo for adults aged ≥18 years in the U.S. population who are at highest risk for potential occupational exposure to Ebola virus species Zaire ebolavirus because they are responding to an outbreak of EVD, work as health care personnel at federally designated Ebola treatment centers in the United States, or work as laboratorians or other staff at biosafety level 4 facilities in the United States. Recommendations for use of Ervebo in additional populations at risk for exposure and other settings will be considered and discussed by ACIP in the future.

As the coronavirus disease 2019 (COVID-19) pandemic has progressed, a large volume of literature has developed delineating the clinical manifestations of acute infection. Recent reports have also started to describe persistent symptoms extending beyond the period of initial illness or hospitalization. Anecdotes of different signs and symptoms occurring after acute infection have also arisen in the lay press. Here we describe the current existing medical literature on the emerging concept of postacute COVID-19 and suggest an approach to classifying different manifestations of the syndrome. We also review long-term clinical manifestations observed in patients who recovered from infection due to other epidemic coronaviruses and briefly discuss potential mechanisms driving the phenomenon of postacute COVID-19.

Background An estimated 6500 undocumented immigrants with end-stage renal disease (ESRD) live in the United States. Those living in states that do not provide undocumented immigrants scheduled hemodialysis receive intermittent hemodialysis only when life-threatening conditions arise. Little is known about catheter-related bloodstream infections (CRBSIs) in this population. Methods We conducted a retrospective cohort study of emergency-only hemodialysis patients in the Harris Health System in Houston, Texas, between January 2012 and December 2015. We assessed CRBSI risk factors including demographics, comorbidities, and duration and frequency of hemodialysis. We investigated the microbiologic etiology of these infections, rates of recurrent CRBSI, and associated morbidity and mortality. Results The cohort included 329 patients; 90% were Hispanic, 60% had diabetes, and the average age was 51 years. A total of 101 CRBSIs occurred, with a rate of 0.84 infections per 1000 catheter-days. Cirrhosis and duration of hemodialysis during the study period were associated with increased risk of CRBSI. Seventeen CRBSIs were recurrent; infection with gram-positive bacteria predicted recurrence. Adherence to catheter-related infection guidelines was improved by infectious diseases consultation and associated with fewer recurrent infections. CRBSI was associated with prolonged hospitalization (mean, 15 days), composite complication rate of 8%, and a 4% mortality rate. Conclusions Patients receiving emergency-only hemodialysis via tunneled catheters have a high CRBSI rate compared with infection rates previously reported in patients receiving scheduled maintenance hemodialysis. Increased CRSBI risk likely contributes to the increased morbidity and mortality seen in ESRD patients receiving emergency-only hemodialysis.

Background: Urine cultures are the most common microbiological tests in the outpatient setting and heavily influence treatment of suspected urinary tract infections (UTIs). Antibiotics for UTI are usually prescribed on an empiric basis in primary care before the urine culture results are available. However, culture results may be needed to confirm a UTI diagnosis and to verify that the correct antibiotic was prescribed. Although urine cultures are considered as the gold standard for diagnosis of UTI, cultures can easily become contaminated during collection. We determined the prevalence, predictors, and antibiotic use associated with contaminated urine cultures in 2 adult safety net primary care clinics. Methods: We conducted a retrospective chart review of visits with provider-suspected UTI in which a urine culture was ordered (November 2018–March 2020). Patient demographics, culture results, and prescription orders were captured for each visit. Culture results were defined as no culture growth, contaminated (ie, mixed flora, non-uropathogens, or ≥3 bacteria isolated on culture), low-count positive (growth between 100 and 100,000 CFU/mL), and high-count positive (>100,000 CFU/mL). A multivariable multinomial logistic regression model was used to identify factors associated with contaminated culture results. Results: There were 1,265 visits with urine cultures: 264 (20.9%) had no growth, 694 (54.9%) were contaminated, 159 (12.6%) were low counts, and 148 (11.7%) were high counts. Encounter-level factors are presented in Table 1. Female gender (adjusted odds ratio [aOR], 15.8; 95% confidence interval [CI], 10.21–23.46; P < .001), pregnancy (aOR, 13.98; 95% CI, 7.93–4.67; P < .001), and obesity (aOR, 1.9; 95% CI 1.31–2.77; P < .001) were independently associated with contaminated cultures. Of 264 patients whose urine cultures showed no growth, 36 (14%) were prescribed an antibiotic. Of 694 patients with contaminated cultures, 153 (22%) were prescribed an antibiotic (Figure 1). Conclusions: More than half of urine cultures were contaminated, and 1 in 5 patients were treated with antibiotics. Reduction of contamination should improve patient care by providing a more accurate record of the organism in the urine (if any) and its susceptibilities, which are relevant to managing future episodes of UTI in that patient. Optimizing urine collection represents a diagnostic stewardship opportunity in primary care.Funding: This study was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant no. UM1AI104681). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Disclosures: None

Background Tularemia is caused by Francisella tularensis , a gram-negative bacterium that has been weaponized as an aerosol. For protection of personnel conducting biodefense research, the United States Army required clinical evaluation of a new lot of tularemia live vaccine strain manufactured in accordance with Current Good Manufacturing Practices. Methods A phase 2 randomized clinical trial compared the new lot (DVC-LVS) to the existing vaccine that has been in use for decades (USAMRIID-LVS). The vaccines were delivered by scarification to 228 participants. Safety, reactogenicity, take and/or antibody levels were assessed on days 0, 1, 2, 8, 14, 28, 56, and 180. Principal Results Both vaccines were safe and had acceptable reactogenicity profiles during six months of follow-up. There were no serious or grade 3 and 4 laboratory adverse events. Moderate systemic reactogenicity (mostly headache or feeling tired) was reported by ∼23% of participants receiving either vaccine. Injection site reactogenicity was mostly mild itchiness and pain. The frequencies of vaccine take skin reactions were 73% (95% CI, 64, 81) for DVC-LVS and 80% (95% CI, 71, 87) for USAMRIID-LVS. The 90% CI for the difference in proportions was −6.9% (−16.4, 2.6). The rates of seroconversion measured by microagglutination assay on days 28 or 56 were 94% (95% CI, 88, 98; n = 98/104) for DVC-LVS and 94% (95% CI, 87, 97; n = 103/110) for USAMRIID-LVS (p = 1.00). Day 14 sera revealed more rapid seroconversion for DVC-LVS relative to USAMRIID-LVS: 82% (95% CI, 73, 89) versus 55% (95% CI, 45, 65), respectively (p Major conclusions The DVC-LVS vaccine had similar safety, reactogenicity, take and antibody responses compared to the older USAMRIID vaccine, and was superior for early (day 14) antibody production. Vaccination take was not a sensitive surrogate for seroconversion in a multi-center study where personnel at five research clinics performed assessments. ClinicalTrials.gov identifier NCT01150695

Background CAR-T is used to treat certain refractory hematological malignancies. B-cell aplasia and immunosuppression used to treat CAR-T side effects increase infection risk. Little data are available describing Norovirus (NoV) infections in CAR-T recipients. Methods We reviewed the medical records of 134 patients with NoV diarrhea (identified by nucleic acid amplification test) between 2016-2019. Of these patients, nine received CAR-T prior to developing NoV. Here we describe their demographics, clinical characteristics, treatments, and complications. Results The median age was 49 years (Table 1). Patients’ underlying malignancies included Non-Hodgkin’s Lymphoma (4), Acute Lymphoblastic Leukemia (3), Chronic Lymphocytic Leukemia (1) and metastatic Sarcoma (1). Prior to development of NoV, six patients had undergone hematopoietic stem cell transplant, and 1 had received checkpoint inhibitor therapy. Five patients experienced cytokine release syndrome after CAR-T, and 1 experienced CAR-T-related encephalopathy syndrome (Table 2). Two patients received interleukin-6 antagonist therapy, and one received high dose steroids. Time to diarrhea onset post-CAR-T cell infusion was variable(median 256days, IQR 26-523 days).Six had an absolute lymphocyte count< 1000/mm3 at diarrhea onset. Three had diarrhea for >14 days; median diarrhea duration in the other 6 patients was 4 days. Other GI complaints included abdominal pain (3), nausea (4), and vomiting (3). For NoV treatment, three received oral immunoglobulin, and 8 received Nitazoxanide. Complications included development of concomitant GI-GVHD(5), ileus (2), need for TPN (3), renal failure requiring dialysis (2), ICU stay (3), and death (2). Two patients were co-infected with other enteropathogens such as rotavirus, enteropathogenic and enteroaggregative E.Coli and Clostridioides difficile. Three patients with diarrhea lasting >14 days had serial samples collected over time; NoV shedding lasted 81-546 days. NoV was genotyped in 6 patients(Table 3) and included GII.2(2), GII.4(2), GII.6(1) and GII.12(1). Table 1: Patient characteristics (N=9) Table 2: CAR-T related factors Table 3: NoV Genotypes Conclusion NoV belonging to various genotypes is an important cause of acute and chronic diarrhea in patients receiving CAR-T cell therapy. Disclosures Adilene Olvera, MPH MLS (ASCP), MERK (Grant/Research Support, Scientific Research Study Investigator) Robert L. Atmar, MD, Takeda Vaccines, Inc. (Grant/Research Support) Mary K. Estes, PhD, Takeda Vaccines (Consultant, Grant/Research Support)

Background: Outpatients with uncomplicated urinary tract infections (UTIs) are often treated empirically without culture, whereas urine cultures are typically collected from patients with complicated UTI. Susceptibilities for fosfomycin (a first-line agent) are not routinely performed or reported in the antibiogram. Understanding the prevalence of antibiotic resistance for UTI is critical for empiric treatment and antibiotic stewardship in primary care. Methods: We developed a UTI-focused antibiogram from a prospective sample of outpatients (women and men) with UTIs from 2 public family medicine clinics in an urban area with a diverse, international population (November 2018 to present). During the study period, providers ordered a urine culture for any adult patient presenting with UTI symptoms, including uncomplicated and complicated infections. We estimated the prevalence of resistance to UTI-relevant antibiotics in the overall study population and compared it between patients born in the United States and other countries. Results: We collected 678 urine cultures from 644 unique patients (79% female). Of these cultures, 158 (23.3%) had no growth, 330 (48.7%) grew mixed urogenital flora, and 190 (28.0%) were positive (>10,000 CFU/mL). Patients with positive cultures were mostly female (88.2%), and their mean age was 46.6 ± 14.8 years. Among patients with positive cultures, 42.7% were born in the United States and 57.3% were born Mexico or Central America. Escherichia coli was the most commonly isolated organism (Fig. 1). Susceptibility results for E. coli and all gram-negative organisms combined are presented in Fig. 2. Susceptibility of uropathogens to TMP-SMX was significantly higher in patients born in the United States compared to patients from Mexico or Central America (82% vs 61%; P = .03). Susceptibility to ciprofloxacin was similar in patients born in the United States and other countries (79% vs 72%; P = .50). Of 77 E. coli isolates, 11 (14%) were positive for extended-spectrum β-lactamase production, including 8 isolates from patients whose country of origin was Mexico or a Central American country. Conclusions: More than 20% of outpatients presenting with UTI symptoms had a negative urine culture. Among outpatients with uncomplicated and complicated UTI, uropathogens had a high prevalence of resistance to ciprofloxacin and TMP-SMX, but susceptibility to fosfomycin (restricted in our system) was 100%. Resistance rates for TMP-SMX were higher in patients from Mexico and Central America. Our findings question whether TMP-SMX should remain a first-line agent in US primary-care settings.Funding: This project was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681.Disclosures: None

Norovirus is a leading cause of acute gastroenteritis worldwide, yet there is limited information on homotypic or heterotypic protection following natural infection to guide vaccine development.A total of 6020 stools collected from 299 Peruvian children between 2010 and 2014 were tested by norovirus real-time reverse-transcription polymerase chain reaction followed by sequence-based genotyping. Cox proportional hazards models were used to derive adjusted hazard ratios (HRs) of infection among children with vs without prior exposure.Norovirus was detected in 1288 (21.3%) samples. GII.4 (26%), GII.6 (19%), and GI.3 (9%) viruses accounted for 54% of infections. Homotypic protection for GI.3 (HR, 0.35; P = .015), GI.7 (HR, 0.19; P = .022), GII.4 (HR, 0.39; P .001), and GII.6 (HR, 0.52; P = .006) infections was observed. Hazard analysis showed that children with prior GII.4 infection exhibited heterotypic protection with a 48% reduction of subsequent GI.3 infection (HR, 0.52; P = .005). Prior exposure to GI.3, GII.2, and GII.17 infections enhanced susceptibility to subsequent infections with several other norovirus genotypes.Children up to 2 years of age infected with GII.4 noroviruses demonstrated both homotypic and heterotypic protection to reinfection with other genotypes. These data support the need for ongoing vaccine development efforts with GII.4 as the main component and caution the inclusion of genotypes that may enhance susceptibility to infections.

BACKGROUND: Increased illness due to antigenically drifted A(H3N2) clade 3C.3a influenza viruses prompted concerns about vaccine effectiveness (VE) and vaccine strain selection. We used US virologic surveillance and US Influenza Vaccine Effectiveness (Flu VE) Network data to evaluate consequences of this clade. METHODS: Distribution of influenza viruses was described using virologic surveillance data. The Flu VE Network enrolled ambulatory care patients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by means of reverse-transcriptase polymerase chain reaction and were sequenced. Using a test-negative design, we estimated VE, comparing the odds of influenza among vaccinated versus unvaccinated participants. RESULTS: During the 2018–2019 influenza season, A(H3N2) clade 3C.3a viruses caused an increasing proportion of influenza cases. Among 2763 Flu VE Network case patients, 1325 (48%) were infected with A(H1N1)pdm09 and 1350 (49%) with A(H3N2); clade 3C.3a accounted for 977 (93%) of 1054 sequenced A(H3N2) viruses. VE was 44% (95% confidence interval, 37%–51%) against A(H1N1)pdm09 and 9% (−4% to 20%) against A(H3N2); VE was 5% (−10% to 19%) against A(H3N2) clade 3C.3a viruses. CONCLUSIONS: The predominance of A(H3N2) clade 3C.3a viruses during the latter part of the 2018–2019 season was associated with decreased VE, supporting the A(H3N2) vaccine component update for 2019–2020 northern hemisphere influenza vaccines.

Background The development of an in vitro cultivation system for human noroviruses allows the measurement of neutralizing antibody levels. Methods Serum neutralizing antibody levels were determined using a GII.4/Sydney/2012-like virus in human intestinal enteroids in samples collected before and 4 weeks after administration of an investigational norovirus vaccine and were compared with those measured in histo-blood group antigen (HBGA)–blocking assays. Results Neutralizing antibody seroresponses were observed in 71% of 24 vaccinated adults, and antibody levels were highly correlated (r = 0.82, P < .001) with those measured by HBGA blocking. Conclusions HBGA-blocking antibodies are a surrogate for neutralization in human noroviruses. Clinical Trials Registration NCT02475278.

PURPOSE OF REVIEW: The majority of norovirus outbreaks in the United States occur in healthcare facilities. With the growing population of immunocompromised hosts who are in frequent contact with healthcare facilities, norovirus is not only a threat to hospitals and nursing homes but also to these individuals. This review summarizes the impact of norovirus infection on healthcare facilities and immunocompromised hosts. RECENT FINDINGS: The natural history of norovirus infection in immunocompromised individuals remains poorly understood. Although host immune responses play a critical role in reducing duration of viral shedding and viral load in norovirus-infected individuals, why some immunocompromised patients spontaneously recover while others develop a chronic and protracted course of illness remains unclear. Norovirus outbreaks occur in healthcare facilities because the virus is highly contagious, resistant to disinfection and efficiently transmitted. The use of real-time metagenomic next-generation sequencing and phylogenetic analyses has provided valuable information on transmission patterns in complex hospital-associated norovirus outbreaks. The development of human intestinal enteroid cultures enables the determination of effectiveness of disinfectants against human noroviruses, circumventing the validity questions with surrogate virus models due to differences in susceptibility to inactivation and disinfectants. SUMMARY: Metagenomics next-generation sequencing can enhance our understanding of norovirus transmission and lead to more timely mitigation strategies to curb norovirus outbreaks in healthcare facilities. With new in vitro cultivation methods for human noroviruses, candidate vaccines and effective antivirals could be available in the near future.

OBJECT Patients with cryptococcal meningitis often develop symptomatic intracranial hypertension. The need for permanent CSF diversion in these cases remains unclear. METHODS Cases of cryptococcal meningitis over a 5-year period were reviewed from a single, large teaching hospital. Sources of identification included ICD-9 codes, operative logs, and microscopy laboratory records. RESULTS Fifty cases of cryptococcal meningitis were identified. Ninety-eight percent (49/50) of patients were HIV positive. Opening pressure on initial lumbar puncture diagnosing cryptococcal meningitis was elevated (> 25 cm H2O) in 33 cases and normal (≤ 25 cm H2O) in 17 cases. Thirty-eight patients ultimately developed elevated opening pressure over a follow-up period ranging from weeks to years. Serial lumbar punctures for relief of intracranial hypertension were performed in 29 cases. Thirteen of these patients ultimately had shunting procedures performed after failing to improve clinically. Two factors were significantly associated with the need for shunting: patients undergoing shunt placement were more likely to be women (5/13 vs 0/16; p = 0.01) and to have a pattern of increasing CSF cryptococcal antigen (10/13 vs 3/16 cases; p = 0.003). All patients re-presenting with mycological relapse either underwent or were offered shunt placement. CONCLUSIONS Neurosurgeons are often asked to consider CSF diversion in cases of cryptococcal meningitis complicated by intracranial hypertension. Most patients do well with serial lumbar punctures combined with antifungal therapy. When required, shunting generally provided sustained relief from intracranial hypertension symptoms. Ventriculoperitoneal shunts are the favored method of diversion. To the authors’ knowledge, the present study is the largest series on diversionary shunts in primarily HIV-positive patients with this problem.

Background Infection prevention and antibiotic stewardship are critical to the safe and effective delivery of patient care. The primary objective of this fellowship rotation is to train infectious diseases fellows to develop key competencies in the fields of infection prevention and antibiotic stewardship. Methods We implemented an infection prevention and antibiotic stewardship rotation for the first-year infectious disease fellows starting July 2017. This new one-month rotation included several lectures by infectious diseases physicians, infection preventionists and pharmacists. Fellows rounded with infection preventionists (isolation, device, environmental, and endoscopy rounds) and participated in infection control subcommittees (CLABSI, CAUTI, Clostridioides difficile colitis and surgical site infections). Fellows were required to present infection control data and develop a proposal for a quality improvement project using the Define, Measure, Analyze, Improve and Control (DMAIC) method. Knowledge was evaluated through a 25 item questionnaire administered before (pre) and after (post) rotation. Topics included definitions, surveillance, isolation, preventive methods, outbreak investigation, policies, antibiotic stewardship, healthcare economics, and leadership. Results Sixteen fellows have participated in the rotation (2017-2019); all completed the pre- and post- evaluations (same questionnaire). Fellows answered a mean of 11.1/25 questions correctly pre-course (SD 2.3). Scores improved significantly to a mean of 21.2/25 correct answers at the end of the course (SD 2.6, P< 0.001). All fellows presented quality improvement proposals at the end of the rotation, with a mean score of 85.7% (SD 4.6). The fellows were highly satisfied with the course with mean evaluation score 6.2/7 (88.5%). Conclusion The one month duration infection control and antibiotic stewardship rotation that provides basic training in the field at the beginning of the fellowship led to significant improvement in the fellows’ knowledge, and was very well received. An additional track has been implemented during the second year to prepare interested fellows for careers in infection control and/or antibiotic stewardship. Disclosures All Authors: No reported disclosures

We read with great interest the article by Pouletty et al reporting 16 paediatric patients presenting with Kawa-COVID-19, an inflammatory syndrome similar to Kawasaki disease (KD) associated with SARS-CoV-2 infection.1 All 16 patients met criteria for complete or incomplete KD. Severe cases in children involving systemic inflammation and multiorgan involvement related to COVID-19 are increasingly being reported. These cases, named multisystem inflammatory syndrome in children (MIS-C) in the USA and pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 in the UK, share features of both KD and macrophage activation syndrome.2–6 In contrast to children, few adults with KD-like cases have been reported.7 8 Herein, we describe an adult who presented with KD-like illness similar to children in the Kawa-COVID-19 cohort 4 weeks following a documented SARS-CoV-2 infection. A 38-year-old Hispanic woman developed fever, dyspnoea, cough, anosmia, myalgias and polyarthralgias of the hands, wrists, elbows and knees 4 weeks prior to admission. At that time, nasopharyngeal SARS-CoV-2 PCR was positive. Her symptoms completely resolved within 2 weeks. Five days prior to …

BackgroundWe previously reported the tolerability and immunogenicity 1 month after intramuscular administration of 2 bivalent virus-like particle (VLP)–based candidate norovirus vaccine formulations in adults. We now describe the persistence of immunity and responses to a memory probe vaccination 1 year later.MethodsA total of 454 healthy men and women aged 18–49 years in 3 equal groups received placebo (saline) or 15/50 or 50/50 vaccine formulations (ie, 15 or 50 µg of GI.1 genotype VLPs, respectively, and 50 µg of GII.4c VLPs) with MPL and Al(OH)3. Immunogenicity and safety were assessed up to day 365, when 351 participants received a memory probe vaccination of 15 µg each of GI.1 and GII.4c VLPs with Al(OH)3.ResultsNo safety signals were detected up to 1 year after the first vaccination. Pan-immunoglobulin, immunoglobulin A, and histo-blood group antigen–blocking (HBGA) antibody levels among vaccinees waned but remained higher than levels before vaccination and levels in placebo recipients on days 180 and 365. Memory probe vaccination increased all antibody titers. Levels of HBGA antibodies to GI.1 but not GII.4c were higher after the first vaccination in candidate vaccine groups, compared with those in the placebo group.ConclusionLevels of antibodies to both candidate norovirus VLP formulations persisted above baseline levels for at least 1 year after primary vaccination. HBGA-blocking responses to the memory probe for GI.1 but not GII.4c displayed characteristics of immune memory.Clinical Trials RegistrationNCT02142504.

Background Norovirus is a leading cause of acute gastroenteritis (AGE); however, few data exist on endemic norovirus disease burden among adults. Candidate norovirus vaccines are currently in development for all ages, and robust estimates of norovirus incidence among adults are needed to provide baseline data. Methods We conducted active surveillance for AGE among inpatients at a Veterans Affairs (VA) hospital in Houston, Texas. Patients with AGE (≥3 loose stools, ≥2 vomiting episodes, or ≥1 episode of both loose stool and vomiting, within 24 hours) within 10 days of enrollment and non-AGE control patients were enrolled. Demographic data and clinical characteristics were collected. Stool samples were tested using the FilmArray gastrointestinal panel; virus-positives were confirmed by real-time reverse transcription polymerase chain reaction and genotyped by sequencing. Results From November 2, 2015 through November 30, 2016, 147 case patients and 19 control patients were enrolled and provided a stool specimen. Among case patients, 139 (95%) were male and 70 (48%) were aged ≥65 years. Norovirus was the leading viral pathogen detected (in 16 of 20 virus-positive case patients) and accounted for 11% of all AGE cases. No viral pathogens were detected among control patients. Incidence of norovirus-associated hospitalization was 20.3 cases/100 000 person-years and was similar among those aged

Background Clinical, virologic, and immunologic characteristics of Zika virus (ZIKV) infections in US patients are poorly defined. Methods US subjects with suspected ZIKV infection were enrolled. Clinical data and specimens were prospectively collected for ZIKV RNA detection and serologic and cellular assays. Confirmed ZIKV infection (cases) and ZIKV-negative (controls) subjects were compared. Dengue-experienced and dengue-naïve cases were also compared. Results We enrolled 45 cases and 14 controls. Commonly reported symptoms among cases and controls were maculopapular rash (97.8% and 81.8%), fatigue (86.7% and 81.8%), and arthralgia (82.2% and 54.5%), respectively. The sensitivity (94%) and duration of infection detection (80% positivity at 65–79 days after disease onset) by polymerase chain reaction were highest in whole-blood specimens. ZIKV-neutralizing antibodies had a half-life of 105 days and were significantly higher in dengue virus–experienced cases than naïve ones (P = .046). In intracellular cytokine staining assays, the ZIKV proteins targeted most often by peripheral blood mononuclear cells from cases were structural proteins C and E for CD4+ T cells and nonstructural proteins NS3, NS5, and NS4B for CD8+ T cells. Conclusions ZIKV RNA detection was more frequent and prolonged in whole-blood specimens. Immunoglobulin G (IgG) and neutralizing antibodies, but not IgM, were influenced by prior dengue infection. Robust cellular responses to E and nonstructural proteins have potential vaccine development implications.

Noroviruses are a major cause of gastroenteritis. This review summarizes new information on noroviruses that may lead to the development of improved measures for limiting their human health impact.GII.4 strains remain the most common human noroviruses causing disease, although GII.2 and GII.17 strains have recently emerged as dominant strains in some populations. Histo-blood group antigen (HBGA) expression on the gut mucosa drives susceptibility to different norovirus strains. Antibodies that block virus binding to these glycans correlate with protection from infection and illness. Immunocompromised patients are significantly impacted by norovirus infection, and the increasing availability of molecular diagnostics has improved infection recognition. Human noroviruses can be propagated in human intestinal enteroid cultures containing enterocytes that are a significant primary target for initiating infection. Strain-specific requirements for replication exist with bile being essential for some strains. Several vaccine candidates are progressing through preclinical and clinical development and studies of potential antiviral interventions are underway.Norovirus epidemiology is complex and requires continued surveillance to track the emergence of new strains and recombinants, especially with the continued progress in vaccine development. Humans are the best model to study disease pathogenesis and prevention. New in-vitro cultivation methods should lead to better approaches for understanding virus-host interactions and ultimately to improved strategies for mitigation of human norovirus-associated disease.

As noroviruses are transmitted through the fecal-oral route, we investigated humoral and mucosal (salivary immunoglobulin A [IgA]) immune responses in a phase 2 trial of Takeda's bivalent norovirus virus-like particle (VLP) vaccine candidate in 50 healthy 18- to 49-year-olds. The vaccine had an acceptable tolerability profile and induced rapid, robust humoral immune responses after 1 intramuscular dose of vaccine candidate. Seroresponses were evident 8 days after vaccination as panimmunoglobulin, IgA, and histo-blood group antigen-blocking antibodies against both vaccine GI.1 and GII.4c genotypes. Salivary IgA levels were approximately 1000-fold lower than serum concentrations, and moderately or strongly correlated with the serum IgA titers at all time-points.

Background Norovirus can cause chronic infections with serious morbidity and mortality in immunocompromised patients. While there are no FDA-approved medications for these infections, nitazoxanide, ribavirin, and enterally administered pooled immunoglobulin (IVIG) are used off-label on the basis of expert opinion. Nitazoxanide and ribavirin show antiviral activity in a murine norovirus infection model and an in vitro replicon model of genotype GI.I human norovirus RNA expression, respectively. However, these drugs have not been evaluated in in vitro infections with GII.4 human noroviruses, responsible for most human norovirus disease. We used the stem cell-derived nontransformed human intestinal enteroid (HIE) system, which supports GII.4 human norovirus replication, to evaluate the antiviral activities of nitazoxanide, ribavirin, and IVIG. Methods We inoculated HIEs with GII.4 human norovirus in the presence of half-log dilutions of nitazoxanide (3 µM to 100 µM), ribavirin (10 µM to 10 mM), or IVIG (1:100 to 1:3,000) and a media control. One and 48 hours after inoculation, we extracted and quantified GII.4 norovirus RNA from the HIEs. To demonstrate that replication inhibition was not due to cytotoxicity, we performed quantitative lactate dehydrogenase release assays on the HIEs across the therapeutic range of each compound. Results Nitazoxanide reduced GII.4 replication at 48 hours in a dose-dependent manner, achieving a >90% reduction in viral replication at 10 µM without cytotoxicity. These findings were confirmed in multiple HIE lines representing different intestinal segments and established from different donors. IVIG completely inhibited GII.4 replication at up to a 1:1,000 dilution and was not cytotoxic at therapeutic concentrations. Ribavirin did not reduce GII.4 replication at concentrations up to 10 mMµM, well in excess of levels achieved in human sera with standard doses. Conclusion Nitazoxanide and IVIG, but not ribavirin, potently inhibit GII.4 human norovirus replication in a biologically relevant in vitro model of human norovirus infection. These data highlight the use of HIEs as a new pre-clinical model for developing therapeutics for human norovirus disease. Disclosures All authors: No reported disclosures.

Purpose The study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses. Methods Adults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus. Results PBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results. Conclusion CMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine.

BACKGROUNDConflicting reports have been published on the association between Clostridium difficile ribotypes and severe disease outcomes in patients with C. difficile infection (CDI); several so-called hypervirulent ribotypes have been described. We performed a multicenter study to assess severe disease presentation and severe outcomes among CDI patients infected with different ribotypes.METHODSStool samples that tested positive for C. difficile toxin were collected and cultured from patients who presented to any of 7 different hospitals in Houston, Texas (2011–2013). C. difficile was characterized using a fluorescent PCR ribotyping method. Medical records were reviewed to determine clinical characteristics and ribotype association with severe CDI presentation (ie, leukocytosis and/or hypoalbuminemia) and severe CDI outcomes (ie, ICU admission, ileus, toxic megacolon, colectomy, and/or in-hospital death).RESULTSOur study included 715 patients aged 61±18 years (female: 63%; median Charlson comorbidity index: 2.5±2.4; hospital-onset CDI: 45%; severe CDI: 36.7%; severe CDI outcomes: 12.3%). The most common ribotypes were 027, 014-020, FP311, 002, 078-126, and 001. Ribotype 027 was a significant independent predictor of severe disease (adjusted odds ratio [aOR], 2.24; 95% confidence interval [CI], 1.53–3.29; PP=.041) compared with all other ribotypes in aggregate. However, in an analysis using all common ribotypes as individual variables, ribotype 027 was not associated with severe CDI outcomes more often than other ribotypes.CONCLUSIONRibotype 027 showed virulence equal to that of other ribotypes identified in this endemic setting. Clinical severity markers of CDI may be more predictive of severe CDI outcomes than a particular ribotype.Infect. Control Hosp. Epidemiol. 2015;36(11):1318–1323

Background Two major antigenically heterogenous norovirus genogroups (GI and GII) commonly infect humans and are the leading cause of foodborne, viral gastrointestinal infections in adults. Methods We assessed B cell responses in participants in a double-blind, placebo-controlled, dose-escalation phase 1 study of the safety and immunogenicity of an intramuscular bivalent norovirus virus-like particle (VLP) vaccine. The vaccine contained a GI.1 VLP (Norwalk) and a consensus GII.4 VLP, representing the two major genotypes that cause human disease, and was administered on days 0 and 28 to healthy adults aged 18–49 years. Four separate cohorts received increasing doses of 5 μg, 15 μg, 50 μg, and 150 μg of each VLP adjuvanted in monophosphoryl lipid A and alum. PBMCs were analyzed for B cell activation and mucosal homing markers (flow cytometry) and VLP-specific and total IgG and IgA Ab-secreting cells (ASCs); and serum titers of VLP-specific IgG, IgA, and Pan-Ig were determined. Results The vaccine elicited CD27+ CD38+ plasmablasts and high frequencies of ASCs specific for both VLP antigens in the peripheral blood at 7 days after the first dose. The plasmablasts exhibited a mucosal-homing phenotype and included a high proportion of IgA ASCs. Serum antibodies increased as early as 7 days after the first immunization. Conclusions The data suggest that a single dose of the IM bivalent norovirus vaccine is effective in activating pre-existing B cell memory. The rapid B cell response and the mucosal homing phenotype of induced ASCs are consistent with anamnestic responses in subjects primed by prior oral norovirus infection. This study is registered at ClinicalTrials.gov Identifier NCT01609257 .

During the 2009 influenza pandemic both seasonal and 2009 pandemic vaccines were recommended. We conducted a randomized trial of monovalent 2009-H1N1 vaccine and seasonal trivalent inactivated influenza vaccine (IIV3) given sequentially or concurrently to adults.Adults randomized to 4 study groups and stratified by age (18-64 and ≥65 years) received 1 dose of seasonal IIV3 or placebo and 2 doses of 2009-H1N1 vaccine or placebo in one of 4 combinations, i.e., H1N1+Placebo/H1N1+Placebo/IIV3 (HP/HP/V3), H1N1+IIV3/H1N1+Placebo/Placebo (HV3/HP/P), H1N1+Placebo/H1N1+IIV3/Placebo (HP/HV3/P), and IIV3+Placebo/H1N1+Placebo/H1N1 (V3P/HP/H). Intramuscular injections were given three times at 21 day intervals. Sera for antibody assays were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored.Eight hundred-five (805) adults were enrolled. All combinations of vaccines were safe and well tolerated. In general, one dose of 2009-H1N1 and one dose of IIV3, regardless of sequence or concurrency of administration, were immunogenic in adults. There were no significant differences in geometric mean titers (GMT) or the proportions of subjects with ≥4-fold rise in antibody responses and titers ≥40 for any vaccine group or between age strata for 2009-H1N1 after the first or second dose, although the vaccine sequence affected the titers to the IIV3 antigens. Hemagglutination inhibition antibody (HAI) GMTs against 2009-H1N1 for the combined age strata 21 days after the first 2009-H1N1 dose were 190.4, 182.1, 232.9 and 157.5 for HP/HP/V3, HV3/HP/P, HP/HV3/P and V3P/HP/H, respectively. While IIV3 GMTs were adequate they were generally lower than the 2009-H1N1 GMTs. In a subset of subjects, there was good correlation between HAI and microneutralization (MN) titers (Spearman's correlation coefficient 0.92).All vaccine combinations were generally well tolerated. Immune responses to one dose of 2009-H1N1 were adequate regardless of the sequence of vaccination in all age groups, but the sequence affected titers to IIV3 antigens.

Purpose Norovirus is the leading cause of acute epidemic gastroenteritis among children under the age of 5 years and adults in the United States and in adults worldwide, accounting for an estimated 20% of episodes of acute gastroenteritis across all ages. No effective vaccine is presently available. This article provides an overview of the current state of norovirus vaccine development, emphasizing barriers and challenges in the development of an effective vaccine, correlates of protection used to assess vaccine efficacy, and the results of clinical trials of the major candidate vaccines. Methods We performed an unstructured literature review of published articles listed in PubMed in the field of norovirus vaccine development, with an emphasis on studies in humans. Findings Two candidate vaccines have reached clinical trials, and a number of other candidates are in the preclinical stages of development. Multivalent vaccination may be effective in inducing broadly neutralizing antibodies protective against challenge with novel and heterologous norovirus strains. Most identified correlates of protection have not been validated in large-scale challenge studies, nor have the degrees to which these correlates covary been assessed. Implications Immune correlates of protection against norovirus infection need to be further developed to facilitate additional studies of the tolerability and efficacy of candidate norovirus vaccines in humans.

Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. A virus-like particle (VLP) candidate vaccine induces the production of serum histo-blood group antigen (HBGA)-blocking antibodies, the first identified correlate of protection from HuNoV gastroenteritis. Recently, virus-specific IgG memory B cells were identified to be another potential correlate of protection against HuNoV gastroenteritis. We assessed B-cell responses following intramuscular administration of a bivalent (genogroup I, genotype 1 [GI.1]/genogroup II, genotype 4 [GII.4]) VLP vaccine using protocols identical to those used to evaluate cellular immunity following experimental GI.1 HuNoV infection. The kinetics and magnitude of cellular immunity to G1.1 infection were compared to those after VLP vaccination. Intramuscular immunization with the bivalent VLP vaccine induced the production of antibody-secreting cells (ASCs) and memory B cells. ASC responses peaked at day 7 after the first dose of vaccine and returned to nearly baseline levels by day 28. Minimal increases in ASCs were seen after a second vaccine dose at day 28. Antigen-specific IgG memory B cells persisted at day 180 postvaccination for both GI.1 and GII.4 VLPs. The overall trends in B-cell responses to vaccination were similar to the trends in the responses to infection, where there was a greater bias of an ASC response toward IgA and a memory B-cell response to IgG. The magnitude of the ASC and memory B-cell responses to the GI.1 VLP component of the vaccine was also comparable to that of the responses following GI.1 infection. The production of IgG memory B cells and persistence at day 180 is a key finding and underscores the need for future studies to determine if IgG memory B cells are a correlate of protection following vaccination. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168401.)

Background Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission. Methods In this randomized, double-blind, placebo-controlled trial, 18- to 50-year-olds received 2 injections of placebo or norovirus GI.1/GII.4 bivalent vaccine-like particle (VLP) vaccine with 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and alum. Participants were challenged as inpatients with GII.4 virus (4400 reverse transcription polymerase chain reaction [RT-PCR] units), and monitored for illness and infection. Results Per protocol, 27 of 50 (54.0%) vaccinees and 30 of 48 (62.5%) controls were infected. Using predefined illness and infection definitions, vaccination did not meet the primary endpoint, but self-reported cases of severe (0% vaccinees vs. 8.3% controls; P = .054), moderate or greater (6.0% vs. 18.8%; P = .068), and mild or greater severity of vomiting and/or diarrhea (20.0% vs. 37.5%; P = .074) were less frequent. Vaccination also reduced the modified Vesikari score from 7.3 to 4.5 (P = .002). Difficulties encountered were low norovirus disease rate, and inability to define illness by quantitative RT-PCR or further antibody rise in vaccinees due to high vaccine-induced titers. By day 10, 11 of 49 (22.4%) vaccinees were shedding virus compared with 17 of 47 (36.2%) placebo recipients (P = .179). Conclusions Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration. NCT01609257.

Background. Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine. Methods. Forty-eight adults aged 18–49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18–49 (n = 16), 50–64 (n = 19), and 65–85 (n = 19) years, received 2 doses of vaccine containing 50 µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose. Results. Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18–49, 50–64, and 65–83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of ≥200. Conclusions. The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks. Clinical Trials Registration. NCT01168401.

Background Histo-blood group antigens (HBGAs), whose expression is controlled in part by fucosyltransferase 2 (FUT2) and 3 (FUT3) genes, serve as receptors for norovirus and rotavirus. Individuals without functional FUT2 (nonsecretors) or FUT3 (Lewis-negative) genes may have decreased susceptibility to norovirus and rotavirus infections. As the prevalence of secretor and Lewis status can vary by race and ethnicity, we assessed this association in a US Veteran population. Methods Stool and saliva specimens were collected from acute gastroenteritis (AGE) cases and age- and time-matched controls through a multisite, active surveillance platform at four Veterans Affairs hospitals (Atlanta, Bronx, Houston, Los Angeles). Stool specimens were tested with the FilmArray Gastrointestinal Panel; norovirus and rotavirus positive specimens were genotyped. Saliva specimens were analyzed for HBGA expression by EIA using glycan-specific monoclonal antibodies and lectins. Chi-squared and Fisher’s exact tests were conducted to evaluate associations between secretor and Lewis status and infection with norovirus or rotavirus. Results From November 4, 2015–December 30, 2017, 670 AGE cases and 319 controls provided both stool and saliva specimens. Norovirus (21 GII.4 Sydney, 13 GII non-4, 7 GI, 10 untyped) and rotavirus (13 G12P[8], 1 G2P[4], 1 untyped) positive cases were more likely to be secretor positive (90% and 100%, respectively) compared with controls (76%) (P = 0.03 for both). Infections with GII.4 Sydney norovirus (P < 0.01) and G12P[8] rotavirus (P < 0.05) were significantly associated with secretor status. This association was not observed with other norovirus or rotavirus genotypes. No association was observed between Lewis status, race, or ethnicity and infection with norovirus or rotavirus. Conclusion Norovirus and rotavirus infections among a US Veteran population were associated with secretor status in a genotype-dependent manner, and with GII.4 Sydney norovirus and G12P[8] rotavirus, the most common strains. These associations are consistent with previously reported results, and suggest that the efficacy of interventions, such as vaccines, should include consideration of secretor status and predominantly circulating virus strains. Disclosures R. L. Atmar, Takeda Vaccines, Inc.: Investigator, Research grant. V. C. Marconi, ViiV: Investigator, Research support and Salary. Gilead: Investigator, Research support. Bayer: Investigator, Research support.

Background Clostridium difficile infection is often considered to result from recent acquisition of a C difficile isolate in a healthcare setting. However, C difficile spores can persist for long periods of time, suggesting a potentially large community environmental reservoir. The objectives of this study were to assess community environmental contamination of toxigenic C difficile and to assess strain distribution in environmental versus clinical isolates. Methods From 2013 to 2015, we collected community environmental swabs from homes and public areas in Houston, Texas to assess C difficile contamination. All positive isolates were tested for C difficile toxins A and B, ribotyped, and compared with clinical C difficile isolates obtained from hospitalized patients in Houston healthcare settings. Results A total of 2538 environmental samples were collected over the study period. These included samples obtained from homes (n = 1079), parks (n = 491), chain stores (n = 225), fast food restaurants (n = 123), other commercial stores (n = 172), and hospitals (n = 448). Overall, 418 environmental isolates grew toxigenic C difficile (16.5%; P < .001) most commonly from parks (24.6%), followed by homes (17.1%), hospitals (16.5%), commercial stores (8.1%), chain stores (7.6%), and fast food restaurants (6.5%). A similar distribution of ribotypes was observed between clinical and environmental isolates with the exception that ribotype 027 was more common in clinical isolates compared with environmental isolates (P < .001). Conclusions We identified a high prevalence of toxigenic C difficile from community environs that were similar ribotypes to clinical isolates. These findings suggest that interventions beyond isolation of symptomatic patients should be targeted for prevention of C difficile infection.

Introduction To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N). Methods Healthy adults 18–40 years of age were randomly assigned to receive MVA vaccine subcutaneously by S&N on Days 1 and 29 (standard), Days 1 and 15, or Days 1 and 22, or to receive the vaccine subcutaneously by JI on Days 1 and 29. Blood was collected at four time points after the second vaccination for plaque reduction neutralization test (PRNT) (primary endpoint) and ELISA (secondary endpoint) antibody assays. For each subject, the peak PRNT (or ELISA) titer was defined by the highest PRNT (or ELISA) titer among all available measurements post second vaccination. Non-inferiority of a non-standard arm compared to the standard arm was met if the upper limit of the 98.33% confidence interval of the difference in the mean log2 peak titers between the standard and non-standard arm was less than 1. Results Non-inferiority of the PRNT antibody response was not established for any of the three non-standard study arms. Non-inferiority of the ELISA antibody response was established for the Day 1 and 22 compressed schedule and for administration by JI. Solicited local reactions, such as redness and swelling, tended to be more commonly reported with JI administration. Four post-vaccination hypersensitivity reactions were observed. Conclusions Evaluations of the primary endpoint of PRNT antibody responses do not support alternative strategies of administering MVA vaccine by S&N on compressed schedules or administration by JI on the standard schedule. Trial Registration: clinicaltrials.gov Identifier: NCT01827371 .