Single and two-dose typhoid conjugate vaccine safety and immunogenicity in HIV-exposed uninfected and HIV-unexposed uninfected Malawian children.

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Analyzing Social Media Messaging on Masks and Vaccines: A Case Study on Misinformation During the COVID-19 Pandemic.

Misinformation and disinformation during infectious disease outbreaks can hinder public health responses. This analysis examines comments about masks and COVID-19 vaccines on Twitter during the first six months of the COVID-19 pandemic. We conducted a content analysis of 6,600 randomly selected English-language tweets, examining tweets for health, political, of societal frames; inclusion of true information, false information, partially true/misleading information, and/or opinion; political components; risk frames; and use of specific types of rumor. We found false and partially false information in 22% of tweets in which we were able to assess veracity. Tweets with misinformation were more likely to mention vaccines, be political in nature, and promote risk elevating messages (p<0.5). We also found false information about vaccines as early as January 2020, nearly a year before COVID-19 vaccines became widely available. These findings highlight a need for new policies and strategies aimed to counter harmful and misleading messaging.

Advancing Legal Preparedness through the Global Health Security Agenda.

The Global Health Security Agenda (GHSA) is a multilateral, multisectoral partnership comprised of more than 70 countries, international organizations, foundations, and businesses to strengthen global health security.

The Promise of Disease Detection Dogs in Pandemic Response: Lessons Learned From COVID-19.

One of the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic is the utility of an early, flexible, and rapidly deployable disease screening and detection response. The largely uncontrolled spread of the pandemic in the United States exposed a range of planning and implementation shortcomings, which, if they had been in place before the pandemic emerged, may have changed the trajectory. Disease screening by detection dogs show great promise as a noninvasive, efficient, and cost-effective screening method for COVID-19 infection. We explore evidence of their use in infectious and chronic diseases; the training, oversight, and resources required for implementation; and potential uses in various settings. Disease detection dogs may contribute to the current and future public health pandemics; however, further research is needed to extend our knowledge and measurement of their effectiveness and feasibility as a public health intervention tool, and efforts are needed to ensure public and political support.

trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo.

Bacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.

Current State of Mass Vaccination Preparedness and Operational Challenges in the United States, 2018-2019.

Mass vaccination is a crucial public health intervention during outbreaks or pandemics for which vaccines are available. The US government has sponsored the development of medical countermeasures, including vaccines, for public health emergencies; however, federally supported programs, including the Public Health and Emergency Preparedness program and Cities Readiness Initiative, have historically emphasized antibiotic pill dispensing over mass vaccination. While mass vaccination and pill dispensing programs share similarities, they also have fundamental differences that require dedicated preparedness efforts to address. To date, only a limited number of public assessments of local mass vaccination operational capabilities have been conducted. To fill this gap, we interviewed 37 public health and preparedness officials representing 33 jurisdictions across the United States. We aimed to characterize their existing mass vaccination operational capacities and identify challenges and lessons learned in order to support the efforts of other jurisdictions to improve mass vaccination preparedness. We found that most jurisdictions were not capable of or had not planned for rapidly vaccinating their populations within a short period of time (eg, 1 to 2 weeks). Many also noted that their focus on pill dispensing was driven largely by federal funding requirements and that preparedness efforts for mass vaccination were often self-motivated. Barriers to implementing rapid mass vaccination operations included insufficient personnel qualified to administer vaccinations, increased patient load compared to pill-dispensing modalities, logistical challenges to maintaining cold chain, and operational challenges addressing high-risk populations, including children, pregnant women, and non-English-speaking populations. Considering the expected availability of a severe acute respiratory syndrome coronavirus 2 vaccine for distribution and dispensing to the public, our findings highlight critical considerations for planning possible future mass vaccination events, including during the novel coronavirus disease 2019 pandemic.

Operational stresses on New York City Health+Hospitals Health System frontline hospitals during the 2017-18 influenza season.

OBJECTIVE: Identify operational lessons to support hospital and health system preparedness and response for sea-sonal and pandemic influenza based on firsthand experiences from the 2017-2018 influenza season. DESIGN: We conducted semistructured, retrospective interviews with New York City Health+Hospitals (NYCH+H) personnel to gather firsthand experiences from the 2017-2018 influenza season and evaluated stress data across four operational domains reported by NYCH+H hospitals during the 2017-2018 influenza season. SETTING: Frontline hospitals in the NYCH+H health system during and after the 2017-2018 influenza season. PARTICIPANTS: Interviews conducted with personnel from 5 NYCH+H frontline hospitals. Operational stress data re-ported by 11 NYCH+H hospitals during the 2017-2018 influenza season. MAIN OUTCOME MEASURES: Operational challenges and lessons from frontline hospitals responding to severe sea-sonal influenza. RESULTS: Operational stresses during the 2017-2018 influenza season varied over the influenza season, between facilities, and across operational domains. Patient surge and staff absenteeism pushed some facilities to their limits, and supply shortages highlighted shortcomings in existing procurement systems. Resources tied to pandemic influ-enza were unavailable without a pandemic declaration. CONCLUSION: Seasonal influenza poses dynamic operational stresses across health systems and cities, potentially causing major impacts outside of declared pandemics. Lessons from NYCH+H can help other hospitals and health systems anticipate operational challenges, but novel solutions are needed to mitigate effects of patient surge and per-sonnel and supply shortages during severe influenza seasons and pandemics. Improved data collection can help health systems better understand operational stresses and challenges across their facilities.

Operational stresses on New York City Health+Hospitals Health System frontline hospitals during the 2017-18 influenza season.

OBJECTIVE: Identify operational lessons to support hospital and health system preparedness and response for sea-sonal and pandemic influenza based on firsthand experiences from the 2017-2018 influenza season. DESIGN: We conducted semistructured, retrospective interviews with New York City Health+Hospitals (NYCH+H) personnel to gather firsthand experiences from the 2017-2018 influenza season and evaluated stress data across four operational domains reported by NYCH+H hospitals during the 2017-2018 influenza season. SETTING: Frontline hospitals in the NYCH+H health system during and after the 2017-2018 influenza season. PARTICIPANTS: Interviews conducted with personnel from 5 NYCH+H frontline hospitals. Operational stress data reported by 11 NYCH+H hospitals during the 2017-2018 influenza season. MAIN OUTCOME MEASURES: Operational challenges and lessons from frontline hospitals responding to severe seasonal influenza. RESULTS: Operational stresses during the 2017-2018 influenza season varied over the influenza season, between facilities, and across operational domains. Patient surge and staff absenteeism pushed some facilities to their limits, and supply shortages highlighted shortcomings in existing procurement systems. Resources tied to pandemic influ-enza were unavailable without a pandemic declaration. CONCLUSION: Seasonal influenza poses dynamic operational stresses across health systems and cities, poten-tially causing major impacts outside of declared pandemics. Lessons from NYCH+H can help other hospitals and health systems anticipate operational challenges, but novel solutions are needed to mitigate effects of patient surge and personnel and supply shortages during severe influenza seasons and pandemics. Improved data collection can help health systems better understand operational stresses and challenges across their facilities.

Misinformation and the US Ebola communication crisis: analyzing the veracity and content of social media messages related to a fear-inducing infectious disease outbreak.

BACKGROUND: The Ebola communication crisis of 2014 generated widespread fear and attention among Western news media, social media users, and members of the United States (US) public. Health communicators need more information on misinformation and the social media environment during a fear-inducing disease outbreak to improve communication practices. The purpose of this study was to describe the content of Ebola-related tweets with a specific focus on misinformation, political content, health related content, risk framing, and rumors. METHODS: We examined tweets from a random 1% sample of all tweets published September 30th - October 30th, 2014, filtered for English-language tweets mentioning "Ebola" in the content or hashtag, that had at least 1 retweet (N = 72,775 tweets). A randomly selected subset of 3639 (5%) tweets were evaluated for inclusion. We analyzed the 3113 tweets that meet inclusion criteria using public health trained human coders to assess tweet characteristics (joke, opinion, discord), veracity (true, false, partially false), political context, risk frame, health context, Ebola specific messages, and rumors. We assessed the proportion of tweets with specific content using descriptive statistics and chi-squared tests. RESULTS: Of non-joke tweets, 10% of Ebola-related tweets contained false or partially false information. Twenty-five percent were related to politics, 28% contained content that provoked reader response or promoted discord, 42% contained risk elevating messages and 72% were related to health. The most frequent rumor mentioned focused on government conspiracy. When comparing tweets with true information to tweets with misinformation, a greater percentage of tweets with misinformation were political in nature (36% vs 15%) and contained discord-inducing statements (45% vs 10%). Discord-inducing statements and political messages were both significantly more common in tweets containing misinformation compared with those without(p < 0.001). CONCLUSIONS: Results highlight the importance of anticipating politicization of disease outbreaks, and the need for policy makers and social media companies to build partnerships and develop response frameworks in advance of an event. While each public health event is different, our findings provide insight into the possible social media environment during a future epidemic and could help optimize potential public health communication strategies.

Responding to a Mumps Outbreak Impacting Immigrants and Low-English-Proficiency Populations.

OBJECTIVES: To examine outbreak response-associated costs, lessons learned, and challenges encountered during a local health department's response to a mumps outbreak. DESIGN: We conducted semistructured interviews with individuals directly involved in the response to a mumps outbreak and analyzed outbreak response-associated cost data. SETTING: In March-July 2018, a mumps outbreak occurred in Chester County, Pennsylvania. The outbreak primarily affected an immigrant community, some of whom spoke little or no English and were uninsured and/or undocumented. This necessitated an urgent response from the Chester County Health Department, which implemented a variety of public health interventions, including outreach to local health care providers and the execution of vaccination clinics at 2 local mushroom farms where case contacts worked. A total of 39 suspected or confirmed mumps cases were reported in Chester County, and 22 suspected or confirmed cases were reported by 2 neighboring jurisdictions. PARTICIPANTS: Health department employees (n = 7) and community partners (n = 2). Areas of expertise included emergency preparedness, nursing, medicine, disease surveillance, and epidemiology. MAIN OUTCOME MEASURE: Operational challenges encountered and lessons learned during the mumps outbreak response, including outbreak response-associated costs, which could inform other communities' planning and preparedness for outbreaks in similar populations and improve outbreak response operations. RESULTS: Immigration status emerged as a key challenge, which highlighted the importance of building trust through community outreach and partnerships and the need for culturally competent communication. In addition, vaccine availability, accessibility, and cost played a major role in response operations and necessitated the involvement of community partners to mitigate these barriers. Outbreak response-associated costs totaled $35 305. CONCLUSIONS: The challenges that occurred in this outbreak are broadly relevant to outbreaks that affect similar immigrant communities. Health departments that serve such populations can utilize these lessons to develop improved outbreak response plans that account for these challenges.

The COPEWELL Rubric: A Self-Assessment Toolkit to Strengthen Community Resilience to Disasters.

Measurement is a community endeavor that can enhance the ability to anticipate, withstand, and recover from a disaster, as well as foster learning and adaptation. This project's purpose was to develop a self-assessment toolkit-manifesting a bottom-up, participatory approach-that enables people to envision community resilience as a concrete, desirable, and obtainable goal; organize a cross-sector effort to evaluate and enhance factors that influence resilience; and spur adoption of interventions that, in a disaster, would lessen impacts, preserve community functioning, and prompt a more rapid recovery. In 2016-2018, we engaged in a process of literature review, instrument development, stakeholder engagement, and local field-testing, to produce a self-assessment toolkit (or "rubric") built on the Composite of Post-Event Well-being (COPEWELL) model that predicts post-disaster community functioning and resilience. Co-developing the rubric with community-based users, we generated self-assessment instruments and process guides that localities can more readily absorb and adapt. Applied in three field tests, the Social Capital and Cohesion materials equip users to assess this domain at different geo-scales. Chronicling the rubric's implementation, this account sheds further light on tensions between community resilience assessment research and practice, and potential reasons why few of the many current measurement systems have been applied.

WHO consultation on ETEC and Shigella burden of disease, Geneva, 6-7th April 2017: Meeting report.

According to the 2015 Global Burden of Disease Study, diarrhea ranked ninth among causes of death for all ages, and fourth among children under 5 years old, accounting for an estimated 499,000 deaths in this young age group. It was also the second most common cause of years lived with disability (2.39 billion YLDs). The goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhea (GAPPD) is to reduce deaths from diarrhea in children under 5 years of age to less than 1 per 1000 live births, by 2025. Development of new and improved vaccines against diarrheal infections is a fundamental element of the strategy towards achieving this goal. Enterotoxigenic Escherichia coli (ETEC) and Shigella are enteropathogens that cause significant global mortality and morbidity, particularly in low- and middle-income countries. In 2016, WHO's Product Development for Vaccines Advisory Committee (PDVAC) recommended that the WHO's Initiative for Vaccine Research (IVR) engage in this area, based on PDVAC's criteria of prioritizing the development of vaccines against pathogens that will address a major unmet public health need, and for which clinical candidates with a good probability of technical success are in the pipeline. As a first step, WHO's IVR convened global subject matter experts to discuss the current global ETEC and Shigella disease burden estimates, including the current understanding of the long-term indirect effects of ETEC and Shigella infection, and how these data may affect future decision making on vaccine development for both pathogens. The available global burden estimates for ETEC and Shigella differ with respect to the relative importance of these two pathogens. The mortality estimates vary between iterations published by the same group, as well as between estimates of different groups, although the uncertainty intervals are broad and overlapping. These variances are attributable to differences in the data available and incorporated in the models; the methods used to detect the pathogens; the modelling methodologies; and, to actual changes in the total number of diarrheal deaths over time. The changes in the most recently reported mortality estimates for these pathogens, as compared to previous iterations, has led to debate as to whether investment in development of stand-alone vaccines, rather than combined vaccines, is warranted from cost-effectiveness and vaccine impact perspectives. Further work will be needed to understand better the variances and uncertainties in the reported mortality estimates to support investment decision making, and ultimately policy recommendations for vaccine use. In addition, a comprehensive assessment of the value proposition for vaccines against these pathogens is needed and will be strengthened if the long-term health consequences associated with diarrhea and dysentery due to these pathogens are better defined.

Considerations for using ETEC and Shigella disease burden estimates to guide vaccine development strategy.

Enterotoxigenic E. coli (ETEC) and Shigella are enteropathogens causing significant global morbidity and mortality, particularly in low-income countries. No licensed vaccine exists for either pathogen, but candidates are in development, with the most advanced candidates potentially approaching pivotal efficacy testing within the next few years. A positive policy recommendation for introduction of any vaccine, following licensure, depends on evidence of vaccine cost-effectiveness and impact on morbidity and mortality. The mortality estimates for these two pathogens have fluctuated over recent years, which has led to uncertainty in the assessment of their relative public health importance for use in low and middle-income countries. This paper summarizes the various ETEC and Shigella disease burden estimates, based on a review of current literature and informal consultations with leading stakeholders in enteric disease modelling. We discuss the factors that underpin the variability, including differences in the modelling methodology; diagnostic tools used to ascertain diarrheal etiology; epidemiological setting; the data that are available to incorporate; and absolute changes in the total number of diarrheal deaths over time. We consider the further work that will strengthen the evidence needed to support future decision making with respect to recommendations on the relative utility of these vaccines.

A yeast functional screen predicts new candidate ALS disease genes.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.