Lassa fever research priorities: towards effective medical countermeasures by the end of the decade.

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade.

Measures to prevent and treat Nipah virus disease: research priorities for 2024-29.

Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses.

Viral Load Dynamics in Plasma and Semen When Antiretroviral Therapy Is Initiated During Early HIV-1 Infection.

We assessed human immunodeficiency virus (HIV) load in plasma and semen during primary HIV infection using serial samples of semen and plasma during the first 24 weeks after diagnosis in untreated participants and those who started antiretroviral therapy (ART) immediately at diagnosis. In the absence of treatment, semen viral load was >1000 copies/mL in almost all specimens (83%) collected 2-10 weeks after the estimated date of HIV acquisition and remained >1000 copies/mL in 35% of untreated participants at the last observed time point. Thus, in the absence of ART, semen viral load remained at a level consistent with transmissibility throughout primary infection.

Protocol for evaluating mechanistic pathways associated with HIV acquisition via nested Least Absolute Shrinkage and Selective Operator analysis.

Statistical analysis to evaluate mechanistic pathways can be limited by non-causal associations as well as co-linearity of high-dimensional data. Here, we present a protocol evaluating statistical associations between multiple exposure variables (sociodemographic and behavioral), immune biomarkers, and HIV acquisition. We describe steps for study setup, combining Least Absolute Shrinkage and Selective Operator with the standard regression approach, and building nested models. This approach can determine to what extent associations between risks for exposure contributes to HIV acquisition with or without associated changes in immune activation. For complete details on the use and execution of this protocol, please refer to Bender Ignacio et al.1.

Sex-disaggregated effectiveness data reporting in COVID-19 vaccine research: a systematic review.

BACKGROUND: Sex and gender are believed to influence vaccine response. Yet, the relationship between sex and gender and COVID-19 vaccine efficacy is poorly understood and remains under-investigated. METHODS: We conducted a systematic review to determine whether and to what extent post-approval COVID-19 vaccine effectiveness (VE) studies report sex-disaggregated VE data. We searched four publication and pre-publication databases and additional grey literature sources for relevant published/preprint studies released between 1 January 2020 and 1 October 2021 (i.e., pre-Omicron era). We included observational studies providing VE estimates for one or more licensed/approved COVID-19 vaccines and including both males and females. Two reviewers independently assessed study eligibility, extracted data, and assessed risk-of-bias through a modified version of Cochrane's ROBINS-I tool. A qualitative data synthesis was performed. RESULTS: Here we show that, among 240 eligible publications, 68 (28.3%) do not report the sex distribution among participants. Only 21/240 (8.8%) studies provide sex-disaggregated VE estimates, and high between-study heterogeneity regarding design, target population, outcomes, and vaccine type/timing prevent the assessment of sex in determining COVID-19 VE across studies. CONCLUSIONS: Our findings indicate that few COVID-19 vaccine research publications account for sex. Improved adherence to recommended reporting guidelines will ensure that the evidence generated can be used to better understand the relationship between sex and gender and VE.

The level of protection that vaccines provide against COVID-19 might depend on a person's sex or gender. However, sex and gender are not always reported in studies on the effectiveness of COVID-19 vaccines. Here, we systematically reviewed the literature on COVID-19 vaccine effectiveness and looked at whether the studies we found separated out their data on vaccine effectiveness by participants' sex. Out of the 240 publications we identified, 68 (28.3%) did not report the sex of the participants in their study, and only 21 studies (8.8%) reported vaccine effectiveness data separated by sex. These results show that a substantial proportion of COVID-19 vaccine research publications do not account for sex. Efforts should be made by researchers to study and report the relationship between sex and vaccine effectiveness, to help to optimise vaccination strategies so that all people are adequately protected.

COVID-19 Vaccine Hesitancy in a Population-Based Study of Minnesota Residents.

COVID-19 continues to be a public health concern in the United States. Although safe and effective vaccines have been developed, a significant proportion of the US population has not received a COVID-19 vaccine. This cross-sectional study aimed to describe the demographics and behaviors of Minnesota adults who have not received the primary series of the COVID-19 vaccine, or the booster shot using data from the Minnesota COVID-19 Antibody Study (MCAS) collected through a population-based sample between September and December 2021. Data were collected using a web-based survey sent to individuals that responded to a similar survey in 2020 and their adult household members. The sample was 51% female and 86% White/Non-Hispanic. A total of 9% of vaccine-eligible participants had not received the primary series and 23% of those eligible to receive a booster had not received it. Older age, higher education, better self-reported health, $75,000 to $100,000 annual household income, mask-wearing, and social distancing were associated with lower odds of hesitancy. Gender, race, and previous COVID-19 infection were not associated with hesitancy. The most frequently reported reason for not receiving a COVID-19 vaccination was safety concerns. Mask-wearing and being age 65 or older were the only strong predictors of lower odds of vaccine hesitancy for both the primary series and booster analyses.

What motivates adults to accept influenza vaccine? An assessment of incentives, ease of access, messaging, and sources of information using a discrete choice experiment.

Seasonal influenza vaccination rates remain low, and contribute to preventable influenza cases, hospitalizations, and deaths in the US. While numerous interventions have been implemented to increase vaccine uptake, there is a need to determine which interventions contribute most to vaccine willingness, particularly among age groups with vaccination rates that have plateaued at suboptimal levels. This study aimed to quantify the relative effect of multiple interventions on vaccine willingness to receive influenza vaccine in three age groups using a series of hypothetical situations with different behavioral interventions. We assessed the relative impact of four categories of interventions: source of vaccine messages, type of vaccination messages, vaccination incentives, and ease of vaccine access using a discrete choice experiment. Within each category, we investigated the role of four different attributes to measure their relative contribution to willingness to be vaccinated by removing one option from each of the intervention categories. Among the 1,763 Minnesota residents who volunteered for our study, participants expressed vaccine willingness in over 80% of the scenarios presented. Easy access to drop-in vaccination sites had the greatest impact on vaccine willingness in all age groups. Among the younger age group, small financial incentives also contributed to high vaccine willingness. Our results suggest that public health programs and vaccination campaigns may improve their chances of successfully increasing vaccine willingness if they offer interventions preferred by adults, including facilitating convenient access to vaccination and offering small monetary incentives, particularly for young adults.

A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy.

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

Stress, anxiety, and sleep among college and university students during the COVID-19 pandemic.

OBJECTIVE: We categorized levels of self-reported stress, anxiety, worry, and sleep among US college and university students during the COVID-19 pandemic. METHODS: We conducted an anonymous online survey between May 7 and June 21, 2020. RESULTS: Nearly all participants reported worry about the pandemic. Nearly half (95% CI: 43.3-51.3) reported moderate-to-severe anxiety, and 42.0% (95% CI: 38.0-45.9) reported experiencing poor sleep quality. Those with moderate-to-severe anxiety were more likely (OR: 3.3; 95% CI: 2.4-4.7) to report poor sleep quality than those with less anxiety. Moderate or extreme worry about the pandemic was associated with poor sleep quality (OR: 1.5; 95% CI: 1.1-2.1). CONCLUSIONS: Our survey found high levels of stress, worry, anxiety, and poor sleep among US college and university students during the early months of the pandemic. Universities should prioritize access to resources for healthy coping to help students manage anxiety and improve sleep quality as the pandemic continues.

The complexity of examining laboratory-based biological markers associated with mortality in hospitalized patients during early phase of the COVID-19 pandemic: A systematic review and evidence map.

IMPORTANCE: The measurement of laboratory biomarkers plays a critical role in managing patients with COVID-19. However, to date most systematic reviews examining the association between laboratory biomarkers and mortality in hospitalized patients early in the pandemic focused on small sets of biomarkers, did not account for multiple studies including patients within the same institutions during overlapping timeframes, and did not include a significant number of studies conducted in countries other than China. OBJECTIVE: To provide a comprehensive summary and an evidence map examining the relationship between a wide range of laboratory biomarkers and mortality among patients hospitalized with COVID-19 during the early phase of the pandemic in multiple countries. EVIDENCE REVIEW: MEDLINE, EMBASE, and Web of Science were searched from Dec 2019 to March 9, 2021. A total of 14,049 studies were identified and screened independently by two raters; data was extracted by a single rater and verified by a second. Quality was assessed using the Joanna Briggs Institute (JBI) Case Series Critical Appraisal tool. To allow comparison across biomarkers, standardized mean differences (SMD) were used to quantify the relationship between laboratory biomarkers and hospital mortality. Meta-regression was conducted to account for clustering within institutions and countries. RESULTS: Our systematic review included 94 case-series studies from 30 countries. Across all biomarkers, the largest and most precise SMDs were observed for cardiac (troponin (1.03 (95% CI 0.86 to 1.21)), and BNP/NT-proBNP (0.93 (0.52 to 1.34)), inflammatory (IL-6 (0.97 (0.67 to 1.28) and Neutrophil-to-lymphocyte ratio (0.94 (0.59 to 1.29)), and renal biomarkers (blood urea nitrogen (1.01 (0.79 to 1.23)) and estimated glomerular filtration rate (-0.96 (-1.42 to -0.50)). There was heterogeneity for most biomarkers across countries with studies conducted in China generally having larger effect sizes. CONCLUSIONS AND RELEVANCE: The results of this study provide an early pandemic summary of the relationship between biomarkers and mortality in hospitalized patients. We found our estimated ESs were generally attenuated compared to previous systematic reviews which predominantly included studies conducted in China. Despite using sophisticated methodology to examine studies across countries, heterogeneity in reporting of case-series studies early in the pandemic limits clinical interpretability.

Willingness to be vaccinated, preventative behaviors, and social contact patterns during the COVID-19 pandemic among US college students.

Objective: To assess the frequency of preventative COVID-19 behaviors and vaccination willingness among United States (US) college and university students during the COVID-19 pandemic. Participants: Participants (N = 653) were ≥18 years old and students at institutions for higher education in the US in March 2020. Methods: Students self-reported preventative behaviors, willingness to be vaccinated, and social contact patterns during four waves of online surveys from May-August 2020. Results: Student engagement in preventative behaviors was generally high. The majority of students intended to be vaccinated (81.5%). Overall, there were no significant differences in the proportion adopting preventative behaviors or in willingness to be vaccinated by sex or geographic location. The most common reason for willingness to get vaccinated was wanting to contribute to ending COVID-19 outbreaks (44.7%). Conclusions: Early in the pandemic, college students primarily reported willingness to vaccinate and adherence to preventative behaviors. Outreach strategies are needed to continue this momentum.

COVID-19 vaccine confidence and reasons for vaccination among health care workers and household members.

BACKGROUND: The majority of healthcare workers (HCW) in the US report being fully vaccinated against COVID-19, yet little is known about vaccine decision-making for their household members, including children. METHODS: Cross-sectional survey July-August 2021 of HCW and their household members in Minnesota. RESULTS: 94 % of eligible participants were vaccinated with the most common reasons being wanting to protect oneself, family and loved ones. Safety concerns were the most commonly reported reasons for not being vaccinated; a significantly higher proportion of unvaccinated compared to vaccinated HCW (58 % vs 12 %, p = 0.0035) and household adults (25 % vs 5 %, p = 0.03) reported prior SARS-CoV-2 infection. Nearly half of unvaccinated adults and two-thirds of unvaccinated children would be vaccinated if a vaccine mandate were in place. CONCLUSIONS: Despite high COVID-19 vaccine acceptance among HCWs, more research is required to identify and address the needs and concerns of healthcare workers who decline COVID-19 vaccination despite availability.

What drives willingness to receive a new vaccine that prevents an emerging infectious disease? A discrete choice experiment among university students in Uganda.

BACKGROUND: There is a critical need to identify the drivers of willingness to receive new vaccines against emerging and epidemic diseases. A discrete choice experiment is the ideal approach to evaluating how individuals weigh multiple attributes simultaneously. We assessed the degree to which six attributes were associated with willingness to be vaccinated among university students in Uganda. METHODS: We conducted a single-profile discrete choice experiment at Makerere University in 2019. Participants were asked whether or not they would be vaccinated in 8 unique scenarios where attributes varied by disease risk, disease severity, advice for or against vaccination from trusted individuals, recommendations from influential figures, whether the vaccine induced indirect protection, and side effects. We calculated predicted probabilities of vaccination willingness using mixed logistic regression models, comparing health professional students with all other disciplines. FINDINGS: Of the 1576 participants, 783 (49.8%) were health professional students and 685 (43.5%) were female. Vaccination willingness was high (78%), and higher among health students than other students. We observed the highest vaccination willingness for the most severe disease outcomes and the greatest exposure risks, along with the Minister of Health's recommendation or a vaccine that extended secondary protection to others. Mild side effects and recommendations against vaccination diminished vaccination willingness. INTERPRETATION: Our results can be used to develop evidence-based messaging to encourage uptake for new vaccines. Future vaccination campaigns, such as for COVID-19 vaccines in development, should consider acknowledging individual risk of exposure and disease severity and incorporate recommendations from key health leaders.

Identification of Natural SARS-CoV-2 Infection in Seroprevalence Studies Among Vaccinated Populations.

Most SARS-CoV-2 antibody assays cannot distinguish between antibodies that developed after natural infection and those that developed after vaccination. We assessed the accuracy of a nucleocapsid-containing assay in identifying natural infection among vaccinated individuals. A longitudinal cohort composed of health care workers in the Minneapolis/St. Paul area was enrolled. Two rounds of seroprevalence studies separated by 1 month were conducted from November 2020 to January 2021 among 81 participants. Capillary blood from rounds 1 and 2 was tested for IgG antibodies against spike proteins by enzyme-linked immunosorbent assay (spike-only assay). During round 2, IgGs reactive to SARS-CoV-2 nucleocapsid protein (nucleocapsid-containing assay) were assessed. Vaccination status at round 2 was determined by self-report. Area under the curve was computed to determine the discriminatory ability of the nucleocapsid-containing assay for identification of recent infection. Participants had a mean age of 40 years (range, 23 to 66 years); 83% were female. Round 1 seroprevalence was 9.5%. Before round 2 testing, 46% reported vaccination. Among those not recently infected, in comparing vaccinated vs unvaccinated individuals, elevated levels of spike 1 (P<.001) and spike 2 (P=.01) were observed, whereas nucleocapsid levels were not statistically significantly different (P=.90). Among all participants, nucleocapsid response predicted recent infection with an area under the curve of 0.93 (95% CI, 0.88 to 0.99). Among individuals vaccinated more than 10 days before antibody testing, the specificity of the nucleocapsid-containing assay was 92%, whereas the specificity of the spike-only assay was 0%. An IgG assay identifying reactivity to nucleocapsid protein is an accurate predictor of natural infection among a partially vaccinated population, whereas a spike-only assay performed poorly.

SARS-CoV-2 seroprevalence among healthcare workers.

BACKGROUND: Monitoring COVID-19 infection risk among health care workers (HCWs) is a public health priority. We examined the seroprevalence of SARS-CoV-2 among HCWs following the fall infection surge in Minnesota, and before and after COVID-19 vaccination. Additionally, we assessed demographic and occupational risk factors for SARS-CoV-2 infection. METHODS: We conducted two rounds of seroprevalence testing among a cohort of HCWs: samples in round 1 were collected from 11/22/20-02/21/21 and in round 2 from 12/18/20-02/15/21. Demographic and occupational exposures assessed with logistic regression were age, sex, healthcare role and setting, and number of children in the household. The primary outcome was SARS-CoV-2 IgG seropositivity. A secondary outcome, SARS-CoV-2 infection, included both seropositivity and self-reported SARS-CoV-2 test positivity. RESULTS: In total, 459 HCWs were tested. 43/454 (9.47%) had a seropositive sample 1 and 75/423 (17.7%) had a seropositive sample 2. By time of sample 2 collection, 54% of participants had received at least one vaccine dose and seroprevalence was 13% among unvaccinated individuals. Relative to physicians, the odds of SARS-CoV-2 infection in other roles were increased (Nurse Practitioner: OR[95%CI] 1.93[0.57,6.53], Physician's Assistant: 1.69[0.38,7.52], Nurse: 2.33[0.94,5.78], Paramedic/EMTs: 3.86[0.78,19.0], other: 1.68[0.58,4.85]). The workplace setting was associated with SARS-CoV-2 infection (p = 0.04). SARS-CoV-2 seroprevalence among HCWs reporting duties in the ICU vs. those working in an ambulatory clinic was elevated: OR[95%CI] 2.17[1.01,4.68]. CONCLUSIONS: SARS-CoV-2 seroprevalence in HCW increased during our study period which was consistent with community infection rates. HCW role and setting-particularly working in the ICU-is associated with higher risk for SARS-CoV-2 infection.

Finding and treating early-stage HIV infections: A cost-effectiveness analysis of the Sabes study in Lima, Peru.

Background: Sabes, a treatment-as-prevention intervention among men who have sex with men and transgender women in Lima, Peru, was developed to identify HIV during early primary infection (<3 months from acquisition) through monthly serologic assays and HIV RNA tests. Newly diagnosed individuals were rapidly linked to care and offered to initiate ART. In this study we sought to study the cost-effectiveness of Sabes compared to the standard of care (SOC) for HIV testing and initiation of treatment. Methods: We adapted a compartmental model of HIV transmission to evaluate the cost-effectiveness of the Sabes approach compared to the SOC using a government health care perspective, 20-year time horizon, and 3% annual discounting. We estimated the proportion of cases of HIV detected during early primary infection, reduction in HIV incidence and prevalence, incremental cost-effectiveness ratio (ICER), and net monetary benefit. We analyzed costs using data from the Sabes study, the Peruvian Ministry of Health, published literature, and expert consultation. Findings: The Sabes intervention is projected to identify 9294 early primary HIV infections in Lima, Peru over 20 years. The intervention costs $6,896 per early primary infection diagnosed and by 2038 is expected to decrease the fraction of early infections among prevalent infections by 62%. Sabes is expected to improve health, resulting in greater total discounted QALYs per person than the SOC (16·7 vs 16·4, respectively). Sabes had an ICER of $1431 (22% per capita GDP in Peru) per QALY compared to SOC. Interpretation: Our analysis suggests that in Lima, Peru the Sabes intervention could be a cost-effective approach to reduce the burden of HIV even under stringent cost-effectiveness criteria. This finding suggests that programs that use frequent HIV testing, rapid linkage to care and initiation of ART should be considered as part of a comprehensive HIV prevention strategy. Funding: National Institutes of Health.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Dose, Infection, and Disease Outcomes for Coronavirus Disease 2019 (COVID-19): A Review.

The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dose, infection, and coronavirus disease 2019 (COVID-19) outcomes remains poorly understood. This review summarizes the existing literature regarding this issue, identifies gaps in current knowledge, and suggests opportunities for future research. In humans, host characteristics, including age, sex, comorbidities, smoking, and pregnancy, are associated with severe COVID-19. Similarly, in animals, host factors are strong determinants of disease severity, although most animal infection models manifest clinically with mild to moderate respiratory disease. The influence of variants of concern as it relates to infectious dose, consequence of overall pathogenicity, and disease outcome in dose-response remains unknown. Epidemiologic data suggest a dose-response relationship for infection contrasting with limited and inconsistent surrogate-based evidence between dose and disease severity. Recommendations include the design of future infection studies in animal models to investigate inoculating dose on outcomes and the use of better proxies for dose in human epidemiology studies.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) screening among symptom-free healthcare workers.

Transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is possible among symptom-free individuals. Patients are avoiding medically necessary healthcare visits for fear of becoming infected in the healthcare setting. We screened 489 symptom-free healthcare workers for SARS-CoV-2 and found no positive results, strongly suggesting that the prevalence of SARS-CoV-2 was <1%.