BACKGROUND: Although substance use rates among adolescents have decreased, drug overdose deaths among adolescents have increased since 2020, driven largely by illegally made fentanyl (IMF). This study explores substance use patterns and characteristics of adolescents who were assessed for substance use disorder (SUD) treatment to inform prevention and response strategies. METHODS: A convenience sample of adolescents aged 10-18 years assessed for SUD treatment from September 2017 to December 2021 was analyzed using the Comprehensive Health Assessment for Teens. The percentage of lifetime and past 30-day substance use was examined. Adolescent characteristics (e.g., demographics, history of overdoses or hospital visits due to drug/alcohol use) were analyzed by lifetime substances used. RESULTS: Among 5,377 assessments, most were male (58.7%), aged 16-18 years (50.5%), non-Hispanic White (43.1%), enrolled in school (87.3%), and living with their parent(s) (72.4%). The most commonly reported lifetime substances used were marijuana (68.0%), alcohol (54.2%), and prescription opioid misuse (13.6%). The most common past 30-day substance use combination was alcohol and marijuana (35.6%). The percentage of assessments indicating past-year overdoses or hospital visits due to drug/alcohol use was greatest among those who reported lifetime use of IMF (24.0%), followed by heroin (21.4%) and cocaine (15.3%). Overall, 2.3% reported lifetime IMF use and 0.6% thought IMF was causing them the most problems. CONCLUSIONS: Findings inform opportunities to address substance use and increased IMF-involved overdose among adolescents. Continued overdose prevention and response strategies such as evidence-based education campaigns, naloxone distribution and harm reduction efforts, and evidence-based SUD treatment expansion are needed.

BACKGROUND: Sapovirus is an important cause of acute gastroenteritis in childhood. While vaccines against sapovirus may reduce gastroenteritis burden, a major challenge to their development is a lack of information about natural immunity. METHODS: We measured sapovirus-specific IgG in serum collected, between 2017 and 2020, of mothers soon after delivery and at 6 time points in Nicaraguan children until 3 years of age (n=112 dyads) using virus-like particles representing three sapovirus genotypes (GI.1, GI.2, GV.1). RESULTS: Sixteen (14.3%) of the 112 children experienced at least one sapovirus gastroenteritis episode, of which GI.1 was the most common genotype. Seroconversion to GI.1 and GI.2 was most common between 5 and 12 months of age, while seroconversion to GV.1 peaked at 18 to 24 months of age. All children who experienced sapovirus GI.1 gastroenteritis seroconverted and developed genotype-specific IgG. The impact of sapovirus exposure on population immunity was determined using antigenic cartography: newborns share their mothers' broadly binding IgG responses, which declined at 5 months of age and then increased as infants experienced natural sapovirus infections. CONCLUSION: By tracking humoral immunity to sapovirus over the first 3 years of life, this study provides important insights for the design and timing of future pediatric sapovirus vaccines.

We detected a novel GII.4 variant with an amino acid insertion at the start of epitope A in viral protein 1 of noroviruses from the United States, Gabon, South Africa, and the United Kingdom collected during 2017-2022. Early identification of GII.4 variants is crucial for assessing pandemic potential and informing vaccine development.

Genogroup II (GII) noroviruses are a major cause of diarrheal disease burden in children in both high- and low-income countries. GII.17 noroviruses are composed of distinct genetic clusters (I, II, IIIa, and IIIb) and have shown potential for replacing historically more prevalent GII.4 strains, but the serological basis for GII.17 antigenic diversity has not been studied in children. Utilizing samples from a birth cohort, we investigated antibody and B-cell responses to GII.17 cluster variants in confirmed GII.17 infections in young children as well as demonstrated that the distinct genetic clusters co-circulate. Polyclonal serum antibodies bound multiple clusters but showed cluster-specific blockade activity in a surrogate virus neutralization assay. Antibodies secreted by immortalized memory B cells (MBCs) from an infant GII.17 case were highly specific to GII.17 and exhibited blockade activity against this genotype. We isolated an MBC-derived GII.17-specific Immunoglobulin A (IgA) monoclonal antibody called NVA.1 that potently and selectively blocked GII.17 cluster IIIb and recognized an epitope targeted in serum from cluster IIIb-infected children. These data indicate that multiple antigenically distinct GII.17 variants co-circulate in young children, suggesting retention of cluster diversity alongside potential for immune escape given the existence of antibody-defined cluster-specific epitopes elicited during infection.

The control of pandemic pathogens depends on early prediction of pandemic variants and, more generally, understanding origins of such variants and factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have suggested that new GII.4 pandemic viruses evolve from previous pandemic variants through substitutions in the antigenic region of the VP1 protein that enable evasion of host population immunity, leading to global spread. In contrast, we show here that the acquisition of new genetic and antigenic characteristics is not the proximal driver of new pandemics. Instead, pandemic GII.4 viruses circulate undetected for years before causing a new pandemic, during which time they diversify and spread over wide geographical areas. Serological data demonstrate that by 2003, some nine years before it emerged as a new pandemic, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically-preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.Significance Norovirus pandemics and their associated public health and economic costs could be prevented by effective vaccines. However, vaccine development and distribution will require identification of the sources and drivers of new pandemics. We here use phylogenetics and serological experiments to develop and test a new hypothesis of pandemic norovirus emergence. We find that pandemic noroviruses preadapt, diversify and spread worldwide years prior to emergence, strongly indicating that genetic changes are necessary but not sufficient to drive a new pandemic. We instead suggest that changes in population immunity enable pandemic emergence of a pre-adapted low-level variant. These findings indicate that prediction of new pandemics will require surveillance of under-sampled virus reservoirs and that norovirus vaccines will need to elicit broad immunity.

Data on monkeypox in children and adolescents aged <18 years are limited (1,2). During May 17-September 24, 2022, a total of 25,038 monkeypox cases were reported in the United States,(dagger) primarily among adult gay, bisexual, and other men who have sex with men (3). During this period, CDC and U.S. jurisdictional health departments identified Monkeypox virus (MPXV) infections in 83 persons aged <18 years, accounting for 0.3% of reported cases. Among 28 children aged 0-12 years with monkeypox, 64% were boys, and most had direct skin-to-skin contact with an adult with monkeypox who was caring for the child in a household setting. Among 55 adolescents aged 13-17 years, most were male (89%), and male-to-male sexual contact was the most common presumed exposure route (66%). Most children and adolescents with monkeypox were non-Hispanic Black or African American (Black) (47%) or Hispanic or Latino (Hispanic) (35%). Most (89%) were not hospitalized, none received intensive care unit (ICU)-level care, and none died. Monkeypox in children and adolescents remains rare in the United States. Ensuring equitable access to monkeypox vaccination, testing, and treatment is a critical public health priority. Vaccination for adolescents with risk factors and provision of prevention information for persons with monkeypox caring for children might prevent additional infections.

There are significant challenges to the development of a pediatric norovirus vaccine, mainly due to the antigenic diversity among strains infecting young children. Characterizing human norovirus serotypes and understanding norovirus immunity in naïve children would provide key information for designing rational vaccine platforms. In this study, 26 Nicaraguan children experiencing their first norovirus acute gastroenteritis (AGE) episode during the first 18 months of life were investigated. We used a surrogate neutralization assay that measured antibodies blocking the binding of 13 different norovirus virus-like particles (VLPs) to histo-blood group antigens (HBGAs) in pre- and post-infection sera. To assess for asymptomatic norovirus infections, stools from asymptomatic children were collected monthly, screened for norovirus by RT-qPCR and genotyped by sequencing. Seroconversion of an HBGA-blocking antibody matched the infecting genotype in 25 (96%) of the 26 children. A subset of 13 (50%) and 4 (15%) of the 26 children experienced monotypic GII and GI seroconversion, respectively, strongly suggesting a type-specific response in naïve children, and 9 (35%) showed multitypic seroconversion. The most frequent pairing in multitypic seroconversion (8/12) were GII.4 Sydney and GII.12 noroviruses, both co-circulating at the time. Blocking antibody titers to these two genotypes did not correlate with each other, suggesting multiple exposure rather than cross-reactivity between genotypes. In addition, GII titers remained consistent for at least 19 months post-infection, demonstrating durable immunity. In conclusion, the first natural norovirus gastroenteritis episodes in these young children were dominated by a limited number of genotypes and induced responses of antibodies blocking binding of norovirus VLPs in a genotype-specific manner, suggesting that an effective pediatric norovirus vaccine likely needs to be multivalent and include globally dominant genotypes. The duration of protection from natural infections provides optimism for pediatric norovirus vaccines administered early in life.

Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity. IMPORTANCE In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Neither evades current adult immunity, yet young children are likely susceptible. By comparing serological responses, we demonstrate that population immunity varies by age/exposure, impacting predicted susceptibility to variants. Repeat exposure to antigenically similar variants broadens antibody responses, providing immunological coverage of diverse variants but compromising response to the infecting variant, allowing continued circulation. These data indicate norovirus GII.4 variant replacement is driven distally by virus evolution and proximally by immunity in adults.

A birth cohort design was used to understand whether heterotypic ligand-blocking norovirus antibodies provide cross-protection within the GII genogroup. We found that almost one-half of children who experienced a norovirus GII episode had preexisting antibodies heterotypic to the infecting genotype; therefore, these antibodies did not provide cross-protection.

The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.

PURPOSE: To synthesize the diverse body of literature on sexual and gender minority youth (SGMY) and sexual health education. METHODS: We conducted a systematic search of the literature on SGMY and sexual health education, including SGMY perspectives on sexual health education, the acceptability or effectiveness of programs designed for SGMY, and SGMY-specific results of sexual health education programs delivered to general youth populations. RESULTS: A total of 32 articles were included. Sixteen qualitative studies with SGMY highlight key perspectives underscoring how youth gained inadequate knowledge from sexual health education experiences and received content that excluded their identities and behaviors. Thirteen studies examined the acceptability or effectiveness of sexual health interventions designed for SGMY from which key characteristics of inclusive sexual health education relating to development, content, and delivery emerged. One study found a sexual health education program delivered to a general population of youth was also acceptable for a subsample of sexual minority girls. CONCLUSIONS: Future research on SGMY experiences should incorporate populations understudied, including younger adolescents, sexual minority girls, and transgender persons. Further, the effectiveness of inclusive sexual health education in general population settings requires further study.

Undetected infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) contributes to transmission in nursing homes, settings where large outbreaks with high resident mortality have occurred (1,2). Facility-wide testing of residents and health care personnel (HCP) can identify asymptomatic and presymptomatic infections and facilitate infection prevention and control interventions (3-5). Seven state or local health departments conducted initial facility-wide testing of residents and staff members in 288 nursing homes during March 24-June 14, 2020. Two of the seven health departments conducted testing in 195 nursing homes as part of facility-wide testing all nursing homes in their state, which were in low-incidence areas (i.e., the median preceding 14-day cumulative incidence in the surrounding county for each jurisdiction was 19 and 38 cases per 100,000 persons); 125 of the 195 nursing homes had not reported any COVID-19 cases before the testing. Ninety-five of 22,977 (0.4%) persons tested in 29 (23%) of these 125 facilities had positive SARS-CoV-2 test results. The other five health departments targeted facility-wide testing to 93 nursing homes, where 13,443 persons were tested, and 1,619 (12%) had positive SARS-CoV-2 test results. In regression analyses among 88 of these nursing homes with a documented case before facility-wide testing occurred, each additional day between identification of the first case and completion of facility-wide testing was associated with identification of 1.3 additional cases. Among 62 facilities that could differentiate results by resident and HCP status, an estimated 1.3 HCP cases were identified for every three resident cases. Performing facility-wide testing immediately after identification of a case commonly identifies additional unrecognized cases and, therefore, might maximize the benefits of infection prevention and control interventions. In contrast, facility-wide testing in low-incidence areas without a case has a lower proportion of test positivity; strategies are needed to further optimize testing in these settings.

BACKGROUND AND AIMS: Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; non-secretors (FUT2(-/-)) express a limited array of HBGAs. Thus, non-secretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. As future human norovirus vaccines will be comprised of GII.4 antigen and since secretor phenotype impacts GII.4 infection and immunity, non-secretors may immunologically mimic young children in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure. METHODS: Utilizing specimens collected from the first characterized non- secretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serological immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry. RESULTS: GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes and dendritic cells and for 180 days for blocking antibody. Multiple cellular lineages expressing IFN-gamma and TNF-alpha dominated the response. Both T cell and B cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to non-secretor HBGAs. CONCLUSION: These data support development of within-genogroup cross-reactive antibody and T cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses following GII.4 vaccination in individuals with limited GII.4 immunity, including young children.

The Centers for Disease Control and Prevention (CDC) Global Rapid Response Team (GRRT) was launched in June 2015 to strengthen the capacity for international response and to provide an agency-wide roster of qualified surge-staff members who can deploy on short notice and for long durations. To assess GRRT performance and inform future needs for CDC and partners using rapid response teams, we analyzed trends and characteristics of GRRT responses and responders, for deployments of at least 1 day during October 1, 2018, through March 31, 2019. One hundred twenty deployments occurred during the study period, corresponding to 2645 person-days. The median deployment duration was 19 days (interquartile range, 5-30 days). Most deployments were related to emergency response (n = 2367 person-days, 90%); outbreaks of disease accounted for almost all deployment time (n = 2419 person-days, 99%). Most deployments were to Africa (n = 1417 person-days, 54%), and epidemiologists were the most commonly deployed technical advisors (n = 1217 person-days, 46%). This case study provides useful information for assessing program performance, prioritizing resource allocation, informing future needs, and sharing lessons learned with other programs managing rapid response teams. GRRT has an important role in advancing the global health security agenda and should continuously be assessed and adjusted to new needs.

Rapidly evolving RNA viruses, such as the GII.4 strain of human norovirus (HuNoV), and their vaccines elicit complex serological responses associated with previous exposure. Specific correlates of protection, moreover, remain poorly understood. Here, we report the GII.4-serological antibody repertoire-pre- and post-vaccination-and select several antibody clonotypes for epitope and structural analysis. The humoral response was dominated by GII.4-specific antibodies that blocked ancestral strains or by antibodies that bound to divergent genotypes and did not block viral-entry-ligand interactions. However, one antibody, A1431, showed broad blockade toward tested GII.4 strains and neutralized the pandemic GII.P16-GII.4 Sydney strain. Structural mapping revealed conserved epitopes, which were occluded on the virion or partially exposed, allowing for broad blockade with neutralizing activity. Overall, our results provide high-resolution molecular information on humoral immune responses after HuNoV vaccination and demonstrate that infection-derived and vaccine-elicited antibodies can exhibit broad blockade and neutralization against this prevalent human pathogen.

Background: Human noroviruses are the leading cause of acute gastroenteritis. Strains of the GII.4 genotype cause pandemic waves associated with viral evolution and subsequent antigenic drift and ligand binding modulation. In November 2015, a novel GII.4 Sydney recombinant variant (GII.P16-GII.4 Sydney) emerged and replaced GII.Pe-GII.4 Sydney as the predominant cause of acute gastroenteritis in the 2016-2017 season in the United States. Methods: Virus-like particles of GII.4 2012 and GII.4 2015 were compared for ligand binding and antibody reactivity using a surrogate neutralization assay. Results: Residue changes in the capsid between GII.4 2012 and GII.4 2015 decreased potency of human polyclonal sera and monoclonal antibodies. Change in epitope A resulted in complete loss of reactivity of a class of blockade antibodies and reduction of a second class. Epitope D changes modulated monoclonal antibody potency and ligand binding patterns. Conclusions: Substitutions in blockade antibody epitopes between GII.4 2012 and GII.4 2015 impacted antigenicity and ligand binding properties. Although the impact of polymerases on fitness remains uncertain, antigenic variation resulting in decreased potency of antibodies to epitope A coupled with altered ligand binding, likely contributed significantly to the spread of GII.4 2015 and replacement of GII.4 2012 as the predominant norovirus outbreak strain.

INTRODUCTION: One of six priorities of CDC's National Comprehensive Cancer Control Program (NCCCP) is to address the needs of cancer survivors within the local population served by individually funded states, tribes, and territories. This report examines cancer survivorship activities implemented in five NCCCP grantees, which have initiated evidence-based activities outlined in A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies (NAP). METHODS: NCCCP action plans, submitted annually to CDC, from 2010 to 2014 were reviewed in February 2015 to assess implementation of cancer survivorship activities and recommended strategies consistent with the NAP. Four state-level and one tribal grantee with specific activities related to one of each of the four NAP strategies were chosen for inclusion. Brief case reports describing the initiation and impact of implemented activities were developed in collaboration with each grantee program director. RESULTS: New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band of Lake Superior Chippewa programs each implemented activities in surveillance and applied research; communication, education, and training; programs, policies, and infrastructure; and access to quality care and services. CONCLUSIONS: This report provides examples for incorporating cancer survivorship activities within Comprehensive Cancer Control programs of various sizes, demographic makeup, and resource capacity. New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band developed creative cancer survivorship activities that meet CDC recommendations. NCCCP grantees can follow these examples by implementing evidence-based survivorship interventions that meet the needs of their specific populations.