Transmission Patterns of Norovirus From Infected Children to Household Members in León, Nicaragua.

Norovirus is a common and highly transmissible gastrointestinal pathogen. Among 34 Nicaraguan households with a norovirus-infected child, 48% experienced norovirus transmission within 1 week, infecting 18% of household members; GII norovirus was more commonly transmitted than GI. Pediatric norovirus vaccines could prevent both index cases and transmission to close contacts.

Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States.

BACKGROUND: Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test. METHODS: A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05. RESULTS: At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP. CONCLUSIONS: Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs. IMPACT: Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.

Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021.

Background: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. Methods: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. Results: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. Conclusions: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. Clinical Trials Registration: NCT04811664.

Epidemiology of pediatric astrovirus gastroenteritis in a Nicaraguan birth cohort.

Background: Astrovirus is a leading cause of acute gastroenteritis in children worldwide. However, few prospective studies have analyzed astrovirus in community-dwelling pediatric populations in low-and-middle-income countries. Methods: We assessed the incidence, risk factors, clinical characteristics, genotypes, viral coinfections and seasonality of astrovirus gastroenteritis in 443 healthy Nicaraguan children born in 2017-2018, followed for 36 months. Children were recruited from maternity hospitals and birth records in an economically-diverse neighborhood of León, the second-largest city in Nicaragua. Astrovirus-positive episodes and genotypes were identified from diarrheal specimens with reverse transcription quantitative polymerase chain reaction and Sanger sequencing. Results: Of 1708 total specimens tested, eighty children (18%) experienced at least 1 astrovirus episode, and 9 experienced repeat episodes, mostly during the rainy season (May-October). The incidence of astrovirus episodes was 7.8/100 child-years (95% CI: 6.2, 9.8). Genotype-specific incidence of astrovirus also exhibited seasonality. Median age of astrovirus episode onset was 16 months (IQR 9, 23). Initial astrovirus episodes were not associated with protection against future episodes during the age span studied. Astrovirus cases were exclusively breastfed for a shorter period than uninfected children, and the human milk oligosaccharide lacto-N-fucopentaose-I was more concentrated in mothers of these children. Home toilets appeared to protect against future astrovirus episodes (HR=0.19, 95% CI 0.04-0.91). Human astrovirus-5 episodes, comprising 15% of all typed episodes, were associated with longer diarrhea and more symptomatic rotavirus co-infections. Conclusion: Astrovirus was a common cause of gastroenteritis in this cohort, and future studies should clarify the role of astrovirus genotype in clinical infection severity.

Acceptability and readiness to promote human papillomavirus vaccination at ages 9-10 years: a feasibility study among North Carolina clinics.

While 9-valent human papillomavirus (HPV) vaccination is approved by the US Food and Drug Administration for use in adolescents as young as age 9, providers typically recommend it at ages 11-12. Studies suggest that recommending HPV vaccination at 9 or 10 years of age could increase up-to-date vaccination by age 13, which could especially benefit rural populations with reduced access to primary health care and lower HPV vaccination coverage than urban areas. This study aimed to assess the feasibility of the age-9 recommendation of HPV vaccination in rural clinics. We conducted in-depth interviews with providers and staff from two primary care clinics in central North Carolina to understand attitudes toward recommending HPV vaccination to 9- and 10-year-olds. All interviewees agreed that HPV vaccination was important for cancer prevention and should be recommended before the onset of sexual activity, agreeing that HPV vaccination could be initiated before age 11 to improve timeliness and completion of the vaccination series. However, opinions were mixed on whether HPV vaccination should be initiated as young as 9 years old. Two key informants recruited from two university-affiliated clinics described their experiences recommending HPV vaccination to 9- and 10-year-olds, including a modified vaccination schedule that promotes HPV vaccination during routine well-child visits, prior to pubertal onset, and alongside other recommended adolescent vaccines. Age-9 recommendation and administration of HPV vaccination is possible with minimal changes to current clinical practices and could increase the convenience and acceptability of HPV vaccination in under-vaccinated settings.

Nonsecretor Phenotype Is Associated With Less Risk of Rotavirus-Associated Acute Gastroenteritis in a Vaccinated Nicaraguan Birth Cohort.

BACKGROUND: Histo-blood group antigens (HBGAs) have been associated with rotavirus vaccine take; but the effect of these HBGAs on rotavirus incidence and risk remains poorly explored in vaccinated populations. METHODS: Rotavirus-associated acute gastroenteritis (AGE) was assessed in 444 Nicaraguan children followed from birth until 3 years of age. AGE episodes were tested for rotavirus by reverse-transcription quantitative polymerase chain reaction, and saliva or blood was used to determine HBGA phenotypes. Cox proportional hazards models were used to estimate the relative hazard of rotavirus AGE by HBGA phenotypes. RESULTS: Rotavirus was detected in 109 (7%) stool samples from 1689 AGE episodes over 36 months of observation between June 2017 and July 2021. Forty-six samples were successfully genotyped. Of these, 15 (35%) were rotavirus vaccine strain G1P[8], followed by G8P[8] or G8P[nt] (11 [24%]) and equine-like G3P[8] (11 [24%]). The overall incidence of rotavirus-associated AGE was 9.2 per 100 child-years, and was significantly higher in secretor than nonsecretor children (9.8 vs 3.5/100 child-years, P = .002). CONCLUSIONS: The nonsecretor phenotype was associated with decreased risk of clinical rotavirus vaccine failure in a vaccinated Nicaraguan birth cohort. These results show the importance of secretor status on rotavirus risk, even in vaccinated children.

Neural tube defects: Prevalence, mortality, and maternal characteristics in two departmental hospitals in the northwestern region of Nicaragua, 2006-2018.

BACKGROUND: Congenital anomalies are the fifth most common cause of neonatal mortality in Nicaragua, and neural tube defects (NTDs) are the most common of all cases of lethality associated with a birth defect. Prevalence and mortality estimates are needed to propose effective intervention strategies that prevent NTDs over time. METHODS: A cross-sectional study was carried out in northwestern Nicaragua from January 2006 to December 2018. All cases of NTDs (anencephaly, spina bifida, and encephalocele) were registered in hospital surveillance systems, and the medical histories of the mothers and newborns were reviewed. Prevalence was calculated by considering the number of live births and stillbirths older than 20 weeks of gestation with NTDs, divided by the total number of live births and stillbirths in each study year. Neonatal mortality rate (NMR) for NTD, and case fatality for spina bifida was calculated. RESULTS: Two hundred fifty cases of NTDs were identified from 178,498 deliveries (177,316 live births and 1,182 stillbirths). The prevalence of NTDs during this time period was 14.01 (95% CI: 12.27-15.74) per 10,000 births. The prevalence of spina bifida (n = 140), anencephaly (n = 97), and encephalocele (n = 13) was 7.84, (95% CI: 6.54-9.14), 5.43 (95% CI: 4.30-6.45), and 0.73 (95% CI: 0.33-1.12) per 10,000 births, respectively. Mothers with fetus or newborns affected with NTDs did not use folic acid prior to conception, and 11% experienced periods of hyperthermia during the first trimester of pregnancy. NMR for NTDs was 0.55 per 1.000 livebirths. Case fatality for all NTDs and for spina bifida were 55% and 18%, respectively. CONCLUSION: The prevalence and mortality of NTDs in the northwestern region of Nicaragua present peaks and troughs during the study period. Spina bifida was the most frequent type of NTD. We believe that these findings could be of use by health policy makers to strengthen the primary prevention of NTDs in the region through the monitoring of the food fortification policy and folic acid supplementation to women of childbearing age. Additional etiologic studies of NTDs should be considered to identify additional prevention measures.

Patterns of use of recombinant zoster vaccine among commercially-insured immunocompetent and immunocompromised adults 50-64 years old in the United States.

PURPOSE: The Centers for Disease Control and Prevention (CDC) recommends recombinant zoster vaccination (RZV) for adults ≥ 50 years to prevent herpes zoster (HZ) and its sequelae. Initially, no distinct recommendation was made for immunocompromised adults, who experience higher HZ rates and more severe outcomes. We characterized receipt of first RZV dose (initiation) and both doses (completion) over time, and the impact of immune function on RZV uptake among adults aged 50-64 years in the United States. METHODS: We identified RZV claims from the IBM MarketScan database between 1/1/2018 and 12/31/2019. We characterized immunocompromised enrollees as having malignancy, HIV, solid organ transplant, primary immunosuppression, or medication-induced immunosuppression using inpatient, outpatient, and prescription claims in the 6 months prior to study start. We evaluated patterns of vaccine uptake by demographic and healthcare access characteristics and immune status. RESULTS: The cumulative incidence of RZV initiation during the study period was 10.0%. Incidence increased with age and number of medical office visits, and was higher among women, urban residents, high-deductible insurance beneficiaries, and those who were immunocompromised compared to immunocompetent. Among immunocompromised adults, RZV initiation was highest among those with HIV and primary immunodeficiencies. Of those who initiated RZV, 89.5% received both doses. RZV completion was highest among those who received the first dose at a pharmacy. Most enrollees (88.6%) who completed RZV vaccination did so within the recommended dosing schedule. CONCLUSIONS: RZV uptake was low in the two years since the CDC recommendation, and differed by demographic, healthcare access, and clinical characteristics. Initiation rates were higher among immunocompromised adults compared to immunocompetent adults, despite no CDC recommendation for vaccination in these groups during the study period. The CDC has since recommended RZV for immunocompromised individuals, and our findings may inform efforts to increase RZV uptake in individuals at higher risk of severe disease.

Timing and genotype distribution of symptomatic and asymptomatic sapovirus infections and re-infections in a Nicaraguan birth cohort.

OBJECTIVES: To characterize the timing and genotype distribution of symptomatic and asymptomatic sapovirus infections and re-infections in a Nicaraguan birth cohort. METHODS: Infants (N = 444) were enrolled at 10-14 days of life and observed weekly until 2 years of age. Stool samples were collected for each acute gastroenteritis (AGE) episode, and routine stool samples were collected monthly. Stool samples were tested for sapovirus using RT-qPCR, and positive samples were genotyped. RESULTS: A total of 348 children completed 2 years of AGE weekly surveillance; 93 (26.7%) of them experienced sapovirus AGE. Most infections occurred after 5 months of age and mainly during the second year of life (62.4%, 58/93) and early in the rainy season. Sapovirus screening in all stools from a subset of 67 children who consistently provided samples showed sapovirus infections in 91 of 330 (27.6%) AGE episodes and in 39 of 1350 (2.9%) routine stools. In this subset, the median age at the first sapovirus AGE was 11.2 months (95% CI, 9.3-15.9 months); 38 of 67 (57%) children experienced re-infections, 19 symptomatic and 19 asymptomatic. On average, sapovirus re-infections were reported 7.2 months after symptomatic and 5.3 months after asymptomatic infections. Genogroup GI (64%, 69/108) was the most common detected. Sapovirus GI.1 was more frequently detected in AGE stool samples than in routine stool samples (47.2%, 43/91 vs. 25.6%, 10/39; p 0.005), and re-infection with the same genotype was uncommon. DISCUSSION: The first sapovirus infections occurred at approximately 11 months of age, whereas the median time to symptomatic re-infection was 7.2 months. Re-infections with the same sapovirus genotype were rare during 2 years of life suggesting genotype-specific protection after natural infection.

Preexisting Heterotypic Ligand-blocking Antibody Does Not Protect Against Genogroup II Norovirus Episodes in Young Children.

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.

Breadth and Dynamics of Human Norovirus-Specific Antibodies in the First Year of Life.

We measured antibody binding to diverse norovirus virus-like particles over 12 months in 16 children. All had maternal antibodies at 2 months, with estimated lowest levels at 5 months of age. Antibody increases after 3 months suggested natural infections. This information could guide the timing of future norovirus vaccines.

First Episodes of Norovirus and Sapovirus Gastroenteritis Protect Against Subsequent Episodes in a Nicaraguan Birth Cohort.

BACKGROUND: Norovirus and sapovirus cause a large burden of acute gastroenteritis (AGE) in young children. We assessed protection conferred by norovirus and sapovirus AGE episodes against future episodes. METHODS: Between June 2017 and July 2018, we recruited 444 newborns in León, Nicaragua. Weekly household surveys identified AGE episodes over 36 months, and AGE stools were tested by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) for norovirus genogroup (G)I/GII and sapovirus. We used recurrent-event Cox models and negative control methods to estimate protection conferred by first episodes, controlling for observed and unobserved risk factors, respectively. RESULTS: Sapovirus episodes conferred a 69% reduced hazard of subsequent episodes using the negative control method. Norovirus GI (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.31, 1.3) and GII (HR = 0.20; 95% CI = 0.04, 0.44) episodes also appeared highly protective. Protection against norovirus GII was enhanced following two episodes. CONCLUSIONS: Evidence of natural immunity in early childhood provides optimism for the future success of pediatric norovirus and sapovirus vaccines.

Rectovaginal Colonization with Serotypes of Group B Streptococci with Reduced Penicillin Susceptibility among Pregnant Women in León, Nicaragua.

Group B Streptococci (GBS) are important causes of neonatal sepsis and meningitis globally. To elucidate the potential benefits of maternal GBS vaccines, data is needed on the epidemiology of maternal GBS rectovaginal colonization, distribution of serotypes, and resistance to intrapartum antibiotic prophylaxis (IAP). We collected rectal and vaginal samples from 305 pregnant women in León, Nicaragua between 35 and 40 weeks gestation. Samples were cultured for GBS and confirmed using latex agglutination. GBS isolates underwent serotyping by quantitative polymerase chain reaction, and antimicrobial susceptibility testing by disk diffusion and microdilution following Clinical Laboratory Standard Institute guidelines. Sixty-three women (20.7%) were colonized with GBS in either the rectum or the vagina. Of 91 GBS isolates collected from positive cultures, most were serotypes II (28.6%), Ia (27.5%), and III (20.9%). Most GBS isolates (52.9%) were resistant to penicillin, the first-line prophylactic antibiotic. Penicillin resistance was highly correlated with resistance to vancomycin, ceftriaxone, and meropenem. The results of our study suggest that one-fifth of pregnant women in the urban area of León, Nicaragua are colonized with GBS and risk transmitting GBS to their offspring during labor. High resistance to commonly available antibiotics in the region suggests that prophylactic maternal GBS vaccination would be an effective alternative to IAP.

SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people.

Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals.

Testing for Sexually Transmitted Infection Using Wet and Dry Self-Collected Brush Samples Among Women in Mombasa, Kenya.

ABSTRACT: We compared detection of Chlamydia trachomatis , Neisseria gonorrhoeae , and Trichomonas vaginalis using dry and wet self-collected samples using brushes among females who engage in sex work in Mombasa, Kenya. Detection of T. vaginalis and N. gonorrhoeae in dry and wet samples was similar, but C. trachomatis detection in dry samples appeared lower.

Students with global experiences during medical school are more likely to work in settings that focus on the underserved: an observational study from a public U.S. institution.

BACKGROUND: Global health interest has grown among medical students over the past 20 years, and most medical schools offer global health opportunities. Studies suggest that completing global health electives during medical school may increase the likelihood of working with underserved populations in a clinical or research capacity. This study aimed to assess the association of global electives in medical school on subsequently working in global health and with underserved populations in the United States (U.S.), additionally considering students' interests and experiences prior to medical school. We also examined whether respondents perceived benefits gained from global electives. METHODS: We surveyed medical school graduates (classes of 2011-2015) from a large public medical school in the U.S. to describe current practice settings and previous global health experience. We evaluated work, volunteer, and educational experiences preceding medical school, socioeconomic status, race and ethnicity using American Medical College Application Service (AMCAS) data. We assessed the association between students' backgrounds, completing global health electives in medical school and current work in global health or with underserved populations in the U.S. RESULTS: In the 5 to 8 years post-graduation, 78% of 161 respondents reported work, research, or teaching with a focus on global or underserved U.S. POPULATIONS: Completing a global health elective during medical school (p = 0.0002) or during residency (p = 0.06) were positively associated with currently working with underserved populations in the U.S. and pre-medical school experiences were marginally associated (p = 0.1). Adjusting for pre-medical school experiences, completing a global health elective during medical school was associated with a 22% greater prevalence of working with an underserved population. Perceived benefits from global electives included improved cultural awareness, language skills, public health and research skills, and ability to practice in technology-limited settings. CONCLUSION: Medical school graduates who participated in global electives as students were more likely than their peers to pursue careers with underserved populations, independent of experiences prior to medical school. We hypothesize that by offering global health experiences, medical schools can enhance the interests and skills of graduates that will make them more likely and better prepared to work with underserved populations in the U.S. and abroad.

Health Care Provider Perceptions of Facilitators and Barriers to Human Papillomavirus Vaccination Delivery in Five Countries.

BACKGROUND: National human papillomavirus (HPV) vaccination programs could reduce global cervical cancer morbidity and mortality with support from health care providers. We assessed providers' perceptions of HPV vaccination in 5 countries. METHODS: We identified providers from 5 countries where national HPV vaccination programs were at various stages of implementation: Argentina, Malaysia, South Africa, South Korea, and Spain. Providers authorized to administer adolescent vaccines completed an in-depth survey, reporting perceptions of barriers and facilitators to initiating and completing HPV vaccination, and logistical challenges to HPV vaccination. RESULTS: Among 151 providers, common barriers to HPV vaccination initiation across all countries were parents' lack of awareness (39%), concerns about vaccine safety or efficacy (33%), and cost to patients (30%). Vaccination education campaign (70%) was the most commonly cited facilitator of HPV vaccination initiation. Common barriers to series completion included no reminder system or dosing schedule (37%), loss to follow-up or forgetting appointment (29%), and cost to patients (25%). Cited facilitators to completing the vaccine series were education campaigns (45%), affordable vaccination (32%), and reminder/recall systems (22%). Among all countries, high cost of vaccination was the most common logistical challenge to offering vaccination to adolescents (33%). CONCLUSIONS: Incorporating provider insights into future HPV vaccination programs could accelerate vaccine delivery to increase HPV vaccination rates globally.