Powassan virus (POWV) and Eastern equine encephalitis virus (EEEV) are regionally endemic arboviruses in the United States that can cause neuroinvasive disease and death. Recent identification of EEEV transmission through organ transplantation and POWV transmission through blood transfusion have increased concerns about infection risk. After historically high numbers of cases of both viruses were reported in 2019, we conducted a seroprevalence survey using blood donation samples from selected endemic counties. Specimens were screened for virus-specific neutralizing antibodies, and population seroprevalence was estimated using weights calibrated to county population census data. For POWV, median county seroprevalence in 4 states was 0.84%, ranging from 0% (95% CI 0%-2.28%) to 11.5% (95% CI 0.82%-40.9%). EEEV infection was identified in a single county (estimated seroprevalence 1.62% [95% CI 0.04%-8.75%]). Although seroprevalence estimates in sampled areas were generally low, additional investigation of higher-prevalence areas could inform risk for transmission from asymptomatic blood and organ donors.

Social science research on polio has been centred in the global south, where countries that remain endemic or vulnerable to outbreaks are located. However, closely-related strains of poliovirus were detected in the sewage systems of several New York State counties and London boroughs in 2022. These detections constituted the first encounters with polio in the United States and United Kingdom for a generation - for both public health agencies and publics alike. This paper takes the transnational spread of poliovirus in 2022 as an opportunity to critique how public health memories of twentieth-century polio epidemics were mobilised to encourage vaccine uptake among groups considered vulnerable to transmission, notably Orthodox Jewish families. The study integrates data collected in London and New York as part of academic engagement with health protection responses to the spread of polio. Methods in both settings involved ethnographic research, and a total of 59 in-depth semi-structured interviews with public health professionals, healthcare providers, and Orthodox Jewish community partners and residents. Analysis of results demonstrate that narratives of epidemiological progress were deployed in public health responses in London and New York, often through references to sugar cubes, iron lungs, and timelines that narrate the impact of routine childhood immunisations. While memories of polio were deployed in both settings to provoke an urgency to vaccinate, vulnerable publics instead considered the more recent legacy of the COVID-19 pandemic when deciding whether to trust recommendations and responses. Critical attention to memory places analysis on the divergences between institutional (public health agencies) and peopled (publics) responses to disease events. Responses to re-emerging infectious disease outbreaks engender a temporal dissonance when historical narratives are evoked in ways that contrast with the contemporary dilemmas of people and parents.

California serogroup viruses (CSGVs) of medical importance in the United States include La Crosse virus, Jamestown Canyon virus (JCV), California encephalitis virus, and snowshoe hare virus. Current diagnosis of CSGVs relies heavily on serologic techniques for detecting immunoglobulin M (IgM), an indication of a recent CSGV infection. However, human-positive control sera reactive to viruses in the serogroup are scarce because detection of recent infections is rare. Here, we describe the development of new murine monoclonal antibodies (MAbs) reactive to CSGVs and the engineering of a human-murine chimeric antibody by combining the variable regions of the broadly CSGV cross-reactive murine MAb, 3-3B6/2-3B2 and the constant region of the human IgM. MAb 3-3B6/2-3B2 recognizes a tertiary epitope on the Gn/Gc heterodimer, and epitopes important in JCV neutralization were mapped to the Gc glycoprotein. This engineered human IgM constitutively expressed in a HEK-293 stable cell line can replace human-positive control sera in diagnostic serological techniques such as IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Compared to the parent murine MAbs, the human-chimeric IgM antibody had identical serological activity to CSGVs in ELISA and demonstrated equivalent reactivity compared to human immune sera in the MAC-ELISA.IMPORTANCEOrthobunyaviruses in the California serogroup cause severe neurological disease in children and adults. While these viruses are known to circulate widely in North America, their occurrence is rare. Serological testing for CSGVs is hindered by the limited availability and volumes of human-positive specimens needed as controls in serologic assays. Here, we described the development of a murine monoclonal antibody cross-reactive to CSGVs engineered to contain the variable regions of the murine antibody on the backbone of human IgM. The chimeric IgM produced from the stably expressing HEK293 cell line was evaluated for use as a surrogate human-positive control in a serologic diagnostic test.

Dengue viruses (DENV) and Zika virus (ZIKV) are related mosquito-borne flaviviruses with similar disease manifestations, vector ecology and geographic range. The ability to differentiate these viruses serologically is vital due to the teratogenic nature of ZIKV and the potential confounding of pre-existing cross-reactive anti-DENV antibodies. Here we illustrate the kinetics of the IgM neutralizing antibody (NAb) response using longitudinal samples ranging from acute ZIKV infection to late convalescence from individuals with evidence of prior DENV infection. By serially depleting antibody isotypes prior to neutralization assay, we determined that IgM contributes predominantly to ZIKV neutralization, and it is less cross-reactive than the IgG NAb. The IgM NAb peaked around 14 days (95% CI: 13-15) with a median duration of 257 days (95% CI: 133-427). These results demonstrate the persistence of IgM NAb after ZIKV infections and imply its potential role in diagnosis, vaccine evaluation, serosurveillance, and research of flaviviral-host interactions.

Salutogenic effects of living near aquatic areas (blue space) remain underexplored, particularly in non-coastal and non-urban areas. We evaluated associations of residential proximity to inland freshwater blue space with new onset type 2 diabetes (T2D) in central and northeast Pennsylvania, USA, using medical records to conduct a nested case-control study. T2D cases (n = 15,888) were identified from diabetes diagnoses, medication orders, and laboratory test results and frequency-matched on age, sex, and encounter year to diabetes-free controls (n = 79,435). We calculated distance from individual residences to the nearest lake, river, tributary, or large stream, and residence within the 100-year floodplain. Logistic regression models adjusted for community socioeconomic deprivation and other confounding variables and stratified by community type (townships [rural/suburban], boroughs [small towns], city census tracts). Compared to individuals living ≥ 1.25 miles from blue space, those within 0.25 miles had 8% and 17% higher odds of T2D onset in townships and boroughs, respectively. Among city residents, T2D odds were 38–39% higher for those living 0.25 to < 0.75 miles from blue space. Residing within the floodplain was associated with 16% and 14% higher T2D odds in townships and boroughs. A post-hoc analysis demonstrated patterns of lower residential property values with nearer distance to the region's predominant waterbody, suggesting unmeasured confounding by socioeconomic disadvantage. This may explain our unexpected findings of higher T2D odds with closer proximity to blue space. Our findings highlight the importance of historic and economic context and interrelated factors such as flood risk and lack of waterfront development in blue space research.

Greenness may impact blood pressure (BP), though evidence is limited among individuals with type 2 diabetes (T2D), for whom BP management is critical. We evaluated associations of residential greenness with BP among individuals with T2D in geographically diverse communities in Pennsylvania. To address variation in greenness type, we evaluated modification of associations by percent forest. We obtained systolic (SBP) and diastolic (DBP) BP measurements from medical records of 9593 individuals following diabetes diagnosis. Proximate greenness was estimated within 1250-m buffers surrounding individuals' residences using the normalized difference vegetation index (NDVI) prior to blood pressure measurement. Percent forest was calculated using the U.S. National Land Cover Database. Linear mixed models with robust standard errors accounted for spatial clustering; models were stratified by community type (townships/boroughs/cities). In townships, the greenest communities, an interquartile range increase in NDVI was associated with reductions in SBP of 0.87 mmHg (95% CI: -1.43, -0.30) and in DBP of 0.41 mmHg (95% CI: -0.78, -0.05). No significant associations were observed in boroughs or cities. Evidence for modification by percent forest was weak. Findings suggest a threshold effect whereby high greenness may be necessary to influence BP in this population and support a slight beneficial impact of greenness on cardiovascular disease risk.

OBJECTIVES: To evaluate associations of community types and features with new onset type 2 diabetes in diverse communities. Understanding the location and scale of geographic disparities can lead to community-level interventions. DESIGN: Nested case-control study within the open dynamic cohort of health system patients. SETTING: Large, integrated health system in 37 counties in central and northeastern Pennsylvania, USA. PARTICIPANTS AND ANALYSIS: We used electronic health records to identify persons with new-onset type 2 diabetes from 2008 to 2016 (n=15 888). Persons with diabetes were age, sex and year matched (1:5) to persons without diabetes (n=79 435). We used generalised estimating equations to control for individual-level confounding variables, accounting for clustering of persons within communities. Communities were defined as (1) townships, boroughs and city census tracts; (2) urbanised area (large metro), urban cluster (small cities and towns) and rural; (3) combination of the first two; and (4) county. Community socioeconomic deprivation and greenness were evaluated alone and in models stratified by community types. RESULTS: Borough and city census tract residence (vs townships) were associated (OR (95% CI)) with higher odds of type 2 diabetes (1.10 (1.04 to 1.16) and 1.34 (1.25 to 1.44), respectively). Urbanised areas (vs rural) also had increased odds of type 2 diabetes (1.14 (1.08 to 1.21)). In the combined definition, the strongest associations (vs townships in rural areas) were city census tracts in urban clusters (1.41 (1.22 to 1.62)) and city census tracts in urbanised areas (1.33 (1.22 to 1.45)). Higher community socioeconomic deprivation and lower greenness were each associated with increased odds. CONCLUSIONS: Urban residence was associated with higher odds of type 2 diabetes than for other areas. Higher community socioeconomic deprivation in city census tracts and lower greenness in all community types were also associated with type 2 diabetes.

In response to the 2016 global public health emergency of international concern announced by the World Health Organization surrounding Zika virus (ZIKV) outbreaks, we developed a purified inactivated Zika virus vaccine (PIZV) candidate from ZIKV strain PRVABC59, isolated during the outbreak in 2015. The virus isolate was plaque purified, creating six sub-isolated virus stocks, two of which were selected to generate PIZV candidates for preclinical immunogenicity and efficacy evaluation in mice. The alum-adjuvanted PIZV candidates were highly immunogenic in both CD-1 and AG129 mice after a 2-dose immunization. Further, AG129 mice receiving 2 doses of PIZV formulated with alum were fully protected against lethal ZIKV challenge and mouse immune sera elicited by the PIZV candidates were capable of neutralizing ZIKVs of both African and Asian genetic lineages in vitro. Additionally, passive immunization of naive mice with ZIKV-immune serum showed strong positive correlation between neutralizing ZIKV antibody (NAb) titers and protection against lethal challenge. This study supported advancement of the PIZV candidate toward clinical development.

Zika virus (ZIKV) has emerged as a major global public health concern due to its link as a causative agent of human birth defects. Laboratory diagnosis of suspected ZIKV infections by serological testing of specimens collected a week or more after symptom onset primarily relies on detection of anti-ZIKV-specific IgM antibodies by enzyme-linked immunosorbent assay coupled with detection of ZIKV-specific neutralizing antibody by neutralization tests. A definitive diagnosis based on serological assays is possible during primary ZIKV infections; however, due to the cross-reactivity of antibodies elicited during flaviviral infections, a definitive diagnosis is not always possible, especially among individuals who have previously been exposed to closely related flaviviruses, such as dengue virus (DENV). Here, we investigated the neutralizing IgM antibody profiles of 33 diagnostic specimens collected from individuals with suspected primary and secondary flaviviral infections acquired when visiting areas experiencing active ZIKV transmission in 2015 and 2016. Specimens collected between 1 day and 3 months postexposure were tested for ZIKV and dengue virus type 1 (DENV1) and type 2 (DENV2) by the plaque reduction neutralization test (PRNT) before and after IgG depletion. We found that IgG depletion prior to neutralization testing had little effect in differentiating samples from individuals with secondary infections taken less than 3 weeks postexposure; however, IgG depletion significantly reduced the cross-reactive neutralizing antibody titers and increased the percentage of cases discernible by PRNT from 15.4% (95% confidence interval [CI], 4.3 to 42.2%) to 76.9% (95% CI, 49.7 to 91.8%) for samples collected between roughly 3 and 12 weeks postexposure. These results highlight the potential of IgG depletion to improve the specificity of PRNT for better confirmation and differential diagnosis of flavivirus infections.

OBJECTIVES: To evaluate knowledge and prescribing changes following a 2-month public health detailing campaign (one-to-one educational visits) about judicious opioid analgesic prescribing conducted among health care providers in Staten Island, New York City, in 2013. METHODS: Three detailing campaign recommendations were (1) a 3-day supply of opioids is usually sufficient for acute pain, (2) avoid prescribing opioids for chronic noncancer pain, and (3) avoid high-dose opioid prescriptions. Evaluation consisted of a knowledge survey, and assessing prescribing rates and median day supply per prescription. Prescribing data from the 3-month period before the campaign were compared with 2 sequential 3-month periods after the campaign. RESULTS: Among 866 health care providers visited, knowledge increased for all 3 recommendations (P < .01). After the campaign, the overall prescribing rate decreased similarly in Staten Island and other New York City counties (boroughs), but the high-dose prescribing rate decreased more in Staten Island than in other boroughs (P < .01). Median day supply remained stable in Staten Island and increased in other boroughs. CONCLUSIONS: The public health detailing campaign improved knowledge and likely prescribing practices and could be considered by other jurisdictions to promote judicious opioid prescribing.

From 2000 to 2011, the rate of unintentional drug poisoning (overdose) deaths involving opioid analgesics increased 435% in Staten Island, from 2.0 to 10.7 per 100,000 residents. During 2005-2011, disparities widened between Staten Island and the other four New York City (NYC) boroughs (Bronx, Brooklyn, Manhattan, and Queens); in 2011, the rate in Staten Island was 3.0-4.5 times higher than in the other boroughs. In response, the NYC Department of Health and Mental Hygiene (DOHMH) implemented a comprehensive five-part public health strategy, with both citywide and Staten Island-targeted efforts: 1) citywide opioid prescribing guidelines, 2) a data brief for local media highlighting Staten Island mortality and prescribing data, 3) Staten Island town hall meetings convened by the NYC commissioner of health and meetings with Staten Island stakeholders, 4) a Staten Island campaign to promote prescribing guidelines, and 5) citywide airing of public service announcements with additional airing in Staten Island. Concurrently, the New York state legislature enacted the Internet System for Tracking Over-Prescribing (I-STOP), a law requiring prescribers to review the state prescription monitoring system before prescribing controlled substances. This report describes a 29% decline in the opioid analgesic-involved overdose death rate in Staten Island from 2011 to 2013, while the rate did not change in the other four NYC boroughs, and compares opioid analgesic prescribing data for Staten Island with data for the other boroughs. Targeted public health interventions might be effective in lowering opioid analgesic-involved overdose mortality rates.

BACKGROUND: Dengue viruses (DENV) infect over 300 million people annually causing 96 million cases of dengue disease and 22,000 deaths. A safe vaccine which protects against DENV disease is a global health priority. METHODS: We enrolled 72 flavivirus-naive healthy adults in a Phase I double-blind randomized placebo-controlled dose escalation trial (low and high dose) of a live attenuated recombinant tetravalent dengue vaccine candidate (TDV) given in two doses 90 days apart. Volunteers were followed for safety, vaccine component viremia, and development of neutralizing antibodies to the four DENV. RESULTS: The majority of adverse events were mild, with no vaccine-related serious adverse events (SAE). Vaccinees reported injection site pain (52% vs. 17%) or erythema (73% vs. 25%) more frequently than placebo recipients. Low levels of TDV-2, -3, and -4 viremia were observed after the first but not second administration. Overall seroconversion rates and geometric mean neutralization titers after two doses were: DENV-1 (84.2%, 54.1), DENV-2 (92.1%, 292.8), DENV-3 (86.8%, 32.3), and DENV-4 (71.1%, 15.0) and>90.0% of high dose recipients had trivalent or broader responses. CONCLUSIONS: TDV was generally well-tolerated, induced trivalent or broader neutralizing antibodies to DENV in most flavivirus-naive vaccinees, and is undergoing further development.

BACKGROUND: Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. METHODS: We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18-45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov, number NCT01224639. FINDINGS: We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. INTERPRETATION: Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. FUNDING: Takeda Vaccines.

OBJECTIVES: Sexually transmitted infections (STIs) are an important cause of morbidity among incarcerated women and female sex workers (FSW). Little is known about FSW incarcerated in New York City (NYC) jails. We reviewed jail health records to identify the STI and HIV prevalence among newly incarcerated FSW in NYC jails. We also examined the relationship of demographics and self-reported clinical and risk behaviour history with FSW status and compared FSW with non-FSW incarcerated women to identify FSW predictors and, guide NYC jail programme planning and policy. METHODS: We retrospectively reviewed routinely collected jail health record data to identify the prevalence of chlamydia (Ct), gonorrhoea (Ng) and HIV infection among women newly incarcerated in NYC jails in 2009-2010 (study period) and studied the relationship of STIs, demographics and self-reported clinical and risk behaviour history with FSW status. RESULTS: During the study period, 10,828 women were newly incarcerated in NYC jails. Of these, 10,115 (93%) women were tested for Ct and Ng; positivity was 6.2% (95% CI 5.7% to 6.7%) and 1.7% (95% CI 1.4% to 1.9%), respectively. Nine percent had HIV infection. Seven hundred (6.5%) were defined as FSW. FSW were more likely to have Ct (adjusted OR (AOR): 1.55; 95% CI 1.17 to 2.05; p<0.0001) but not Ng or HIV. FSW were more likely to report age 20-24 years, reside in boroughs other than Manhattan, ≥6 prior incarcerations, ≥2 incarcerations during the study period, condom use with current sex partners, multiple sex partners and current drug use. CONCLUSIONS: Women incarcerated in NYC jails had high rates of Ct, Ng, and HIV infection. FSW were at higher risk for Ct than non-FSW incarcerated women. These findings are being used to design targeted interventions to identify FSW, provide clinical and preventive services in jail and coordinate care with community partners.

BACKGROUND: We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses. These viruses, containing the pre-membrane (prM) and envelope (E) genes of dengue serotypes 1-4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. METHODOLOGY/PRINCIPAL FINDINGS: After deriving vaccine viruses from RNA-transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai) Aedes aegypti mosquito vectors. CONCLUSION/SIGNIFICANCE: All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia.

Using an infectious cDNA clone we engineered seven mutations in the putative heparan sulfate- and receptor-binding motifs of the envelope protein of dengue virus serotype 2, strain 16681. Four mutant viruses, KK122/123EE, E202K, G304K, and KKK305/307/310EEE, were recovered following transfection of C6/36 cells. A fifth mutant, KK291/295EE, was recovered from C6/36 cells with a compensatory E295V mutation. All mutants grew in and mediated fusion of virus-infected C6/36 cells, but three of the mutants, KK122/123EE, E202K, G304K, did not grow in Vero cells without further modification. Two Vero cell lethal mutants, KK291/295EV and KKK307/307/310EEE, failed to replicate in DC-SIGN-transformed Raji cells and did not react with monoclonal antibodies known to block DENV attachment to Vero cells. Additionally, both mutants were unable to initiate negative-strand vRNA synthesis in Vero cells by 72h post-infection, suggesting that the replication block occurred prior to virus-mediated membrane fusion.

In fall 2009, the New York City Department of Health and Mental Hygiene (DOHMH) operated 58 points of dispensing (PODs) over 5 weekends to provide influenza A (H1N1) 2009 monovalent vaccination to New Yorkers. Up to 7 sites were opened each day across the 5 boroughs, with almost 50,000 New Yorkers being vaccinated. The policies and protocols used were based on those developed for New York City's POD Plan, the cornerstone of the city's mass prophylaxis planning. Before the H1N1 experience, NYC had not opened more than 5 PODs simultaneously and had only experienced the higher patient volume seen with the H1N1 PODs on 1 prior occasion. Therefore, DOHMH identified factors that contributed to the success of POD operations, as well as areas for improvement to inform future mass prophylaxis planning and response. Though this was a relatively small-scale, preplanned operation, during which a maximum of 7 PODs were operated on a given day, the findings have implications for larger-scale mass prophylaxis planning for emergencies.