An Industry Proposal for a Cell and Gene Therapy Safety Data Sheet.

Introduction: A safety data sheet (SDS) is an established hazard communication tool for chemicals, for which no comparable document exists in the biotherapeutics industry. As the cell and gene therapy (CGT) field expands, industry leaders have identified a growing need to address this gap in communication of the unique occupational health and safety risks posed by CGT materials and products. Methods: Following the sections of a traditional chemical SDS, information was modified by industry subject matter experts, relevant to CGT biological materials. This guide was developed based on assumptions of a maximum biosafety level 2, and any chemical components present in the material were excluded from the hazard classification. Results: The guide contains necessary information to conduct a workplace risk assessment and communicate the unique workplace hazards posed by potential exposures to the material. The target audience is intended to be entities handling and producing these materials, plus collaborators, contractors, or operations sites receiving and handling the CGT material. An example of a CGT SDS is provided in Table 1. Discussion: The CGT SDS provides industry with a best practice to address an existing gap in hazard communication for CGT. We expect that, as the field evolves, so may the contents. The CGT SDS can be used as a reference for other biological modalities in the field. Conclusions: This initial CGT SDS communicates workplace hazards and assesses the unique risks posed by these biological materials and can assist in creating exposure control plans specific to the workplace hazards.

Analysis of Zika Virus Sequence Data Associated with a School Cohort in Haiti.

Zika virus (ZIKV) infections occurred in epidemic form in the Americas in 2014-2016, with some of the earliest isolates in the region coming from Haiti. We isolated ZIKV from 20 children with acute undifferentiated febrile illness who were part of a cohort of children seen at a school clinic in the Gressier region of Haiti. The virus was also isolated from three pools of Aedes aegypti mosquitoes collected at the same location. On phylogenetic analysis, three distinct ZIKV clades were identified. Strains from all three clades were present in Haiti in 2014, making them among the earliest isolates identified in the Western Hemisphere. Strains from all three clades were also isolated in 2016, indicative of their persistence across the time period of the epidemic. Mosquito isolates were collected in 2016 and included representatives from two of the three clades; in one instance, ZIKV was isolated from a pool of male mosquitoes, suggestive of vertical transmission of the virus. The identification of multiple ZIKV clades in Haiti at the beginning of the epidemic suggests that Haiti served as a nidus for transmission within the Caribbean.

Isolation of a Novel Recombinant Canine Coronavirus From a Visitor to Haiti: Further Evidence of Transmission of Coronaviruses of Zoonotic Origin to Humans.

We isolated a novel coronavirus from a medical team member presenting with fever and malaise after travel to Haiti. The virus showed 99.4% similarity with a recombinant canine coronavirus recently identified in a pneumonia patient in Malaysia, suggesting that infection with this virus and/or recombinant variants occurs in multiple locations.

Independent infections of porcine deltacoronavirus among Haitian children.

Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, the emergence of coronavirus in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae, human infections reported so far have been limited to alphacoronaviruses and betacoronaviruses3-5. Here we identify porcine deltacoronavirus strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the genes encoding Nsp15 and the spike glycoprotein. In particular, structural analysis predicts that one of the changes in the spike S1 subunit, which contains the receptor-binding domain, may affect the flexibility of the protein and its binding to the host cell receptor. Our findings highlight the potential for evolutionary change and adaptation leading to human infections by coronaviruses outside of the previously recognized human-associated coronavirus groups, particularly in settings where there may be close human-animal contact.

Orthobunyaviruses in the Caribbean: Melao and Oropouche virus infections in school children in Haiti in 2014.

We report the identification of two orthobunyaviruses, Melao virus (MELV) and Oropouche virus (OROV), in plasma specimens from Haitian children with acute febrile illness who presented during outbreaks caused by alpha- and flaviviruses in 2014. Heretofore not described as a human pathogen, MELV was isolated in cell culture from the plasma of five case patients. OROV RNA was detected in the plasma of an additional child, using an unbiased sequencing approach, with phylogenetic inference suggesting a close relationship with strains from Brazil. Abdominal pain was reported by four case patients with MELV infections, with lymphadenopathy noted in two cases. Our findings document the occurrence of these orthobunyaviruses within the Caribbean region and highlight the critical importance of surveillance with viral genome sequence analyses to identify outbreaks caused by these and other emerging viruses.

Emergence of porcine delta-coronavirus pathogenic infections among children in Haiti through independent zoonoses and convergent evolution.

Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, coronavirus emergence in our species has been associated with zoonotic transmissions from animal reservoirs 1,2 , underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae - Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gammacoronavirus , - human infections reported to date have been limited to alpha- and betacoronaviruses 3 . We identify, for the first time, porcine deltacoronavirus (PDCoV) strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the nsp15 and the spike glycoprotein genes by convergent evolution. In particular, structural analysis predicts that one of the changes in the Spike S1 subunit, which contains the receptor-binding domain, may affect protein's flexibility and binding to the host cell receptor. Our findings not only underscore the ability of deltacoronaviruses to adapt and potentially lead to human-to-human transmission, but also raise questions about the role of such transmissions in development of pre-existing immunity to other coronaviruses, such as SARS-CoV-2.

Emergence of Madariaga virus as a cause of acute febrile illness in children, Haiti, 2015-2016.

Madariaga virus (MADV), also known as South American eastern equine encephalitis virus, has been identified in animals and humans in South and Central America, but not previously in Hispaniola or the northern Caribbean. MADV was isolated from virus cultures of plasma from an 8-year-old child in a school cohort in the Gressier/Leogane region of Haiti, who was seen in April, 2015, with acute febrile illness (AFI). The virus was subsequently cultured from an additional seven AFI case patients from this same cohort in February, April, and May 2016. Symptoms most closely resembled those seen with confirmed dengue virus infection. Sequence data were available for four isolates: all were within the same clade, with phylogenetic and molecular clock data suggesting recent introduction of the virus into Haiti from Panama sometime in the period from October 2012-January 2015. Our data document the movement of MADV into Haiti, and raise questions about the potential for further spread in the Caribbean or North America.

Keystone Virus Isolated From a Florida Teenager With Rash and Subjective Fever: Another Endemic Arbovirus in the Southeastern United States?

Keystone virus, a California-serogroup orthobunyavirus, was first isolated in 1964 from mosquitoes in Keystone, Florida. There were no prior reports of isolation from humans, despite studies suggesting that ~20% of persons living in the region are seropositive. We report virus isolation from a Florida teenager with a rash and fever.

Clinical and Epidemiologic Patterns of Chikungunya Virus Infection and Coincident Arboviral Disease in a School Cohort in Haiti, 2014-2015.

BACKGROUND: Beginning in December 2013, an epidemic of chikungunya virus (CHIKV) infection spread across the Caribbean and into virtually all countries in the Western hemisphere, with >2.4 million cases reported through the end of 2017. METHODS: We monitored a cohort of school children in rural Haiti from May 2014, through February 2015, for occurrence of acute undifferentiated febrile illness, with clinical and laboratory data available for 252 illness episodes. RESULTS: Our findings document passage of the major CHIKV epidemic between May and July 2014, with 82 laboratory-confirmed cases. Subsequent peaks of febrile illness were found to incorporate smaller outbreaks of dengue virus serotypes 1 and 4 and Zika virus, with identification of additional infections with Mayaro virus, enterovirus D68, and coronavirus NL63. CHIKV and dengue virus serotype 1 infections were more common in older children, with a complaint of arthralgia serving as a significant predictor for infection with CHIKV (odds ratio, 16.2; 95% confidence interval, 8.0-34.4; positive predictive value, 66%; negative predictive value, 80%). CONCLUSIONS: Viral/arboviral infections were characterized by a pattern of recurrent outbreaks and case clusters, with the CHIKV epidemic representing just one of several arboviral agents moving through the population. Although clinical presentations of these agents are similar, arthralgias are highly suggestive of CHIKV infection.

Spondweni Virus in Field-Caught Culex quinquefasciatus Mosquitoes, Haiti, 2016.

Spondweni virus (SPONV) and Zika virus cause similar diseases in humans. We detected SPONV outside of Africa from a pool of Culex mosquitoes collected in Haiti in 2016. This finding raises questions about the role of SPONV as a human pathogen in Haiti and other Caribbean countries.

Detection and phylogenetic characterization of arbovirus dual-infections among persons during a chikungunya fever outbreak, Haiti 2014.

In the context of recent arbovirus epidemics, questions about the frequency of simultaneous infection of patients with different arbovirus species have been raised. In 2014, a major Chikungunya virus (CHIKV) epidemic impacted the Caribbean and South America. As part of ongoing screening of schoolchildren presenting with acute undifferentiated febrile illness in rural Haiti, we used RT-PCR to identify CHIKV infections in 82 of 100 children with this diagnosis during May-August 2014. Among these, eight were infected with a second arbovirus: six with Zika virus (ZIKV), one with Dengue virus serotype 2, and one with Mayaro virus (MAYV). These dual infections were only detected following culture of the specimen, suggesting low viral loads of the co-infecting species. Phylogenetic analyses indicated that the ZIKV and MAYV strains differ from those detected later in 2014 and 2015, respectively. Moreover, CHIKV and ZIKV strains from co-infected patients clustered monophyletically in their respective phylogeny, and clock calibration traced back the common ancestor of each clade to an overlapping timeframe of introduction of these arboviruses onto the island.

Madariaga Virus: Identification of a Lineage III Strain in a Venezuelan Child With Acute Undifferentiated Febrile Illness, in the Setting of a Possible Equine Epizootic.

We report identification of Madariaga virus (MADV) in plasma and urine samples from a child with acute undifferentiated febrile illness in Venezuela. Our data document the occurrence of milder MADV infections (ie, without encephalitis), with a symptom complex that resembles that seen with other arboviral infections, including dengue and zika.

Evidence for Mother-to-Child Transmission of Zika Virus Through Breast Milk.

Zikavirus (ZIKV) is an emerging viral pathogen that continues to spread throughout different regions of the world. Herein we report a case that provides further evidence that ZIKV transmission can occur through breastfeeding by providing a detailed clinical, genomic, and virological case-based description.

Complete Genomic Sequence of Dengue Virus Serotype 4 Isolated from Plasma Collected from a Haitian Child in 2014.

While data are limited, there is increasing evidence that infections by dengue viruses are endemic in Haiti. In 2014, an outbreak caused by dengue virus 4 (DENV-4) followed a chikungunya fever outbreak. We present here the complete genome sequence of one isolate grouped within the genotype II South America and Caribbean DENV-4 clades.

Complete Genome Sequence of Dengue virus Type 2 from a Resident of North-Central Florida with Locally Transmitted Dengue Fever.

The majority of dengue fever cases reported in the United States recently have been imported. We isolated dengue virus type 2 (DENV-2) from a North-Central Florida resident with locally acquired dengue fever in May 2016. This is the first evidence of autochthonous transmission of the virus in north-central Florida.

Complete Genome Sequences of Identical Zika virus Isolates in a Nursing Mother and Her Infant.

Complete genome sequences were obtained for Zika viruses isolated from the breast milk of a Venezuelan patient and her child, who was exclusively breastfeeding at the time. These sequences are the first to be reported from a presumptive autochthonous postnatal transmission case from mother to child in Venezuela.

Complete Genome Sequences of Chikungunya Viruses Isolated from Plasma Specimens Collected from Haitians in 2014.

Ten chikungunya virus isolates from human plasma collected in Haiti from May to August 2014, in the midst of a chikungunya fever outbreak, were fully sequenced. The resulting genomic sequences are nearly identical, and phylogenetic analyses indicate they belong to the Asian lineage of the virus.

Coinfection With Zika and Dengue-2 Viruses in a Traveler Returning From Haiti, 2016: Clinical Presentation and Genetic Analysis.

Zika virus and dengue virus serotype 2 were isolated from a patient with travel to Haiti who developed fever, rash, arthralgias, and conjunctivitis. The infecting Zika virus was related to Venezuelan and Brazilian strains but evolved along a lineage originating from strains isolated in 2014 in the same region of Haiti.

Serologic evidence of exposure to influenza D virus among persons with occupational contact with cattle.

BACKGROUND: Influenza D virus (IDV), a novel influenza virus with proposed classification: family Orthomyxoviridae, genus Influenzavirus D, species Influenza D virus, has been associated with influenza-like illness in cattle and swine. More recently, anti-IDV antibodies have also been detected in small ruminants. A seroprevalence of approximately 1.3% has been estimated for the general human population. OBJECTIVES: To gain insights on the zoonotic potential of IDV to human adults with occupational exposure to cattle in north central Florida. STUDY: A cross-sectional serological study was performed on human serum samples from 35 cattle-exposed and 11 non-cattle-exposed adults to screen for IDV antibodies using hemagglutination inhibition (HI) and microneutralization (MN) assays. RESULTS: A seroprevalence of 91% was detected via HI assay, and 97% by MN assay among individuals working with cattle in Florida. Among non-cattle-exposed individuals, seropositivity determined via MN assay (only) was lower (18%). CONCLUSIONS: IDV poses a zoonotic risk to cattle-exposed workers, based on detection of high seroprevalence (94-97%). Whereas it is still unknown whether IDV causes disease in humans, our studies indicate that the virus may be an emerging pathogen among cattle-workers.

Zika and Chikungunya virus co-infection in a traveller returning from Colombia, 2016: virus isolation and genetic analysis.

INTRODUCTION: Zikavirus (ZIKV) and Chikungunyavirus (CHIKV) can share the same mosquito vector, and co-infections by these viruses can occur in humans. While infections with these viruses share commonalities, CHIKV is unique in causing arthritis and arthralgias that may persist for a year or more. These infections are commonly diagnosed by RT-PCR-based methods during the acute phase of infection. Even with the high specificity and sensitivity characteristic of PCR, false negatives can occur, highlighting the need for additional diagnostic methods for confirmation. CASE PRESENTATION: On her return to the USA, a traveller to Colombia, South America developed an illness consistent with Zika, Chikungunya and/or Dengue. RT-PCR of her samples was positive only for ZIKV. However, arthralgias persisted for months, raising concerns about co-infection with CHIKV or Mayaro viruses. Cell cultures inoculated with her original clinical samples demonstrated two types of cytopathic effects, and both ZIKV and CHIKV were identified in the supernatants. On phylogenetic analyses, both viruses were found to be related to strains found in Colombia. CONCLUSION: These findings highlight the need to consider CHIKV co-infection in patients with prolonged rheumatological symptoms after diagnosis with ZIKV, and the usefulness of cell culture as an amplification step for low-viremia blood and other samples.