SciCombinator

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Concept: Rabies

273

Background Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has been linked to adverse birth outcomes. Previous reports have shown that person-to-person transmission can occur by means of sexual contact. Methods We conducted a prospective study involving men with symptomatic ZIKV infection to determine the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. Specimens were obtained twice per month for 6 months after illness onset and were tested by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for ZIKV RNA and by Vero cell culture and plaque assay for infectious ZIKV. Results A total of 1327 semen samples from 184 men and 1038 urine samples from 183 men were obtained 14 to 304 days after illness onset. ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. ZIKV RNA shedding in semen decreased substantially during the 3 months after illness onset but continued for 281 days in 1 man (1%). Factors that were independently associated with prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness. Infectious ZIKV was isolated from 3 of 78 semen samples with detectable ZIKV RNA, all obtained within 30 days after illness onset and all with at least 7.0 log10 ZIKV RNA copies per milliliter of semen. Conclusions ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. In contrast, shedding of infectious ZIKV appeared to be much less common and was limited to the first few weeks after illness onset. (Funded by the Centers for Disease Control and Prevention.).

Concepts: DNA, Infectious disease, Virus, Infection, Transmission and infection of H5N1, Rabies, Vero cell, Viral shedding

166

BACKGROUND: Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible. METHODOLOGYPRINCIPAL FINDINGS: We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four. CONCLUSIONSSIGNIFICANCE: These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.

Concepts: HIV, Immune system, Antibody, Rabies, Serology, Mononegavirales, Lyssavirus, Seroconversion

147

This is the first comprehensive epidemiological analysis of rabies in Costa Rica. We characterized the occurrence of the disease and demonstrated its endemic nature in this country. In Costa Rica, as in other countries in Latin America, hematophagous vampire bats are the primary wildlife vectors transmitting the rabies virus to cattle herds. Between 1985 and 2014, a total of 78 outbreaks of bovine rabies was reported in Costa Rica, with documented cases of 723 dead cattle. Of cattle outbreaks, 82% occurred between 0 and 500 meters above sea level, and seasonality could be demonstrated on the Pacific side of the country, with significantly more outbreaks occurring during the wet season. A total of 1588 animal samples, or an average of 55 samples per year, was received by the veterinary authority (SENASA) for rabies diagnostic testing at this time. Of all samples tested, 9% (143/1588) were positive. Of these, 85.6% (125/1588) were from cattle; four dogs (0.3% [4/1588]) were diagnosed with rabies in this 30-year period. Simultaneously, an extremely low number (n = 3) of autochthonous rabies cases were reported among human patients, all of which were fatal. However, given the virus' zoonotic characteristics and predominantly fatal outcome among both cattle and humans, it is extremely important for healthcare practitioners and veterinarians to be aware of the importance of adequate wound hygiene and postexpositional rabies prophylaxis when dealing with both wild and domestic animal bites.

Concepts: Epidemiology, Spanish language, Veterinary medicine, Bat, Rabies, Latin America, Nicaragua, Costa Rica

117

The delivery of genetic information has emerged as a valid therapeutic approach. Various reports have demonstrated that mRNA, besides its remarkable potential as vaccine, can also promote expression without inducing an adverse immune response against the encoded protein. In the current study, we set out to explore whether our technology based on chemically unmodified mRNA is suitable for passive immunization. To this end, various antibodies using different designs were expressed and characterized in vitro and in vivo in the fields of viral infections, toxin exposure, and cancer immunotherapies. Single injections of mRNA-lipid nanoparticle (LNP) were sufficient to establish rapid, strong, and long-lasting serum antibody titers in vivo, thereby enabling both prophylactic and therapeutic protection against lethal rabies infection or botulinum intoxication. Moreover, therapeutic mRNA-mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge. In conclusion, the present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.

Concepts: Immune system, Antibody, Infectious disease, Bacteria, Vaccination, Infection, Immunology, Rabies

87

The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.

Concepts: Protein, Evolution, Receptor, Severe acute respiratory syndrome, Bat, Rabies, Vero cell, Microbat

36

BACKGROUND: Roughly half the world’s population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. METHODS: In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4-11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. FINDINGS: 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI -13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. INTERPRETATION: These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. FUNDING: Sanofi Pasteur.

Concepts: Epidemiology, Clinical trial, Malaria, Randomized controlled trial, ClinicalTrials.gov, Dengue fever, Rabies, Louis Pasteur

31

Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a previously unidentified coronavirus (CoV), likely transmitted to humans by infected camels. There is no licensed vaccine or antiviral for MERS, therefore new prophylactic and therapeutic strategies to combat human infections are needed. In this study, we describe, for the first time, to our knowledge, the isolation of a potent MERS-CoV-neutralizing antibody from memory B cells of an infected individual. The antibody, named LCA60, binds to a novel site on the spike protein and potently neutralizes infection of multiple MERS-CoV isolates by interfering with the binding to the cellular receptor CD26. Importantly, using mice transduced with adenovirus expressing human CD26 and infected with MERS-CoV, we show that LCA60 can effectively protect in both prophylactic and postexposure settings. This antibody can be used for prophylaxis, for postexposure prophylaxis of individuals at risk, or for the treatment of human cases of MERS-CoV infection. The fact that it took only 4 mo from the initial screening of B cells derived from a convalescent patient for the development of a stable chinese hamster ovary (CHO) cell line producing neutralizing antibodies at more than 5 g/L provides an example of a rapid pathway toward the generation of effective antiviral therapies against emerging viruses.

Concepts: Immune system, Antibody, Protein, Bacteria, Virus, Infection, Monoclonal antibodies, Rabies

28

Human dog-bite injuries are a major public health problem, particularly where there are large populations of free-roaming or street dogs. Dog bites are also the major source of human rabies infections. There is little information on the means to reduce these injuries. Monthly human animal-bite injury records from January 2003 to June 2011 were obtained from the main government hospital in Jaipur, India. The data were analysed and compared with records of pregnancy in street dogs in Jaipur obtained from a street dog sterilisation programme. Human animal-bite injuries showed a seasonal pattern which followed by approximately 10 weeks the seasonal peak of street dog breeding. The number of human animal bites has declined significantly since 2003. It is concluded that a street dog sterilisation programme can reduce human dog-bite injuries by reducing the maternal protective behaviour of the street dogs, as well as reducing the total size of the roaming dog population.

Concepts: Photosynthesis, Carbon, Injuries, Rabies, Apex predator, Dogs, Fox, Neutering

26

Objective-To determine direct and indirect costs associated with raccoon rabies incidents involving cattle herds in Hampshire County, WV, in 2008 and Guernsey County, Ohio, in 2010. Design-Ex post cost analysis. Animals-1 cattle herd in Hampshire County, WV, in 2008 and 1 cattle herd in Guernsey County, Ohio, in 2010. Procedures-Data were collected for each incident through telephone and email interviews with 16 federal, state, and county agency personnel involved in the case investigations and coordinated responses for rabies in the cattle herds. To characterize the economic impact associated with rabies in the 2 cattle herds, cost analysis was conducted with 7 cost variables (salary and benefits for personnel involved in the response, human postexposure prophylaxis, indirect patient costs, rabies diagnostic testing, cattle carcass disposal, market value of euthanized cattle, and enhanced rabies surveillance). Estimates of direct costs were determined on the basis of agency records and other relevant data obtained from notes and reports made by agency staff at the time of the incident and from a review of the literature. Results-Primary costs included the market value of euthanized cattle ($51,461 in West Virginia; $12,561 in Ohio), human postexposure prophylaxis ($17,959 in West Virginia; $11,297 in Ohio), and salary and benefits for personnel involved in the response ($19,792 in West Virginia; $14,496 in Ohio). Conclusions and Clinical Relevance-These results should provide a basis for better characterization of the economic impact of wildlife rabies in cattle in the United States.

Concepts: United States, U.S. state, Rabies, Post-exposure prophylaxis, Virginia, Humid continental climate, West Virginia, Romney, West Virginia

23

Evidence suggests that rabies vaccine may have non-specific protective effects in animals and children. We analyzed four years of data (2012-2015) from an observational study of the health and demographics of a population of owned, free-roaming dogs in a low-income community in South Africa. The objective of this analysis was to assess the association between rabies vaccine and all-cause mortality in dogs, stratified by age group (0-3months, 4-11months, and 12months and older), and controlling for the effects of sex and number of dogs in the residence. Rabies vaccination reduced the risk of death from any cause by 56% (95% CI=16-77%) in dogs aged 0-3months, by 44% (95% CI=21-60%) in dogs aged 4-11months and by 16% (95% CI=0-29%) in dogs aged 12months and older. We hypothesize that the protective association between rabies vaccination status and all-cause mortality is due to a protective effect of rabies vaccine against diseases other than rabies. Existence of a strong non-specific protective effect of rabies vaccine on mortality in dogs would have implications for the design of dog rabies control programs that aim to eliminate dog-mediated human rabies cases. Further, we propose that owned domestic dogs in high mortality settings provide a useful animal model to better understand any non-specific protective effect of rabies vaccine in children, due to dogs' high numbers, high morbidity and mortality rates, relatively short lifespan, exposure to a variety of infectious and parasitic diseases, and shared environment with people.

Concepts: Death, Mortality rate, Vaccination, Demography, Smallpox, Rabies, Dog, Dog health