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PLoS Negl Trop Dis ; 15(5): e0009414, 2021 05.
Article in English | MEDLINE | ID: covidwho-1238752


In Latin America, there has been tremendous progress towards eliminating canine rabies. Major components of rabies elimination programs leading to these successes have been constant and regular surveillance for rabid dogs and uninterrupted yearly mass dog vaccination campaigns. Unfortunately, vital measures to control COVID-19 have had the negative trade-off of jeopardizing these rabies elimination and prevention activities. We aimed to assess the effect of interrupting canine rabies surveillance and mass dog vaccination campaigns on rabies trends. We built a deterministic compartment model of dog rabies dynamics to create a conceptual framework for how different disruptions may affect rabies virus transmission. We parameterized the model for conditions found in Arequipa, Peru, a city with active rabies virus transmission. We examined our results over a range of plausible values for R0 (1.36-2.0). Also, we prospectively evaluated surveillance data during the pandemic to detect temporal changes. Our model suggests that a decrease in canine vaccination coverage as well as decreased surveillance could lead to a sharp rise in canine rabies within months. These results were consistent over all plausible values of R0. Surveillance data from late 2020 and early 2021 confirms that in Arequipa, Peru, rabies cases are on an increasing trajectory. The rising rabies trends in Arequipa, if indicative to the region as whole, suggest that the achievements made in Latin America towards the elimination of dog-mediated human rabies may be in jeopardy.

COVID-19/epidemiology , Dog Diseases/epidemiology , Mass Vaccination/veterinary , Pandemics , Rabies virus/immunology , Rabies/epidemiology , SARS-CoV-2/physiology , Animals , COVID-19/virology , Disease Eradication , Dog Diseases/prevention & control , Dog Diseases/virology , Dogs , Humans , Latin America/epidemiology , Peru/epidemiology , Rabies/prevention & control , Rabies/virology , Rabies Vaccines/administration & dosage , Vaccination Coverage
Mol Ther ; 29(3): 1174-1185, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-985497


Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.

Immunity, Innate/drug effects , Immunogenicity, Vaccine , Protein Biosynthesis/drug effects , Vaccines, Synthetic/pharmacology , Viral Envelope Proteins/administration & dosage , Animals , Cell Line , Encephalitis Virus, Venezuelan Equine/drug effects , Encephalitis Virus, Venezuelan Equine/immunology , Encephalitis Virus, Venezuelan Equine/pathogenicity , Fibroblasts , Gene Expression Regulation , HeLa Cells , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunoglobulin G/biosynthesis , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/immunology , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/immunology , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , NF-kappa B/genetics , NF-kappa B/immunology , Nitriles , Parainfluenza Virus 5/drug effects , Parainfluenza Virus 5/immunology , Parainfluenza Virus 5/pathogenicity , Pyrazoles/pharmacology , Pyrimidines , Rabbits , Rabies virus/drug effects , Rabies virus/immunology , Rabies virus/pathogenicity , Rats , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction , Vaccines, Synthetic/biosynthesis , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology
PLoS Pathog ; 17(3): e1009383, 2021 03.
Article in English | MEDLINE | ID: covidwho-1150561


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials.

Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19 , Rabies virus/immunology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/prevention & control , Disease Models, Animal , Humans , Mesocricetus