Thomas Jefferson University

The United States of America, as Represented by the Secretary, Department of Health and Human Services

University System of Maryland

Institut Pasteur

Yale University

Icahn School of Medicine at Mount Sinai

Matthias Johannes Schnell

Christoph Wirblich

Bernhard Dietzschold

Drishya Kurup

Reed F Johnson

Monique Lafon

Christophe Prehaud

Lisa E Hensley

D Craig Hooper

Christopher M Coleman

Joseph E Blaney

Charles E Rupprecht

John K Rose

Peter B Jahrling

Gene Tan

Milosz Faber

Matthew B Frieman

Jason Paragas

Marie Luise Faber

E Erik Johnson

Christine Rettew Fisher

Matthew S Frieman

The present disclosure provides methods and compositions for inducing an immune response that confers dual protection against infections by either or both of a rabies virus and a coronavirus, and/or which can be used therapeutically for an existing infection with rabies virus and/or a coronavirus to treat at least one symptom thereof and/or to neutralize or clear the infecting agents. In particular, the present disclosure provides a recombinant rabies virus vector comprising a nucleotide sequence encoding at least one coronavirus immunogenic glycoprotein fragment, as well as pharmaceutical compositions comprising the vaccine vectors.

Multivalent vaccines for rabies virus and coronaviruses

The present invention includes a vaccine comprising a SARS-CoV-2 spike protein (S) or portion thereof, and methods of use thereof.

Coronavirus disease (COVID-19) vaccine

The present disclosure is directed towards chimeric glycoproteins wherein the clip region, a core region, a flap region, and a transmembrane and cytoplasmic domain are defined by starting from the amino terminus of the protein, these domains are comprised of the following amino acid residue ranges: clip, 1 through 40 to 60; core, 40 to 60 through 249 to 281; flap, 249 to 281 through 419 to 459; the transmembrane domain is comprised of amino acids 460 through 480, and the remaining amino acids 481 through 525 comprise the cytoplasmic domain; and wherein the clip, core, flap, transmembrane, and cytoplasmic domain comprise a chimeric combination of at least two lyssavirus, wherein the chimeric glycoprotein is advantageously inserted into a rabies-based vaccine vector.

Compositions and administration of chimeric glycoprotein lyssavirus vaccines for coverage against rabies

The present invention provides methods and compositions for inducing an immune response that confers dual protection against infections by either or both of a rabies virus and a filovirus, and/or which can be used therapeutically for an existing infection with rabies virus and/or a filovirus to treat at least one symptom thereof and/or to neutralize or clear the infecting agents. In particular, the present invention provides a recombinant rabies virus vector comprising a nucleotide sequence encoding at least one filovirus glycoprotein or an immunogenic fragment thereof, as well as pharmaceutical compositions comprising the vaccine vectors.

Multivalent vaccines for rabies virus and filoviruses

The invention demonstrates that, contrary to apoptotic rabies virus G proteins, certain non-apoptotic rabies virus G proteins, such as the G protein of the CVS-NIV strain, have a neurite outgrowth promoting effect. The invention further demonstrates that this neurite outgrowth promoting effect is due to the cytoplasmic tail of the non-apoptotic rabies virus G proteins, more particularly to their PDZ-BS, which shows a single-point mutation compared to the one of apoptotic rabies virus G proteins. The invention provides methods for inducing and/or stimulating neurite outgrowth, which are useful in inducing neuron differentiation, for example for the treatment of a neoplasm of the nervous system, as well as in regenerating impaired neurons, for example for the treatment of a neurodegenerative disease, disorder or condition or in the treatment of a microbial infection, or in protecting neurons from neurotoxic agents or oxidative stress.

Neuron generation, regeneration and protection

The invention demonstrates that, contrary to apoptotic rabies virus G proteins, certain non-apoptotic rabies virus G proteins, such as the G protein of the CVS-NIV strain, have a neurite outgrowth promoting effect. The invention further demonstrates that this neurite outgrowth promoting effect is due to the cytoplasmic tail of said non-apoptotic rabies virus G proteins, more particularly to their PDZ-BS, which shows a single-point mutation compared to the one of apoptotic rabies virus G proteins. The invention provides means for inducing and/or stimulating neurite outgrowth, which are useful in inducing neuron differentiation, for example for the treatment of a neoplasm of the nervous system, as well as in regenerating impaired neurons, for example for the treatment of a neurodegenerative disease, disorder or condition or in the treatment of a microbial infection, or in protecting neurons from neurotoxic agents or oxidative stress.

Recombinant rabies viruses in which the arginine residue of the glycoprotein (G) at amino acid position 333 is exchanged, renders these viruses nonpathogenic for immunocompetent mammals regardless of the route of infection. Some of these recombinant rabies viruses after several serial virus passages in newborn mice can become pathogenic for adult mice. The reversion to the pathogenic phenotype is associated with a thymidine to adenosine mutation (T&#x2192;A) at position 639 of the G gene, which results in an asparagine to lysine exchange at position 194 of G. The codon at position 637-639 was changed by site directed mutagenesis to replace asparagine at position 194 by an amino acid that minimized the possibility for an Asn&#x2192;Lys exchange at amino acid position 194 of G and prevents reversion to a pathogenic form of the virus.

Recombinant rabies virus compositions

Live rabies virus vaccines comprising a recombinant rabies virus genome which overexpresses the rabies virus G protein increase apoptotic activity in infected cells, and enhance the generation of anti-rabies immunity in a subject.

Recombinant rabies vaccine and methods of preparation and use

Replication-competent recombinant rhabdoviruses that lack a functional glycoprotein gene and express at least one foreign polypeptide such as a celluar receptor for another virus in their viral envelopes are useful in the treatment of pathogenic viruses. In one embodiment, a recombinant vesicular stomatitis virus (VSV) lacking its glycoprotein (G) gene and expressing instead the HIV receptor and a coreceptor is employed in a method for treating persons infected with HIV. The recombinant virus is defective for entry into normal cells but is able to control HIV infection in a T cell line by replicating in, and killing, HIV-infected cells.

Rhabdoviruses with reengineered coats

Live, attenuated recombinant rabies virus vaccines are generated using reverse genetics to combine the antigenic determinants that render the rabies virus non-pathogenic with the determinants that are responsible for the elicitation of an effective anti-rabies immune response. These vaccines do not affect the antigenic, and therefore the immunogenic, properties of the virus. The present invention further relates to recombinant rabies virus vaccines that express a pro-apoptotic protein, such as cytochrome c, to increase the capacity to induce apoptosis, thereby enhancing the protective immunity against rabies. This new generation of live rabies virus vaccines represents a safe and effective approach to the eradication of rabies in wildlife, and subsequently humans and livestock.

Growing community of inventors

Harleysville, PA, United States of America

Matthias Johannes Schnell