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Novel rsv RNA molecules and compositions for vaccination

a technology of rsv and rna, which is applied in the field of new rsv rna molecules and compositions for vaccination, can solve the problems of unlicensed human rsv vaccine, too expensive and impractical for universal use, and the use of dna as a vaccine may be dangerous

Pending Publication Date: 2021-06-10
CUREVAC SE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new invention related to a vaccine for Respiratory syncytial virus (RSV). The inventors found that a specific part of the RSV F protein, when expressed in a mammalian cell using an artificial RNA, can induce protective immune responses in cotton rats. The use of specific regions of the RNA molecule, called 3-UTR and 5'-UTR, can further improve the immune response. The artificial RNA can also be efficiently expressed in low doses and can be delivered using lipid nanoparticles. The invention also includes compositions and vaccines that induce a Th1-biased immune response, which is important for a potential RSV vaccine. The technical effects of this patent are the development of a novel RSV F protein vaccine that can effectively protect against RSV infection.

Problems solved by technology

The neutralizing monoclonal antibody Palivizumab is used for prophylaxis of infants at highest risk for severe infection but is too expensive and impractical for universal use.
This enhancement of an RSV infection due to vaccination is a specific problem for the development of vaccines against RSV infections.
More than 40 years of effort have not yet resulted in a licensed RSV vaccine for humans.
Despite the above mentioned humanized monoclonal antibody Palivizumab, live-attenuated vaccine viruses were developed which elicit a strong immune response, but which are not recommended for use in the specific target groups (infants, children, the elderly and immunocompromised patients).
However, the use of DNA as a vaccine may be dangerous due to unwanted insertion into the genome, possibly leading to interruption of functional genes and cancer or the formation of anti-DNA antibodies.
Apart from some approaches cited above, there remains an unmet medical need for an efficient vaccine for prophylaxis or treatment of RSV infections.
This means that the cells of the innate system may recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.

Method used

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  • Novel rsv RNA molecules and compositions for vaccination
  • Novel rsv RNA molecules and compositions for vaccination
  • Novel rsv RNA molecules and compositions for vaccination

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of DNA and mRNA Constructs and Compositions for In Vitro and In Vivo Experiments

[0818]The present Example provides methods of obtaining the artificial RNA of the invention as well as methods of generating a composition or a vaccine of the invention.

[0819]1.1. Preparation of DNA and mRNA constructs:

[0820]For the present examples, DNA sequences encoding different RSV F proteins (e.g. F0, F-del, F-del_DSCav1, F-del_DSCav1_mut5, etc.) were prepared and used for subsequent RNA in vitro transcription reactions. Said DNA sequences were prepared by modifying the wild type encoding DNA sequences by introducing a G / C optimized coding sequence (e.g., “cds opt1”) for stabilization. Sequences were introduced into a pUC19 derived vector to comprise stabilizing 3′-UTR sequences derived from a 3′-UTR of a gene selected from PSMB3, ALB7, alpha-globin, CASP1, COX6B1, GNAS, NDUFA1 and RPS9 and 5′-UTR sequences derived from a 5′-UTR of a gene selected from HSD17B4, RPL32, ASAH1, ATP5A1, MP68, NDUFA4...

example 2

on of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study

[0833]The present Example shows that LNP-formulated mRNA encoding RSV-F induces strong and functional immune responses in cotton rats.

[0834]For the development of RSV vaccines the cotton rat is an accepted animal model, especially for the challenge infection. Cotton rats that have received formalin-inactivated RSV virus vaccine preparations respond to RSV infection with enhanced lung pathology. This allows the evaluation of the safety of a vaccination in terms of enhanced disease phenomenon.

[0835]To optimize the RSV-specific immune response, mRNA vaccines encoding the pre-fusion stabilized RSV F protein F-del_DSCav were prepared according to Example 1, formulated either with LNPs (see Example 1.4.) or with protamine (see Example 1.5.) and were applied on days 0 and 28 intramuscularly (i.m.) or intradermally (i.d) with different doses of RNA as shown in Table 10. Control animals received a sin...

example 3

on of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study

[0848]The present Example shows that LNP-formulated mRNA encoding different RSV-F antigens induce strong and functional immune responses in cotton rats for mRNA constructs having UTR combination RPL32 / ALB7 (i-2).

[0849]This experiment compared mRNA-LNPs encoding three different RSV-F variants: full-length RSV F0, truncated RSV F-del, and pre-fusion stabilized truncated F-del_DSCav1. The mRNA-LNP vaccines were prepared according to Example 1. Cotton rats received two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprised 10 μg or 100 μg mRNA-LNPs. Control animals received a single vaccination at day 0 with 105 pfu live RSV / A2 virus intranasally or two vaccinations at days 0 and 28 with formalin-inactivated RSV virus (FI RSV) intramuscularly. Additional control animals received buffer only (see Table 11).

TABLE 11Animal groups and vaccination schedule of Example 3...

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Abstract

The present invention is directed to an artificial nucleic acid, particularly to an artificial RNA suitable for use in treatment and / or prophylaxis of an infection with Respiratory syncytial virus (RSV) or a disorder related to such an infection. The invention further concerns a method of treating or preventing a disorder or a disease, first and second medical uses of the artificial RNA, compositions, and vaccines. Further, the invention is directed to a kit, particularly to a kit of parts, comprising the artificial RNA, compositions and vaccines.

Description

INTRODUCTION[0001]The present invention is directed to artificial RNA suitable for use in the treatment or prophylaxis of an infection with Respiratory syncytial virus (RSV) or of a disorder related to such an infection. In particular, the artificial RNA of the invention comprises at least one heterologous untranslated region (UTR), preferably a 3′-UTR and / or a 5′-UTR, and a coding region encoding at least one antigenic peptide or protein derived from RSV, in particular at least one antigenic peptide or protein derived from RSV fusion (F) protein. The artificial RNA is preferably characterized by increased expression efficacies of coding regions operably linked to said UTR elements. The present invention is also directed to compositions and vaccines comprising said artificial RNA in association with a polymeric carrier, a polycationic protein or peptide, or a lipid nanoparticle (LNP). Further, the invention concerns a kit, particularly a kit of parts comprising the artificial RNA or...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/155C07K14/005C12N7/00A61P31/14A61P37/04C12N15/88
CPCA61K39/155C07K14/005C12N7/00A61P31/14A61K2039/53C12N15/88C12N2760/18522C12N2760/18534A61P37/04C12N15/67A61K39/12A61K47/44A61P31/12A61K2039/6018
Inventor LUTZ, JOHANNESRAUCH, SUSANNEHEIDENREICH, REGINAPETSCH, BENJAMIN
Owner CUREVAC SE
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