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  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
  • A61K39/092—Streptococcus
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
  • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
  • C12Y304/22—Cysteine endopeptidases (3.4.22)
  • C12Y304/2201—Streptopain (3.4.22.10)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
  • A61K2039/552—Veterinary vaccine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/70—Multivalent vaccine

Definitions

• the invention pertains to the protection of pigs against a pathogenic infection with Streptococcus suis bacteria of various serotypes, in particular the most prevalent serotypes 1 , 2 and 7, preferably also of serotype 9.
• Streptococcus suis (S. suis) is one of the principal etiologic agents of contagious bacterial disease in pigs.
• the pathogen can cause a variety of clinical syndromes including meningitis, arthritis, pericarditis, polyserositis, septicaemia, pneumonia and sudden death.
• S. suis is a gram-positive facultatively anaerobic coccus, originally defined as Lancefield groups R, S, R/S or T. Later, a new typing system based on the type-specific capsular polysaccharide antigens located in the cell wall was proposed.
• Streptococcus suis is a commensal and opportunistic pathogen of swine. Apparently, the immune system is not triggered in each and every occasion of an infection. Next to this, Streptococcus suis is a well-encapsulated pathogen and uses an arsenal of virulence factors to evade the host immune system. Together, these characteristics have challenged the development of efficacious vaccines to fight this important pathogen.
• sow vaccination is less costly and labor intensive, thus representing an economical alternative to piglet vaccination.
• sow vaccination with bacterins is also a matter of controversy. In many cases vaccinated sows, even when vaccinated twice before parturition, respond poorly or not at all to vaccination which results in low maternal immunity transferred to the litters. And even if maternal immunity is transferred at a sufficient level, in many cases the maternal antibodies are too low to provide protection in the most critical period of 4-7 weeks of age.
• IgM protease antigens either the whole protein or the highly conserved Mac-1 domain representing only about 35% of the full protein
• a vaccine scheme of administering two doses of the IgM protease antigen optionally in combination with a prime vaccination containing a bacterin.
• the IgM protease antigen due to the fact that it is highly conserved throughout most if not all Streptococcus suis serotypes, in particular the most prevalent serotypes 1, 2, 7 and 9, that the IgM protease antigen can be used to arrive at broad cross protection among Streptococcus suis serotypes, in particular among serotypes 1, 2, 7 and 9.
• WO 2020/094762 describes the use of an IgM protease antigen of serotype 2 against a challenge with serotype 14. It appears that very adequate protection can be obtained.
• a vaccine comprising a whole IgM protease antigen of Streptococcus suis, the antigen comprising in its amino acid sequence less than four repeats, and a pharmaceutically acceptable carrier.
• heterologous protection afforded by an IgM protease antigen of a serotype 7 bacterium on its turn is very good, in particular against serotype 1 and 2.
• the level of heterologous protection afforded against serotype 2 is markedly better than the heterologous protection afforded by serotype 2 against serotype 7 is totally unexpected.
• the heterologous protection afforded by an IgM protease antigen of a serotype 1 bacterium on its turn is also very good, in particular against serotype 2 and 7.
• the level of heterologous protection afforded against serotype 2 is markedly better than the heterologous protection afforded by serotype 2 against serotype 1 is totally unexpected.
• the invention pertains to the use of a whole IgM protease antigen of Streptococcus suis, the antigen comprising in its amino acid sequence less than four repeats, for the manufacture of a vaccine for protecting pigs against a pathogenic infection with Streptococcus suis, as well as to a method for protecting pigs against a pathogenic infection with Streptococcus suis, by administering to the pigs a whole IgM protease antigen of Streptococcus suis, the antigen comprising in its amino acid sequence less than four repeats.
• IgM proteases of Streptococcus suis of various serotypes have a sequence identity higher than 75%, in particular expected to be 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 , 87, 88, 90, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% up to 100%.
• a pharmaceutically acceptable carrier capable of stimulating the immune system of the target subject sufficiently to at least reduce the negative effects of a challenge of the wild-type micro-organisms), typically combined with a pharmaceutically acceptable carrier, which upon administration to the subject induces an immune response for treating an infection, i.e. aiding in preventing, ameliorating or curing the infection or any disease or disorder arising from that infection.
• Protection against a pathogenic infection with a micro-organism is the same as arriving at protective immunity, i.e. aiding in preventing, ameliorating or curing the pathogenic infection with that micro-organism or a disorder arising from that infection, for example to prevent or reduce of the actual infection or one or more clinical signs resulting from the pathogenic infection with the pathogen.
• a bacterin is a suspension of killed bacteria for use as a vaccine.
• a combination of antigens is a joined use of these (individually distinct) antigens in one vaccination strategy, either by joining the distinct antigens in one vaccine formulation or by using separate antigen formulations for concurrent administration of the separate formulations.
• a combination vaccine i.e. a vaccine comprising a combination of antigens
• a combination vaccine is one (unitary) formulation that at the same time comprises different antigens.
• These different antigens can be mixed in a factory to provide a so-called ready-to-use combination vaccine, or mixed right before administration or during administration (e.g. using a device having two separate chamber for the separate antigens, the content of these chambers being mixed upon using the device for administration), as long as the antigens do end up in the same formulation.
• a pig is any of the animals that belong to the family of Suidae.
• a pharmaceutically acceptable carrier is a biocompatible medium, viz. a medium that after administration does not induce significant adverse reactions in the treated subject, capable of presenting the antigen to the immune system of the subject after administration of the composition comprising the carrier.
• a pharmaceutically acceptable carrier may for example be a liquid containing water and/or any other biocompatible solvent or a solid carrier such as commonly used to obtain freeze-dried vaccines (based on sugars and/or proteins), optionally comprising immunostimulating agents (also called an adjuvant).
• immunostimulating agents also called an adjuvant
• other substances such as stabilisers, viscosity modifiers or other components are added depending on the intended use or required properties of the corresponding vaccine.
• the IgM protease antigen of Streptococcus suis comprises in its amino acid sequence less than three repeats, such as for example 2.
• the whole IgM protease antigen is of Streptococcus suis serotype 7 or of Streptococcus suis serotype 1.
• the IgM protease antigen is of Streptococcus suis serotype 7 sequence type 29, or of Streptococcus suis serotype 1, sequence type 13.
• a Streptococcus suis strain of Sequence Type 16 is used. This was found later by typing the used challenge strain according to the multilocus sequence typing as described by King et al (see above). Apparently, against the later type (S. suis of serotype 9, sequence type 16) the IgM protease antigen provides protection at a substantially lower level. The reason for this is not completely clear, but possibly also related to the CNV region. This region is completely different for the serotype 9, sequence type 16 bacteria, comprising many more repeats (about 12) but of a considerably smaller length (about 12 AA’s).
• the method comprises administering the whole IgM protease antigen of Streptococcus suis to a sow in order to protect a pig (usually a piglet) through the intake of colostrum of this sow.
• a whole IgM protease antigen see WO2019/193078
• the whole IgM protease antigen of Streptococcus suis is administered twice to the sow before the pig takes the said colostrum.
• Example 3 studies cross protection of IgM protease serotype 2 against serotype 7.
• Region 5 (Thr 920 - Lys 1141): contains a predicted transmembrane region indicating cell wall anchor function.
• the signal peptide is highly conserved among Streptococcus suis strains
• the IgM protease of serotype 2 does not afford protection against a challenge with a serotype 1 Streptococcus suis bacterium.
• the aim of this study was to test the actual level of protection with the same antigen as used in Examples 2 and 3 (viz. IgM protease of serotype 2) against a serotype 9 challenge, in particular a challenge with a bacterium of serotype 9, sequence type 16.
• the IgM protease of serotype 2 does not afford protection against a challenge with a serotype 9, sequence type 16 Streptococcus suis bacterium.
• the protection against a serotype 7 challenge is assessed for IgM protease antigens of a serotype 1 and a serotype 7 Streptococcus suis strains.
• the challenge strain was a serotype 7, sequence type 29 strain, representative for strains in the field.
• the aim of this study was find a protective antigen against a serotype 9 challenge, in particular a challenge with a bacterium of serotype 9, sequence type 16, representative for strains circulating in the field.
• the options assessed were a bacterin alone and a bacterin in combination with an IgM protease, which is understood in the art to improve the efficacy of a bacterin (see Seele et al, Journal of Bacteriology, p. 930-940 March 2013, Volume 195 Number 5, “Identification of a Novel Host-Specific IgM Protease in Streptococcus suis”; and confirmed in WO2015/181356)
• Example 4 The study design was the same as used in Example 4, albeit that non SPF piglets were used and allotted to three groups (evenly distributed over the different litters) of 12 piglets each.
• Group 1 was vaccinated twice intramuscularly at 3 and 5 weeks of age with a bacterin vaccine containing inactivated Streptococcus suis bacteria of serotype 9, sequence type 16, at a level of 2x10 9 cells.
• Group 2 in addition contained the IgM protease of Example 2 at 80pg per dose. Both vaccines were formulated in the oil-in- water adjuvant as used the other examples.
• Group 3 was left as unvaccinated challenge control group. At 7 weeks of age the pigs were challenged intra-tracheally with a virulent culture of S.
• the object of the invention can be met by using a whole IgM protease antigen containing less than 4 repeats, optionally combining the IgM protease with a Streptococcus suis bacterin of serotype 9, sequence type 16, to arrive at adequate protection against all four prevalent serotypes, viz. serotypes 1 , 2, 7 and 9. Also, it is believed that the two IgM protease antigens may be combined as well if needed to arrive at better protection against both serotype 1 and 7 challenge. Also, though not believed to be necessary to meet the object of the invention, other antigens, even other Streptococcus suis antigens, may be included in the vaccine.

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• 2022
  • 2022-06-29 US US18/293,380 patent/US20240325514A1/en active Pending
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