A VACCINE FOR PROTECTION AGAINST STREPTOCOCCUS SUIS

Abstract

The present invention pertains to a vaccine comprising an immunologically effective amount of an IgM protease antigen of Streptococcus suis, for use in a method for protecting pigs against a pathogenic infection with Streptococcus suis by administering the vaccine only once, wherein the vaccine comprises at most 120 μg per dose of the antigen.

Claims

1-7. (canceled)

8. A method for protecting a pig against a pathogenic infection with Streptococcus suis by administering a vaccine comprising an immunologically effective amount of an IgM protease antigen of Streptococcus suis only once to the pig, wherein the vaccine comprises at most 120 μg of the antigen per dose.

9. The method claim 8, wherein the administering of the vaccine to the pig is performed when the pig is at an age of at most 28 days.

10. The method claim 8, wherein the administering of the vaccine to the pig is performed before the pig is at an age at which the pig is weaned.

11. The method of claim 8, wherein the pig has maternally derived anti-Streptococcus suis antibodies.

12. The method of claim 8, wherein the method of administering of the vaccine to the pig is for conferring protection against mortality associated with a pathogenic infection with Streptococcus suis.

13. The method of claim 8, wherein the method of administering of the vaccine to the pig is for conferring protection against clinical signs associated with a pathogenic infection with Streptococcus suis.

Description

EMBODIMENTS OF THE INVENTION

[0020] In an embodiment of the vaccine for use according to the invention, the method comprises administering the vaccine to the pigs at an age of at most 28 days. In the art there is the general concern that pigs, in particular when younger than 28 days when vaccinated, do not have an mature adaptive immune system and thus, that arriving at protective immunity might be impaired. However, it was found that when using the IgM protease antigen in line with the new vaccination strategy (low dose, one shot), is able to elicit adequate protective immunity. The age of vaccination with the IgM protease antigen can be any age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days. As is known form the art, in particular from WO2017/005913, a positive immune response against an IgM protease antigen can be obtained in young pigs from the day of birth and onwards. This means that by the present showing of actual protection in 3 week old pigs, it is understood that protection can be obtained even at a younger age.

[0021] In another embodiment the method comprises administering the vaccine before an age at which the pigs are weaned. In other words, the vaccine is administered before the piglets are actually weaned. It has been shown that the vaccination at this early age, can protect against a pathogenic infection with Streptococcus suis, induced by stress within a short window of 2-3 weeks right after weaning. This was not beforehand expected since a potential protective effect of the IgM protease antigen as such is only known (see WO2015/181356) for animals that have passed the critical stage of 2-3 weeks after weaning, namely at an age of 5-7 weeks at vaccination, well after the period in which the animals were stressed due to weaning. It is known that the critical period for getting a pathogenic infection with Streptococcus suis is right after weaning. So any successful vaccination strategy in healthy animals after the weaning process was completed and stress was no longer involved, does not provide any proof of successful vaccination against Streptococcus suis before the animals are weaned.

[0022] In yet another embodiment the method comprises administering the vaccine to pigs having maternally derived anti-Streptococcus suis antibodies. Active vaccination of very young pigs has the concern of possible interference with maternal antibodies, either produced by natural infection or by active immunization of sows (Baums C G, Bruggemann C, Kock C, et al. “Immunogenicity of an autogenous Streptococcus suis bacterin in preparturient sows and their piglets in relation to protection after weaning”, in: Clin Vaccine Immunol. 2010; 17:1589-1597). Indeed, neither vaccination of suckling nor of weaning piglets from immunized sows was associated with a prominent active immune response and protection at 8 weeks of age. This failure was associated with a strong inhibitory effect of maternal antibodies or other colostrum components. In this regard, interference between maternal antibodies and active production of antibodies against S. suis could also be demonstrated in a field study after vaccination with an autogenous S. suis capsular type 1/2 vaccine formulation (Lapointe L, D'Allaire S, Lebrun A, et al.: “Antibody response to an autogenous vaccine and serologic profile for Streptococcus suis capsular type 1/2.” in: Can J Vet Res. 2002; 66:8-14. A field study aimed at determining the efficacy of a single-dose S. suis serotype 14 bacterin protocol in 4-day-old suckling piglets also failed to protect piglets against homologous challenge (Amass S F, Stevenson G W, Knox K E, et al. “Efficacy of an autogenous vaccine for preventing streptococcosis in piglets” in: Vet Med. 1999, 94, 480-484. Surprisingly, it has been found that by using the IgM protease antigen at a low dose and administering only one shot of the antigen, interference with maternal anti-Ssuis antibodies is not a problem for arriving at protection against a pathogenic infection with Streptococcus suis. This provides the unique option to vaccinate the piglets themselves and induce active protection, instead of relying on the short live passive protection that can be obtained via the colostrum of immunised mother animals. It has been shown that the vaccination may even take place before the piglets are weaned in order to have them protected against a disease resulting from Streptococcus suis, induced by the stress of weaning or the transportation of young animals right or soon after the weaning procedure. For the first time now, an antigen that was shown to have a potential protective effect in older animals, in which animals interference with MDA's is typically not a problem, has been shown to be useful for vaccinating MDA positive animals to arrive at a clear protective effect induced by stress at an early age, typically in the window of 2-3 weeks after weaning. It is noted that the data in WO2015/181356 only show successful vaccination in piglets having an age of 5-7 weeks and receiving a challenge infection at an age of 9 weeks, thus well after the risk period (i.e. the period of peak incidence of pathogenic Streptococcus suis infections) of 2-3 weeks after weaning, i.e. 5-7 weeks of age. There is no indication whether the IgM protease antigen is able to overcome the common problem of interference with maternal immunity. On the contrary, the choice of animals being vaccinated at an age of 5-7 weeks, is a clear indication that the interference with MDA's, if present, was meant to be avoided.

[0023] In still another embodiment the vaccine is for conferring protection against mortality associated with a pathogenic infection with Streptococcus suis.

[0024] In yet another embodiment the vaccine is for conferring protection against clinical signs associated with a pathogenic infection with Streptococcus suis. Typical clinical signs associated with a pathogenic infection with Streptococcus suis are increased rectal temperature, impaired locomotion (limping, swollen joints), increased respiration rate and neurological signs (e.g. tremors, convulsions, torticollis, ataxia). Preventing, amelioration are curing one or more of these signs will be beneficial for the pig, not only since it is an indication that the pathogenic infection is being suppressed.

[0025] The invention will now be further explained based on the following non-limiting examples.

EXAMPLES

Example 1

[0026] The objective of this experiment was to test the dose-response efficacy of a one-shot low dose (120 μg or less per dose; as determined by a Bradford protein assay using bovine serum albumin as a standard) IgM protease vaccine against Streptococcus suis challenge.

[0027] Study Design

[0028] For this study, fifty 3-week-old piglets were used. The piglets were allotted to five groups (different litters evenly distributed over the groups) of 10 piglets each. Group 1 to 4 were vaccinated once intramuscularly at 3 weeks of age with either of the different vaccine doses, i.e. 120 μg, 40 μg, 13.3 μg and 4.4 μg respectively of the recombinant rldeSsuis IgM protease antigen (see par 2.2. of Seele at in Vaccine 33:2207-2212 for the used antigen) per dose, formulated in a water-in-oil adjuvant. Group 5 was left as unvaccinated challenge control. At 4 weeks of age the piglets were weaned. At 6 weeks of age the piglets were transported to the challenge room and challenged immediately. There was no acclimatization period between the transport and the challenge to mimic natural stress. After challenge the pigs were observed daily for clinical signs of S. suis infection (such as depression, locomotory problems and/or neurological signs) and scored using a regular scoring system going from 0 (no signs) to 3 for severe cases. Severely affected animals were euthanized and post-mortem examined. At the end of the study (7 days after challenge) all surviving pigs were euthanized and post-mortem examined. Just before vaccination and challenge, serum blood was collected for antibody determination. At regular times before and after challenge heparin blood was collected for re-isolation of the challenge strain.

[0029] Results

[0030] None of the vaccines induced any unacceptable site or systemic reactions and thus could be considered safe. On day of vaccination (3 weeks of age) most pigs were seronegative or had a low maternally derived antibody titre. After vaccination, all vaccine groups showed antibody responses and a clear serological dose-response effect was observed with average group titers of 6.5, 6.0, 4.9, 4.4 and 3.5 log.sub.2, respectively. The results for the different parameters post-challenge are shown below in Table 1.

TABLE-US-00001 TABLE 1 Post challenge data study 1 Avg survival Avg clinical Avg blood # pos. Dead after Group time (days) score reisol score blood challenge 1 6.7  9.2 0.7 3/10 2/10 2 6.5  8.6 0.2 1/10 1/10 3 6.6  7.7 0.8 2/10 1/10 4 6.6  7.4 0.3 1/10 1/10 5 5.1 30.9 1.7 6/10 6/10

CONCLUSION

[0031] The results demonstrate that all four vaccine doses of the one-shot IgM protease vaccine induced protection in 3-week-old piglets, partly (about 20% on average) MDA positive) against a challenge with pathogenic Streptococcus suis 3 weeks after vaccination. The level of protection appeared to correspond to the level of protection obtainable when using a two shot approach with 250 μg of the IgM protease per shot (500 μg in total per animal; as used in WO2015/181356). No dose-response effect was observed and a vaccine dose as low as 4.4 μg showed convincing protection at least at the same level (or even better) than when using 120 μg of the antigen. Based on this it is believed that a lowest practical dose could be as low as 1.0 μg or even 0.1 μg of the IgM protease.

Example 2

[0032] As protection against Streptococcus suis for pigs is preferably obtained even when the animals have maternally derived antibodies directed against Streptococcus suis, it was assessed whether an IgM protease containing vaccine is efficacious as a one shot vaccine in maternally derived anti-Streptococcus suis positive pigs at an age of 3 weeks.

[0033] Study Design

[0034] For this study 2 groups of 10 pigs each were used. Group 1 consisted of 3 week old anti-Ssuis MDA positive piglets (only 1 out of 10 animals appeared to have an MDA level below detection limit). These animals vaccinated once intramuscularly with the IgM protease antigen formulated in an oil-in-water adjuvant. Group 2 served as a negative challenge control group. At 4 weeks of age the piglets were weaned. At 6 weeks of age the piglets were transported to the challenge room and challenged immediately. The piglets were challenged with a virulent culture of Streptococcus suis serotype 2. At regular times before and after challenge heparin blood was collected for re-isolation of