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Typhoid fever and paratyphoid fever combined vaccine and preparation method thereof

A technology combining vaccines and paratyphoid fever, applied in vaccines, multivalent vaccines, pharmaceutical formulations, etc., can solve problems such as virulence reversion, poor reproductive ability of vaccines, and unsatisfactory effects

Active Publication Date: 2014-01-22
罗益(无锡)生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the 1960s and 1970s, inactivated whole-bacteria vaccines were clinically studied in many countries, but the effect was not satisfactory and their use has been discontinued.
Streptomycin-dependent typhoid mutant live vaccines have poor reproductive ability in normal humans, and the effect after immunization is unsatisfactory, and the freeze-dried vaccine has completely lost its protective power, and research has also stopped
The typhoid typhoid Ty21a live attenuated vaccine has undergone a large number of clinical trials and has been proven to be one of the safest and most effective typhoid vaccines without serious side effects. However, some scholars have raised the following controversial questions about the Ty21a mutant strain for a long time: The genetic stability of the attenuated strain cannot be determined, and it is speculated that its virulence may return to the ancestor; the mutation of the gale gene cannot fully explain the attenuation mechanism of the vaccine; there are mutations in other unknown parts of the gene; Irregular stability and excessive number of oral inoculations, etc.
However, the vaccine extracts the outer membrane protein, and the outer membrane protein is a group of proteins. The different protein components are relatively complex, and most of them form a complex, which is difficult to purify. Many bacterial proteins and other impurities

Method used

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  • Typhoid fever and paratyphoid fever combined vaccine and preparation method thereof
  • Typhoid fever and paratyphoid fever combined vaccine and preparation method thereof
  • Typhoid fever and paratyphoid fever combined vaccine and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0029] The preparation method of typhoid Vi polysaccharide:

[0030] 1. Strain preparation: Inoculate Salmonella typhi (50098) in glucose broth medium, culture at 35-37°C for 16-20 hours, transfer the second generation and the third generation to normal agar slant culture under the same conditions On the base, cultivate at 35-37°C for 16-20 hours, and then collect the third-generation strains in strain tanks equipped with a certain amount of improved semi-comprehensive liquid medium, and cultivate at 35-37°C for 4-8 hours.

[0031] 2. Cultivation in large tanks: press the strains in the strain tank into a fermenter equipped with a certain amount of improved semi-comprehensive liquid medium, carry out expanded culture, and culture in deep layer at 35-37°C for 6-8 hours.

[0032] 3. Sterilization: Add 1-2% (V / V) formaldehyde solution to the tank for sterilization of the culture, stir for more than half an hour and let stand overnight.

[0033] 4. Bacteria removal: use a high-sp...

Embodiment 2

[0037] The preparation method of O-SP polysaccharide of paratyphoid fever bacterium:

[0038] 1. Strain preparation: Inoculate Salmonella paratyphi A (50073) in glucose broth medium, culture at 35-37°C for 16-20 hours, transfer the second generation and third generation to ordinary agar under the same conditions On the slant medium, cultivate at 35-37°C for 16-20 hours, and then collect the third-generation strains in strain tanks equipped with a certain amount of improved semi-comprehensive liquid medium, and cultivate at 35-37°C for 4-8 hours.

[0039] 2. Cultivation in large tanks: press the strains in the strain tank into a fermenter equipped with a certain amount of improved semi-comprehensive liquid medium, carry out expanded culture, and culture in deep layer at 35-37°C for 6-8 hours.

[0040] 3. Sterilization: Add 1-2% (V / V) formaldehyde solution into the tank for the culture to sterilize, and stir for more than half an hour.

[0041] 4. Collect bacterial cells: colle...

Embodiment 3

[0048] The preparation method of typhoid Vi polysaccharide-carrier protein conjugate:

[0049] Tetanus toxoid (TT) was used as the carrier protein of typhoid Vi polysaccharide.

[0050] 1. TT derivatization: Dilute TT to 10 mg / ml according to the protein amount, add 3.5 mg of 1,6-adipic dihydrazide (ADH) per mg of protein at room temperature 20-26°C, mix well, adjust the pH value to 5.75, add Carbodiimide (EDAC) makes the ratio of EDAC to protein 0.1-0.8, maintains pH 5.75 and stirs for 1 hour, and uses 30k ultrafiltration membrane to ultrafilter small molecular impurities such as ADH and EDAC. The protein content and ADH residue (-AH) content were measured, and the derivation rate was calculated.

[0051] When derivatizing proteins, EDAC / TT is set between 0.1 and 0.15, which can have a more appropriate degree of derivatization.

[0052] 2. Combination of typhoid Vi polysaccharide with derivatized carrier protein: adjust the pH value of typhoid Vi polysaccharide to 5.75 with...

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Abstract

The invention discloses a typhoid fever and paratyphoid fever combined vaccine. The typhoid fever and paratyphoid fever combined vaccine comprises typhoid Vi polysaccharide and paratyphoid fever thallus specific polysaccharide O-SP. The invention further discloses a preparation method of the vaccine. The preparation method comprises the steps of preparing the typhoid Vi polysaccharide, preparing the paratyphoid fever thallus specific polysaccharide O-SP, preparing typhoid Vi polysaccharide-carrier protein conjugate, preparing paratyphoid fever thallus specific polysaccharide O-SP-carrier protein conjugate and preparing end products. Animal experiments prove that the typhoid fever and paratyphoid fever combined vaccine can induce high-level anti-typhoid Vi polysaccharide and anti-paratyphoid fever lipopolysaccharide (LPS) antibody, has immunologic memory reaction, and has no acute toxicity reactions.

Description

technical field [0001] The invention relates to the field of pharmaceutical products containing antigens, in particular to a typhoid type A paratyphoid conjugate vaccine and a preparation method thereof. Background technique [0002] Typhoid fever is a systemic, acute, febrile infectious disease caused by Salmonella typhi bacillus, which is pathogenic to humans. The main manifestations are persistent high fever, abdominal pain, malaise, headache and inflammation of the small intestine and colon. The incidence of typhoid fever can be reduced by improving public health conditions, but the best way to effectively control the epidemic is still preventive immunization. [0003] Salmonella has a complex antigen structure, which can be generally divided into three types of antigens: (1) Vi antigen or surface antigen, i.e. capsular polysaccharide; (2) O antigen or cell wall antigen, which is lipopolysaccharide of cell wall, i.e. endotoxin; (3) ) H antigen or flagellar antigen, is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/116A61K39/112A61K47/48A61P31/04
CPCA61K39/0275A61K2039/6037A61K2039/70Y02A50/30
Inventor 周富昌陈宣洪周家富任晓莉朱少军
Owner 罗益(无锡)生物制药有限公司
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