CN1919341A - Application of hepatitis B surface antigen-antibody complexes in preparing prophylaxis product with no response or low response to hepatitis B vaccine - Google Patents
Application of hepatitis B surface antigen-antibody complexes in preparing prophylaxis product with no response or low response to hepatitis B vaccine Download PDFInfo
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- CN1919341A CN1919341A CN 200610082284 CN200610082284A CN1919341A CN 1919341 A CN1919341 A CN 1919341A CN 200610082284 CN200610082284 CN 200610082284 CN 200610082284 A CN200610082284 A CN 200610082284A CN 1919341 A CN1919341 A CN 1919341A
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Abstract
The invention discloses a new utility of hepatitis B surface antigen-antibody compound in the hepatitis B vaccine non-respond or low-respond prevention agent, which is characterized by the following: purifying recombined HBsAG or inactivated serum HBsAG in the mammal cell, adopting hepatitis B with antibody serum or vaccine globulin as compound, improving anti-HBs ability for non-respond or low-respond mouse.
Description
Technical field
The invention belongs to field of biological product.The new purposes that relates to hepatitis B surface antigen-antibody complexes is specifically related to hepatitis B surface antigen-antibody complexes and is preparing Hepatitis B virus vaccine no response or low purposes of replying in the prevention goods.
Background technology
Domestic and international existing hepatitis b precaution vaccine is being made significant contribution (Beasley RP et al, Lancet, 2:1099,1983 aspect the generation that prevents hepatitis B and hepatocarcinoma, the development at present; Lo KJ et al, J Inf Dis152:817,1985; Sha Qinghong etc., viral journal vol 7 suppl:56,1991.Now be used to prevent the vaccine of hepatitis B to make by hepatitis b surface antigen protein (HBsAg), its source for express from deactivation behind the blood plasma purification, with recombination yeast gene engineering fungus or with the mammal cellular expression after hepatitis b surface antigen protein (the Xu Zhi first-class of purification, virus journal vol 7 suppl:48,1991; It is first-class to open power, viral journal vol 7 suppl:108; 6 Sung JL, et al.Vaccine, 8 (suppl): 95,1990).Normal adult, child or baby inoculate protective effect behind the above-mentioned Hepatitis B virus vaccine mainly show as serum can produce antibody to hepatitis B surface antigen (anti--HBs).Though yet the omnidistance Hepatitis B virus vaccine of ensuring the quality of products of having inoculated of the healthy inoculator that 5-10% is arranged in vaccination person approximately, but Hepatitis B virus vaccine is not produced anti--HBs, or only generation is hanged down anti--HBs of titre (generally with 10mIU/ml, iu is minimum effective protection index), be called as Hepatitis B virus vaccine no response or low responder (Chiou SS et al Immunology, 64:545,1988; Magafuchi S et al.Lancet, 2:1522,1987; Leroux-Roels, G et al.Acta Clin Belg 56:209,2001).Report was once arranged, and these no responses or low responder still can infected and can fall ill (HadlerSC.New Engl J Med 315:209,1986) as the contact hepatitis B virus.Heilongjiang Province's report, anti-behind total man group's immunity inoculation Hepatitis B virus vaccine-HBs sun rate of rotation is 81.97% (Chen Meizheng etc., virus journal vol 7 suppl:73,1991), the scholar of Beijing follows up a case by regular visits to through the baby to vaccination for many years, find that low, unresponsive incidence rate is 4.68-8.18% (Gong Xiaohong etc., disease surveillance 13:447,1998), low, unresponsive incidence rate accounts for 10-20% (Gong Xiaohong etc. among middle school student and the adult, Chinese Journal of Preventive Medicine 5:(3), 1991).The Hepatitis B virus vaccine that carries out in Qidong, Jiangsu inoculates against in the hepatocarcinoma colony scene, and 5% the vaccination person of also finding to have an appointment is low, nonresponder.Das etc. also will be decided to be 5-10% (DasK, etal Trop Gastroenterol 25:113,2004) to Hepatitis B virus vaccine no response or low responder.
Very complicated for Hepatitis B virus vaccine no response or low mechanism of replying, at present still under study for action.Outside getting rid of vaccine quality, inoculation technique or the problematic factor of process, it is mainly lowly relevant with individual immunne response that most scholars think.Wherein both comprised the low person of whole immunne response (as the kidney dialysis patient); Also comprise to produce normal immunne response, only to Hepatitis B virus vaccine no response or low responder to other vaccines.There is the scholar to think specific type relevant (De Silvestri et al.Genes Immun 2:367,2001 with histocompatibility antigen; Kremer J, et al.Immunol Lett.59; 13,1997; Stachowski J, et al.NephrolDial Transplant 9:144,1994).Taked both at home and abroad with increasing the dosage (being enlarged to the 20-30 microgram) that existing hepatitis b vaccine immune is used by the 5-10 microgram, increase frequency injection methods such as (increasing to 5-6 time), though the anti--HBs. that induces out qualified titre in for Hepatitis B virus vaccine no response or low responder in part still has a certain proportion of normal person can not produce resisting-HBs of qualified titre by 3 times.Other has the scholar to adopt to add the method with adjuvant.Decombere is with the altogether immune HLA DQ2 type health of Hepatitis B virus vaccine and adjuvant AS04 people (may for for Hepatitis B virus vaccine no response or low responder), but because of HLA DQ2 fails to obtain result (Desobere I for Hepatitis B virus vaccine no response or low good index of replying, et al.Vaccine 20:2597,2002).Usefulness such as Mcdermott have the proteic HBsAg immunity of PreS1/PreS2 for Hepatitis B virus vaccine no response or low responder, though there are groups of people anti--HBs to occur, the titre of anti--HBs descends rapidly among the crowd in this section, and still some is no response (McDermott AB, et al.J Viral Hepat Supp; 2; 9,1998).Hervas-Stubbs has then used HBsAg to add one section peptide no response mice SJL/J immune result mice has been produced anti--HBs, think it to be a kind of goods (Hervas-Stubbs S that is hopeful to change for Hepatitis B virus vaccine no response or low responder's state, et al.Vaccine 12:867,1994).Jungers etc. use the HBsAg/Pre-S2/IL-2 immunity for Hepatitis B virus vaccine no response or low responder, but fail to show its effect (Jungers P, et al.Lancet 344:856,1994).So far, Shang Weijian is relevant is used for hepatitis B surface antigen-antibody complexes to make it produce report or the patent application of the anti--HBs of qualified titre for Hepatitis B virus vaccine no response or low responder.File related to the present invention also has: Stachowski J, etal.Nephrol Dial Transplant 9:144,1994; Desobere I, et al.Vaccine20:2597,2002; McDermott AB, et al.J Viral Hepat Supp; 2; 9,1998; Hervas-Stubbs S, et al.Vaccine 12:867,1994; Jungers P, et al.Lancet344:856,1994; Wen YM et al.Lancet 345:67; Wen YM et al.Int Rev Immunol18:351,1998; Wen YM et al US patent 6,221,664; Thoma et al US patent6,589,530; Chinese invention patent ZL931124093 such as Wen Yumei.
Summary of the invention
The new purposes of prevention that the purpose of this invention is to provide hepatitis B surface antigen-antibody complexes is specifically related to hepatitis B surface antigen-antibody complexes and is preparing Hepatitis B virus vaccine no response or low purposes of replying in the prevention goods.
The complex that the present invention adopts hepatitis B surface antigen-antibody to form is used and is given Hepatitis B virus vaccine no response or low responder, makes this crowd produce the anti--HBs of qualified amount, thereby protects this crowd not by hepatitis B virus infection.
The present invention provides the new purposes of prevention of hepatitis B surface antigen-antibody complexes on the basis of existing establishment hepatitis B surface antigen-antibody complexes as the therapeutic vaccine technology.The technology of preparing of described hepatitis B surface antigen-antibody complexes is prior art (ZL931124093), but application of the present invention is different fully, and the mechanism of action is also different.Existing hepatitis B surface antigen-antibody complexes is to treat hepatitis B virus infection, serum hepatitis b surface antigen positive, and the chronic viral hepatitis B patient who has fallen ill.Its mechanism is the antigen-presenting cell that hepatitis B surface antigen has been in immunologic tolerance by the regulation and control of the antibody in the complex originally, the picked-up hepatitis B surface antigen, change is to the processing of hepatitis B surface antigen and present, by this modification, again make patient's T, the B cell produces immunne response, reaches the effect of removing virus.Therefore be the biological product for the treatment of usefulness as a kind of, essence is a class medicine.Similarly the goods limit is not limited only to hepatitis, also can be used for treating tumor etc.In the world this class medicine is called therapeutic vaccine (Cohen J Science 264:503,1994.).
Contribution of the present invention is hepatitis B surface antigen-antibody complexes is used for Hepatitis B virus vaccine no response or low human body of replying.Described human body did not infect hepatitis B virus, so did not have hepatitis B virus in the body, did not have hepatitis B surface antigen yet.The problem of this colony is through can not normal response after the injection of existing Hepatitis B virus vaccine, can not produce qualified anti--HBs.In this class crowd, the antibody in the hepatitis B surface antigen-antibody complexes is as a kind of adjuvant, by the effect of assisting a ruler in governing a country of antibody, activates body and produces effectively anti--HBs.As answering booster injection when in the selective body antibody being arranged in injection during some existing preventative vaccines (as typhoid-paratyphoid vaccine etc.), thereby can obtain higher antibody titer.The present invention adopts hepatitis B surface antigen-antibody complexes can induce effectively anti--HBs at these in the human body to Hepatitis B virus vaccine no response or low replying, and protection prevents hepatitis B virus infection to Hepatitis B virus vaccine no response or low responder.Can be used as prevention goods at a kind of new enhance immunity of existing Hepatitis B virus vaccine no response or low responder's special population.
Technical scheme of the present invention is: the hepatitis B surface antigen (HBsAg) that adopts gene engineering microzyme to express, or the recombinant HBsAg of mammal cellular expression, or deactivation blood source HBsAg, purified, (anti--HBs) serum or immunoglobulin formed complex with the antibody that contains hepatitis B surface antigen, be used for Hepatitis B virus vaccine no response or low responder, produce effectively anti--HBs to impel them.Its characteristics are: HBsAg is making different dilution square formation titration determination FAXIA respectively with anti--HBs, and different according to the characteristic of HBsAg and affinity of antibody are determined the optimal proportion of HBsAg and anti--HBs consumption.Select the HBsAg and anti--HBs of optimal proportion amount, after the mixing, 37 ℃ hatch 2-4 hour after, 12,000 rev/mins, centrifugal 30-40 minute, detect HBsAg residual in the supernatant and anti--HBs amount, all should be very low, expression HBsAg and anti--fully combination of HBs.Supernatant is removed in suction, adds the HBsAg of original institute consumption in precipitate again, contains excessive antigen to guarantee complex, and adds aluminium hydroxide agent and antiseptic.
Hepatitis B surface antigen-antibody complexes of the present invention is made up of the antibody of hepatitis B virus envelope antigen and anti-hepatitis B virus envelope antigen.Wherein said hepatitis B virus envelope antigen is a hbs antigen, can be selected from the hepatitis B virus surface antigen or the synthetic hbs antigen of blood source, gene engineering expression; Described antibody is the antibody of hbs antigen, from the antibody of people, animal or recombinant expressed anti-hepatitis B virus surface antigen; Described Hepatitis B virus vaccine no response or low replying are meant normal adult, child or baby inject conventional Hepatitis B virus vaccine and fail the hepatitis B surface antibody of generation＞10mIU/ml behind 3 pins; Or suffer from other diseases or because of treatment other diseases or the immunocompromised that causes because of factors such as age, working environments to Hepatitis B virus vaccine no response or low replying; Or because of the special type of histocompatibility antigen conventional Hepatitis B virus vaccine is injected and to be failed the hepatitis B surface antibody of generation＞10mIU/ml behind 3 pins Hepatitis B virus vaccine no response or low replying.
Characteristics of the present invention are: (1) can be in the unresponsive mouse species to HBsAg with these goods, as B10.S, or SJL/j, induce anti--HBs that height is tired, confirmation because of histocompatibility antigen type (HLA) special to Hepatitis B virus vaccine no response or low responder in, HBsAg-is anti--the HBs complex can induce qualified anti--HBs.(2) causing in the mice of immunocompromised with cyclosporin A (cyclosporin A), with HBsAg-anti--the HBs immunity, can produce than with simple HBsAg immunity higher resisting-HBs of tiring.The main effect of cyclosporin A is to make the cytokine of body such as IL-2, and the IFN-gamma level descends, and the increment of T cell reduces, and secondary ground influences the B cell function.And HBsAg-of the present invention anti--the HBs complex can induce higher anti--HBs than simple HBsAg, show these goods can be used for preparing because of immunologic hypofunction to Hepatitis B virus vaccine no response or low prevention goods of replying.
The specific embodiment
Embodiment 1:
Mice B10 to two kinds of different strains, (the tissue compatible type is H2f to B10s, (Jackson co.) the former to HBsAg for replying strain, the latter is not for replying strain) resist-the HBs immunity with HBsAg and HBsAg-respectively, the simple HBsAg of result can not induce in B10s and the suitable anti--HBs of level of B10 strain, but HBsAg-anti--HBs can induce in B10s and the suitable anti--HBs of level of B10 strain.
According to the square formation titration of having carried out and to residual HBsAg, anti--the HBs measurement result, get the HBsAg 27.5 μ g (dividing 2 addings) of blood source purification, add dilution in 1: 30, the ELISA that tires is 1: 3200 mouse-anti-HBs 47 μ l, makes HBsAg-and resists-HBs, and other gets with crowd HBsAg 27.5 μ g, add phosphate buffer 47 μ l, be the contrast of HBsAg injection.Respectively get 10 B10 respectively, 10 B10s mices do not add adjuvant, every Mus intramuscular injection 1 μ g HBsAg or contain the HBsAg-of 1 μ g HBsAg anti--the HBs complex, immunity is 2 times altogether, at interval 4 weeks.Clear the 1st, 2 immunity back 2 week blood sampling respectively, with ELISA measure serum anti--HBs tires.The results are shown in Table 1.
Table 1 B10 (normal response Mus) and B10s (low reply Mus) to HBsAg-anti--the HBs complex and
Produce anti--HBs tire (not adding aluminum hydroxide) after the HBsAg immunity
| B10 | B10s | |
| The 1st immune HBsAg-be anti--and the 2nd immune HBsAg-of HBs HBsAg be anti--HBs HBsAg | 112±4.24mIU/ml ＜10mIU/ml 52468±423mIU/ml 5524±35.6mIU/ml | 10±4.32mIU/ml ＜10mIU/ml 52468±423mIU/ml 984±9.19mIU/ml |
By above-mentioned table as seen after simple HBsAg immunity once, no matter B10 or B10s Mus are that serum all fails to survey and antibody, but with HBsAg-anti--the HBs immunity after B10 Mus system produced anti--HBs of 112 ± 4.24mIU/ml, but B10s Mus system has only produced the low-level antibody of 10 ± 4.32mIU/ml.But after immunity once more, anti--HBs that B10s Mus serum can reach similar B10 Mus tires, and is respectively anti--HBs of 52,468 ± 423mIU/ml and 52468 ± 423mIU/ml.Simple anti--HBs that is with the B10s Mus of HBsAg immunity tires, and (98 ± 9.19mIU/ml) anti--HBs than B10 Mus system tire and hang down about 50 times (98 ± 9.19mIU/ml).Presentation of results HBsAg-is anti--HBs can improve Hepatitis B virus vaccine (HBsAg) no response or lowly reply the ability that Mus produces anti--HBs, can be used for because of the HLA type special in Hepatitis B virus vaccine (HBsAg) no response or low replying as the prevention goods.
Embodiment 2:
With Hepatitis B virus vaccine (HBsAg) is had the Balb/c Mus of replying, earlier with cyclosporin A (cyclosporinAclin Exp Immunol 1989,78:263-70; World J Gastroenterol 1999,5:209-212; ), HBsAg-and the mouse-anti-HBs immunity expressed of simple HBsAg that expresses with Yeast gene engineering respectively or Yeast gene engineering then, take behind the serum with ELISA method mensuration resist-HBs tires.As a result HBsAg-anti--anti--HBs of HBs immunized mice tires and tires apparently higher than simple anti--HBs with the HBsAg immunized mice, illustrate HBsAg-anti--the HBs complex can be used for because of immunocompromised to Hepatitis B virus vaccine (HBsAg) no response or hang down the body of replying as preventing goods.
Get 24 of the Balb/c Mus of 16-20 grammes per square metre, and 20 every lumbar injection cyclosporin A (cyclosporinA) 0.5mg (with the normal saline dilution, injection 0.1-2 cyclosporin next day of later every.Other 4 only injecting normal saline for the contrast.Stand-by flow cytometer and/or cytokines measurement are used 2 microgram HBsAg respectively after confirming that T cell number or function reduce, or contain the HBsAg-of 2 microgram HBsAg anti--HBs is lumbar injection 1-3 time.Take respectively determination of serum anti--HBs tires.The result singly with the HBsAg mice immunized anti--it only is below 1: 40 that HBs tires, and through HBsAg-anti--tiring of HBs immunized mice can be up to more than 1: 160.Presentation of results HBsAg-is anti--and the HBs complex can more effectively induce out anti--HBs that height is tired than HBsAg in occur Hepatitis B virus vaccine (HBsAg) no response or low body of replying because of immunosuppressant.Therefore HBsAg-anti--the HBs complex can be used for because of immunocompromised Hepatitis B virus vaccine (HBsAg) no response or low body of replying as the prevention goods.
Claims (9)
1, hepatitis B surface antigen-antibody complexes is preparing Hepatitis B virus vaccine no response or low purposes of replying in the prevention goods.
2, the described purposes of claim 1, wherein said hepatitis B surface antigen-antibody complexes is made up of the antibody of hepatitis B virus envelope antigen and anti-hepatitis B virus envelope antigen.
3, the described purposes of claim 1, wherein said hepatitis B virus envelope antigen is a hbs antigen.
4, the described purposes of claim 1, wherein said hepatitis B virus surface antigen are from the hepatitis B virus surface antigen of blood source, gene engineering expression or synthetic hbs antigen.
5, the described purposes of claim 1, wherein said antibody is the antibody of hbs antigen.
6, the described purposes of claim 1, wherein said antibody are the antibody from people, animal or recombinant expressed anti-hepatitis B virus surface antigen.
7, the described purposes of claim 1 wherein saidly is meant normal adult to Hepatitis B virus vaccine no response or low replying, and child or baby inject conventional Hepatitis B virus vaccine and fail the hepatitis B surface antibody of generation＞10mIU/ml behind 3 pins.
8, the described purposes of claim 1, wherein said is the immunocompromised of suffering from other diseases or causing because of the treatment other diseases or because of factors such as age, working environments to Hepatitis B virus vaccine no response or low replying.
9, the described purposes of claim 1, wherein said is because of the special type of histocompatibility antigen conventional Hepatitis B virus vaccine to be injected to fail the hepatitis B surface antibody of generation＞10mIU/ml behind 3 pins to Hepatitis B virus vaccine no response or low replying.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102665687A (en) * | 2009-09-29 | 2012-09-12 | 遗传工程与生物技术中心 | Hepatitis B virus antigen formulation for cell stimulation followed by therapeutic immunization |
| CN103468826A (en) * | 2012-06-06 | 2013-12-25 | 复旦大学 | Method for detection and evaluation of anti-virus-infection activity |
| CN113350500A (en) * | 2021-07-16 | 2021-09-07 | 山西医科大学 | Application of PD-1 inhibitor in preparation of biological agent for improving hepatitis B vaccine immune effect of chronic nephropathy patient |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102665687A (en) * | 2009-09-29 | 2012-09-12 | 遗传工程与生物技术中心 | Hepatitis B virus antigen formulation for cell stimulation followed by therapeutic immunization |
| CN103468826A (en) * | 2012-06-06 | 2013-12-25 | 复旦大学 | Method for detection and evaluation of anti-virus-infection activity |
| CN103468826B (en) * | 2012-06-06 | 2016-07-13 | 复旦大学 | A kind of detection and the method evaluating viral infection resisting activity |
| CN113350500A (en) * | 2021-07-16 | 2021-09-07 | 山西医科大学 | Application of PD-1 inhibitor in preparation of biological agent for improving hepatitis B vaccine immune effect of chronic nephropathy patient |
| CN113350500B (en) * | 2021-07-16 | 2023-02-24 | 山西医科大学 | Application of PD-1 inhibitor in preparation of biological agent for improving hepatitis B vaccine immune effect of chronic nephropathy patient |
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