22.1. LCH S Antoni van Leeuwenhock pht minh ra knh hin vi v nhn thy vi khun vo nm 1684. Hn 100 nm sau Edward Jenner l ngi u tin tr thnh phng php chng u phng nga bnh u ma. Trong giai on t 1857 n 1885 Louis Pasteur tr thnh ng t ca ngnh Vi sinh vt v cng l ngi u tin ch to ra vacxin phng bnh than v bnh di.
Hnh 22.1: Edward Jenner
Bng 22.1: Nin biu pht hin mm bnh v sn xut vacxin a- Qu trnh pht hin mm bnh Nm Mm bnh Ngi pht hin 1863 1873
1938 1940 1953 Vi khun than Vi khun hi (phong) Vi khun st hi quy Vi khun t cu Vi khun lu Vi khun thng hn Vi khun lao Vi khun t Vi khun lin cu Vi khun bch hu, un vn Vi khun E.coli Vi khun Bruccela Vi khun no m cu Vi khun l Vi khun dch hch Vi khun gy ng c tht Virut st vng Vi khun giang mai Vi khun ho g Virut gy ung th Virut bi lit Virut Thy u Virut cm Virut quai b v virut vim no Nht Bn Virut si Virut st xut huyt Dengue L.Pasteur H.Hansen O.Obermeier L.Pasteur A.Neisser K.Eberth. G.Gaffky R.Koch R.Koch T.Bilroth , L.Pasteur E.Klebs, F.Loffler,A.Nicolaev T.Escherichi D.Bruce,B.Bang, G.Traum A.Weichselbaum K.Shiga A.Yersin E.Van Ermengen W.Reed E.Schaudina, E.Holiman Bordet-Gengou Ellerman-Bang
Virut Adeno Virut vim gan B Marburg Lazza Dengue Virut vim gan A Virut Ebola Virut vim gan D Virut HIV Virut Vim gan C Virut vim gan E Virut vim gan G
W.Row Blumberg Fill
Frinston
Rizzetto Montagnier Choo Reyes Simons
b- Sn xut vacxin Nm Loi vacxin Ngi xut 1796 1880 1885 1892 1896 1898 1915 1921 1923 1926 1927 1932 Vacxin u ma Vacxin bnh than Vacxin di bt hot Vacxin t Vacxin t Vacxin thng hn Vacxin chng hoi th Vacxin BCG phng lao Vacxin ho g Vacxin bch hu Vacxin un vn Vacxin sng st vng E.Jenner Louis Pasteur Louis Pasteur Haffkine Kolle Raita Weinberg L.C.A.Calmette-A.F.Mguerin Blum-Madsen G.Ramon-Glenny Ramon-Zoeller M.Theiler 1933 1937 1938 1940 1943 1949 1953 1957 1960 1967 1968 1969 1971 1974 1978
1979 1980 1981 1983 1983
1986 1988 1992 1993
1996 1998 Vacxin Weils Vacxin cm bt hot Vacxin vim no Vacxin di bt hot Vacxin cm sng Vacxin Lepto Vacxin bi lit cht (Salk) Vacxin bi lit sng ung Vacxin si sng Vacxin quai b bt hot Vacxin vim no m C Vacxin Rubella sng Vacxin vim no m A Vacxin Rubella sng Vacxin vim gan B huyt tng Vacxin Vim ph cu Vacxin di nui cy t bo Vacxin ho g v bo Vacxin thy u Vacxin vim gan B ti t hp Vacxin si+quai b+Rubella Vacxin Hib Vacxinvim gan A Vacxin cng hp 5 thnh phn DTP-IPV-Hib Vacxin DPT-Hib-HepB Vacxin Rota v Lyme Wani Salk A.Cmorodinsov-E.Levkovich D.Semple Francis A. Varpholomeev-G.Kovalxkii Salk Sabin J.F.Enders,Yokuno,A.A.Smordints ev (Hoa K) Gotschlich (Hoa K-B) Gotschlich Takahashi
22.2. VACXIN 22.2.1. S pht trin ca vacxin Vacxin hc (Vacxinology) c m u thnh cng vo cui th k 18 bi bc s th y E.Jenner (Anh) vi vacxin lm t chng gy bnh u b, tim cho cu b 13 tui J.Philip. Hin nay, T chc Y t Th gii (WHO) cng nhn tim vacxin l phng cch bo v hiu qu, gip nhn loi trnh c cc bnh truyn nhim. T 1880, Louis Pasteur (Php) sng ch thnh cng vacxin chng bnh Than v nhiu loi vacxin khc trn tng ca Jenner, to ra mt trng phi ring tn ti cho n ngy nay. Sang na th k 20, mc d cng ngh vacxin c nhng bc tin vt bc v t nhiu thnh tch ng k, nhng cng ny sinh nhiu thch thc, nhiu bnh dch nguy him ti pht v mi xut hin. Tnh trng min dch m c th c c sau khi s dng vacxin l kt qu ca s p ng min dch i vi cc thnh phn khng nguyn c trong vacxin. Ty tng loi vacxin, hiu lc bo v c th do min dch dch th, min dch qua trung gian t bo hoc phi hp c hai loi. Ngoi min dch c hiu, vacxin cn c kh nng tng cng c min dch khng c hiu nh lm tng qu trnh thc bo nh khng th ng vai tr l yu t opsonin c hiu v nh lymphokin hot ha i thc bo 22.2.2. Nguyn tc s dng vacxin Vic s dng vacxin phi m bo cc nguyn tc sau y: - Tim chng trn phm vi rng, t t l cao. - Tim chng ng i tng. - Bt u tim chng ng lc; bo m ng khong cch gia cc ln tim chng; tim chng nhc li ng thi gian. - Tim chng ng ng v ng liu lng. - Nm vng phng php phng v x tr cc phn ng khng mong mun do tim chng. - Bo qun vacxin ng quy nh. 22.2.2.1. Phm vi v t l tim chng - V phm vi tim chng: Phm vi tim chng c quy nh theo tnh hnh dch t ca tng bnh. Phm vi tim chng ng nhin khng ging nhau gia cc nc. Ngay c cc khu vc trong mt nc cng c th c s khc nhau. Nhng quy nh ny li c th thay i theo thi gian do s thay i v dch t dch t hc ca bnh nhim khun. V l thuyt, ngi ta thng ni tim chng cng rng cng tt. Thc t th khng th thc hin c iu v nhng l do sau y: Th nht, s rt tn km (chi ph cho vic mua hoc sn xut vacxin v cho vic t chc tim chng); th hai, tuy cc phn ng khng mong mun do vacxin gy ra rt t nhng khng phi l khng c. - V t l tim chng: Nhng khu vc c lu hnh bnh truyn nhim, tim chng phi t trn 80% i tng cha c min dch mi c kh nng ngn nga c dch. Nu t l tim chng ch t trong khong t 50% n 80%, nguy c xy ra dch ch gim bt. Nu t l tim chng di 50% dch vn d dng xy ra. 22.2.2.2. i tng tim chng i tng cn c tim chng mt loi vacxin no l tt c nhng ngi c nguy c nhim vi sinh vt gy bnh m cha c min dch. Tr em l i tng cn c c bit quan tm. Sau khi ht min dch th ng do m truyn (trong thi gian khong 6 thng) nguy c mc bnh ca tr rt ln. Mt khc min dch th ng nh khng th truyn qua rau thai hoc qua sa ch c i vi nhng bnh m c ch bo v ch yu do min dch dch th. i vi nhng bnh m c ch bo v l min dch qua trung gian t bo th tr c th b bnh ngay t nhng thng u tin sau khi sinh. Nhng hiu bit ny l c s cho vic quy nh thi im bt u tim chng cho tr em. Tr nhng i tng chng ch nh, tt c tr em u phi c tim chng. i vi ngi ln, i tng tim chng thu hp hn. Thng ch tin hnh tim chng cho nhng nhm ngi c nguy c cao. Trong thi k m ca, s lng ngi i du lch gia cc nc ngy cng ln, tim chng cho ngi du lch tr thnh yu cu bt buc i vi c nc c cng dn i du lch v c nc n khch du lch. Trong nhng nm gn y, phng bnh un vn s sinh, ph n la tui sinh c tim phng un vn.
Hnh 22.2: Tim chng vacxin Din chng ch nh tim chng (khng c tim chng) c hng dn ring i vi mi vacxin. Ni chung khng c tim chng cho cc i tng sau y: - Nhng ngi ang b st cao. Nhng trng hp ang b nhim khun nh khng st hoc ch st nh th khng cn phi hon tim chng. - Nhng ngi ang trong tnh trng d ng. Nhng ngi c c a d ng hoc c lch s gia nh b d ng vn tim chng c, nhng cn phi theo di cn thn hn. - Vacxin sng gim c lc khng c tim chng cho nhng ngi b thiu ht min dch, nhng ngi ang dng thuc n p min dch hoc nhng ngi mc bnh c tnh. - Tt c cc loi vacxin virut sng gim c lc khng c tim chng cho ph n ang mang thai. 22.2.2.3. Thi gian tim chng Vic tim chng c tin hnh thng xuyn hoc tp trung tim chng hng lot ty thuc vo yu cu ca mi loi vacxin v cc iu kin c th khc. - Thi im t chc tim chng: Khi xc nh c quy lut xut hin dch, cn phi tin hnh tim chng n trc ma dch, c th c thi gian hnh thnh min dch. i vi vacxin c tim chng ln u, thi gian tim tng ko di t 24 gi n 2 tun (trung bnh khong 1 tun), ty thuc vo bn cht vacxin v tnh phn ng ca c th. Hiu gi khng th t c nh cao nht sau khong 4 ngy n 4 tun (trung bnh 2 tun). l kt qu ca p ng min dch tin pht. Khi tim chng nhc li, thi gian tim tng s rt ngn, hiu gi khng th t c nh cao nht ch sau mt s ngy nh nhng t bo lympho c tr nh min dch. l kt qu ca p ng min dch th pht. - Khong cch gia cc ln tim chng: i vi nhng vacxin phi tim chng nhiu ln (khi to min dch c bn), khong cch hp l gia cc ln tim chng l 1 thng. Nu khong cch ny ngn hn, mc d tim chng ln sau nhng kt qu p ng ca c th vn ch nh tin pht, p ng min dch th pht s khng c hoc b hn ch. Ngc li, v mt l do no phi tim chng ln tip theo sau hn 1 thng, hiu qu min dch vn c m bo, v vy ln tim chng trc vn c tnh. Tuy nhin, khng nn ko di vic tim chng nu khng c nhng l do bt buc, v tr c th b mc bnh trc khi c tim chng y . - Thi gian tim chng nhc li: Ty thuc vo thi gian duy tr c tnh trng min dch c hiu lc bo v ca mi loi vacxin. Thi gian ny khc nhau i vi cc loi vacxin khc nhau. Khi tim chng nhc li thng ch cn 1 ln. Vi ln tng cng ny, c th s p ng min dch nhanh v mnh hn, cho d khng th ca ln tim chng trc ch cn li rt t.
22.2.2.4. Liu lng v ng a vacxin vo c th a- Liu lng Liu lng vacxin ty thuc vo loi vacxin v ng a vo c th. Liu lng qu thp s khng kh nng kch thch c th p ng min dch. Ngc li, liu lng qu ln s dn n tnh trng dung np c hiu i vi ln tim chng tip theo. b- ng tim chng - Chng (rch da): y l ng c in nht, c thc hin ngay t lc Jenner sng ch ra vacxin phng bnh u ma. i vi vacxin ny, ng chng vn c dng cho ti khi bnh u ma b tiu dit hon ton trn hnh tinh ca chng ta (1979), khng cn phi chng u na. Ngy nay ng chng vn cn c s dng cho mt s t vacxin. - ng tim: C th tim trong da, tim di da hoc tim bp, khng bao gi tim vacxin vo ng tnh mch. Tim trong da c th c thc hin bng bm kim tim hoc bng bm nn p lc khng kim. - ng ung: ng ung l ng a vacxin vo c th d thc hin nht. Tuy nhin ch thc hin c i vi vacxin khng b dch ng tiu ha ph hy. Cng vi tin b trong s hiu bit v vai tr ca min dch ti ch do IgA tit, nhng vacxin phng bnh ng tiu ha (hoc bnh ni khc nhng vi sinh vt xm nhp vo c th theo ng tiu ha) c s dng hoc ang c nghin cu a vo c th bng cch ung. ng ung kch thch min dch tit ti ch mnh hn nhiu so vi ng tim. Ngoi 3 ng ni trn, vacxin cn c vo c th theo mt s ng khc nh kh dung, t di li, tht vo i trng, nhng ng ny t c s dng. 22.2.2.5. Cc phn ng ph do tim chng V nguyn tc, vacxin phi m bo an ton. Song trn thc t khng th t c mc an ton tuyt i. Tt c cc vacxin u c th gy ra phn ng ph mt s ngi. - Phn ng ti ch: Nhng phn ng nh thng gp sau tim chng l ni tim c th hi au, mn , hi sng hoc ni cc nh. Nhng phn ng ny s mt i nhanh chng sau mt vi ngy, khng cn phi can thip g. Nu tim chng khng m bo v khun, ni tim c th b vim nhim, mng m. - Phn ng ton thn: Trong cc phn ng ton thn, st hay gp hn c (10% n 20%). St thng ht nhanh sau mt vi ngy. Co git c th gp nhng vi t l rt thp (1/10.000), hu ht khi khng li di chng g. Mt s vacxin c th gy ra phn ng nguy him hn, trong c sc phn v, tuy nhin t l rt thp. Khi bn v nhng phn ng do vacxin, rt cn phi nhn mnh rng mc nguy him do vacxin nh hn rt nhiu so vi mc nguy him do bnh nhim khun tng ng gy ra. Th d, t l bin chng nguy him do bnh ho g gp hng trm n hng nghn ln phn ng nguy him do vacxin bch hu ho g un vn (vacxin DPT) gy ra. 22.2.2.6. Bo qun vacxin Vacxin rt d b hng nu khng c bo qun ng. Cht lng vacxin nh hng trc tip n hiu lc to min dch, v vy cc vacxin cn phi c bo qun tt ngay t lc n c sn xut cho ti khi c tim chng vo c th. Thng quy trnh bo qun cc vacxin khng ging nhau, nhng ni chung cc vacxin u cn c bo qun trong iu kin kh, ti v lnh. Nhit v nh sng ph hy tt c cc loi vacxin, nht l nhng vacxin sng nh vacxin si, bi lit v vacxin BCG sng. Ngc li, ng lnh ph hy nhanh cc vacxin gii c t (nh vacxin phng un vn v bch hu). Trong qu trnh s dng cng ng, cc vacxin cn c bo qun nhit trong khong t 2 o C n 8 o C. Mt trong nhng cng vic quan trng nht trong vic t chc tim chng l to lp c dy chuyn lnh. Dy chuyn lnh khng n thun l c cc nh lnh, t lnh, cc phch hoc cc hp cch nhit m cn phi lu c nhng khu trung gian trong qu trnh vn chuyn vacxin v tin hnh tim chng. Vacxin nu b ph hy d c c bo qun lai iu kin thch hp cng khng th c hiu lc tr li, cng khng c tc dng na, phi loi b. Mt im cng cn c lu l cc ha cht ty u, st trng u c th ph hy vacxin. Nu cc dng c tim chng c kh trng bng ha cht th ch cn mt lng rt t dnh li cng c th lm hng vacxin. V vy cc dng c tim chng trc khi dng phi c ra sch sau kh trng nhit cao bng cch luc hoc hp. 22.3. TIU CHUN CA VACXIN Hai tiu chun c bn nht ca vacxin l an ton v hiu lc. 22.3.1. An ton Mt vacxin l tng khi s dng s khng gy bnh, khng gy c v khng gy phn ng. Sau khi sn xut vacxin phi c c quan kim nh nh nc kim tra cht ch v mt v khun, thun khit v khng c. - V khun: Vacxin khng c nhim cc vi sinh vt khc, nht l cc vi sinh vt gy bnh. - Thun khit: Ngoi khng nguyn a vo kch thch c th p ng min dch chng vi sinh vt gy bnh, khng c ln cc thnh phn khng nguyn khc c th gy ra cc phn ng ph bt li. - Khng c: Liu s dng phi thp hn rt nhiu so vi liu gy c. Tuy nhin, nh nu phn 2.5., khng c vacxin no t c an ton tuyt i. Khi cn nhc quyt nh xem mt vacxin no c c a vo s dng hay khng, cn phi so sch gia mc phn ng do vacxin v tnh nguy him ca bnh nhim khun tng ng. 22.3.2. Hiu lc Vacxin c hiu lc ln l vacxin gy c min dch mc cao v tn ti trong mt thi gian di. Hiu lc gy min dch ca vacxin trc ht c nh gi trn ng vt th nghim, sau trn thc a. Trn ng vt th nghim: Cch th nht, nh gi mc p ng min dch thng qua vic xc nh hiu gi khng th hoc xc nh mc dng tnh ca phn ng da. Cch nh gi ny khng cho bit hiu lc bo v. Cch th hai, xc nh t l ng vt c tim chng sng st sau khi th thch bng vi sinh vt gy bnh. D c c quan kim nh nh nc kim tra v c nh gi trn ng vt, trc khi a ra tim chng rng ri, vacxin u phi c th nghim trn thc a (field test): Vacxin c tim chng cho mt cng ng, theo di thng k tt c cc phn ng ph v nh gi kh nng bo v khi ma dch ti. Ngoi 2 tiu chun trn, chn mt vacxin tim chng, ngi ta cn quan tm n gi thnh v tnh thun li cho vic tin hnh tim chng. 22.3.3. Cc nhn t nh hng n hiu lc ca vacxin 22.3.3.1. Bn cht v liu lng ca vacxin Hiu lc ca vacxin s cao nu cha cc khng nguyn c tnh sinh min dch mnh. Mt khc vacxin phi c sn xut t cc chng vi sinh vt t cch i din cho tc nhn gy bnh. 22.3.3.2. ng a vacxin vo c th 22.3.3.3. Cc cht ph gia min dch Cc cht ph gia min dch c dng rng ri nht l cc hp cht ca nhm (aluminum hydroxit hoc aluminum photphat). Cht ph gia min dch c tc dng lm cho vacxin chm ging ha, v vy c th gim c liu lng v s ln tim chng. Cht ph gia cn c tc dng kch thch c th p ng min dch mnh hn. Nh vy cht ph gia min dch va c tc dng lm tng hiu qu kinh t, va c tc dng lm tng hiu qu min dch. 22.3.3.4. Tnh trng dinh dng Nhng nh hng ca tnh trng dinh dng n p ng min dch c xc nh. Nhng kt qu nghin cu cho thy, suy dinh dng lm gim p ng min dch qua trung gian t bo r hn min dch dch th. Tuy nhin cc tr suy dinh dng vn cn c tim chng v 2 l do: Th nht, chng vn c kh nng p ng min dch; th hai, chng rt d b mc cc bnh truyn nhim. 22.3.3.5. Khng th do m truyn Khng th do m truyn c kh nng c ch p ng min dch ca loi vacxin tng ng. V vy hiu lc min dch ca mt s vacxin s b hn ch nu tim chng qu sm khi hiu gi khng th do m truyn cn tng i cao. Nhng bnh nh lao, bi lit c c ch khng ch yu l min dch qua trung gian t bo, a tr khng c m truyn, v vy phi c tim vacxin phng lao v ung vacxin phng bi lit t rt sm ngay nhng ngy u tin sau khi sinh. 22.4. PHN LOI VACXIN Vacxin c th chia thnh 3 loi: 1) Vacxin gii c t, 2) Vacxin cht ton th hoc khng nguyn tinh ch, v 3) Vacxin sng gim c lc. 22.4.1. Vacxin gii c t Loi vacxin ny c sn xut t ngoi c t ca vi khun c lm mt tnh c nhng vn gi c tnh khng nguyn. Vacxin gii c t kch thch c th sn xut ra khng c t, l loi khng th c kh nng trung ha ngoi c t. Vacxin ny nhm phng chng cc bnh nhim trung do vi khun gy bnh ch yu bng ngoi c t. 22.4.2. Vacxin cht ton th hoc khng nguyn tinh ch Loi vacxin ny sn xut t cc vi sinh vt gy bnh. Sau khi vi sinh vt b git cht c th ly ton b huyn dch lm vacxin (vacxin ton th), hoc tinh ch ly cc thnh phn khng nguyn quan trng, l cc khng nguyn bo v (protective antigens). Cc khng nguyn ny ch yu kch thch p ng min dch dch th. Cc khng th c hnh thnh c th trc tip git cht vi sinh vt, ngn cn s bm dnh ca chng vo t bo c th vt ch, lm tng kh nng thc bo , hoc phi hp cc c ch trn. 22.4.3. Vacxin sng gim c lc Loi vacxin ny sn xut t vi sinh vt gy bnh hoc vi sinh vt ging vi sinh vt gy bnh v cu trc khng nguyn, c lm gim c lc khng cn kh nng gy bnh. Vacxin sng to ra trong c th mt qu trnh nhim khun t nhin, kch thch c th p ng c min dch ton th v min dch ti ch, c min dch dch th v min dch qua trung gian t bo. Tuy nhin iu phi quan tm c bit l tnh an ton ca vacxin sng, phi m bo khng cn kh nng gy bnh hoc ch gy bnh rt nh, v vi sinh vt phi c tnh di truyn n nh khng tr li c lc ban u. 22.5. PHI HP VACXIN Mc ch chnh ca vic phi hp vacxin l m gim bt s mi tim chng hoc lm gim bt s ln t chc tim chng. C 2 loi phi hp vacxin: 1) Tim chng vacxin phi hp (trn cc vacxin vi nhau, tim chng cng mt ln, cng mt ng) 2) Tim chng nhiu vacxin ring bit trong cng mt thi gian, c th cc v tr khc nhau hoc theo nhng ng khc nhau.
Hnh 22.4: Tim vacxin cho tr em Phi hp vacxin phi m bo gi c hiu lc to min dch v khng gy ra tc hi g. Hiu lc to min dch i vi mi thnh phn vacxin t nht phi bng khi chng c tim chng ring r. Mt s trng hp khi phi hp vacxin to ra c p ng min dch mnh hn. Ngc li c nhng trng hp phi hp khng hp l lm gim hiu lc to min dch. S phi hp vacxin hp l s khng lm tng t l phn ng ph. Ngha l an ton vn c m bo nh khi chng c tim chng ring r nhng thi gian khc nhau. 22.6. PHT TRIN VACXIN 22.6.1. Tiu chun chp nhn - Tuyt i v khun v an ton khi s dng vi s lng ln. - Hiu qu bo v cng ng tng i cao v phi ko di (c th sut i ngi). - Thch ng vi tnh hnh dch t a phng. - c dung np tt, d s dng, n nh cht lng k c cc nc vng nhit i nng m v gi c c chp nhn. 22.6.2. Thi k s khai u ma, sau bnh s khng mc li, bin php min dch ch ng do Jenner (1796) xut vi chng u B. Kapikian v cng s ngh tim vacxin cho tr chng bnh vim d dy rut qua ng ung Rotavirut t kh theo phng php Jenner.
Hnh 22.6: Phn lp mm bnh Hnh 22.7: Nui cy mm bnh trn phi g
Hnh 22.8: Nui cy t bo ng vt trong ni ln men Nm 1985 Pasteur dng vacxin lm yu qua cy truyn trn th phng di pht sinh t vacxin. T to nguyn l lm yu mm bnh bng cy truyn sang c cht khng thch hp cn gi l phng php c nh. 22.6.3. Thi k gii c t v vacxin bt hot - 1884 Laffler pht hin vi khun bch hu v Roux Yersin pht hin c t bch hu gy bnh. - Sau khi Behring Kitasato pht hin khng huyt thanh th Gleumy Ramon gii c c t bng formalin ra i vacxin gii c t bch hu 1923. - Tin n pht minh vacxin ton thn t bo bt hot chng vi khun thng hn, t, ho g, vacxin virut bt hot khc nh: Bi lit Salk, vim no Nht Bn, cm. 22.6.4. Thi k vacxin sng Nui cy virut trong phng th nghim thnh cng vo gia th k 20 nh vic sn xut vacxin pht trin. Enders to mi trng nui virut t 1948. Nm 1954 Sabin pht trin vacxin bi lit bt hot bng k thut nui cy t bo thn kh ng thi Sabin v cng s lm vacxin bi lit sng gm 3 typ, thc a Rumani thnh cng. Tip l cc vacxin sng nh: St vng, si, quai b, rubella (thp k 60), Rota, Bi lit Sabin. 22.6.5. Thi k cng ngh gen Virut hc v nui cy m pht trin l tin cho pht trin vacxin. c bit khi min dch hc hin i v cng ngh gen ti t hp ra i kch thch mnh m nghin cu sn xut vacxin cng ngh cao. Trc y ch c cc bc s nhn y v th y quan tm n vacxin. n nay, nhiu nh khoa hc thuc cc lnh vc sinh, ha, l v cng ngh kt hp vi nhau nghin cu ng dng cng ngh gen v protein trong pht trin vacxin. u tin l vi vacxin vim gan B: Tc nhn gy bnh l virut nhm ADN m tiu phn HBs c trong mu bnh nhn l khng nguyn chnh. V cha c th sn xut ln, vic thu nhm HBs lc u da vo ngun mu bnh nhn nn d ly nhim, s lng c hn v khng an ton. Khc phc iu ny c hai nh sn xut Merck (M) v Matsubaz (Nht) ng thi tm ra phng php ti t hp dng nm men sn xut khng nguyn HBs. ADN ca virut vim gan B c gn vo nm men thng qua plasmid v nui cy nm men ti t hp s sn sinh s lng ln khng nguyn dng pha ch vacxin. Phng php mi thay th hon ton cng ngh c in v a ngnh sn xut vacxin bc vo k nguyn mi.
Hnh 22.9: Vacxin phng trnh mt s ung th 22.6.6. Nm hng pht trin trong tng lai - S dng cc ph gia (adjuvant) mi, nhm gy ra loi p ng min dch mong mun. Th d, cht nhm photphat v cc oligonucleotit cha CpG demetyl ha a vo vacxin khin p ng min dch pht trin theo hng dch th (to khng th) thay v t bo. - Vacxin polypeptit: tng cng tnh sinh min dch nh lin kt tt hn vi cc phn t MHC: peptit nhn to ging virut, kia gn MHC; on peptit m phng mt quyt nh khng nguyn (epitop). - Anti-idiotyp: idiotyp l cu trc khng gian ca khng th ti v tr gn khng nguyn, c hiu vi khng nguyn tng ng. Anti-idiotyp l cc khng th c hiu i vi idiotyp, do anti-idiotyp xt v mt c hiu li tng t vi khng nguyn. Vy, thay v dng khng nguyn X lm vacxin, ngi ta dng idiotyp anti-anti-X. - Vacxin ADN: ADN ca tc nhn gy bnh s c biu hin bi t bo ngi c chng nga. Li th ca ADN l r, bn, d sn xut ra s lng ln nn thch hp cho nhng chng trnh tim chng rng ri. Ngoi ra, vacxin ADN cn gip nh hng p ng min dch: tc nhn gy bnh ngoi bo c trnh din qua MHC loi II, dn n p ng CD4 (dch th v t bo). Khi khng nguyn ca tc nhn c chnh c th ngi biu hin, n s c trnh din qua MHC loi I, lc ny p ng min dch t bo qua CD8 c kch thch. Tuy nhin phng php ny l con dao hai li bi l t bo mang ADN l c nguy c b nhn din l khng ta, sinh ra bnh t min. - S dng vc-t - dng cc virut hoc Protein ti v cng hp khng nguyn.
Hnh 22.10: nh hng sn xut vacxin chng HIV/AIDS 22.6.7. Cng ngh mi trong sn xut vacxin 22.6.7.1. i cng Cc cng ngh mi trong sn xut vacxin gp phn quan trng trong qu trnh phng chng bnh tt cho con ngi. S bng n v s lng cc cng ngh nh ti t hp ADN, tinh khit i phn t, sinh ho hc Protein to ra nhiu ng dng trong sn xut cc loi vacxin c hiu cho nhiu loi bnh m y hc tng nh b tay (Vim gan B, vim no Nht Bn, ). Trong khong hai thp k cui ca thin nin k th 2 c s bng n v s lng nhng vn k thut trong sn xut vacxin mi. C c s pht trin ny l do nhng tin b nhanh chng trong nhiu lnh vc, bao gm sinh hc phn t, cng ngh ti t hp ADN (rADN), sinh ho hc protein, ho hc polysaccharit, sinh ho hc phn tch, tinh khit i phn t, virut hc, vi khun hc, huyt thanh hc v min dch hc. Mt vi ng dng sm nht ca nhng cng ngh mi hn dnh cho nhng vacxin c, vi mc ch l tng s lng sn xut (nh vacxin vim gan B) hoc c s an ton hn (nh vacxin ho g). Tuy nhin, phn ln nhng ng dng u hng vo vic pht trin nhng vacxin mi m t trc n nay cha lm c. Cc cng ngh mi cn c m rng sang nhng lnh vc khc nh thay i sinh l hc (th tinh), d ng, ung th, iu tr min dch v hi chng suy gim min dch mc phi. Mc tiu ca mt vacxin ch ng l kch thch c th to ra mt trng thi min dch bo v ngi c tim. C hai loi vacxin ch ng: Vacxin sng l mt vi sinh vt hot ng nh mt tc nhn gy min dch, c kh nng gy nhim cho cc t bo v nhn ln tc ch m khng gy ra bnh; Vacxin cht hay bt hot l mt khng nguyn gy min dch, khng c kh nng gy bnh truyn nhim tc ch. Bng 22.2: Cng ngh mi trong vacxin hc Lnh vc Cng ngh p dng Di truyn
ADN ti t hp (rADN)
- Nhn bit khng nguyn - Tch khng nguyn - Tng hp khng nguyn - Loi tr t bin - Loi tr c lc Ha sinh
Tng hp peptid
- Nhn bit cc biu v peptid - Tng hp biu v peptid
Cu trc protein v cacbonhydrat
- D on bng vi tnh v cc biu v t bo T - Nhn bit khng nguyn - Tch khng nguyn - Xc nh dao ng ca biu b - T cht mi Min dch Khng th n dng
- Nhn dng khng nguyn - Tch khng nguyn - Xc nh s bin i ca biu v - Kch hot biu v khng l protein - Tim nng ca t cht mi iu ha min dch - Tnh min dch phn t - Khm ph min dch nim mc i vi bnh ng rut
22.6.7.2. Vacxin sng Mt vi vacxin sng p ng v c bn nhng tiu chun cho mt vacxin l tng. l: C kh nng to ra mt s bo v sut i vi mt phn ng ti thiu gn nh ton th nhng ngi nhn mt hoc hai liu vacxin. Nhng vacxin loi ny cha cc vi sinh vt thng l cc virut; chng gy nhim cc t bo v nhn ln tc ch, ging nh s nhn ln ca vi sinh vt hoang di gy ra nhim khun t nhin. Nh vy, vi sinh vt c trong vacxin s gy ra mt p ng min dch ca c th ging nh p ng vi vi sinh vt hoang di. Vacxin sng c gim c lc, tc l kh nng gy bnh ca vi sinh vt hu nh c loi b bng cc th thut sinh hc hay k thut. Cc vacxin sng thng to ra c hai loi min dch, l min dch dch th (khng th) v min dch t bo (t bo Limpho T). Vacxin sng gm c 2 loi sau: a/ Vacxin c in Thut ng c in cp ti nhng chin lc vacxin khng dng ti cng ngh rADN. Chin lc vacxin c in u tin lm gim c lc trong nui t bo tr nn hin thc trong cc thp k 40 v 50 vi nui t bo hin i invitro (trong phng th nghim) v kh nng nui virut trong cc nui t bo , to ra vacxin ung poliovirut, cc vacxin tim nh si, quai b, thu u, rubella. Mt cch ch to vacxin c in th hai l phn lp v nui virut ng vt, gy ra mt bnh ng vt tng t nh bnh ngi. Virut ng vt ny to ra c min dch ngi nhng khng gy bnh cho ngi. l trng hp Jenner dng virut Vacxina (u b) lm vacxin phng bnh u ma ngi (Variola virut) 200 nm v trc. Chnh vacxin ny dn n vic thanh ton bnh u ma trn phm vi ton th gii vo gia thp k 70, y cng chnh l cn bnh u tin c thanh ton bng vacxin.
Hnh 22.11: Kim tra di knh hin vi in t b/ Vacxin ti t hp C 2 hng trong cng ngh rADN c ng dng pht trin nhng vacxin virut sng mi: ng dng th nht l to ra nhng bin i c hiu hoc nhng xo b gen ca virut, iu s lm cho virut c gim c lc mt cch vng bn. Nh vy, chng s khng cn c kh nng quay tr li c lc. y l hng i to vacxin H5N1 ca Vin V sinh dch t T (H Ni). ng dng th hai ca cng ngh ADN cho vic pht trin nhng vacxin sng mi l lm cho nhng virut tr thnh cc vecto ca nhng Polypeptit ngoi lai hay nhng Epitop peptit t nhng tc nhn gy bnh khc ca ngi. Mc ch to ra nhng vecto nh vy l gii thiu Polypeptit hay peptit ngoi lai cho h thng min dch, trong khun kh ca mt virut sng, lm sao cho h thng min dch p ng vi Polypeptit ngoi lai nh mt khng nguyn min dch sng. Nh vy s pht trin c mt min dch rng ri hn (dch th, t bo hay c hai). L mt phn ca mt virut sng, Polypeptit ngoi lai c biu th bn trong bo tng ca t bo b nhim, c lm gy thnh nhng on peptit, ri c chuyn vn ti b mt ca t bo. T , chng s kch thch s p ng ca t bo Limpho T c vi t bo. Vecto virut mu thng c dng rng ri trong vic to ra vacxin sng mi l virut u ma. lm cho virut ny tr thnh mt vecto, phi to ra mt plasmid c cha gen cho polypeptit ngoi lai, vi nhng trnh t ni tip hng s biu th ca n vo trong cc t bo, s kt hp c gi l mt ct xt biu th. Virut Vaccinia v ct xt biu th c a cng vo nui t bo, cc t bo c th tip nhn c hai cng mt lc vo trong bo tng. xy ra qu trnh ti t hp, sn xut ra mt virut Vaccinia ti t hp biu th ra Polypeptit ngoi lai.
Hnh 22.12: Sn xut vacxin ADN 22.6.7.3. Vacxin bt hot So vi vacxin sng th cc vacxin bt hot d sn xut hn. Theo nh ngha, cc vacxin bt hot khng th nhn ln hoc lan ta c th gy ra bnh. Ni chung, chng c dung np tt hn, c bit phn ln cc vacxin bt hot qua x l tinh khit loi b cc i phn t khc. Ngoi ra, do cng ngh pht trin hin nay, c th d thc hin c vic sn xut cc vacxin bt hot. Kh nng to min dch ca mt vacxin bt hot thng c nng cao nh thm t dc. T dc duy nht c cp giy php dng cho ngi l mui nhm hydroxit hay photphat, c dng tim cho hn 1 t ngi trn ton cu. Khng nguyn ca vacxin gn mt cch vng bn vo mui nhm nh tc ng tng h in v lm thnh mt hn dch. Cc vacxin cht thng c chc nng kch thch cc p ng min dch dch th, cng nh khi ng cho min dch t bo. a/ Vacxin bt hot nguyn t bo Sn xut vacxin bt hot nguyn t bo vi khun hay ton ht nh virut, vi mc ch kch thch vic hnh thnh cc khng th i vi nhiu khng nguyn; mt vi vacxin cn c tc dng trung ho tc nhn gy bnh. Trong trng hp vacxin vim gan A chng hn, cc t bo b nhim virut vim gan A c lm dung gii bi cc ht virut tinh khit bng phng php sinh ho hc, bt hot bng Formalin, ri sau hp ph vo mt mui nhm.Chin lc c in ny dn n vic sn xut ra nhng vacxin c hiu lc, n nay vn cn l mt cng ngh la chn cho nhiu vacxin virut. b/ Vacxin bt hot protein i vi nhiu tc nhn gy bnh th vic pht trin mt vacxin da trn Protein l chin lc c la chn. Phng php ch to ra mt vacxin da trn Protein bng cc k thut min dch, di truyn v sinh ho hc xc nh tnh c hiu khng nguyn. K thut ni trn cho php cc biu v bo v v nhng Polypeptit c xc nh rt c hiu. Vacxin vim gan B lm t ngun huyt tng ngi l vacxin u tin trong th loi ny. Protein b mt ca virut vim gan B (HBsAg), c xc nh l mt Lipoprotein, mt khng nguyn c nhng biu v bo v trn b mt. HBsAg ly t huyt tng ca nhng ngi mang virut vim gan B mn c tinh khit ri bt hot lm vacxin. Vacxin vim gan B ti t hp l ng dng u tin ca cng ngh rADN cho vic sn xut vacxin dng cho ngi. 22.6.8. nh hng pht trin vacxin mi pht trin 1 vacxin mi c nhiu tr ngi thng lm nn lng cc nh nghin cu v u t: - Cn thi gian lu 10-20 nm - Ri ro cao: Khong 80% gp tht bi trong nghin cu lm sng - Khng ngc nhin khi cc doanh nghip nh nc cc nc t bn khng tip tc pht trin sn xut vacxin na. - Bo trc/tn ti mt h su ngn cch gia cam kt ca cng ng quc t, quc gia v nhu cu sc khe cng ng vi vn thng mi. - Cc t chc thng mi lun cn nhc v kh nng thu hi vn, gi c v th trng. Ni chung, pht trin vacxin mi cn xem xt cc vn cng ngh sau: So snh cng ngh bo ch C in: - Vacxin sng gim c lc hay c bt hot. - Vacxin nguyn t bo hay vacxin tiu n v Mi: - Nhng vecto sng, vt ly truyn khc. - Nhng mm bnh c bin i v di truyn. - Cng hp. - T dc. - Hp thu qua nim mc. - Ti t hp ADN. - Nhng k thut pht hin khng nguyn. - Cc thit b chit tch. Vi cc t bo vi khun hoc nm men c lp ghp thm cc gen mi, ngi ta c th nui cy quy m ln sn xut cc loi protein khng nguyn ch to ra cc loi vacxin th h mi. u im ca cc loi vacxin ny l: - Rt an ton v khng s dng cc tc nhn gy bnh. - Gi thnh h v khng phi nui cy trn phi g hoc trn cc t chc ng vt, trong cc thit b t tin. - Hn ch c kinh ph kim nh. - H thp gi thnh trong bo qun v vn chuyn. Thuc v cc loi vacxin th h mi c th k n vacxin khng nguyn nhn to, vacxin riboxom, vacxin cc mnh ca virut, vacxin cng ngh ADN. Cc vacxin chng ung th gan nguyn pht, chng ung th c t cung , chng ung th bch cu Burkih l nhng bc tin quan trng u tin ca con ngi trong vic tm kim bin php min dch chng him ho ung th. Nh ghp c ADN ca vi khun Hansen vo vi khun E.coli m ngi ta hy vng lm ra c vacxin chng phong th h hai nga mt bnh nan y ang lm kh s 15 triu ngi trn th gii. Theo Vane v Cuatrecasas (1984) c th tm tt cc tin b lai ca vacxin tng lai nh sau: a. Vacxin thng thng: Vacxin sng gim c v vacxin bt hot m vic sn xut ch yu da trn kin thc kinh nghim. b. Vacxin ci tin: vic sn xut da trn nui cy invitro (k c t bo ng vt c v), nm chc tnh cht cc khng nguyn hiu bit r cc v tr sinh min dch v ADN ca chng. c. Vacxin protein n: bao gm vic phn lp khng nguyn tinh khit sao nhn m ho cc khng nguyn , phn tch cu trc bc nht a vo s dng cng ngh khng th n dng v t dc ci tin. d. Vacxin peptit tng hp: vic ch to da trn ho min dch, nghin cu cu trc peptit trn my tnh v hiu bit c ch ca hin tng cng hp. e. Vacxin qua ng ung, kh dung v thc phm. 22.6.8. Cc dng trnh by mi ca vacxin tng lai l cc loi: ADN ti t hp di truyn, vacxin n qua ming, vacxin tinh th Trehaloz, vacxin dn trn da.Mt gen khng nguyn c ghp vo h gen ca mt vi khun hay virut (vecto) di s iu ho ca mt promoter, ri gy nhim cho c th, kch thch to min dch. Vacxin ti t hp c vecto dn truyn ny, cng nh loi hnh vacxin sng gim c, cn nhiu hn ch. Trc ht n kh cng knh do phi duy tr ngun virut hay vi khun sng. Do vy, ngi ta phi tm kim mt phng thc khc, a gen khng nguyn vo mt vecto n gin l plasmid. Thc nghim cho thy, khi a ADN ca mt loi plasmid ti t hp mang gen khng nguyn ngoi lai vo c th th c th li to min dch chng li. Vic nghin cu th nghim ny v cn tip tc trong nhng nm ti y. Vacxin nucleic bao gm vacxin ADN v vacxin ARN. l cc ADN hoc ARN ca mt loi plasmid ti t hp mang gen khng nguyn ngoi lai v promoter. 22.6.8.1. Vacxin ti t hp dng tim Loi vacxin ny ang to mt cuc cch mng trong cng ngh sn xut vacxin. Nm 1989, Gustav (USA) tnh c pht hin ra liu php gen trong phng th nghim dng t bo ng vt c v sn xut mt loi protein m ho trong gen. Ba nm sau, S. Johnston i hc Texas pht minh k thut nhn chui ADN to sn phm protein ngoi lai trn t bo ng vt. T protein n vacxin phi ch n bc t ph tip theo ca cc nh bc hc M Harriet Robinson, David Weiner v nhm S.Johnstons tin hnh thnh cng vo nm 1991. Vacxin ADN c tc dng chng ung th, cha bnh t min dch v d ng. Vacxin ADN c kh nng dung np cao, an ton, n nh v hiu qu ko di so vi vacxin c in. Ngoi ra, vic d dng sn xut ln, gi thnh chp nhn c rt c li cho cc nc ang pht trin. 22.6.8.2. Vacxin n qua ming (thc phm) Gia nhng nm 80, RoyCutiss III v Guy Gardinau (USA) xut tng cy gen ADN ngoi lai ca virut, vi khun vo thc vt. Nm 1992 nh thc vt hc Boyce Thompson New-York c tng lm vacxin t nhin cho ngi qua vic n cc thc phm cy gen trn. Hin c t nht 5 cng ty cng ngh sinh hc ln ang nghin cu pht trin vacxin n c kiu ny. 22.6.8.3. Vacxin ha hc dng tinh th Trehaloz lm vt mang L loi ng i c nhiu trong cc m sinh hc, c kh nng tch tr nng lng duy tr s sng khi gp iu kin bt li. Nm 1990 B.Roz Anh xut vic gn cc khng nguyn vi tinh th ny v xoa trn da, d dng xm nhp vo m sng phng thch khng nguyn nh kiu tim chng c in. Trehaloz cn l t dc ng kh vacxin, dng kh dung dng qua ng th (vacxin cm). Nh kh nng bt gi v thi chm, vacxin Trehaloz rt n nh lun gi c cng hiu cao trong thi gian di bt k nhit bo qun no (60oC/1 thng khng mt cng hiu). 22.6.8.4. Vacxin dn trn da Ngi M cho rng vic thm qua da cng l mt cch a vacxin vo tip cn h thng min dch ca c th ngi. Nhm nghin cu ca G.Glenm th dn ming giy thm cha c t t CT. CT l cht kch thch min dch mnh nhng nu c lm gim c tnh (cc tiu phn) th chnh n tr thnh mt t dc chun cho nhiu loi vacxin khc, vic a CT qua da rt an ton sau khi th trn mt s ngi tnh nguyn. Th vi LT ca E.coli trn chut cng cho kt qu tt. c 30 loi khng nguyn lm vacxin th dng ny (bch hu, un vn, cm, di ) thm ch khng gy min dch cho vi CT. Min dch qua da bc u c th trn 18 ngi tnh nguyn vi hai khng nguyn CT v LT dn trn cnh tay trong 6 gi. Sau 3 tun o hiu gi khng th thy rt cao, khng gy phn ng ph so vi chng. C th vacxin ny s phi ci tin bng vic thay dng trc tip cc c t vi khun bng cc vector plasmid ADN. 22.6.8.5. Vacxin kh dung: Phun xt qua ng ht th (Vacxin cm) 22.7. TIM CHNG V NHNG S C SAU TIM CHNG 22.7.1. Li ch v thch thc Trong 2 th k qua vacxin gp phn rt ln y li nhiu bnh tt v gim t l t vong cho con ngi. Trc khi b khai t bi vacxin bnh u ma tng l ni kinh hong ca c Chu u trong th k 18, cp i sinh mng ca hng triu ngi. Vacxin cng l v kh hu hiu chng li cc bnh truyn nhim nguy him nh Bi lit, Si, Vim no gp phn quan trng hn ch nhng di chng gy tn ph cho bnh nhn, tit kim c nhiu chi ph cho gia nh v x hi. Trung bnh hng nm, tim chng cu sng c khong 3 triu ngi trn ton th gii, khng ch v loi tr c nhiu cn bnh mi ny sinh nhng con ngi cha c vacxin phng chng.
Hnh 22.13: Bit bao tr em cn cha c tim chng vacxin hng nm Vi mt s bnh c th sau, nu c min dch bng vacxin, s ngi trn ton th gii s c cu sng hng nm s l: - T bnh u ma: (5 triu ngi). Thc t bnh chm dt t nm 1997 n nay. - T bnh tiu chy (3 triu ngi), ring Rotavirut l 0,9 triu ngi. - Nhim khun h hp: (3,7 triu ngi), trong do ph cu l 1,2 triu do virut 0,5 triu. - T lao (3,2 triu ngi), si (2,7 triu ngi), st rt (2,1 triu ngi). - Un vn (2 triu ngi), vim gan siu vi B (1,2 triu ngi), HIV/AIDS (1 triu ngi), ho g (1 triu ngi), bi lit (0,6 triu ngi), bch hu (0,3 triu ngi), st xut huyt (0,03 triu ngi). Tng cng: 24.395.000 ngi (ngun CVI/GPV1-1997). Li ch ca tim chng vacxin cho cng ng trong nhiu thp k qua c th gii cng nhn. Thnh tu ni bt nht l vic thanh ton vnh vin bnh u ma trn phm vi ton cu t nhng nm 1980. nhiu quc gia trong c Vit Nam cng b xa b bnh bi lit vo nm 2000. Trong vng 10 nm ti, c th chng ta s y li bnh un vn s sinh bng vacxin. Vit Nam d n tim chng m rng quc gia trin khai 10 loi vacxin, hai thp k qua gim ng k t l mc v t vong do cc bnh truyn nhim nh ho g, bch hu, t, thng hn, lao. Tim vacxin si c th gim 80% nguy c mc v t vong do bnh si gy ra tr em, song trong s tr c tim c mt t l nh b phn ng. Khoa hc ngy cng pht trin trong cc lnh vc vi sinh vt hc, min dch hc, sinh hc phn t, di truyn hc, ha hc, vt l, tin hc v cng ngh nano h tr c lc cho cng cuc tm kim nhng vacxin an ton, cng hiu hn. Vacxin hc tip cn sang nhiu lnh vc mi nh bnh d ng, bnh x hi hc, cc bnh nan y (ung th, HIV/ADIS), bnh k sinh trng st rt v t nhiu thnh qu ng k. Gi vacxin cng tng bc c tho g bng nhng bin php h tr ca cc t chc Quc t (UNICEF tha thun vi cc nh sn xut gim gi cc vacxin thit yu cho tr em) v chnh ph cc nc (tr gi cc vacxin chng trnh, gim thu, xa b s rng buc ca lut c quyn s hu tr tu). Nhiu nm qua, Vit Nam mnh dn thc hin chin lc t tc vacxin, Nh nc h tr sn xut vacxin trong nc v vn ng nhn dn s dng vacxin ni a, gi c gi vacxin mc hp l. Vic ci tin phng thc sn xut theo li cng hp c vacxin a gi (1 mi tim phng c nhiu bnh) v thay vacxin th h mi nhm gim au n v lo lng cho ngi dng (nht l vi tr em) to iu kin thun li cho vic trin khai cc chin dich tim chng. Cc t chc phi chnh ph nh GAVI, qu Bill Gates cng to nhiu ngun ti tr mi cho vic nghin cu v pht trin vacxin. Nhng thch thc: a/ Tnh an ton: Nhng phn ng ph khng an ton ca vacxin cho ngi c tim ang l mt tri, gy cn tr ln cho cng tc vn ng tim chng. Mc d t l xut hin nhng phn ng ph nghim trng do vacxin rt thp, nhng vn xc nh ng nguyn nhn v cch khc phc vn l nhng thch thc khng nh i vi mi quc gia. b/ Chi ph: Vic u t sn xut vacxin rt tn km. Chi ph t giai on nghin cu u tin n vic sn xut th, trang thit b v cui cng l nh gi lm sng hiu qu ca mt vacxin mi ra i c tnh t 200 400 triu USD. y qu l mc chi khng tng cho cc nc ngho. c/ Nhiu bnh mi xut hin cha c vacxin: T 3 thp k qua xut hin nhiu bnh truyn nhim mi nh: HIV/AIDS, b in, st xut huyt, SARS, cm g l thch thc ln cho gii khoa hc v cc nh qun l y t ca cc nc. Trc ht nhn loi ang tp trung tm hiu nguyn nhn gy dch, ch ng phng v dp tt cc v dch bng nhiu bin php tng hp, song khng th b qua gii php ton din v trit nht l s dng vacxin. Mt khc, vn phi tip tc tm kim cc vacxin hu hiu phng chng cc bnh khc nh: st rt, phong ci, tim mch, ung th, d ng cng nhiu bnh nhim khun v khng nhim khun khc.
Hnh 22.14: Vng dch St vng Chu Phi v Nam M Mi nm c 130 triu tr em c sinh ra nhng vn c 30 triu tr trong s ny khng c tim phng, t l tim phng cho tr di 5 tui gim t 80% (nm 1990) xung 74% (nm 1999) s tr mi sinh ra khng c hng vacxin min ph ca chng trnh tim chng m rng phng 6 bnh c bn si, bi lit, un vn, bch hu, ho g v lao. Tr em cc nc ang pht trin vn c nguy c cht v nhng bnh c vacxin phng nga cao gp 10 ln so vi tr cc nc pht trin. Tim chng l s la chn ng n, cn min dch bo v c cng ng, tim chng tiu dit mm bnh, bo v khng ch mt th h m cn cho cc th h tip ni. u t cho tim chng vn l gii php r nht trong cc bin php phng chng dch bnh: 50 USD cho tim chng c th tit kim hng chc ngn USD cho vic cu sng mt sinh mng do bnh tt cp i. 22.7.2. Chng trnh tim chng m rng (TCMR) Chng trnh TCMR hnh thnh khi nim t u nhng nm 1974 ra mc tiu nm 1990 chng 6 bnh nguy him. c im 6 bnh: - Si git 2 triu tr/nm. - Un vn git 800.000 tr/nm (2 mi bo v c m v con 80% trong 3 nm). - Ho g git 600.000 tr/nm (cng hiu bo v 62 80% nu tim 3 liu t 6 tun tui/cch 1 thng). - Lao: 2 triu tr di 5 tui mc/nm (60.000 s lao mng no, t vong 50 100%). BCG gi 2 nm <80C. Bng 22.3: Nhn bit v chng trnh TCMR Ni dung Th gii Vit Nam Khi ng WHO 1974 1984 Loi vacxin 6 loi (Bch hu, ho g, un vn, lao, bi lit, 6 loi (Bch hu, ho g, un vn, lao, bi lit, si) si) B sung loi vacxin (1997) Vim gan B, thng hnVi, st vng (ty dch t tng nc). 1997/ Vim gan B, thng hn Vi, vim no, t (4 loi). i tng mc tiu < 5 tui < 5 tui
ln v th trng 130 triu tr s sinh/nm (cc nc AZAN 26 triu), 65% s tr cc nc ang pht trin 1,6 triu tr s sinh/nm
- Bch hu: 10 18% t vong trong cc bnh bch hu (25.000 trng hp/nm tr em) hiu qu bo v 100% DTP nu bo qun tt. T nm 1997 TCMR ca Vit Nam b sung thm 4 loi vacxin: T ung, vim gan virut B, vim no Nht Bn B v Thng hn. Trong TCMR t l sau 20 nm thc hin Vit Nam gim 100 ln t l mc cc bnh trn tr em. Chng trnh tim chng Vit Nam: - i tng tim chng gm tr em, ph n c thai, ph n tui sinh . - Khong 17 triu lt i tng tim chng trong 1 nm trong TCMR. - Hn 50% nhu cu vacxin s dng trong TCMR c sn xut trong nc.
Hnh 22.17: Chng trnh Tim chng m rng 22.8.3. Mt s lu v ch nh tim chng Khng c nhiu chng ch nh trong tim chng. Tt c tr em cn c tim chng, tr mt s trng hp sau: a) Nhng liu tim tip theo i vi nhng trng hp c phn ng qu mn vi liu tim trc hoc nhng ngi c tin s d ng vi cc thnh phn ca vacxin. b) Khng nn tim vacxin BCG cho tr em b bnh AIDS. Ch : Tr b nghi ng nhim HIV hoc c du hiu ca bnh AIDS nn tim vacxin si cho tr khi c 6 thng tui v nhc li khi tr c 9 thng. c) Trong trng hp tr b m nu b m tr khng ng tim, khng tim cho tr, cn b y t cn ngh b m mang tr tr li khi khi m. Nhng tr c phn ng qu mn vi ln tim trc th khng nn tim tip. Nu tr b tiu chy khi ung OPV, cn cho tr ung 1 liu b sung cch liu th 3 t nht 4 tun.
Lu khi tim vacxin: * Nu tim hn 1 loi vacxin trong cng mt thi im, hy s dng mt bm kin tim cho mi loi vacxin v khng c tim cng mt ch a hoc tay. Mi loi vacxin cn c tim nhng v tr khc nhau. * Khng tim hn mt liu cng mt loi vacxin cho ph n hoc tr em trong mt ln tim chng. * Tim ng khong cch gia cc mi tim theo hng dn. (V d: phi i ti thiu 4 tun gia cc liu i vi Bi lit, DTP v vim gan B) * Nhng trng hp sau khng chng ch nh: - C tin s d ng hoc hen (tr trng hp bn bit r d ng vi thnh phn no ca vacxin). - Cc trng hp m nh, nh vim nhim ng h hp hoc tiu chy c thn nhit di 38,50C. - Tin s gia nh co git, ng kinh hoc ngt. - ang iu tr cc thuc khng sinh. - Nhim hoc nghi ng nhim HIV nhng cha biu hin triu chng AIDS. - Du hiu v triu chng ca AIDS, ngoi tr vacxin BCG. - Bnh mn tnh nh cc bnh v tim, phi, thn hoc bnh gan. - Cc bnh thn kinh bm sinh: Bi no hoc hi chng Down. - non hoc nh cn (khng nn tr hon tim vacxin). - hoc sp phu thut. - Suy dinh dng. - C tin s vng da khi .
22.8.3. Lch tim chng Bng 22.4: Lch tim chng min dch c bn cho tr em Vit Nam. Thng tui Vacxin cn tim Mi tim S sinh (cng sm cng tt) BCG (phng lao) Vim gan B 1 mi Vacxin vim gan B mi 1 2 thng tui Bi lit Bch hu, ho g, un vn Vim gan B Bi lit ln 1 Bch hu, ho g, un vn, mi 1 Vacxin vim gan B mi 2 3 thng tui Bi lit Bch hu, ho g, un vn Bi lit ln 2 Bch hu, ho g, un vn, mi 2 4 thng tui Bi lit Bch hu, ho g, un vn Vim gan B Bi lit ln 3 Bch hu, ho g, un vn, mi 3 Vacxin vim gan B mi 3 9 thng tui Vacxin si Mi 1 khi tr 9 thng tui V a tr i tim trong chin dch tim nhc vacxin si T 1-5 tui Vim no Nht Bn* Vacxin vim no mi 1 Vacxin vim no mi 2 (Hai tun sau mi 1) Vacxin vim no mi 3 (mt nm sau mi 2) T 2 5 tui Vacxin t* 2 ln ung (ln 2 sau ln 1 hai tun) T 3 5 tui Vacxin thng hn* Tim 1 mi duy nht * Ch tim chng cc vng c nguy c bnh 22.8.4. Nhng s c sau tim chng Li ch ca tim chng cho sc khe cng ng ai cng r v l iu khng th ph nhn. Song, nhng s c hay nhng phn ng c hi cho sc khe tng c nhn trong cng ng th cn nhn nhn ng. Cng nh thuc, vacxin dng trong tim chng lun t yu cu v tnh an ton v hiu lc bo v mi c lu hnh. Nhng khng th c mt lai vacxin no hon ton an ton v vn cn nhng t l nht nh nhng s c xy ra sau tim chng. Thm vo nguyn nhn do chnh bn cht vacxin th qu trnh tim chng cng l mt nguyn nhn gy s c . Vic gim st hn ch tc dng ca cc s c ang l yu cu bc thit trong chin lc tim chng nc ta hin nay. Cn c h thng t Trung ng n c s thng k cc bo co trung thc v nhng phn ng c hi ch thc do vacxin, do tim chng hay do tc ng ngu nhin trng hp khi tim chng. c ci nhn trung thc y, cn phn loi nhng phn ng sau tim nh trong bng di y. Bng 22.5. Nm loi s c sau tim chng Loi phn ng Nguyn nhn Phn ng ca vacxin Do bn cht vacxin gy ra vi t l vt qu gii han cho php v mc v phm vi Sai st trong tim chng Sai st trong sn xut, bo qun vacxin hay khi tim vacxin. Ngu nhin Do tnh c kt hp nguyn nhn khc khng phi do vacxin v tim chng. Phn ng tm l Do lo u, s hi lm tng au n v phn ng ph Khng r Khng xc nh c nguyn nhn Chong phn v d c kh nng gy t vong nhng vn c th iu tr c m khng li hu qu lu di. Cc phn ng nng khc do tc ng ngu nhin trng hp nhiu hn do phn ng ch thc ca vacxin. Trong chin dch tim chng, cn nm vng cc thng tin d on t l v loi phn ng sau tim chng, phi tin hnh iu tra ngay nu thy t l xy ra cao hn v phn ng nng hn. Ngt xu thng xy ra tr trn 5 tui (khng i hi phi x l g ngoi vic t bnh nhn t th nm nghing). C th ngn nga trc bng cch rt ngn thi gian ch i, gi nhit phng mc va phi d chu, khi chun b vacxin ng cho tr thy v tim ring r tng tr mt. Khng tr c tim b ng v phi tr t th ngi khi tim. Cm gic trng gi l kt qu ca s lo s khi i tim chng vi nhng triu chng c bit nh nhc u nh, chng mt, t xung quanh ming v cc bn tay, hn na hay gp cc tr nh, thm ch ngng th, c khi ht trn chy. Lo s c th dn n mt vi trng hp co git. C tnh hung gy hysteria hng lot (khi u thng ngt xu t mt tr). Gii hn nhng tc ng c hi ca tim chng v cch iu tr th hin trong bng sau y. Bng 22.6: Triu chng, cch iu tr v loi vacxin gy ra. VACXIN PHN NG GIAI ON BC PHT T L TRONG 1 TRIU LIU BCG - Vim hch m 2-6 thng 100-1000 - Vim tai - Vim nhim lan ta 2-6 thng
1-12 thng 1-12 thng 1-700 2 Vim gan B - Chong phn v - Hi chng Guilain- Barre 1-6 tun 1-2 5 Si - St co git - Gim tiu cu - Chong phn v 5-12 ngy 15-35 ngy 0-1 gi 333 33 1-50 OPV - Lit lin quan n vacxin bi lit (VAPP). - Nguy c cao hn vi liu u tin 4-30 ngy 0,76-1,3 (liu u) 0,17 (liu tip theo) 0,15 (ngi tip xc) Un vn - Vim dy thn kinh cnh tay. - Chong phn v - p xe 2-28 ngy 0-1 Gi 1-6 tun 1-6 6-10 DTP - Khc tht dai dng >3 gi - Cn co git - Gim trng lc, gim phn x (HHE). - Chong phn v - Hi chng no 0-24 gi 0-2 ngy 0-24 gi 0-1 gi 0-3 ngy 1000-6000
570 570
20 0-1 Vim no Nht Bn B - Phn ng d ng nng - Triu chng lin quan 10-1000 1-2.3 n h thn kinh St vng -Vim no ty - D ng, chong phn v 7-21 ngy 0-1 gi
500-4000 tr s sinh di 6 thng tui 5-20 gim thiu tc hi ca s c sau tim cn c h thng gim st, bo co thng k, hnh ng x l kp thi t cp c s n Trung ng. Ngoi ra, vic iu tra sau tm ng nguyn nhn sai st cn c lm minh bch, trung thc. Vic tuyn truyn trn an d lun vi cha m v qun chng nhn dn cn c lm nghim tc trn c s khoa hc c tnh, c l. Vic x l v thng tin qua cc c quan truyn thng l cng vic ht sc t nh nhy cm cn thn trng v ng hng nhm to nim tin lu di ca cng ng vi cng tc tim chng.
22.9. TRIN VNG CA CNG NGH SN XUT VACXIN Vacxin l sn phm c ch to t cc vi sinh vt (virut, vi khun, nm men) hoc cc khng nguyn c hiu, c a vo c th ngi gy min dch ch ng nhm phng nhim khun do cc vi sinh vt tng ng gy ra. Thut ng vacxin E.Jenner dng u tin bt ngun t ch Latinh vacca (con b) ch cht ch t vy u b dng chng cho ngi nhm phng bnh u ma. Sau ny, L.Pasteur dng thut ng vacxin rng ri ghi nh cng trnh c ngha lch s ca E.Jenner. Nhn chung cc vacxin hin ny thuc hai nhm chnh: Vacxin bt hot (cn gi l vacxin cht) cha cc vi sinh vt b dit hoc cc ngoi c t ca chng c gim c khng cn kh nng gy bnh (tc nhn bt hot nhit, bc x, siu m, ho cht nh formalin, phenol, beta probiolactol, merthiolate). Nhng tc nhn ny phi c tc dng lm gim c v bo v khng nguyn. Vacxin gim c lc (Vacxin sng) cha vi khun hoc virut c gim c bng cch cy chuyn hoc x l sao cho mt kh nng gy c hoc b bin chng khng cn kh nng gy c na nhng cn kh nng min dch. Khi u 200 nm trc y l s ra i ca vacxin u ma. Ri gn 100 nm sau vacxin di ln u tin c chng nga cho ngi, n nhng nm 1890 ln lt ra i vacxin t, thng hn, dch hch Thp k u th k l vacxin ho g, lao. n nhng nm 80 ca th k 20, hn 20 loi vacxin khc c a vo sn xut. Trong 27 loi vacxin, tt c u c tim tr 3 loi c vacxin ung l bi lit, t, thng hn. Khng phi tt c cc tr em trn th gii u c th c dng vacxin v nh vacxin t, thng hn, st vng ch cn cho ngi sng trong mt vng dch hoc c gh qua vng . Trong s min dch chun ang dng cc nc ang pht trin cng c ti t ra t 5-6 mi tim. M tr em c tim chng vi 14 loi (11 loi trc 8 thng tui) nhiu gp i s lng yu cu 10 nm trc. Vi hn 200 loi vacxin ang nghin cu v pht trin, k c vacxin phng bnh do ph cu khun v no cu khun gy ra, s ln tim s khng gim i. ng Walter-vADNermissen ca hng SB pht biu trong cuc hp ca CVI gn y cho rng t nht s c 25 loi vacxin cho tr em vo nm 2010. Nh vy tr em ang qu ti v nhng mi tim ! V nhng thy thuc y hc d phng c lin quan n s qu ti ny hn chnh cha m ca nhng a tr khe mnh phi tim vacxin. Vn ny phc tp hn nhng nc pht trin v c nhng mi tim khng an ton na. Vic phi hp hu ht cc vacxin vo mt mi tim l mt cch hn ch s ln tim vacxin. Cc tin b k thut trong tng lai d nhin s sn xut c nhiu loi khc nh vacxin ung nhng trc mt cn Mt hn hp khng nguyn trn vo mt sn phm n thch hp vn l mt gii php hp l trnh qu ti cho tr. 22.9.1. Thnh tu (1949 - 1983) 1949: Vacxin a gi u tin, lin kt cc khng nguyn bch hu v ho g, bch hu v ung vn, bch hu ho g un vn (DTP: Diphteria- Pertussis-Tetanus). 1955: Vacxin n gi (1 bnh) a chng u tin vacxin bi lit bt hot (IPV: Inactivated Polio Vacxine) lin kt 3 tp virut polio c dng tim v vacxin thng hn, ph thng hn A v B/ 1957: Phi hp aenovirut, cm (c chp nhn s dng nm 1980)/ 1958: Vacxin bi lit 3 tp theo ng ung (OPV) sabin c s dng rng ri Lin bang X Vit t nm 1958 v c ng k M nm 1963. 1967: Phi hp si u ma (c chp nhn nm 1985 sau khi thanh ton bnh u ma). 1970: Phi hp si c (rubella) quai b. 1971: Phi hp si rubella v si quai b Si c. 1973: Phi hp si quai b. 1975: Vacxin cng hp 2 chng (A-C) ca no cu khun s dng khng nguyn v vi khun polyxacarit (MenPS) 1977: Vacxin ph cu polyxacarit (PnPS) cng hp 14 chng ca ph cu khun 1981: Vacxin vim mng no th h 2 phi hp 4 chng ca no cu khun (A, C, Dch v v W 135). 1983: Vacxin ph cu 23 chng thay th loi 14 chng. Vi t chc CVI khuyn khch dng vacxin a gi v n gin ha vic tim chng nhm tng s lng tr min dch vi khng nguyn mi cng sm cng tt. Nhng li im ca vacxin - V thc tin: + Ngi c chng nga v gia nh: gim au v lo lng v b tim t hn, gim s ln i tim. Nm 2001, ti Php, nh s dng vacxin lin hp, tr < 2 tui, ch phi tim 7 mi, thay v phi tim 88 mi; tr < 18 tui, ch phi tim 11 mi, thay v phi tim tng cng 55 mi. + Nhn vin chng nga: tit kim thi gian, gim nguy c b kim chm. - V y t cng ng: + Tng t l chng nga. + Cc khng nguyn mi d c chp nhn hn. + Li im v lch chng nga. - V kinh t: Tit kim trong cc khu + Sn xut: th tc xut l, bao b, kho cha, chuyn ch, kim k. + a thuc v c th: ng tim, kim tim, nhn vin tim. a, Cc kh khn khi pht trin mt vacxin phi hp Phi bo m s tng thch gia cc loi thnh phn ca cc vacxin c lin hp vi nhau (khng th, cht bo qun, cht ph gia, t dc, cht n nh) Phi bo m c bn vng ca cc vacxin thnh phn. Phi bo m tnh gy min dch v hiu qu bo v ca tng khng nguyn. Phi bo m phi hp khng lm tng tc dng ph ca cc vacxin c phi hp. b. Nguyn l phi hp Khi cng ngh vacxin pht trin, nh Ph tng Gim c hng SB Francis ADNres nh gi, vacxin phi hp 10 loi khng nguyn l k thut c th thc hin c. Ngi ta cho rng vacxin DTP s l b khung ch cn p thm cc khng nguyn khc s c tc dng hiu qu ton cu. S la chn ny c 2 l do chnh: DTP c s dng rng ri, ng thi DTP cn c xem l mt vacxin n nh v vn gi vai tr chnh ca cc chng trnh tim chng quc gia trn ton th gii (nhng chng trnh ny chng nga c khong 75-80% tr em trn th gii di 2 tui). Vo nm 1991, mt loi vacxin DTP mi thnh phn khng nguyn ho g v bo (DPaT) c ng k M. Vacxin ho g v bo ny c pht trin u tin Nht gn 20 nm trc, s dng mt hoc nhiu khng nguyn tinh khit ca vi khun ho g thay cho vacxin ho g ton t bo c in (wP) DtaP cng hiu nh DTwP nhng t c phn ng ph hn. Song loi ny t gi, cao gp ri so vi DTwP trn th trng nc M.
Hnh 22.16: Sn xut vacxin t quy m ln S xut hin cc khng nguyn ha hc mi nh Hep B (Vim gan B) hoc Hib (Haemophilus influenza typ b) gy vim mng no v vim ph qun to thm cc dng phi hp mi, DTwP vi HepB hoc Hib hoc vi Hib v IPV, cng c khi ngi ta dng ca vacxin DTwP-HepB dng nc tim cng vacxin Hib ng kh. Bn cng c th phi hp Hib v HepB vi HepA. Cho n nay, c 17 kiu phi hp vacxin theo nhiu phng php thch hp. V s khng c l do g chng ta khng thy c 17 loi vacxin phi hp khc thnh 34 loi. phi hp tt ra i k cng hp. Cc vn ny sinh cn gii quyt vacxin l gi c, liu lng thch hp, quy thnh sn xut, nhu cu bo qun lnh, tui th vacxin, phn ng ph, hiu qu bo v v nhiu iu khc. Nh my tnh vi vacxin phng 5 bnh (bch hu, un vn, ho g, Hib v vim gan B), c 16.000 kiu phi hp khc nhau, v th phi hp l mt s thay th hp l tit kim mi tim. D th no, cn loi tr cc khng nguyn tha khi phi vacxin. cc nc ang pht trin cn cn nhc khi phi a HepB hoc Hib vo chng trnh tim chng m rng. C tht s cn phi hp vacxin, liu c tha khi ghp thm c khng nguyn mi cha gy dch cng nh vn gi c v h thng dy chuyn lnh. Trng hp t sn xut DTP th c nn nhp DTP-HepB-HiB hay ch nhp n l cc khng nguyn dng bn thnh phm? Mun vy, vacxin DTP t sn xut phi t cht lng cao ca quc t quy nh. Vi cc nc cn ang t sn xut DTwP th c nn nhp DtaP ? Ni chung cc nc ang pht trin vn thch dng DTwP hn v r tin, v cn nghi ng cng hiu ca Pa v cn duy tr nn sn xut ang c ca chnh cc nc . Gi cn t l cn tr trc nht cho vic s dng vacxin phi hp cc nc ang pht trin. Cc vacxin phi hp bn M (14-20 USD/liu) nu mua s lng ln c UNICEF tr gi vi cc nc ngho c th thp hn 10 USD nhng chc khng di 2 USD/liu. Trong khi cc nc ngho cn phi lo bao cp cc vacxin cn thit hn nh DTP, BCG, bi lit, si th cc vacxin phi hp qu l kh bn c rng ri cc nc ny. gim gi cn tng cng tip th mi ngi dn thy c ci li ca con em h khi dng vacxin phi hp, tng s lng bn ra song song vi vic gim bt cc chi ph trung gian nh cng tim chch v o to cc nhn vin y t, cc chi ph do dng c tim, ph vn chuyn v bo qun, gim t l hao ht vacxin nh ng l liu ph hp ty loi, ty th trng. Tr ngi cui cng ph cp vacxin phi hp l vn thng tin tuyn truyn v cng thc phi hp, hiu qu phng bnh cao v cc phn ng ph t ca vacxin mi cha k nhng thng tin cng ngh phi hp vacxin cho cc nc ang pht trin. 22.9.2. Nhng vn cng ngh Bn cht khng nguyn, s tng tc trong hn hp, cng hp v dung np, nh lng khng nguyn. Tnh hiu qu v an ton so snh gia phi hp vi tng thnh phn n. Cng thc v nh hng ca cht m, pH, bo qun trong vacxin a gi. Chi ph cho kim nh in vitro v in vitro kt qu thc a theo tng vng dn c v dch t khc nhau. S tng ng gia hiu qu huyt thanh hc vi dch t hc (nht l cc thnh phn n nguyn tng t nh khng nguyn vi khun ho g). Thc a vi vacxin hn hp kh nh gi ht hiu qu ca tng hp phn nu dng ring. Tng chi ph cho ra i mt loi vacxin phi hp mi cn u t 100-200 triu USD. 22.9.3. Vn th trng Phi hp vacxin cho ph hp nhu cu ca khi cc nc pht trin v ngho hay cho c hai. Liu c thu ht tham gia chung ca tt c cc nh sn xut vacxin hay ch khu tr 5 cng ty ln. Liu c c quyn cng thc phi hp v c quyn phn phi vacxin ha hn u t ? Tui th vacxin phi hp liu c di nh vacxin n hay d b thay th trong thi i pht trin cng ngh nh hin nay. Nu tui th ngn, cn cn nhc u t sao cho gi c phi chng nu khng s kh tiu th vacxin phi hp. Cui cng l thi quen v tiu th v chnh sch t lc sn xut vacxin cc nc ang pht trin cng nh hng n kh nng u t pht trin cc vacxin phi hp mi. D sao cng c nhng s liu kh quan v th trng tiu th cc vacxin phi hp v d th trng Anh quc t 1,2t USD nm 1992 tng dn 1,7 t USD nm 1997 v nm 2002 s l 3,8 t USD (trong 10 nm qua vacxin phi hp chim 40-50 th phn vacxin). Phi hp vacxin cn m ng pht trin cho cc nh sn xut khi cn y mnh s lng bn ra bng cch ph cp vacxin n gi thp vo mt loi a gi v ngc li. Phi nm bt yu cu ca th trng ring mi nc theo kiu bnh tng a phng kp a vo nhng vacxin ph hp l chin lc pht trin ca cc nh sn xut ln hin nay. C nhng bnh cha phi ti nguy him nh thy u hoc quai b nhng nu c thm vacxin ny trong vacxin phi hp a gi s hp dn cng ng trnh hi chng lm dng vacxin v nh vic phi hp mt s khng nguyn nht nh trong nhiu nguyn nhn tiu chy ch nh rch ri cho ngi du lch hay ch dng cho dn c nhng ni c cc bnh a phng. Cc t chc quc t WHO, CVI s nh hng pht trin vacxin phi hp chung ton cu trong mt ngy gn y pht huy sc mnh ca dng vacxin phi hp mi nhm tng hiu qu an ton cho ngi s dng.