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'''Atenuované viry''' se využívají jako '''očkovací látky'''. Jde o nejstarší a velmi účinný způsob vakcinace. I jejich objevení souvisí s hledáním účinné prevence proti dříve velmi rozšířeným a smrtelným onemocněním, z nichž některá v dnešní době byla již zcela eradikována celosvětově, vymýcena ve vyspělých zemích nebo alespoň byl snížen jejich výskyt a úmrtnost.
'''Attenuated viruses''' are used as '''vaccines'''. It is the oldest and very effective method of vaccination. Their discovery is also linked to the search for effective prevention against previously widespread and fatal diseases, some of which have now been completely eradicated worldwide, eradicated in developed countries, or at least reduced in incidence and mortality.


Používání živých, byť oslabených, virů s sebou přináší určitá '''rizika'''. Největším z nich je možnost ''reverze'', tj. návrat k virulenci a vznik onemocnění. Zároveň jsou i vyšší nároky na skladování očkovacích látek, neboť porušení chladového řetězce může vést ke ztrátě antigenních vlastností. V dnešní době probíhá několik vědeckých studií, které se snaží pomocí kontroly replikace a virulence navrhnout způsob výroby bezpečnějších vakcín, které by mohly například pomoci v eradikaci viru [[Poliomyelitida|poliomyelitidy]].
The use of live, albeit attenuated, viruses carries certain '''risks'''. The greatest of these is the possibility of reversion, i.e. a return to virulence and the emergence of disease. There are also higher storage requirements for vaccines, as cold chain disruption can lead to loss of antigenic properties. Several scientific studies are now underway to try to design a way of producing safer vaccines by controlling replication and virulence, which could, for example, help in the eradication of [[poliomyelitis virus]].


== Historie použití ==
== History of use ==
[[Soubor:Polio.jpg |náhled| Poliovirus (negativně barvený preparát z buněčné kultury; transmisivní elektronová mikroskopie; měřítko má délku 50 nm)]]
The first vaccination with attenuated vaccinia virus, the causative agent of '''cowpox''', was carried out in 1796 by Edward Jenner as a defence against variola virus, the causative agent of [[smallpox]]. Thanks to an aggressive vaccination campaign, smallpox was eradicated in 1980. Today, smallpox is no longer routinely vaccinated against. However, smallpox virus remains available in some laboratories, raising concerns about its possible use for bioterrorism.
První vakcinace atenuovaným virem rodu ''Vaccinia'', původce kravských '''neštovic''', byla provedena v roce 1796 Edwardem Jennerem jako obrana proti viru varioly, původci [[Pravé neštovice|pravých neštovic]]. Díky agresivní očkovací kampani se podařilo v roce 1980 pravé neštovice eradikovat. Dnes se již proti neštovicím rutinně neočkuje. Virus pravých neštovic však zůstává dostupný v některých laboratořích, což vzbuzuje obavy z možného využití k bioterorismu.


Dalším úspěchem ve válce proti virovým onemocněním bylo použití '''Sabinovy vakcíny''' proti '''[[Poliomyelitida|poliomyelitidě]]'''. Vakcína obsahuje 3 oslabené kmeny označované 1, 2, 3 a podává se orálně (OPV, ''oral polio vaccine''). Kromě této živé atenuované vakcíny existuje i '''Salkova vakcína''' obsahující usmrcené viry, která se podává injekčně (IPV); ta však nevyvolává slizniční střevní imunitu. Dítě očkované IPV je sice chráněno před onemocněním, může však virus poliomyelitidy předávat dál, přijde-li s ním do styku.
Another success in the war against viral diseases was the use of '''Sabin's [[poliomyelitis]] vaccine'''. The vaccine contains 3 attenuated strains called 1, 2, 3 and is administered orally (OPV, oral polio vaccine). In addition to this live attenuated vaccine, there is a '''Salk vaccine''' containing killed viruses which is administered by injection (IPV); however, it does not induce mucosal intestinal immunity. Although a child vaccinated with IPV is protected from disease, it can pass on poliomyelitis virus if it comes into contact with it.


Výhodou '''OPV''' je navození silnější imunitní reakce již po první dávce. Očkovaný také vylučuje oslabené viry ve stolici, což může vyvolat imunitní odpověď u neočkovaných osob, které se s ním setkávají. Použití OPV s sebou ovšem nese riziko mutace a reverze atenuovaného viru, a tedy rozvoj nemoci u očkovaných. Podle WHO onemocní v důsledku očkování kolem 60 dětí ročně<ref>{{Citace
'''OPV''' has the advantage of inducing a stronger immune response after the first dose. The vaccinated person also excretes the weakened viruses in the stool, which can trigger an immune response in unvaccinated people who come into contact with it. The use of OPV, however, carries the risk of mutation and reversion of the attenuated virus, and thus the development of disease in vaccinated persons. According to the WHO, around 60 children a year fall ill as a result of vaccination<ref>The Global Polio Eradication Initiative. ''Circulating vaccine-derived poliovirus (cVDPV) 2000-2013'' [online]. ©2010. Poslední revize 2013-02-26, [cit. 2013-03-06]. <<nowiki>http://polioeradication.org/Dataandmonitoring/Poliothisweek/Circulatingvaccinederivedpoliovirus.aspx</nowiki>>.</ref>, which can spread the mutated virus further to the unvaccinated. The largest outbreak of poliomyelitis caused by a vaccine strain occurred in 2005 in Nigeria and the virus is still circulating. Despite these isolated cases, poliomyelitis has been successfully eradicated in developed countries and only three endemic areas remain - Afghanistan, Nigeria and Pakistan. Worldwide, 650 cases were recorded in 2011 and 223 cases in 2012.<ref>The Global Polio Eradication Initiative. ''Polio this week - As of 24 April 2013'' [online]. ©2010. [cit. 2013-04-30]. <<nowiki>http://polioeradication.org/polio-today/polio-now/</nowiki>>.</ref>
| typ = web
[[File:Polio.jpg|thumb|Poliovirus (negatively stained cell culture preparation; transmission electron microscopy; scale bar 50 nm)]]
| korporace = The Global Polio Eradication Initiative
The '''WHO'''-sponsored global campaign to eradicate poliomyelitis virus began in 1988 and was originally planned to end by 2000. However, the goal has still not been achieved.Wild type 2 virus has been eradicated, but vaccine-derived poliovirus (VDPV) infections remain a problem. In 90% of cases, it is a reversion-derived type 2 virus. A possible solution is to remove type 2 from the oral vaccine and introduce the current Salk vaccine, which protects against all three types, but this is a costly procedure. In developed countries, there has been a move to inactivated virus vaccination (IPV), which has been used in this country since 2007 and in the USA since 2000.
| url = http://polioeradication.org/Dataandmonitoring/Poliothisweek/Circulatingvaccinederivedpoliovirus.aspx
| název = Circulating vaccine-derived poliovirus (cVDPV) 2000-2013
| rok = 2010
| datum_revize = 2013-02-26
| citováno = 2013-03-06
}}
</ref>, které mohou šířit mutovaný virus dále na neočkované. Největší výskyt poliomyelitidy způsobené vakcinačním kmenem se vyskytl v roce 2005 v Nigerii a virus stále koluje. I přes tyto ojedinělé případy se ve vyspělých zemích povedlo poliomyelitidu eradikovat a zůstávají jen tři endemické oblasti výskytu – Afghánistán, Nigérie a Pákistán. Celosvětově bylo evidováno 650 nakažených za rok 2011 a 223 nakažených v roce 2012<ref>{{Citace
| typ = web
| korporace = The Global Polio Eradication Initiative
| url = http://polioeradication.org/polio-today/polio-now/
| název = Polio this week - As of 24 April 2013
| rok = 2010
| citováno = 2013-04-30
}}
</ref>.


Globální kampaň pod záštitou '''WHO''' na eradikaci viru poliomyelitidy začala v roce 1988, její ukončení se původně plánovalo do r. 2000. Cíle však stále nebylo dosaženo.Podařilo se vymýtit divoký virus typu 2, problémem ale zůstávají infekce virem odvozeným od očkování (VDPV, ''vaccine-derived poliovirus''). V 90 % jde o reverzí vzniklý virus typu 2. Možným řešením je vyřazení typu 2 z orální vakcíny a zavedení současné vakcinace Salkovou vakcínou, která chrání proti všem třem typům, jde však o finančně nákladný postup. Ve vyspělých zemích se přechází na očkování neživými viry (IPV), které se používá u nás od roku 2007, v USA od roku 2000.
== Prospects for the future ==
The traditional method of attenuating viruses by repeated passaging on cell cultures under suboptimal conditions carries certain risks, and scientific teams are trying to find ways to obtain a non-pathogenic strain with preserved immunogenicity in a rational way. With a deeper understanding of the molecular nature of viruses, in particular the discovery of pathogenicity- and immunogenicity-associated genes, possible routes to safer vaccines are emerging. However, research is still being carried out in animal models and the possible use in human medicine is not yet on a nearer time horizon.


== Výhledy do budoucna ==
Four new methods appear most promising:
Tradiční způsob atenuace virů opakovaným pasážováním na buněčných kulturách za suboptimálních podmínek s sebou přináší určitá rizika a vědecké týmy se pokouší nalézt způsoby, jak získat nepatogenní kmen se zachovanou imunogenitou racionálním způsobem. Díky hlubšímu porozumění molekulární podstaty virů, zejména objevem genů asociovaných s patogenitou a imunogenitou, se rýsují možné cesty pro získání bezpečnějších vakcín. Výzkumy jsou však stále prováděny na zvířecích modelech a možné použití v humánní medicíně zatím nemá bližší časový horizont.


Nejslibněji se jeví 4 nové metody:
* increasing replication accuracy,
* zvýšení přesnosti replikace,
* codon deoptimisation,
* deoptimizace kodonů,
* the use of miRNAs,
* využití miRNA,
* the use of nucleases with zinc finger motifs.
* použití nukleáz s motivy zinkových prstů.


Vysoká frekvence mutací u [[RNA viry|RNA virů]] je způsobena z velké části velkou chybovostí virové RNA polymerázy, která je přibližně '''0,1–10 mutací/replikaci genomu''' o cca 10 000 nukleotidů, což je o několik řádů více než u [[DNA viry|DNA virů]]. Tato skutečnost umožňuje velmi rychlou evoluci a adaptaci a díky tomu snížení chybovosti polymerázy sníží diversitu populace a vede ve zvířecím modelu k atenuaci.
The high mutation rate of [[RNA viruses]] is largely due to the high error rate of viral RNA polymerase, which is approximately '''0.1-10 mutations/genome replication''' of about 10,000 nucleotides, which is several orders of magnitude higher than that of [[DNA viruses]]. This fact allows for very rapid evolution and adaptation, and as a result, a reduction in polymerase error rate will reduce population diversity and lead to attenuation in the animal model.


Tým z Californské Univerzity v San Francisku pod vedením M. Vignuzzi<ref>{{Citace
The team from the University of California, San Francisco, led by M. Vignuzzi<ref>VIGNUZZI, Marco, Emily WENDT a Raul ANDINO. Engineering attenuated virus vaccines by controlling replication fidelity. ''Nature Medicine'' [online]''. ''2/2008, roč. 14, s. 154-16, dostupné také z <<nowiki>http://www.nature.com/articles/doi:10.1038/nm1726</nowiki>>. ISSN 1078-8956. </ref>, performed the assays on poliomyelitis virus polymerase using ribavirin, an analogue of nucleotide bases. Polymerase variants with mutations in the 64th amino acid in the chain, which plays a key role in controlling the amino acids inserted during transcription, were found to be resistant even to high concentrations of this analogue. Variants with 6 possible amino acids at position 64 - glycine, valine, alanine, serine, threonine and leucine - show low error rates, correlating with ribavirin resistance.
|typ = článek
|korporace =
|příjmení1 = Vignuzzi
|jméno1 = Marco
|příjmení2 = Wendt
|jméno2 = Emily
|příjmení3 = Andino
|jméno3 = Raul
|kolektiv =
|článek = Engineering attenuated virus vaccines by controlling replication fidelity
|časopis = Nature Medicine
|rok = 2/2008
|ročník = 14
|strany = 154-16
|issn = 1078-8956
|url=http://www.nature.com/articles/doi:10.1038/nm1726
}}</ref> prováděl testy na polymeráze viru poliomyelitidy a pomocí ''ribavirinu'', analogu nukleotidových bazí. Bylo zjištěno, že varianty polymerázy s mutacemi v 64. aminokyselině v řetězci, která hraje klíčovou roli v kontrole zařazených aminokyselin během přepisu, jsou rezistentní i k vysokým koncentracím tohoto analogu. Nízkou chybovost, korelující s rezistencí k ribavirinu, vykazují varianty s 6 možnými aminokyselinami na pozici 64 – glycin, valin, alanin, serin, threonin a leucin.


Při testování vykazovaly varianty se změnou v pozici 64 snížený výskyt mutací během přepisu (wild type – 5,32/genom, pozice 64 – podle AK 2,15–2,96) a i po delším pasážováním vykazovaly virové kmeny s mutací '''sníženou diversitu populace'''. Mutace v pozici 64 jsou tedy stabilní. Snížená diversita populace viru výrazně snižuje patogenitu a varianty se sníženou chybovostí jsou silně atenuované a nedovolí rozvoj infekce v centrálním nervovém systému myši, ale neovlivní replikaci v jiných tkáních a tím umožní rozvoj imunitní reakce<ref>{{Citace
When tested, variants with a change at position 64 showed a reduced mutation rate during transcription (wild type - 5.32/genome, position 64 - AK 2.15-2.96) and even after prolonged passaging, viral strains with the mutation showed '''reduced population diversity'''. Thus, mutations at position 64 are stable. The reduced population diversity of the virus greatly reduces pathogenicity and the reduced missense variants are strongly attenuated and will not allow infection to develop in the central nervous system of the mouse but will not affect replication in other tissues and thus allow the development of an immune response<ref>LAURING, Adam S., Jeremy O. JONES a Raul ANDINO. Rationalizing the development of live attenuated virus vaccines. ''Nature Biotechnology'' [online]''. ''6/2010, roč. 28, s. 573-579, dostupné také z <<nowiki>http://www.nature.com/articles/doi:10.1038/nbt.1635</nowiki>>. ISSN 1087-0156. </ref>.
|typ = článek
|korporace =
|příjmení1 = Lauring
|jméno1 = Adam S.
|příjmení2 = Jones
|jméno2 = Jeremy O.
|příjmení3 = Andino
|jméno3 = Raul
|kolektiv =
|článek = Rationalizing the development of live attenuated virus vaccines
|časopis = Nature Biotechnology
|rok = 6/2010
|ročník = 28
|strany = 573-579
|issn = 1087-0156
|url=http://www.nature.com/articles/doi:10.1038/nbt.1635
}}</ref>.


Výše popsaný postup by bylo možné aplikovat na další ''picornaviry'', ale u dalších RNA virů je potřeba nejdříve určit klíčové aminokyselinové zbytky, jejichž nahrazení by vedlo ke snížení chybovosti polymerázy. V září roku 2011 byla publikována studie vědců z Institut Pasteur v Paříži pod vedením Lark L. Coffey<ref>{{Citace
The approach described above could be applied to other picornaviruses, but for other RNA viruses, it is necessary to first identify the key amino acid residues whose replacement would lead to reduced polymerase error rates. In September 2011, a study published by scientists at the Institut Pasteur in Paris, led by Lark L. Coffey, described the successful attenuation of chikungunya virus arbovirus (CHIKV) by replacing one AK in the polymerase chain, leading to a reduction in error rate comparable in percentage to the study on poliovirus. The experiment was performed in '''a natural model of infection''' - transmission from mosquito to vertebrate mouse, which naturally expresses receptors for this virus. The authors further hypothesise that similar results could be achieved with other arboviruses and could lead to the development of genetically stable vaccines, thus preventing millions of human infections per year with CHIKV.
|typ = článek
|korporace =
|příjmení1 = Coffey
|jméno1 = L. L.
|příjmení2 = Beeharry
|jméno2 = Y.
|příjmení3 = Borderia
|jméno3 = A. V.
|příjmení4 = Blanc
|jméno4 = H.
|příjmení4 = Vignuzzi
|jméno4 = HM.
|kolektiv =
|článek = Arbovirus high fidelity variant loses fitness in mosquitoes and mice
|časopis = Proceedings of the National Academy of Sciences
|rok = 38/2011
|ročník = 108
|strany = 16038–16043
|issn = 0027-8424
|url=http://www.pnas.org/content/108/38/16038
}}</ref>, ve které popisují úspěšnou atenuaci [[arboviry|arboviru]] ''viru chikungunya'' (CHIKV) díky záměně jedné AK v řetězci polymerázy, která vede ke snížení chybovosti, procentuálně srovnatelné se studií na polioviru. Experiment byl proveden na '''přirozeném modelu infekce''' – přenos z komára na obratlovce, myš, která přirozeně exprimuje receptory pro tento virus. Autoři dále předpokládají, že obdobných výsledků by šlo dosáhnout i u jiných arbovirů a mohly by vést k vývoji geneticky stabilních vakcín a u CHIKV tak zabránit milionům infekcí lidí ročně.


Další nové metody umožňují získání atenuovaných kmenů díky vložení '''synonymních kodonů''' do genomu, které jsou však hostitelskou buňkou méně preferované, čímž se prodlouží doba translace a vznikne menší množství virových potomků – virus je silně atenuovaný bez dopadu na imunogenicitu a geneticky stabilní.
Other new methods allow for the production of attenuated strains by inserting s'''ynonymous codons''' into the genome, but these are less preferred by the host cell, thus increasing translation time and producing fewer viral progeny - the virus is strongly attenuated without affecting immunogenicity and is genetically stable.


Vložením sekvence vázající specifickou [[miRNA]] do genomu viru lze zastavit translaci určitého genu nebo celého genomu díky navázání komplementární miRNA exprimované hostitelskou buňkou. Tento princip je '''normální regulační cestou''', kterou buňka reguluje genovou produkci, ale v jeho využití k atenuaci naráží na problémy, že inzertovaná miRNA sekvence je přepisována jen v určitých tkáních a může akumulovat mutace.
By inserting a sequence binding a specific [[RNA - types, structure and function|miRNA]] into the virus genome, translation of a specific gene or the entire genome can be stopped by binding a complementary miRNA expressed by the host cell. This principle is the '''normal regulatory pathway''' by which the cell regulates gene production, but it runs into problems in its use for attenuation in that the insertion miRNA sequence is transcribed only in certain tissues and can accumulate mutations.


Jiná metoda využívá ''zinkové prsty'', specifické domény vážící se na DNA, které mohou sloužit jako negativní [[transkripční faktory]] nebo fúzí s nukleázou mohou štěpit specifický úsek virové DNA. Jejich využití je omezeno na neintegrující se DNA viry, jelikož excise integrované virové DNA by mohla vést k chromozomovým zlomům hostitelské DNA.
Another method uses zinc fingers, specific DNA-binding domains that can serve as negative [[transcription factors]] or, by fusing with nuclease, can cleave a specific stretch of viral DNA. Their use is limited to non-integrating DNA viruses, as excision of integrated viral DNA could lead to chromosomal breaks in the host DNA.


== Použití atenuovaných vakcín v ČR ==
== Use of attenuated vaccines in the Czech Republic ==
V naší zemi je podle platné legislativy '''povinné očkování''', využívající živé oslabené viry, proti spalničkám, zarděnkám a příušnicím, dříve i proti dětské obrně. Doporučené, ale nepovinné jsou vakcíny proti planým neštovicím a průjmovým onemocněním způsobených rotaviry.
In our country, according to the current legislation, vaccination using live attenuated viruses is '''compulsory against measles, rubella and mumps''', formerly also against '''polio'''. Vaccines against chickenpox and diarrhoeal diseases caused by rotavirus are recommended but not compulsory.


Od roku 2006 je u nás dostupná vakcína proti viru [[Herpes zoster]], doporučená pro jedince starší 50 let, která snižuje incidenci pásového oparu o 50 % oproti skupině, které bylo podáno placebo.
A vaccine against [[Herpes zoster|Herpes zoster virus]], recommended for individuals over 50 years of age, has been available since 2006 and reduces the incidence of shingles by 50% compared to a placebo group.


Vakcína proti [[žlutá zimnice|žluté zimnici]] je povinná při cestování do endemických oblastí, zemí vyžadujících mezinárodní očkovací průkaz a pro osoby manipulující s infekčním materiálem.<br />
The [[yellow fever]] vaccine is mandatory for travel to endemic areas, countries requiring an international vaccination card and for persons handling infectious material.<noinclude>


 
== Sources ==
<noinclude>
=== Related articles ===
== Odkazy ==
=== Související články ===
* [[Poliomyelitis anterior acuta]]
* [[Poliomyelitis anterior acuta]]
* [[Pravidelné očkování v Česku]]
* [[Regular vaccination in the Czech Republic]]
* [[Členění očkování v Česku]]
* [[Breakdown of vaccinations in the Czech Republic]]
* [[Aktivní imunizace]]
* [[Active immunisation]]


=== Reference ===
=== Reference ===
<references />
<references />
=== Použitá literatura ===
=== Used literature ===
 
* BERAN, Jiří a Jiří HAVLÍK. ''Lexikon očkování. ''1. vydání. Praha : Maxdorf, 2008. 352 s. <nowiki>ISBN 978-80-7345-164-6</nowiki>.
 
* BRANSWELL, Helen. Polio's Last Act. ''Scientific American'' [online]''. ''4/2012, roč. 306, s. 60-65, dostupné také z <<nowiki>http://www.nature.com/articles/doi:10.1038/scientificamerican0412-60</nowiki>>. ISSN 0036-8733. 
 
* COFFEY, L. L., Y. BEEHARRY a A. V. BORDERIA. Arbovirus high fidelity variant loses fitness in mosquitoes and mice. ''Proceedings of the National Academy of Sciences'' [online]''. ''38/2011, roč. 108, s. 16038–16043, dostupné také z <<nowiki>http://www.pnas.org/content/108/38/16038</nowiki>>. ISSN 0027-8424. 
 
* LAURING, Adam S., Jeremy O. JONES a Raul ANDINO. Rationalizing the development of live attenuated virus vaccines. ''Nature Biotechnology'' [online]''. ''6/2010, roč. 28, s. 573-579, dostupné také z <<nowiki>http://www.nature.com/articles/doi:10.1038/nbt.1635</nowiki>>. ISSN 1087-0156. 
 
* VIGNUZZI, Marco, Emily WENDT a Raul ANDINO. Engineering attenuated virus vaccines by controlling replication fidelity. ''Nature Medicine'' [online]''. ''2/2008, roč. 14, s. 154-16, dostupné také z <<nowiki>http://www.nature.com/articles/doi:10.1038/nm1726</nowiki>>. ISSN 1078-8956. 
 
* BIO Ventures for Global Health. ''Live attenuated vaccines'' [online]. [cit. 2013-04-30]. <<nowiki>https://bvgh.org/Biopharmaceutical-Solutions/Global-Health-Primer/Targets/cid/ViewDetails/ItemID/6.aspx</nowiki>>.
 
* Centers for Disease Control and Prevention. ''Vaccinia Virus Infections in Martial Arts Gym, Maryland, USA, 2008'' [online]. [cit. 2013-04-30]. <<nowiki>https://wwwnc.cdc.gov/eid/article/17/4/10-1010_article</nowiki>>.
 
* Centers for Disease Control and Prevention. ''Polio Disease - Questions and Answers'' [online]. [cit. 2013-04-30]. <<nowiki>https://www.cdc.gov/vaccines/vpd-vac/polio/dis-faqs.htm</nowiki>>.
 
* Irish Pharmaceutical Healthcare Association. ''Vaccines History'' [online]. [cit. 2013-04-30]. <<nowiki>https://www.ipha.ie/alist/vaccines-historical-timeline.aspx</nowiki>>.
 
* olecich.cz. ''Očkovací kalendář'' [online]. [cit. 2013-04-30]. <<nowiki>http://www.olecich.cz/modules/vaccine/vaccine.php?tab=def_age&category=childhood</nowiki>>.
 
* The Global Polio Eradication Initiative. ''Polio this week - As of 24 April 2013'' [online]. [cit. 2013-04-30]. <<nowiki>http://polioeradication.org/polio-today/polio-now/</nowiki>>.
 
* The Global Polio Eradication Initiative. ''Circulating vaccine-derived poliovirus'' [online]. [cit. 2013-04-30]. <<nowiki>http://polioeradication.org/Dataandmonitoring/Poliothisweek/Circulatingvaccinederivedpoliovirus.aspx</nowiki>>.
 
* Bulletin of the World Health Organization. ''Ending polio, one type at a time'' [online]. [cit. 2013-04-30]. <<nowiki>http://www.who.int/bulletin/volumes/90/7/12-020712/en/</nowiki>>.
 
* {{Citace  
* {{Citace  
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Revision as of 12:19, 2 February 2022

Attenuated viruses are used as vaccines. It is the oldest and very effective method of vaccination. Their discovery is also linked to the search for effective prevention against previously widespread and fatal diseases, some of which have now been completely eradicated worldwide, eradicated in developed countries, or at least reduced in incidence and mortality.

The use of live, albeit attenuated, viruses carries certain risks. The greatest of these is the possibility of reversion, i.e. a return to virulence and the emergence of disease. There are also higher storage requirements for vaccines, as cold chain disruption can lead to loss of antigenic properties. Several scientific studies are now underway to try to design a way of producing safer vaccines by controlling replication and virulence, which could, for example, help in the eradication of poliomyelitis virus.

History of use

The first vaccination with attenuated vaccinia virus, the causative agent of cowpox, was carried out in 1796 by Edward Jenner as a defence against variola virus, the causative agent of smallpox. Thanks to an aggressive vaccination campaign, smallpox was eradicated in 1980. Today, smallpox is no longer routinely vaccinated against. However, smallpox virus remains available in some laboratories, raising concerns about its possible use for bioterrorism.

Another success in the war against viral diseases was the use of Sabin's poliomyelitis vaccine. The vaccine contains 3 attenuated strains called 1, 2, 3 and is administered orally (OPV, oral polio vaccine). In addition to this live attenuated vaccine, there is a Salk vaccine containing killed viruses which is administered by injection (IPV); however, it does not induce mucosal intestinal immunity. Although a child vaccinated with IPV is protected from disease, it can pass on poliomyelitis virus if it comes into contact with it.

OPV has the advantage of inducing a stronger immune response after the first dose. The vaccinated person also excretes the weakened viruses in the stool, which can trigger an immune response in unvaccinated people who come into contact with it. The use of OPV, however, carries the risk of mutation and reversion of the attenuated virus, and thus the development of disease in vaccinated persons. According to the WHO, around 60 children a year fall ill as a result of vaccination[1], which can spread the mutated virus further to the unvaccinated. The largest outbreak of poliomyelitis caused by a vaccine strain occurred in 2005 in Nigeria and the virus is still circulating. Despite these isolated cases, poliomyelitis has been successfully eradicated in developed countries and only three endemic areas remain - Afghanistan, Nigeria and Pakistan. Worldwide, 650 cases were recorded in 2011 and 223 cases in 2012.[2]

Poliovirus (negatively stained cell culture preparation; transmission electron microscopy; scale bar 50 nm)

The WHO-sponsored global campaign to eradicate poliomyelitis virus began in 1988 and was originally planned to end by 2000. However, the goal has still not been achieved.Wild type 2 virus has been eradicated, but vaccine-derived poliovirus (VDPV) infections remain a problem. In 90% of cases, it is a reversion-derived type 2 virus. A possible solution is to remove type 2 from the oral vaccine and introduce the current Salk vaccine, which protects against all three types, but this is a costly procedure. In developed countries, there has been a move to inactivated virus vaccination (IPV), which has been used in this country since 2007 and in the USA since 2000.

Prospects for the future

The traditional method of attenuating viruses by repeated passaging on cell cultures under suboptimal conditions carries certain risks, and scientific teams are trying to find ways to obtain a non-pathogenic strain with preserved immunogenicity in a rational way. With a deeper understanding of the molecular nature of viruses, in particular the discovery of pathogenicity- and immunogenicity-associated genes, possible routes to safer vaccines are emerging. However, research is still being carried out in animal models and the possible use in human medicine is not yet on a nearer time horizon.

Four new methods appear most promising:

  • increasing replication accuracy,
  • codon deoptimisation,
  • the use of miRNAs,
  • the use of nucleases with zinc finger motifs.

The high mutation rate of RNA viruses is largely due to the high error rate of viral RNA polymerase, which is approximately 0.1-10 mutations/genome replication of about 10,000 nucleotides, which is several orders of magnitude higher than that of DNA viruses. This fact allows for very rapid evolution and adaptation, and as a result, a reduction in polymerase error rate will reduce population diversity and lead to attenuation in the animal model.

The team from the University of California, San Francisco, led by M. Vignuzzi[3], performed the assays on poliomyelitis virus polymerase using ribavirin, an analogue of nucleotide bases. Polymerase variants with mutations in the 64th amino acid in the chain, which plays a key role in controlling the amino acids inserted during transcription, were found to be resistant even to high concentrations of this analogue. Variants with 6 possible amino acids at position 64 - glycine, valine, alanine, serine, threonine and leucine - show low error rates, correlating with ribavirin resistance.

When tested, variants with a change at position 64 showed a reduced mutation rate during transcription (wild type - 5.32/genome, position 64 - AK 2.15-2.96) and even after prolonged passaging, viral strains with the mutation showed reduced population diversity. Thus, mutations at position 64 are stable. The reduced population diversity of the virus greatly reduces pathogenicity and the reduced missense variants are strongly attenuated and will not allow infection to develop in the central nervous system of the mouse but will not affect replication in other tissues and thus allow the development of an immune response[4].

The approach described above could be applied to other picornaviruses, but for other RNA viruses, it is necessary to first identify the key amino acid residues whose replacement would lead to reduced polymerase error rates. In September 2011, a study published by scientists at the Institut Pasteur in Paris, led by Lark L. Coffey, described the successful attenuation of chikungunya virus arbovirus (CHIKV) by replacing one AK in the polymerase chain, leading to a reduction in error rate comparable in percentage to the study on poliovirus. The experiment was performed in a natural model of infection - transmission from mosquito to vertebrate mouse, which naturally expresses receptors for this virus. The authors further hypothesise that similar results could be achieved with other arboviruses and could lead to the development of genetically stable vaccines, thus preventing millions of human infections per year with CHIKV.

Other new methods allow for the production of attenuated strains by inserting synonymous codons into the genome, but these are less preferred by the host cell, thus increasing translation time and producing fewer viral progeny - the virus is strongly attenuated without affecting immunogenicity and is genetically stable.

By inserting a sequence binding a specific miRNA into the virus genome, translation of a specific gene or the entire genome can be stopped by binding a complementary miRNA expressed by the host cell. This principle is the normal regulatory pathway by which the cell regulates gene production, but it runs into problems in its use for attenuation in that the insertion miRNA sequence is transcribed only in certain tissues and can accumulate mutations.

Another method uses zinc fingers, specific DNA-binding domains that can serve as negative transcription factors or, by fusing with nuclease, can cleave a specific stretch of viral DNA. Their use is limited to non-integrating DNA viruses, as excision of integrated viral DNA could lead to chromosomal breaks in the host DNA.

Use of attenuated vaccines in the Czech Republic

In our country, according to the current legislation, vaccination using live attenuated viruses is compulsory against measles, rubella and mumps, formerly also against polio. Vaccines against chickenpox and diarrhoeal diseases caused by rotavirus are recommended but not compulsory.

A vaccine against Herpes zoster virus, recommended for individuals over 50 years of age, has been available since 2006 and reduces the incidence of shingles by 50% compared to a placebo group.

The yellow fever vaccine is mandatory for travel to endemic areas, countries requiring an international vaccination card and for persons handling infectious material.

Sources

Related articles

Reference

  1. ↑ The Global Polio Eradication Initiative. Circulating vaccine-derived poliovirus (cVDPV) 2000-2013 [online]. ©2010. Poslední revize 2013-02-26, [cit. 2013-03-06]. <http://polioeradication.org/Dataandmonitoring/Poliothisweek/Circulatingvaccinederivedpoliovirus.aspx>.
  2. ↑ The Global Polio Eradication Initiative. Polio this week - As of 24 April 2013 [online]. ©2010. [cit. 2013-04-30]. <http://polioeradication.org/polio-today/polio-now/>.
  3. ↑ VIGNUZZI, Marco, Emily WENDT a Raul ANDINO. Engineering attenuated virus vaccines by controlling replication fidelity. Nature Medicine [online]. 2/2008, roč. 14, s. 154-16, dostupné také z <http://www.nature.com/articles/doi:10.1038/nm1726>. ISSN 1078-8956. 
  4. ↑ LAURING, Adam S., Jeremy O. JONES a Raul ANDINO. Rationalizing the development of live attenuated virus vaccines. Nature Biotechnology [online]. 6/2010, roč. 28, s. 573-579, dostupné také z <http://www.nature.com/articles/doi:10.1038/nbt.1635>. ISSN 1087-0156. 

Used literature

  • BERAN, Jiří a Jiří HAVLÍK. Lexikon očkování. 1. vydání. Praha : Maxdorf, 2008. 352 s. ISBN 978-80-7345-164-6.
  • BRANSWELL, Helen. Polio's Last Act. Scientific American [online]. 4/2012, roč. 306, s. 60-65, dostupné také z <http://www.nature.com/articles/doi:10.1038/scientificamerican0412-60>. ISSN 0036-8733. 
  • COFFEY, L. L., Y. BEEHARRY a A. V. BORDERIA. Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proceedings of the National Academy of Sciences [online]. 38/2011, roč. 108, s. 16038–16043, dostupné také z <http://www.pnas.org/content/108/38/16038>. ISSN 0027-8424. 
  • LAURING, Adam S., Jeremy O. JONES a Raul ANDINO. Rationalizing the development of live attenuated virus vaccines. Nature Biotechnology [online]. 6/2010, roč. 28, s. 573-579, dostupné také z <http://www.nature.com/articles/doi:10.1038/nbt.1635>. ISSN 1087-0156. 
  • VIGNUZZI, Marco, Emily WENDT a Raul ANDINO. Engineering attenuated virus vaccines by controlling replication fidelity. Nature Medicine [online]. 2/2008, roč. 14, s. 154-16, dostupné také z <http://www.nature.com/articles/doi:10.1038/nm1726>. ISSN 1078-8956. 
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