oral, live, attenuated - World Health Organization

92 Pages·2014·0.55 MB·English

Annex 2
Recommendations to assure the quality, safety and
efcacy of poliomyelitis vaccines (oral, live, attenuated)
Replacement of Annex 1 of WHO Technical Report Series, No. 904,
and Addendum to Annex 1 of WHO Technical Report Series, No. 910
Introduction 51
General considerations 52
Scope of the Recommendations 58
Part A. Manufacturing recommendations 58
A.1 Defnitions 58
A.2 General manufacturing recommendations 61
A.3 Control of source materials 61
A.4 Control of vaccine production 66
A.5 Filling and containers 76
A.6 Control tests on fnal lot 76
A.7 Records 79
A.8 Retained samples 79
A.9 Labelling 79
A.10 Distribution and transport 80
A.11 Stability, storage and expiry date 80
Part B. Nonclinical evaluation of poliomyelitis vaccines
(oral, live, attenuated) 81
B.1 Characterization of a new virus submaster seed from the WHO master seed 81
B.2 Characterization of virus working seeds from an established master seed where
passage level between master seed and working seed is increased 82
B.3 Characterization following changes in the manufacturing process 82
Part C. Clinical evaluation of poliomyelitis vaccines (oral, live, attenuated) 82
C.1 General considerations 83
C.2 Safety and immunogenicity studies 84
C.3 Post-marketing studies and surveillance 86
Part D. Recommendations for NRAs 87
D.1 General 87
D.2 Release and certifcation by the NRA 88
Part E. Recommendations for poliomyelitis vaccines
(oral, live, attenuated) prepared in primary monkey kidney cells 88
E.1 Control of vaccine production 89
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WHO Expert Committee on Biological Standardization Sixty-third report
tuA oh r s and acknolw edgement s 95
eR ef rence s 100
pA pendix 1
Ore v weiv fo suriv sdes desu ni VPO cudo rp noit 104
pA pendix 2
I n o viv stse t ro f , e cneluriv o ruen dna snoit a redisno c ni noit ale r ot y asa eciohc 108
pA pendix 3
noit a rape r P fo sitile y moilop senic ca v , la ro ( , e vil )de t aune t a gnisu le c sknab –
elpmax e fo a tehs w o� 114
pA pendix 4
-le eC rutluc seuqinhce t ro f gninimre ted eht suriv tne t no c fo sitile y moilop
senic ca v , la ro ( , e vil )de t aune t a 116
pA pendix 5
M ledo lo co to rp ro f eht cafunam gnirut dna lo rt no c fo sitile y moilop senic ca v
,la ro ( , e vil )de t aune t a 118
pA pendix 6
M ledo re c et ac�it ro f eht esaele r fo sitile y moilop senic ca v , la ro ( , e vil )de t aune t a
yb RN sA 137
pA pendix 7
noit a rape r P fo sitile y moilop senic ca v , la ro ( , e vil )de t aune t a gnisu ramirp y
yeknom k yendi sle c – elpmax e fo a tehs w o� 139
eR oc em dn ta io sn pilbu hs ed yb OHW ra e itn edn ed to be sic etn i c�
dna da visory i n tan ru e . Ehca o f the of lol wi gn sectio sn oc tsn ittu e s
reoc em dn ta io sn of r tan ioan l retugal ory tua horitie s )s ARN( dna
of r cafutn am ru er s o f ib ool gica l prodcut .s f I n a ARN so deis re ,s these
OHW eR oc em dn ta io sn yam be da opted sa dein� tiev tan ioan l
reiu q reem tn ,s or om ditac � io s n yam be tsu j ie� d dna dam e yb the . AR N
tI i s reoc em dn ed thta om ditc�a io sn to these eR oc em dn ta io sn
be dam e oynl o n oc dn itio n thta hcus om ditc�a io sn erus n e thta the
ic a v en i s ta el ts a s a ef as dn a eicac � o su s a thta prepra ed i n oc a rdecn a
with the eR oc em dn ta io sn set otu beol . w e� pra t s o f ehca sectio n
pritn ed i n amsl l type ra e oc em tn s or expma el s itn edn ed to provide
da ditioan l iug decna to cafutn am ru er s dna .s ARN
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Annex 2
Introduction
WHO Requirements for oral poliomyelitis vaccine (OPV) were frst formulated
in 1962 (1), and revised in 1965 (2), and then again in 1971 (3), when an
appendix describing the production of OPV in human diploid cells was added.
Te Requirements were further updated in 1982 (4) following an accumulation
of data, particularly on the performance and evaluation of the monkey
neurovirulence test (MNVT) and tests on the karyology of human diploid cells.
Te Requirements for poliomyelitis vaccine (oral) were updated in full in 1989 (5)
to take account of the general requirements for the characterization of continuous
cell lines for the preparation of biologicals, which were adopted in 1985 (6),
and afer a WHO study group concluded that, in principle, such cell lines are
acceptable as substrates for the production of biologicals (7). An addendum was
subsequently adopted (8) that introduced changes in the tests used to confrm
freedom from detectable DNA sequences of simian virus 40 (SV40); introduced
the mutant analysis by polymerase chain reaction (PCR) and restriction enzyme
cleavage (MAPREC) assay as an optional additional in vitro test for poliovirus
type 3; increased levels of laboratory containment for wild polioviruses (WPVs)
(9); and provided guidance on additional antibody screening tests (for foamy
viruses) for animals from closed primate colonies used as a source for primary
monkey kidney cells.
Te Requirements (now Recommendations) were last revised in full
in 1999 (10) when the use of transgenic mice expressing the human poliovirus
receptor (TgPVR21 mice) (11) as an alternative to the MNVT for type-3 virus was
included in the revision, and the MAPREC test was introduced as the in vitro test
of preference for the evaluation of fltered bulk suspensions for poliovirus type 3
(12). Te previously mandated reproductive capacity at elevated temperature
(rct40) test then became an optional, additional test. Te studies with poliovirus
types 1 and 2 in TgPVR21 mice were completed by June 2000, and an addendum
to the WHO Recommendations for the production and control of poliomyelitis
vaccine (oral) was adopted in 2000 (13) that included the neurovirulence test in
TgPVR21 mice as an alternative to the MNVT for all three poliovirus serotypes.
Since then, advances in scientifc knowledge have been made, novel
laboratory techniques have become available and new vaccine formulations (such
as monovalent and bivalent OPV) are being used. In 2008, the WHO Expert
Committee on Biological Standardization advised that the Recommendations for
OPV should be revised. In addition, various tests are now applicable to all three
types of polioviruses, and their signifcance needs to be better explained and
rationalized. Sections on the nonclinical and clinical evaluation of new candidate
OPVs are also required. To facilitate this process, WHO convened a working
group to initiate the revision of the Recommendations for the production
and control of OPV, as outlined in WHO Technical Report Series No. 904 and
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WHO Expert Committee on Biological Standardization Sixty-third report
oN . .0 1 9 Expert s rf om academia , national reglu ator y atu oh ritie s ,) s A R N ( national
control laboratorie s CN( )sL and indtsu r y inov lev d in teh researc ,h manafu ctru e ,
atu oh rization and tets ing or release o f O VP from conu trie s aronu d teh ow rld
met from 2–02 ulJ y 0102 to identif y and disc su teh ieus s to be conis dered in
reviis ng eT cnh ical Report Serie s oN . 409 and oN . 019 .)41(
e� major ieus s addresed dru ing tih s reviis on proce s incldu ed:
� pu dating inof rmation on teh origin o f die� rent ts rain s of r O VP
prodcu tion , and teh addition o f a ne w pA pendix ;1
� pu dating teh section on international ts andard s and reef rence
preparation;s
� pu dating teh section on general manafu ctru ing recommendation s
and control tets ;s
� pu dating inof rmation on neru ovirulence tets s in monek sy )s VNM( T
and in trangs enic mice gT( m ,)s VN T and on teh ERPAM C tets ,
wih c h i s extended to all trh ee tpy e s o f seed s and ulb ;sk
� a ne w pA pendix ,2 giving rationale s of r teh coh ice o f monek y or
mosue neru ovirulence tets ;s
� conis deration o f ne w av ccine of rmulation s m( onoav lent O VP and
ib av lent OVP;)
� an pu date on terminolog , y and teh introdcu tion o f teh vi“ r su
mbus ats er seed lot , ” wih c h i s applicalb e onl y to teh mats er seed
pus plied yb WHO;
� inclisu on o f ne w section s on teh nonclinical and clinical eav luation
o f O; VP
� pu dating teh appendice;s
� pu dating teh ts andard operating procedru e s S( O )s P of r gT m s VN T
and ERPAM C asa ,sy and of r ne w s VNM T in ligth o f tecnh ical
deev lopment.s
dA ditional cah nge s ah ev been made to rb ing teh docmu ent into line iw t h
oteh r WHO Recommendation s plbu iehs d is nce teh lats reviis on.
Geen r la oc isn derta iosn
oP liomey litis is an actu e communicalb e disease of umh ans caused y b three
dits inct polioiv r su es rotpy e s t( py e s ,1 2 and )3 dits ingiu ahs lb e y b a netu ralization
tets (15) . oP liovirus is a ps ecies C umh an enterovirus of teh vr oiP eci a adi n
famil, y and is composed of a single-ts randed, positiev -sense A RN genome and
a protein capis d.
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Annex 2
Where sanitation is poor, these viruses are believed to be spread mainly
by faecal-to-oral transmission, whereas the oral-to-oral mode of transmission
probably dominates in settings with higher standards of sanitation. However,
in most settings, mixed patterns of transmission are likely to occur. In the pre-
vaccine era, roughly one in 200 susceptible individuals infected by polioviruses
developed paralytic poliomyelitis (15).
Progress in polio control (and, since 1988, polio eradication) has
occurred mainly due to the widespread use of vaccines. An inactivated
poliomyelitis vaccine (IPV Salk vaccine) was licensed in 1955; live-attenuated
OPV (Sabin vaccine) was licensed as a monovalent OPV (mOPV) in 1961, and
as a trivalent OPV (tOPV) in 1963. Te Sabin strains of poliovirus used in the
production of OPV were shown to be both immunogenic and highly attenuated
when administered orally to susceptible children and adults. Most countries that
initially introduced vaccination with IPV later changed to OPV because OPV
provided many advantages, including easier administration, suitability for mass
vaccination campaigns, superior induction of intestinal mucosal immunity, and
lower production costs. In 1974, OPV was recommended as part of the Expanded
Programme on Immunization, and OPV was again the vaccine of choice in 1988
when the World Health Assembly resolved to eradicate polio globally by the year
2000. By 2010, three of the six WHO Regions had been certifed as free of WPVs,
and WPV2 has not been detected worldwide since 1999 (15).
In addition to tOPV, which is used in many countries for routine or
supplementary vaccination, monovalent OPV against type 1 (mOPV1) and
against type 3 (mOPV3), and bivalent OPV against type 1 and type 3 (bOPV)
(15), as used by the Global Polio Eradication Initiative (GPEI) have been
licensed for use in endemic countries or for outbreak control in situations where
one or two types may re-emerge. In addition, mOPV against type 2 has been
licensed but is expected to be used primarily for emergency response stockpiles.
In 2012, the Strategic Advisory Group of Experts on Immunization was asked
by WHO to consider the possibility of replacing tOPV with bOPV for routine
immunization globally.
Following the introduction and widespread use of mOPV1 and mOPV3
in supplementary immunization activities in 2005, the GPEI reported substantial
reductions in these poliovirus types. Te last reported case of polio in India
involved poliovirus type 1 and occurred in January 2011. Since polio is now
considered to have been eradicated in India, the country has been removed from
the list of endemic countries. However, the co-circulation of WPV1 and WPV3
in the three remaining polio-endemic countries requires that huge quantities of
bOPV be used to supplement the tOPV given during routine immunization and
mass immunization campaigns. A clinical trial to evaluate the immunogenicity
of diferent OPV formulations (mOPV1, mOPV3 and bOPV) compared with
tOPV in an Indian population was conducted by WHO. Te seroconversion
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WHO Expert Committee on Biological Standardization Sixty-third report
rate s to poliovir su tpy e 1 and tpy e 3 of llowing immnu ization wit h Ob VP ew re
is gnic� antl y ih geh r tah n toh se indcu ed yb tO , VP and teh y ew re not loew r tah n
toh se indcu ed yb immnu ization wit h eiteh r mO 1VP or mO 3VP .)61(
Altoh gu h O VP i s a saef av ccine , adev rse eev nt s ma y occru on rare
occasions (15) with vaccine-asociated paralytic poliomey litis AP) (V being
teh mots serious of teh se rare adev rse eev nts. Cases of AP V are clinicall y
indits ingiu ahs lb e from poliomey liti s casued yb W , VP tub can be dits ingiu ehs d
y b laboratory analysis. �e incidence of AP V has been estimated at
4� cases/1 0 0 ib rth cohort per ey ar in countries using OPV (17 ) . Saib n
iv resu s can alos ps read in poplu ation s ehw re teh coev rage o f O VP i s lo . w nI cus h
situations, Saib n viruses can acuiq re teh neurovirulence and transmisiib lit y
characterits ics of W, PV and can cause polio cases and otu rb eaks as circulating
av ccined- eriev d poliovir su c( VP )DV .)81(
Liev av ccine s prepared from teh Saib n ts rain s o f poliomey liti s virsue s
tpy e s ,1 2 and 3 ew re introdcu ed of r larges-cale immnu ization in .7591 nI ,2791
Albert Saib n proposed tah t WHO ohs uld be teh ctsu odian o f ih s poliovir su
seed ts rain .s e� iD rectorG-eneral o f WHO agreed to amus e reps onis ib lit y of r
enrus ing teh proper esu o f teh ts rain ,s and ets alb iehs d a cs ientic� committee , teh
Conuls tatiev rG opu on oP liomey liti s aV ccine ,s to advise WHO on all matter s
pertaining to teh ir sue . Detailed inof rmation on teh ow r k o f teh conuls tatiev
gropu , and teh preparation o f teh ts rain s y b Berh ingew rek o f aM rrub g , eG rman , y
ah s been plbu iehs d yb Cocrubk n .)91( s RN A ohs uld decide on wih c h ts rain s to
sue and on teh appropriate procedru e s of r preparing vir su seed lot s of r O VP in
teh ir own conu trie.s
e� original poliovir su seed s prodcu ed yb Saib n – Saib n original S( O )
)02( – ew re sent to eM rc ,k wih c h generated seed s from teh m deis gnated Saib n
original eM rc k S( O .)M lA iouq t s o f SO M ew re pus plied to oteh r manafu ctru er s to
enalb e teh m to deev lop teh ir onw es ed .s Some es ed lot s ew re contaminated iw t h
S ,04V iwh c h ah d been present in teh primar y eRh su s ik dne y cell ,s teh preef rred
cellc- ultru e tsys em at tah t time of r vir su propagation . O VP manafu ctru er s sued
av rio su ts rategie s to redcu e teh contamination , incldu ing paas ge in teh prees nce
o f a ps ecic� antibod , y treatment wit h toliu dine lb eu or teh rmal inactiav tion
o f S 04V in teh presence o f M1 magneis mu chloride gM( Cl 2 ,) wih c h ts aib lize s
poliovirus. nI 197 4 , Behringew rek generously agreed to produce SO+1 seed s
of r WHO free of charge. �e Behringew rek type 1 and type 2 seeds haev been
widel y sued is nce teh .s0791
nI teh ,s0591 it aw s ets alb iehs d tah t , particularl y of r teh tpy e 3- ts rain ,
increase s in teh pasage nmu ber correlated wit h an increase in reactivit y in teh
. VNM T i� s n� ding led to teh ets alb imhs ent o f rigoro su limit s on teh pasage
leev l of r av ccine prodcu tion of r all tpy e s o f O. VP
e� tpy e 3- av ccine aw s of nu d to be le s ts alb e on pasage tah n eiteh r
tpy e� 1 or tpy e ;2 tih s aw s manief ts ed in a ih geh r nmu ber o f tpy e 3- av ccine lot s
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WHO Technical Report Series No. 980, 2014
Annex 2
failing the MNVT. In order to develop a more stable strain, a new seed was
prepared by Pfzer; susceptible cells were transfected with viral RNA extracted
from poliovirus at the SO+2 level. One plaque, designated 457-III, was identifed
as having particularly favourable properties (21). Teoretically, vaccine derived
from this stock was at passage SO+7 level. However, the purpose of tracking
the passage history of seed viruses is to reduce the accumulation of mutations
that takes place during the course of their serial propagation. Since plaque
purifcation represents the cloning of a single infectious particle, it eliminates
the heterogeneity of the viral population, and the passage level is efectively
reset to zero. Tus the cloned stock 457-III was renamed RNA-derived Sabin
original (RSO).
Two additional passages were used to prepare virus master seeds (RSO1)
and working seeds (RSO2), and vaccines produced from this virus are at RSO3
level. Retrospectively, the RSO sequence has been shown to be the same as the
consensus of SO (22), but more homogeneous and containing smaller quantities
of mutant viruses.
Te RSO seed was not used for the production of type-3 vaccine until
the 1980s when it became clear that the stocks of material passaged from the
SOM and other SO+1 seeds were inadequate. Since then, it has been widely used
by European and American manufacturers because it is of lower virulence in
laboratory tests than the SO+1 type-3 seed. Te RSO seeds were bought from
Pfzer by Sanof Pasteur which donated them to WHO.
Te virus seeds available from WHO (WHO master seeds) are types 1,
2 and 3 at SO+1 level produced by Behringwerke from SO seeds, and the type-3
RSO seed donated by Sanof Pasteur. Te seeds are kept at the National Institute
for Biological Standards and Control (NIBSC) in England, and include a
proportion of the stocks of the SO+1 seeds formerly held at Istituto Superiore
di Sanità in Italy (19, 21).
In addition to vaccines based upon the RSO type-3 seed, a number of
manufacturers in China, Japan and the Russian Federation have produced
vaccines using their own purifed seed stocks of the Sabin 3 strain derived by
plaque purifcation (cloning). Sequencing of these seed viruses demonstrated
that, although they had only a low content of neurovirulent mutants, there
were diferences among these strains and the consensus sequence of SO virus
(22). However, there are no reports of any diferences in clinical safety between
OPV produced from Pfzer stocks and the alternative seeds of Sabin 3 virus. An
overview of virus seeds used in OPV production is given in Appendix 1.
Te MNVT, as described in the 1989 Requirements (5), has been used
as a quality-control test, and is based on the level and the distribution of virus-
specifc lesions within the central nervous system produced by vaccine virus when
compared with an appropriate reference preparation (23). Because nonhuman
primates are used, eforts to complement and eventually replace the test are of
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WHO Expert Committee on Biological Standardization Sixty-third report
conis deralb e importance . WHO ah s encoru aged and pus ported researc h on
av rio su aps ect s o f poliovir su ib olog , y incldu ing teh deev lopment o f alternatiev
animal model ,s a s part o f it s initiatiev to promote teh deev lopment o f ne w norm s
and ts andard s of r av ccine .s ow T gropu s o f scientits s deev loped trangs enic mice
yb introdcu ing into teh mosue genome teh muh an gene encoding teh cellular
receptor of r poliovir su ,42( .)52 i� s receptor , known a s C ,51D maek s gT RVP
mice csu s eptilb e to polioiv r su inef ction iw t h clinical is gn s o f a� ccid paralisy s and
wit h ih ts ological leis on s in teh central nerov su tsys em is milar to toh se osberev d
in monek .sy
nI ,291 WHO initiated a project to eav luate teh ius taib lit y o f cus h
trangs enic mice of r tets ing teh neru oiv rlu ence o f O , VP iw t h teh aim o f replacing
monek sy wit h mice . e� adav ntage s o f a neru ovirulence tets in trangs enic
micea� re:
� a redcu tion in teh nmu ber o f primate s sued of r uaq lit y control
oO�f ; VP
� teh sue o f animal s wit h ih ghl y den� ed genetic and microib ological
uaq lit y ts andard;s
� a redcu tion in ah zard s to laborator y personnel trh ogu h a redcu ed
need to ah ndle primate;s
� in some conu trie ,s a redcu tion in teh cots o f uaq litc-y ontrol tets s
of rO� . VP
Stdu ie s ew re carried otu initiall y on mO 3VP av ccine s isu ng teh gT 12 R V P
mosue line , provided free o f cah rge yb teh Central nI ts ittu e of r Experimental
nA imal s in aJ pan . eR es arceh r s at teh aJ pan oP liomey liti s eR es arc h nI ts ittu e and at
teh nU ited State s oF od and rD gu dA minits ration Center of r Biologic s Eav lau tion
and Researc h C( BE )R deev loped an intraps inal inoculation metoh d ius talb e of r
tets ing av ccine lot .s i� s metoh d aw s eav luated in an international collaboratiev
ts du y deis gned to ets alb i hs a ts andardized gT mVN T tets of r O VP .)62( Seev ral
laboratorie s participated in teh ts du , y and teh reuls t s ew re asesed yb WHO
at meeting s eh ld in ,591 ,791 891 and .91 s A a reuls t , teh revised WHO
Recommendation s of r teh prodcu tion and control o f poliomey liti s av ccine o( ral )
)01( introdcu ed teh mru ine model a s an alternatiev to teh VNM T of r tpy e 3-
poliovir ,su and fru teh r ts du ie s demonts rated tah t tih s tets aw s also ius talb e a s
an alternatiev to teh VNM T of r poliovir su tpy e 1 and tpy e 2 .)31( Laboratorie s
mtsu compl y iw t h ps ecic� ation s of r containment o f teh trangs enic animal s .)7 2 (
s A wit h teh , VNM T teh gT mVN T can also provide evidence o f teh conis ts enc y
o f prodcu tion.
e� moleclu ar mecah nims s and genetic determinant s o f attenau tion and o f
reev ris on to iv rulence o f all trh ee tpy e s o f Saib n polioiv rseu s seu d to manafu ctru e
O VP ah ev been ew ll ts du ied . Evidence ts rongl y gus gets s tah t mtu ation s in teh
�5 noncoding region o f teh poliovir su genome , eps eciall y of r teh Saib n tpy e 3-
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WHO Technical Report Series No. 980, 2014
Annex 2
strain, are critical in determining the attenuated phenotype (28). A molecular
biological test, known as the MAPREC assay, was developed by researchers at
CBER to quantify reversion at the molecular level (29). Studies showed that all
analysed batches of type-3 OPV contained measurable amounts of revertants,
with C instead of U at nucleotide 472. Batches that failed the MNVT contained
signifcantly higher quantities of 472-C than batches that passed the test. Studies
with coded samples at CBER identifed 100% of lots that failed the MNVT (30).
In 1991, WHO initiated a series of international collaborative studies
to evaluate the MAPREC assay for all three types of poliovirus, and to validate
appropriate reference materials. Several laboratories participated in the
collaborative studies, and the results were assessed by WHO at meetings held
in 1995 and 1997 in Geneva, Switzerland. It was concluded that the MAPREC
assay was a sensitive, robust and standardized molecular biological assay
suitable for use by manufacturers and NRAs for monitoring the consistency of
the production of type-3 OPV. Te revised WHO Recommendations for the
production and control of poliomyelitis vaccine (oral) (10) introduced MAPREC
as  the preferred in vitro test for type 3 poliovirus in place of the rct40 test.
Reference materials for the MAPREC assay for comparable positions in type 1
and type 2 have now been established. While the results do not correlate with
neurovirulence in the range studied, they provide a measure of production
consistency. Te quantity of other mutants (such as 2493-U in Sabin 3 virus)
can also be used to identify types of seed virus, and to monitor the consistency
of manufacturing. Afer appropriate validation, quantitative profles of other
mutations in stocks of OPV could be used for this purpose.
Te manufacturer of the fnal lot must be responsible for ensuring
conformity with all of the recommendations applicable to the fnal vaccine (see
Part A, sections A.5–A.11), even where manufacturing involves only the flling of
fnal containers with vaccine obtained in bulk from another manufacturer. Te
manufacturer of the fnal lot must also be responsible for any production and
control tests performed, with the approval of the NRA, by an external contract
laboratory, if applicable.
OPV has been in worldwide use since the 1960s, and although vaccines
produced from human diploid cells or continuous cell lines have been used
to a lesser extent than those produced in cultures of primary monkey kidney
cells, experience has indicated that all three cell substrates produce safe and
efective vaccines.
In 1986, a WHO study group (7) stated that the risks for residual cellular
DNA (rcDNA) in vaccines produced in continuous cell lines should be considered
negligible for preparations given orally. Tis conclusion was based on the fnding
that polyomavirus DNA was not infectious when administered orally (31).
For such products, the principal requirement is the elimination of potentially
contaminating viruses. Additional data on the uptake of DNA via the oral route
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WHO Expert Committee on Biological Standardization Sixty-third report
ah ev been plbu iehs d .)23( e� se ts du ie s demonts rated tah t teh ec� ienc y o f
teh pu taek o f A N D introdcu ed orall y aw s is gnic� antl y loew r tah n tah t o f A N D
introdcu ed intramsucularl . y eN ev rteh le ,s teh ps ecic� s o f teh manafu ctru ing
proce ss and teh of rmulation o f a giev n prodcu t ohs uld be conis dered yb sRN A
( )3 and , ewh re pois lb e , data ohs uld be accmu ulated on teh leev l s o f rc A N D in
O VP prodcu ed in eV ro cell.s
e� re i s increais ng interets in deev loping alternatiev ts rain s o f polioiv r su
of r sue in O VP prodcu tion isu ng molecularm- anipulation tecnh ieuq .s e�
poliovirps-su ecic� uaq lit y eav luation o f cus h ts rain s – eg. . of r neru ovirulence
tets ing or of r teh ERPA M C aas y – a s decs ribed in teh es eR commendation s and
asociated SO ,s P ma y not be appropriate . e� tets ing o f cus h av ccine s – wih c h
i s liek l y to incldu e extenis ev preclinical and clinical ts du ie s to demonts rate
attenau tion , genetic ts aib lit , y and teh as ef t y and tranms iis ib lit y o f teh proposed
ts rain s – will need to be conis dered on a casec-y b- ase bais ,s and ma y die� r
fnu damentall y from teh approaceh s described in teh cru rent docmu ent.
Soc pe o f the eR oc em dn ta iosn
e� scope o f teh present Recommendation s encompases s poliomey liti s av ccine s
o( ral , liev , attenuated ) deriev d from teh original Saib n ts rain ,s some yb is mple
pasas ge and oteh r s y b more complex rotu e ,s incldu ing plaeuq pru ic� ation . i� s
docmu ent i s intended to appl y to all Saib n poliovir su ts rain s regardle s o f teh ir
ih ts or . y tI doe s not necesaril y appl y to oteh r ts rain s tah t ma y be deev loped.
i� s docmu ent ohs uld be read in connuj ction wit h oteh r releav nt WHO
iuG deline ,s cus h a s toh se on teh nonclinical )43( and clinical eav luation )53(
oav�f ccine.s
ra P t .A M cafunatru i gn reoc em dn ta iosn
A.1 Defnitions
A.1.1 International name and proper name
e� international name ohs uld be poliomey liti s av ccine o( ral , liev , attenuated )
wit h addition s to indicate teh vir su serotpy e or serotpy e s o f teh av ccine . e�
proper name ohs uld be teh eiuq av lent o f teh international name in teh langau ge
o f teh conu tr y o f origin.
e� sue o f teh international name ohs uld be limited to av ccine s tah t
satifs y teh recommendation s of rmulated belo. w
A.1.2 Descriptive defnition
oP liomey liti s av ccine o( ral , liev , attenuated ) i s a preparation o f liev a- ttenuated
polioiv r su tpy e ,1 2 or 3 gronw in in iv tro clu tru e s o f ius talb e cell s containing an y
58
WHO Technical Report Series No. 980, 2014