Epidemiological Impact of a Genital Herpes Type 2 Vaccine for Young Females

8/20/2019 Epidemiological Impact of a Genital Herpes Type 2 Vaccine for Young Females

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Epidemiological Impact of a Genital Herpes Type 2 Vaccine for Young

Females• Yijun Lou ,

• Redouane Qesmi ,

• Qian Wang ,

• Marc Steben,

• Jianhong Wu,

• Jane M. Heffernan

• Published !ctober "", #$"#

• %!& "$."'(")journal.*one.$$+$#(

Abstract

-enital Her*es, hich is caused b/ Her*es Sim*le0 1irus2" or 2# 3HS12", 2#, *redominantl/

HS12#4 is a se0uall/ transmitted infection 3S5&4 that causes a chronic latent infection ith

outbrea6 e*isodes lin6ed to transmission. 7nti8iral thera*ies are effecti8e in reducing 8iral

shedding during these e*isodes, but are ineffecti8e as a hole since man/ outbrea6s are

as/m*tomatic or ha8e mild s/m*toms. 5hus, the de8elo*ment of a 8accine for genital her*es is

needed to control this disease. 5he 9uestion of ho to im*lement such a 8accine *rogram is an

im*ortant one, and ma/ be similar to the 8accination *rogram for Human Pa*illoma 1irus 3HP14

for /oung females. We ha8e de8elo*ed a mathematical model to describe the e*idemiolog/ of

8accination targeting /oung females against HS12#. 5he model *o*ulation is delineated ith

res*ect to age grou*, se0ual acti8it/ and infection status including oral infection of HS12",

hich ma/ affect 8accine efficac/. 7 threshold *arameter , hich determines the le8el of 8accine u*ta6e needed to eradicate HS12#, is found. :om*uter simulation shos that an

adolescent2onl/ 8accination *rogram ma/ be effecti8e in eliminating HS12# disease, hoe8er,

the success of e0tinction greatl/ de*ends on the le8el of 8accine u*ta6e, the 8accine efficac/, the

age of se0ual maturit/ and safe se0 *ractices. Hoe8er, the time course of eradication ould

ta6e man/ /ears. We also in8estigate the *re8alence of infection in the total *o*ulation and in

omen beteen ";'$ /ears of age before and after 8accination has been introduced, and sho

that the adolescent2onl/ 8accination *rogram can be effecti8e in reducing disease *re8alence in

these *o*ulations de*ending on the le8el of 8accine u*ta6e and 8accine efficac/. 5his ill also

result in a decrease of maternal2fetal transmission of HS12# infection. 7nother im*ortant, if

commonsense, conclusion is that 8accination of some females reduces infection in men, hich

then reduces infection in omen.


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Introduction

-enital her*es is one of the most *re8alent se0uall/ transmitted infections 3S5&4 in the orld. &t

is estimated that there are ne cases of genital her*es in :anada *er /ear ith

a**ro0imatel/ ne cases each da/


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7:7M2>#B 8accine su**orted b/ Sanofi Pasteur are undergoing clinical trials


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&n this *a*er, e de8elo* a mathematical model to e8aluate the effecti8eness of a 8accination

*rogram against HS12#. We focus our stud/ on a 8accination *rogram targeting female school

children aged "#;"+ /ears. !ur model also includes age structure and gender differences in

transmission. We also include 8ar/ing efficacies of the 8accine against HS12#, hich ma/ not be

effecti8e in indi8iduals that are HS12" *ositi8e. 5he details of our model and model assum*tions

are outlined in the ne0t section.

Methods

5he mathematical model, shon in Gig. ", illustrates ho genital her*es can s*read in a

*o*ulation. 5he *o*ulation is di8ided into com*artments de*ending on gender 3male or female4,

disease status 3infected or uninfected4, and susce*tibilit/ to the 8irus 3su*erscri*t denotes

*rotection4. 5he female *o*ulation is then further di8ided according to age 3children "';" /ears

old 3 4, and adults beteen ";'$ /ears of age 3 4 and o8er /ears of age 3 44


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5he mathematical model can be described as follos female children 3 4 enter the *o*ulation at

rate . Gemale children that are HS12" seronegati8e 3 4, 8accinated 3 4 and ac9uire immunit/

from the 8accine 3 4 mo8e to the 8accinated)*rotected class and all others remain in the non2

immune class 3 4. Since se8eral 8accine trails ha8e shon some success in *re8enting disease,

but onl/ in females that are HS12" and 2# negati8e, e incor*orate here the HS12" seronegati8e

*ro*ortion to account for this *ossible 8accine limitation


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#arameter Values

Parameter 8alues are listed in 5able " and are chosen so that the/ agree ith current :anadian

and orth 7merican statistics, and data re*orted in the medical literature. 5he mortalit/ rate is

assumed to be a**ro0imatel/ /ears", here /ears is the mean life e0*ectanc/ of

:anadians beteen #$$$;#$$


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Table ! $ist of notations and symbols!

&t is assumed that the a8erage age of *rogression of female children to se0ual acti8it/ 3 4 is

beteen /ears


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higher *robabilit/ of entering into monogamous relationshi*s, and that the *robabilit/ of se0ual

acti8it/ out of these monogamous relationshi*s is small.

Similar to


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5he threshold can be e0*lained relati8e to the underl/ing biolog/ as follos hen an

infecti8e male is introduced into the *o*ulation, ne infected males can be made through three

*ossible *atha/s

hich corres*ond to the first, second and third terms of @9. 3"4 res*ecti8el/. Gor instance, using

the second *ath, e see that hen one infected male is introduced into the *o*ulation, the male

*roduces, on a8erage, infected /oung adult females aged ";'$ /ears during his

a8erage se0ual lifes*an 3 4. 5hese /oung adult females then gro into adult females

aged '$ /ears and older o8er their lifes*an at a rate and then each infected

older adult female *roduces, on a8erage, infected males during her se0ual

lifes*an . 5hus through the second *ath, the a8erage number of ne infected males

*roduced b/ a single infected male in a *o*ulation consisting onl/ of susce*tible females and

males is . With the *arameter 8alues listed in 5able ", the

basic re*roduction number is , that is, one infected male ma6es ".> ne infected

males 3or " infected female ma6es ".> ne infected females4 hen this indi8idual is introducedinto a *o*ulation com*osed onl/ of susce*tible males and females. &f e assume the *arameters

related to a 8accine *rogram are , , and , then the re*roduction

number becomes .

ote that a reduction in the infecti8it/ 3 4 ill also decrease . Moreo8er, in order to

eradicate HS12# from a *o*ulation, the 8accination *rogram must be effecti8e in

reducing 3see 5heorem 7' in 7**endi0 S" for theoretical results4. Grom @9. 3#4 e find

that this ill occur hen a critical 8accination threshold 3 4 is achie8ed, here

'umerical (imulations

7n adolescent2onl/ 8accination *rogram ma/ be effecti8e in eliminating HS12# 3Gig. #4.

Hoe8er, regardless of the 8accine efficac/ and u*ta6e, the time course of eradication ould

ta6e man/ decades 3Gig. '4. 7lso eradication ma/ not result 3Gig. '4. Gor similar 8accination

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u*ta6e to that of the HP1 8accination *rogram 3>';A$N4, HS12# elimination ma/ not be

achie8ed 3Gig. +a, solid line4. &f 8accine efficac/ is , or if the *ro*ortion of children that

are HS12")HS12# negati8e decreases 3 4, then eradication is more li6el/, but high 8accination

u*ta6e is still re9uired 3Gig. +a4. 7n im*ortant, if commonsense, conclusion is that 8accination of

some females reduces infection in men, hich then reduces infection in omen 3Gig. 'b,c4.

Figure 2! #re)alence of H(V*2 +ith different le)els of )accination!

Pre8alence of HS12# decreases as 8accine u*ta6e increases in the total *o*ulation 3solid line4,omen ages ";'$ /ears 3dot2dashed line4, omen ages o8er /ears 3dashed line4, omen

ages o8er /ears 3blac6 dotted line4 and men 3gra/ dotted line4. 1accine efficac/ 3 4 le8els are

assumed to be 3a4 and 3b4 res*ecti8el/. 5he *ro*ortion of females b/ age "# that are

HS12" and HS12# seronegati8e 3 4 is assumed to be .

doi"$."'(")journal.*one.$$+$#(.g$$#

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Figure ,! #re)alence of infection o)er time!


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Pre8alence of infection in the total *o*ulation 3to*4, omen ages o8er /ears 3bottom left4 and

men 3bottom right4 are shon hen 8accination is started at /ear " and is gi8en for BBB /ears.

1accination le8els, from to* to bottom, are $, "$, #$, '$, +$, >$, $, ($, A$, B$ and "$$N.

1accine efficac/ 3 4 is assumed to be and the *ro*ortion of females b/ age "# that are HS12

" and HS12# seronegati8e 3 4 is assumed to be .

doi"$."'(")journal.*one.$$+$#(.g$$'


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Figure -! Thresholds of )accination!


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1accination thresholds for eradication de*end on the efficac/ of the 8accine 3to*4, age of

se0ual maturit/ 3bottom left4 and rate of transmission 3bottom right4. 3a4 5hreshold cur8es

de*ending on 8accine efficac/ for three le8els of HS12" and HS12# negati8e children 3 >$, >

and B>N, solid line, dashed line, dot2dashed line res*ecti8el/4 at the time of 8accination. 7ll

lines denote threshold corres*onding to a 8accine immunogenecit/ of B>N. 3b4 5hreshold cur8es

de*ending on age of se0ual maturit/ for three le8els of 8accine efficac/ 3 >$, ($ and B$N,

dashed line, solid line, dot2dashed line res*ecti8el/4 5he 8ertical line at age #> re*resents the

ma0imum age at hich age of se0ual maturit/ could be achie8ed to sustain a *o*ulation. 3c4

5hreshold cur8es de*ending on reduced transmission rates 3 , to 4 for three le8els of

8accine efficac/ 3 >$, ($ and B$N, dashed line, solid line, dot2dashed line res*ecti8el/4.

doi"$."'(")journal.*one.$$+$#(.g$$+

5o aid in the reduction of HS12# *re8alence, education *rograms about genital her*es ma/ be

im*lemented. 5hese *rograms ill ha8e an im*ortant effect if 8accination u*ta6e or if the

efficac/ of the 8accine is lo. 7 *ossible effect of these *rograms is an increase in the a8erageage of *rogression of children to se0ual acti8it/. Gig. +b demonstrates that as the a8erage age of

se0ual maturit/ 3 4 increases, the *ro*ortion of females needed to 8accinate to eradicate

HS12# decreases. Hoe8er, eradication ithout 8accination ould not be feasible since it is

im*ossible for the age of se0ual maturit/ to be high 3Gig. +b4 as *o*ulations ould not be

sustained. 7lso, e8en ith high le8els of efficac/ 3 4 8accination is unli6el/ to eradicate HS12#

since 8er/ high le8els of 8accine u*ta6e, hich are greater than hat is seen in HP1, are

re9uired.

7nother *ossible effect of education *rograms is an increase in safe se0 *ractices. 5his includes

the use of condoms, and can include the use of anti8irals in those infected ith HS12#. 5he use

of condoms ha8e been routinel/ recommended for the *re8ention of transmission of se0uall/

transmitted diseases such as HS12# $N


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demonstrates that for similar 8accination u*ta6e to that of the HP1 8accination *rogram 3>';

A$N4, HS12# *re8alence can be reduced b/ , hoe8er, this reduction in *re8alence can

still ta6e man/ decades to achie8e 3Gig. '4.

Figure .! %eduction in pre)alence!

1accination thresholds for reduction in *re8alence b/ are shon for three different

le8els of 8accine efficac/ 3 >$, ($ and B$N, dashed line, solid line, dot2dashed line

res*ecti8el/4.

doi"$."'(")journal.*one.$$+$#(.g$$>

Pregnant females infected ith genital HS12# 3*articularl/ those ith a *rimar/ infection4 can

transmit infection to the neonate, hich can lead to serious neonatal com*lications, such as

neurologic *roblems and e8en death. 5hus, it is im*ortant to consider the im*act of 8accination

on the *re8ention of HS12# in the child2bearing age grou*. Gig. # shos the *re8alence of

infection in omen o8er ";'$ /ears of age before and after 8accination has been introduced

3dot2dashed line4. Since the majorit/ of *regnant mothers are from this age grou*, this

demonstrates that the adolescent2onl/ 8accination *rogram results in a decrease in the number of

infected *regnant females. 5his ill in turn result in a decrease of maternal2fetal transmission of

HS12# infection.

&ntensi8e sensiti8it/ anal/ses can be *erformed in 8arious a/s to determine hich *arameters

*la/ a major role in affecting the *redicted results. We *erform the sensiti8it/ anal/sis b/ using

the Latin H/*ercube Sam*ling 3LHS4 *rocess, hich is numericall/ com*uted using the method

described in


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calculated. PR:: 8alues *ro8ide a measure of the relationshi* beteen model in*uts and out*uts

and are *articularl/ useful for such relationshi*s that are nonlinear but monotonic. PR:: 8alues

range beteen " and " ith the sign determining hether an increase in the *arameter 8alue

ill decrease 34 or increase 3O4 the s*ecified model out*ut. 5he PR:: results for disease

*re8alence in the total *o*ualtion are shon in Gig. . 5his figure indicates that the transmission

rates and *arameters related to the 8accination *rograms 3 , , 4 are statisticall/ significant

3ith 4. &n contrast, the *rogression rates and are relati8el/ insignificant.

5hese results highlight the im*ortance of 8accine u*ta6e, 8accine efficac/, HS12" and HS12#

status, and safe se0 in the control of genital her*es. 5he PR:: results for HS12# *re8alence in

men, adult and older omen, and the control re*roduction number are similar to that shon

in Gig. .

Figure /! (enstiti)ity analsysis!

5he *artial ran6 correlation coefficients are shon using the total *o*ulation as the inde0.

doi"$."'(")journal.*one.$$+$#(.g$$

"iscussion

-enital her*es is one of the most *re8alent se0uall/ transmitted diseases in the orld. :urrentl/,

the de8elo*ment of a 8accine againt HS12#, the main cause of genital her*es, is a major focus of

stud/. We ha8e de8elo*ed a model of HS12# transmission that delineates the *o*ulation b/

gender and age, to factors that ha8e been shon to be effecti8e *redictors of HS12# ris6, to

assess the efficac/ of a 8accination *rogram against HS12# similar to the 8accination *rogram

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alread/ im*limented against HP1. ?sing this model e ha8e found that eradication of HS12#

ma/ be achie8able, hoe8er, this feasibilit/ of eradication de*ends on se8eral factors.

Girstl/, eradication greatl/ de*ends on the rate of 8accine u*ta6e and the efficac/ conferred b/

the 8accine. 1accine u*ta6e needs to be 8er/ high 3 4 e8en if the 8accine is 8er/ effecti8e

in inducing *rotection against the disease. Hoe8er, e8en if 8accine u*ta6e is high, eradication

ill not be seen for se8eral decades.

5he *ossibilit/ of eradication also de*ends on education *rograms that ma/ dela/ the age of

se0ual maturit/ and increase the le8el of safe se0 *ractices. &n these cases, hoe8er, 8accination

u*ta6e still needs to be 8er/ high and ma/ e0ceed hat is actuall/ achie8able.

7lthough eradication ill be difficult to achie8e, the 8accination *rogram can be effecti8e in

reducing disease *re8alence to a large e0tent. Reduction le8els of can be achie8ed,

hoe8er, these also greatl/ de*end on the 8accine efficac/ and the time since the initiation of the

8accination *rogram.

7n e0tension of the current model ma/ be to stud/ the effects of 8accination in age grou*s less

than "+ /ears of age 3and *erha*s infants4 here HS12" *re8alence is decreased, and stud/ the

effects of a 8accine that is onl/ *artiall/ affected b/ HS12" *re8alence. Foth of these scenarios

can be com*ared to a 8ariation in *arameter . ?sing the current model e see that the

*ro*ortion of children needed to 8accinate to eradicate HS12# is decreased considerabl/ hen

increases.

7nother future direction ma/ be to stud/ the effects of booster 8accines in adult females, since

8accine induced immunit/ to HS12# ma/ ane o8er time. Gurther delineation of the *o*ulation

including oral infection 8ersus genital infection and se0ual *reference ma/ also be im*ortant

hen considering the number of booster 8accinations re9uired and the time beteen them.

7 limitation of the current model is e do not model 8ar/ing rates of 8irus shedding. HS12#

infection is actuall/ characteriCed b/ ra*id e*isodes of as/m*tomatic shedding *unctuated b/

increased 9uantities of 8irus


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HS12# ould not be *ossible ith 8accines that merel/ decrease s/m*toms and the fre9uenc/ of

recurrences, since transmission is still *ossible in these instances.

(upporting Information

7**endi0S".*df


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Mathematical analysis of the model! 5he mathematical model is formulated as a s/stem of

ordinar/ differential e9uations. We find the model e9uilibria, the basic re*roducti8e ratio, and

*ro8ide some local and global stabilit/ anal/sis of the model. Justification of the S& frameor6 is

also *ro8ided.

Mathematical analysis of the model! 5he mathematical model is formulated as a s/stem of

ordinar/ differential e9uations. We find the model e9uilibria, the basic re*roducti8e ratio, and

*ro8ide some local and global stabilit/ anal/sis of the model. Justification of the S& frameor6 is

also *ro8ided.

doi"$."'(")journal.*one.$$+$#(.s$$"

3P%G4

Ac0no+ledgments

5he authors ould li6e to than6 Professors Pauline 8an den %riessche and Robert Smith for

their hel*ful insights on the de8elo*ment of the mathematical model. We ould also li6e to than6

the anon/mous re8ieers for their su**orti8e comments.

Author &ontributions

:oncei8ed and designed the e0*eriments QW RQ JMH JW MS. Performed the e0*eriments

QW RQ YL JMH. 7nal/Ced the data QW RQ YL JMH. :ontributed reagents)materials)anal/sis

tools QW RQ 5L JMH JW MS. Wrote the *a*er QW RQ YL JMH JW MS.

%eferences

". Steben M, Mone/ %, Wong 5, -ruslin 7, Yudin M, et al. 3#$$A4 -enital her*es

g/naecological as*ects. J !bstet -/naecol :an '$ '+(;'".#. Schiffer J5, 7bu2Raddad L, Mar6 D@, hu J, Sel6e S, et al. 3#$$B4 Gre9uent Release of Lo

7mounts of Her*es Sim*le0 1irus Grom eurons Results of a Mathematical Model. Sci

5ransl Med " (ra". doi "$.""#)scitranslmed.'$$$"B'

'. MertC -J, Rosenthal SL, Stanberr/ LR 3#$$'4 &s her*es sim*le0 8irus t/*e " 3HS12"4 nomore common than HS12# in first e*isodes of genital her*es Se0 5ransm %is '$ A$";A$#.

doi "$."$B()$".ol9.$$$$$B'$A$.>>#$".d"

+. World Health !rganiCation. 3#$$"4 Her*es sim*le0 8irus t/*e # *rogrammatic and research *riorities in de8elo*ing countries. Re*ort of a WH!)?7&%S)LSH5M or6sho*, London,

"+;" Gebruar/ #$$".

>. .!7rmstrong -L, Schillinger J, Mar6oitC L, ahmias 7J, Johnson R@, et al. 3#$$"4&ncidence of her*es sim*le0 8irus t/*e # infection in the united states. 7m J @*idemiol ">'

B"#;B#$. doi "$."$B')aje)">'.B.B"#


20/22

. :enters for %isease :ontrol and Pre8ention. 78ailable.cdc.go8)std)her*es)stdfact2

her*es.htm. 7ccessed #$"# Mar ".

(. 1eCina :, Steben M 3#$$"4 -enital Her*es Ps/chose0ual &m*acts and :ounselling. :an J:ont Med @d "' "#>;"'(.

A. Greeman @, Weiss H, -l/nn J, :ross P, Whitorth J7, et al. 3#$$4 Her*es sim*le0 8irus

t/*e # increases H&1 ac9uisition in men and omen s/stematic re8ie and meta2anal/sis of longitudinal studies. 7&%S #$ (';A'. doi "$."$B()$".aids.$$$$"BA$A".$B''(.a(

B. Wald 7, Lin6 D 3#$$#4 Ris6 of human immunodeficienc/ 8irus infection in her*es sim*le0

8irus t/*e #2sero*ositi8e *ersons a meta2anal/sis. J &nfect %is "A> +>;>#. doi"$."$A)''A#'"

"$. !Fron 7, Fenedetti J, 7shle/ R, Furchett S, Sel6e S, et al. 3"BB"4 eonatal her*es sim*le0

8irus infection in relation to as/m*tomatic maternal infection at the time of labor. e

@ngland Journal of Medicine '#+ "#+(;"#>#. doi "$."$>)nejm"BB"$>$#'#+"A$+"". -la0oSmithDline. -s6 data on file rm#$$$)$$'"()$$.

"#. Wald 7, 7ndria , Langenberg , DrantC @, %ouglas JM, et al. 3#$$>4 5he relationshi* beteen

condom use and her*es sim*le0 8irus ac9uisition. 7nn &ntern Med "+' ($(;("'. doi

"$.('#)$$$'2+A"B2"+'2"$2#$$>""">$2$$$$("'. Frugha R, Deersmae6ers D, Renton 7, Meheus 7 3"BB(4 -enital her*es infection a re8ie.

&nt J @*idemiol # BA;($B. doi "$."$B')ije)#.+.BA"+. ational &nstitute of 7llerg/ and &nfectious %iseases 3&7&%4. 7ccessed #$"# Mar ".

">. SenCer , Daufman HL, 7matruda 5, emunaitis M, Reid 5, et al. 3#$$B4 Phase && clinical

trial of a granuloc/te2macro*hage colon/2stimulating factor2encoding, second2generationoncol/tic her*es8irus in *atients ith unresectable metastatic melanoma. J :lin !ncol #(

>(';>((". doi "$."#$$)jco.#$$B.#+.'(>

". G!:?S 3#$$A4 Her*es 1accine %e8elo*ed at HMS Licensed for Preclinical 5rials.

78ailable htt*))archi8es.focus.hms.har8ard.edu)#$$A)$'$($A)licensing.shtml. 7ccessed#$"# Mar ".

"(. 7lsalla9 R7, Schiffer J5, Longini &M, Wald 7, :ore/ L, et al. 3#$"$4 Po*ulation le8el im*act

of an im*erfect *ro*h/lactic 8accine for her*es sim*le0 8irus2#. Se0uall/ transmitteddiseases '( #B$;#B(. doi "$."$B()ol9.$b$"'e'"A"d'd$#'

"A. Goss 7M, 1ic6erman P5, :halabi , Ma/aud P, 7lar/ M, et al. 3#$$B4 %/namic modeling of

her*es sim*le0 8irus t/*e2# 3HS12#4 transmission &ssues in structural uncertaint/. Full MathFiol (" (#$;(+B. doi "$."$$()s"">'A2$$A2B'(B2"

"B. -arnett -P, %ubin -, Slaoui M, %arcis 5 3#$$+4 5he *otential e*idemiological im*act of a

genital her*es 8accine for omen. Se0 5ransm &nfect A$ #+;#B. doi

"$.""')sti.#$$#.$$'A+A#$. Podder :, -umel 7F 3#$"$4 Qualitati8e d/namics of a 8accination model for HS12#. &M7

J 7**l Math (> (>;"$(. doi "$."$B')imamat)h0*$'$

#". SchartC @J, Floer S 3#$$>4 Predicting the *otential indi8idual and *o*ulation2le8el effectsof im*erfect her*es sim*le0 8irus t/*e # 8accines. J &nfect %is "B" "('+;"(+. doi

"$."$A)+#B#BB

##. Gleming %5, McQuillan -M, Johnson R@, ahmias 7J, 7ral S!, et al. 3"BB(4 Her*essim*le0 8irus t/*e # in the united states, "B( to "BB+. e @ngland Journal of Medicine

''( ""$>;"""". doi "$."$>)nejm"BB("$"''("$"

http://www.cdc.gov/std/herpes/stdfact-herpes.htmhttp://www.cdc.gov/std/herpes/stdfact-herpes.htmhttp://archives.focus.hms.harvard.edu/2008/030708/licensing.shtmlhttp://www.cdc.gov/std/herpes/stdfact-herpes.htmhttp://www.cdc.gov/std/herpes/stdfact-herpes.htmhttp://archives.focus.hms.harvard.edu/2008/030708/licensing.shtml


21/22

#'. Eu G, Sternberg MR, Dottiri FJ, McQuillan -M, Lee GD, et al. 3#$$4 5rends in her*es

sim*le0 8irus t/*e " and t/*e # sero*re8alence in the ?nited States. J 7m Med 7ssoc #B

B+;B('. doi "$."$$")jama.#B.A.B+#+. ahmias 7J, Lee GD, Fec6man2ahmias S 3"BB$4 Sero2e*idemiological and sociological

*atterns of her*es sim*le0 8irus infection in the orld. Scand J &nfect %is Su**l B "B;'.

#>. MertC -J, Fenedetti J, 7shle/ R, Sel6e S7, :ore/ L 3"BB#4 Ris6 factors for the se0ualtransmission of genital her*es. 7nn &ntern Med "" "B(;#$#. doi "$.('#)$$$'2+A"B2""2

'2"B(

#. Debede Y, %origo2etsma W, Mengistu Y, Me6onnen Y, Schaa* 7, et al. 3#$$+4 5ransmissionof her*es sim*le0 8irus 5/*e # among factor/ or6ers in @thio*ia. J &nfect %is "B$ '>;

'(#. doi "$."$A)+##$'A

#(. Stanberr/ LR, S*ruance SL, :unningham 7L, Fernstein %&, Mindel 7, et al. 3#$$#4

-l/co*rotein2 d2adju8ant 8accine to *re8ent genital her*es. e @ngland Journal of Medicine '+( ">#;"". doi "$."$>)nejmoa$""B">

#A. 7merican Social Health 7ssociation. 78ailable .ashastd.org)std2sti)Her*es)learn2about2

her*es. 7ccessed #$"# Mar ".

#B. Lohagen -F, 5unbac6 P, Fergstrom 5 3#$$#4 Pro*ortion of her*es sim*le0 8irus 3HS14t/*e " and t/*e # among genital and e0tragenital HS1 isolates. 7cta %erm 1enereol A# ""A;

"#$. doi "$."$A$)$$$">>>$#>#B+A">A'$. Public Health 7genc/ of :anada :anadian &mmuniCation :ommittee 3#$$(4

Recommendations on a human *a*illoma8irus immuniCation *rogram. 78ailable.*hac2

as*c.gc.ca)*ublicat)#$$A)*a*illoma8irus2*a*illome)*a*illoma8irus2*a*illome2""2eng.*h*.7ccessed #$"# Mar ".

'". Floer SM, Porco 5:, %arb/ - 3"BBA4 Predicting and *re8enting the emergence of anti8iral

drug resistance in HS12#. at Med + (';(A. doi "$."$'A)nm$BA2('

'#. Roberts M-, Heesterbee6 J7P 3#$$+4 Mathematical models in e*idemiolog/. &n Gilar J7,DracC/6 JF, eds. Mathematical Models, in @nc/clo*edia of Life Su**ort S/stems

3@!LSS4. !0ford, ?D %e8elo*ed under the 7us*ices of the ?@S:!, @olss Publishers.

''. ,,!Webb PM, imet -%, Ma/s R, Gortenberr/ J% 3"BBB4 H&1 immuniCation acce*tabilit/and antici*ated effects on se0ual beha8ior among adolescents. J 7dolescent Health #> '#$;

'##. doi "$."$")s"$>+2"'B03BB4$$$20

'+. Straus S, Sa8arese F, Drause P, Dost R, Meier J, et al. 3"BB+4 Placebo2controlled trial of 8accination ith recombinant gl/co*rotein d of her*es sim*le0 8irus t/*e # for

immunothera*/ of genital her*es. 5he Lancet '+' "+$;"+'. doi "$."$")s$"+$2

('3B+4B#>A"20

'>. :anada S 3#$$"4 :ansim table "$#2$>"" and catalogue no. A+2>'(20ie.78ailable.statcan.gc.ca)tables2tableau0)sum2som)l$")cst$")health(#a2eng.htm.

7ccessed #$"# Mar ".

'. Patric6 %M, %aar M, :oo6 %7, Drajden M, g H:, et al. 3#$$"4 7ntenatal sero*re8alenceof her*es sim*le0 8irus t/*e # 3HS12#4 in :anadian Women HS12# Pre8alence increases

throughout the re*roducti8e /ears. Se0 5ransm %is #A +#+;+#A. doi "$."$B()$$$$(+'>2

#$$"$($$$2$$$""'(. Singh 7, Wong 5, Holett R 3#$$A4 Human *a*illoma8irus 8accines Wh/ the time is right

to im*lement immuniCation and sur8eillance *rograms in :anada. :an J &nfect %is Med

Microbiol B #B+;#B.

http://www.ashastd.org/std-sti/Herpes/learn-about-herpeshttp://www.ashastd.org/std-sti/Herpes/learn-about-herpeshttp://www.ashastd.org/std-sti/Herpes/learn-about-herpeshttp://www.phac-aspc.gc.ca/publicat/2008/papillomavirus-papillome/papillomavirus-papillome-11-eng.phphttp://www.phac-aspc.gc.ca/publicat/2008/papillomavirus-papillome/papillomavirus-papillome-11-eng.phphttp://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health72a-eng.htmhttp://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health72a-eng.htmhttp://www.ashastd.org/std-sti/Herpes/learn-about-herpeshttp://www.ashastd.org/std-sti/Herpes/learn-about-herpeshttp://www.phac-aspc.gc.ca/publicat/2008/papillomavirus-papillome/papillomavirus-papillome-11-eng.phphttp://www.phac-aspc.gc.ca/publicat/2008/papillomavirus-papillome/papillomavirus-papillome-11-eng.phphttp://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health72a-eng.htm


22/22

'A. Warren :W, Santelli JS, @8erett S7, Dann L, :ollins JL, et al. 3"BBA4 Se0ual beha8ior

among ?.S. high school students, "BB$;"BB>. Gam Plann Pers*ect '$ "($;#$$. doi

"$.#'$()#BB"(A'B. Floer S, Wald 7, -ershengorn H, Wang G, :ore/ L 3#$$+4 5argeting 8irological core

grou*s a ne *aradigm for controlling her*es sim*le0 8irus t/*e # e*idemics. J &nfect %is

Soci 7m "B$ ""$;""(. doi "$."$A)+#+A>$+$. Le*6os6i JM, Mosher W%, %a8is D@, -ro8es RM, 1an Hoe/6 J 3#$"$4 5he #$$;#$"$

national sur8e/ of famil/ groth Sam*le design and anal/sis of a continuous sur8e/. # ";

'.+". Statistics :anada 3#$""4 :anadian :ommunit/ Health Sur8e/;7nnual :om*onent 3::HS4.

+#. LlamaCares M, Smith RJ 3#$$A4 @8aluating human *a*illoma8irus 8accination *rograms in

:anada should *rimar/ healthcare *a/ for adult 8accination FM: Public Health A ""+.

doi "$.""A)"+("2#+>A2A2""++'. Schillinger J7, McDinne/ :M, -arg R, -/nn R:, White D, et al. 3#$$A4 Sero*re8alence

of her*es sim*le0 8irus t/*e # and characterisitics associated ith undiagnosed infection

e Yor6 cit/, #$$+. Se0 5ransm %is '> >BB;$. doi "$."$B()ol9.$b$"'e'"A"fb"

++. Heffernan JM, Smith RJ, Wahl LM 3#$$>4 Pers*ecti8es on the basic re*roducti8e ratio. J R Soc &nterface # #A";#B'. doi "$."$BA)rsif.#$$>.$$+#

+>. Heesterbee6 J7P, %ietC D 3"BB4 5he conce*t of R$ in e*idemic theor/. Stat eerl >$ AB; ""$. doi "$."""")j."+(2B>(+."BB.tb$"+A#.0

+. :ore/ L, Wald 7, Patel R, Sac6s SL, 5/ring SD, et al. 3#$$+4 !nce2dail/ 8alac/clo8ir to

reduce the ris6 of transmission of genital her*es. e @ngland Journal of Medicine '>$ ""; #$. doi "$."$>)nejmoa$'>"++

+(. Floer SM, %olatabadi H 3"BB+4 Sensiti8it/ and ?ncertaint/ 7nal/sis of :om*le0 Models

of %isease 5ransmission 7n H&1 Model, as an @0am*le. &nternational Statistical

Re8ie)Re8ue &nternationale de Statisti9ue # ##B;#+'. doi "$.#'$()"+$'>"$+A. Marino S, Hogue &F, Ra/ :J, Dirschner %@ 3#$$A4 7 methodolog/ for *erforming global

uncer2taint/ and sensiti8it/ anal/sis in s/stems biolog/. J 5heor Fiol #>+ "(A;"B. doi

"$."$")j.jtbi.#$$A.$+.$""+B. Mar6 D@, Wald 7, Magaret 7S, Sel6e S, !lin L, et al. 3#$$A4 Ra*idl/ cleared e*isodes of

her*es sim*le0 8irus reacti8ation in immunocom*etent adults. J &nfect %is "BA ""+";""+B.

doi "$."$A)>B"B"'>$. World Health !rganiCation. &nitiati8e for 8accine research 3i8r4. Se0uall/ transmitted

diseases. 78ailable .ho.int)8accineresearch)diseases)soastd)en)inde0'.html.

7ccessed #$"# Mar ".
http://www.who.int/vaccine_research/diseases/soa_std/en/index3.htmlhttp://www.who.int/vaccine_research/diseases/soa_std/en/index3.html

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