Pre-existing immunity against vaccine vectors - friend or foe?

2013·0.31 MB·English

by  Saxena, Manvendra

Microbiology(2013),159,1–11 DOI10.1099/mic.0.049601-0
Pre-existing immunity against vaccine vectors –
Review
friend or foe?
Manvendra Saxena,13 Thi Thu Hao Van,23 Fiona J. Baird,3 Peter J. Coloe2
and Peter M. Smooker2
Correspondence 1Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia
PeterM.Smooker
2School of Applied Sciences, RMITUniversity, Bundoora, Victoria, Australia
[email protected]
3Comparative Genomics Centre, School ofPharmacy andMolecular Sciences,
James Cook University, Townsville, Queensland, Australia
Overthelastcentury,thesuccessfulattenuationofmultiplebacterialandviralpathogenshasled
toaneffective,robustandsafeformofvaccination.Recently,thesevaccineshavebeenevaluated
asdeliveryvectorsforheterologousantigens,asameansofsimultaneousvaccinationagainsttwo
pathogens.Thegeneralconsensusfrompublishedstudiesisthatthesevaccinevectorshavethe
potentialtobebothsafeandefficacious.However,someofthecommonlyemployedvectors,for
example Salmonella andadenovirus, often havepre-existing immune responses inthehost and
this has thepotential tomodify the subsequent immuneresponse toa vectored antigen. This
reviewexaminestheliteratureonthistopic,andconcludesthatforbacterialvectorstherecanin
fact,insome cases,beanenhancement inimmunogenicity, typicallyhumoral, while forviral
vectorspre-existingimmunityisahindranceforsubsequentinductionofcell-mediatedresponses.
Introduction et al., 1997) and Salmonella (Dougan et al., 1987) are
considered to be suitable candidates for the delivery of
Inthefieldsofmedicineandveterinarymedicine,thereare
vaccine antigens due to their capability to induce robust T
numerouslive,attenuatedbacterialandviralvaccinesinuse
cellimmuneresponses(Aldertonetal.,1991;Loetal.,1999;
todayworldwide.Thesafetyandefficacyofsuchvaccinesis
Mastroeni et al., 2001; Mittru¨cker & Kaufmann, 2000;
well established and allows further development as vector
Nauciel, 1990). Salmonella is one genus that has been well
systemstodeliverantigenoriginatingfromotherpathogens.
examined as a vector, building on the extensive research
Various attenuated bacteria, including Escherichia coli,
available on the micro-organism’s physiology and patho-
Vibrio cholerae, lactic acid bacteria (LAB), specifically
Lactococcus lactis, Mycobacterium, Listeria, Shigella and genesis (Basso et al., 2000; Killeen & DiRita, 2000; Sirard
Salmonella, have been tested for the targeted delivery of et al., 1999; Ward et al., 1999). There exist several
heterologousantigensofbacterial,viralandparasiticorigin commercial vaccines that are used as anti-Salmonella
into a variety of animal hosts (Bahey-El-Din et al., 2010; vaccines in humans and animals (e.g. Ty21a for typhoid
Innocentin et al., 2009; Johnson et al., 2011; Tobias et al., fever in humans, several Salmonella serovars against
2008,2010;Tobias&Svennerholm,2012).Bacteriasuchas salmonellosis in chickens and other animals). The general
E.coliandlacticacidbacteriahaverecentlygainedfavour,as strategy for vectoring heterologous antigen is depicted in
E.coliisacommensalandlacticacidbacteriaarepresentin Fig. 1. The first clinical trial of a recombinant, which was
most fermented food items and are therefore naturally conductedover20yearsagousinganattenuatedSalmonella
presentinthehost.Theyarealsoamuchsaferoptionthan as a delivery vector, led to the widespread testing of this
traditional attenuated vaccines in children and immune- bacterium as a mucosal delivery system for antigens from
compromisedpeople.Asthisreviewdiscussestheeffectsof non-Salmonella pathogens (Dougan et al., 1987). These
pre-existing immune responses to attenuated vaccines, studies have demonstrated the utility of live bacteria to
further discussion of LAB and E. coli as potential vectors deliver expressed antigens and DNA vaccines to the host
will not be undertaken; however, the reader is directed to immune system (Atkins et al., 2006; Husseiny & Hensel,
severalinterestingreviews(Bermu´dez-Humara´netal.,2011; 2008;Jiangetal.,2004;Kirbyetal.,2004).Sincethenseveral
Wells&Mercenier,2008). other intracellular bacterial vectors have been successfully
IntracellularbacteriafromthegeneraMycobacterium(Guleria tested for their capability to deliver a variety of antigens
etal.,1996),Listeria(Gentschevetal.,2001),Shigella(Levine from various pathogens, as well as vaccination against
cancer.Onegenuswhichhasbeenwidelytestedasvectoris
3Theseauthorscontributedequallytothiswork. Listeria. Listeria species are Gram-positive intracellular
049601G2013SGM PrintedinGreatBritain 1
M.Saxenaandothers
(a) (b) M N pMOInv
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64

50

36

22
Fig.1.(a)Generalapproachtousingbacteriaasvaccinevectors.Inthiscase,theheterologousantigenisdepictedasbeing
expressed on the bacterial surface. (b) Salmonella secretion of heterologous antigen. STM-1 was engineered to secrete a
haemolysin protein. Western blot probed with anti-haemolysin antisera. M, Marker lane (in kDa); N, concentrated growth
medium after STM-1 growth (no plasmid); pMOInv, medium after growth of STM-1 with the pMOInv plasmid, encoding
haemolysin.
food-bornepathogens.TheadvantagesofListeriaarethatit Stoyanov et al., 2010; Weli & Tryland, 2011). Amongst
can invade a variety of cells, including antigen presenting them, YFV (YF-17D strain) was the first to be licensed for
cells (APCs). After invading the host cell, Listeria resides use in humans, where the cDNAs encoding the envelope
inside the phagosome; however, it can escape the phago- proteins of YFV were replaced with the corresponding
somewiththehelpoflisteriolysinO(LLO;Hly)andreside genes of an attenuated Japanese encephalitis virus strain,
in the cytoplasm of the cells, thereby efficiently presenting SA14-14-2(Appaiahgari&Vrati,2010;Rollieretal.,2011).
antigentobothCD8andCD4Tcells(Cossart&Mengaud, Poxvirusesarealsostudiedextensivelyascandidatevectors
1989; Kaufmann, 1993; Pamer et al., 1997). Several studies for human use, among which attenuated derivatives of
have demonstrated the effectiveness and ease of using vaccinia virus [such as modified vaccinia virus Ankara
Listeria monocytogenes to deliver heterologous vaccine (MVA) and New York attenuated vaccinia virus NYVAC
antigens and DNAvaccines (Brockstedt et al., 2004; Jensen strains] are the most promising vectors (Esteban, 2009;
et al., 1997; Johnson et al., 2011; Peters et al., 2003; Shen Go´mezetal.,2008;Rimmelzwaan&Sutter,2009).Theyare
etal.,1995;Yinetal.,2011). ideal candidate vectors due to their large DNA-packing
capacity and their thermal and genetic stability (Minke
Similarly,variousviralvectorshavebeensuccessfullytested
etal.,2004).TheNYVACvectorhasbeenshowntoinduce
for their capability to deliver heterologous vaccine
+
CD4 T cell-dominant responses, and MVA induces both
antigens, and this generally results in the induction of
+ +
strong CTL immune responses. In the veterinary field, CD4 andCD8 Tcellresponses(Mooijetal.,2008).The
there are numerous viral vector vaccines that are currently adenovirus (Ad) vector is another of the most widely
licensed for use in livestock and domesticated animals. evaluated vectors to date to express heterologous antigens,
These recombinant vaccines are based on both DNA due to ease of production, safety profile, genetic stability,
viruses (such as fowlpox virus-based vaccines which target the ease of DNA genome manipulation, and the ability to
avian influenza virus and fowlpox virus, or vaccinia virus- stimulate bothinnateandadaptiveimmuneresponses and
based vectorsagainsttherabiesvirus inwildlife) andRNA inducebothTandBcellresponses(Alexanderetal.,2012;
viruses [such as Newcastle disease virus-based vaccines to Fitzgerald et al., 2003; Gabitzsch & Jones, 2011; Lasaro &
be used in poultry or yellow fever virus (YFV)-based Ertl, 2009; Vemula & Mittal, 2010; Weyer et al., 2009).
vaccines to be used in horses against West Nile virus] Theyhavebeenextensivelyexaminedasadeliveryvectorin
(Draper&Heeney,2010).Basedonthesafetyrecordinthe several preclinical and clinical studies for infectious
veterinaryfield,manyviruseshavebeenstudiedforhuman diseases such as anthrax, hepatitis B, human immunodefi-
use as a vector in vaccine development (Beukema et al., ciency virus (HIV)-1, influenza, measles, severe acute
2006; Esteban, 2009; Schirrmacher & Fournier, 2009; respiratory syndrome (SARS), malaria and tuberculosis
2 Microbiology159
Pre-existingimmunityagainstvaccinevectors
(Chengalvalaetal.,1994;Gaoetal.,2006;Hashimotoetal., thevector strain. Whittle& Verma (1997)reported similar
2005; Hsu et al., 1992; Limbach & Richie, 2009; Radosevic findings. Mice immunized via the intra-peritoneal route
et al., 2007; Shiver et al., 2002). with a Salmonella dublin aroA mutant expressing hetero-
logous antigen after being exposed to the same vector
However,beforevectoredvaccinescanbeusedinthehuman
showedahigherimmuneresponsetothevectoredantigenin
population they need to satisfy several important criteria.
comparison to mice without any immunological memory
Safety is a major concern, as even a low level of toxicity is
againstthevector.
unacceptable (of course the minor discomfort that accom-
panies many vaccinations is normal). Secondly, a vaccine Subsequently, several studies have been conducted to
should be inexpensive, so that it can be administered to a examine the effect of pre-existing immunity in the host
large population at minimal cost, and this is particularly againstSalmonella.TheseresultsaresummarizedinTable1.
important in resource-poor countries (Killeen & DiRita, The various reports are contradictory in their findings and
2000).Similarconstraintsapplytoveterinaryvaccines,with seem to paint a rather confusing picture. Some studies
cost often an even more important consideration. Finally, concludedthatpre-existingimmunityagainsttheSalmonella
long-lasting cellular and (where appropriate) humoral vector leads to stronger immune responses against the
immuneresponsestothevectoredantigenmustbeinduced deliveredantigen(Bao&Clements,1991;Jespersgaardetal.,
followingadministrationofthesevaccines,preferablywitha 2001; Kohler et al., 2000a, b; Metzger et al., 2004; Saxena
singledose(Atkinsetal.,2006). et al., 2009; Sevil Dome`nech et al., 2008; Whittle & Verma,
1997),withothersconsideringpre-existingimmunitytobea
Assomeofthevectorsinusewillhavebeenseenbythehost
limiting factor in the long-term use of Salmonella as an
immune system prior to vaccination, whether the presence
efficient vector for antigen delivery (Attridge et al., 1997;
of pre-existing immune responses is detrimental for the
Gahanetal.,2008;Robertsetal.,1999;SevilDome`nechetal.,
further development of a vector-based vaccine scheme, or
2007;Vindurampulle&Attridge,2003a,b).
canaugmentresponsestothevectoredantigen,needstobe
considered in detail. This is the subject of this review. In Aslightmajority of thestudies listedinTable 1(10 versus
discussingthepossibleeffectsonpre-existingimmunity,the eight)indicatetheupregulationofimmuneresponsesafter
natural immunity to the vector needs to be considered. animalshavebeenexposedtoeitherhomologousorrelated
Therefore,consideringavectorsuchasSalmonella,ifahost
strains before the delivery of heterologous antigen using a
haspreviouslybeeninfectedtherewillexistrobustBandT
Salmonella vector. A study by Metzger and co-workers on
memory responses, and as such, when a vaccination is
human volunteers using Salmonella Typhi as a vector
delivered,ananamnesticresponsetotheSalmonellaantigens
suggested that there was no change in the T cell immune
willbeinduced(whiletheresponsetothevectoredantigen
response against the heterologous antigen in human
willbeaprimaryresponse).Thiswilltheoreticallyreducethe
volunteers who were exposed to empty vector in compar-
exposureoftheheterologousantigentotheimmunesystem,
ison with volunteers who were immunologically naive of
asthevectorisrapidlycleared.Surprisingly,aswillbeseenin
the vector strain (Metzger et al., 2004). In these subjects,
someoftheexamplesgivenbelow,thiscanhaveresultsthat
humoral responses were moderately elevated in pre-
differ depending on the magnitude of the response to the
exposed individuals. Similarly, Saxena et al. (2009)
vectoredantigen.Similarly,forvirallyvectoredantigens,the
indicated higher humoral and T cell responses in mice
existence of pre-existing immunity to the vector (particu-
pre-exposed to homologous or heterologous Salmonella
larlyneutralizingantibody)willrestrictdeliveryofthevirus
strains. The interleukin 4 (IL4) response was significantly
into cells, thereby effectively reducing the dose of the
higher when the animal host was exposed to the
vectoredantigen.Again,thismightbeexpectedtoresultina
homologous strain, whereas pre-exposure to a related
reduction intheantigenicityofthevectoredantigen.
species did not have such an impact on IL4 responses.
Conversely interferon (IFN)-c responses were higher,
Effects of prior immunological exposure to irrespective of the strain to which mice were pre-exposed.
vectors – bacterial vectors This study also indicated that the presence of homologous
or heterologous opsonizing antibodies leads to a higher
In the case of bacterial vectors, the effect of pre-existing
uptake of Salmonella by macrophages in vitro, which may
immune responses has only been tested using Salmonella
explain the higher immune responses in exposed mice. As
serovarsandListeriaspp.Concernthatpriorimmunological
maybeexpected,uptakewashigherwhenhomologoussera
experience of the host with either the homologous
were used as the opsonin rather than heterologous sera.
Salmonellavectorstrainorarelatedstrainmightcomprom-
This is depicted in Fig. 2.
iseitsabilitytodeliverheterologousvaccineantigenwasfirst
raised in 1987 (Dougan et al., 1987). Bao and Clements Conversely,therearereportsthatindicatethatpre-existing
subsequently reported experimental evidence of the con- immunity against the bacterial vector downregulates
sequences of prior exposure of animals to the vector strain immune responses against the delivered heterologous
(Bao&Clements,1991).Thisworkshowedthatbothserum antigen using similar or related vectors. Attridge and co-
andmucosalantibodyresponsesagainsttheforeignantigen workersreportedthatthepresenceofimmunityagainstthe
were in fact upregulated in animals with prior exposure to bacterial vector prior to the delivery of vectored antigenic
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Table1. Summary ofpublished reportsandtheir conclusions
NA,Notapplicable;ND,notdetermined.
Vaccine Vaccinevector Pre-existingimmunity Vectoredantigen CMIresponse Humoral Reference
recipient organism response
Mouse S.dublin S.dublin NA ND + Bao&Clements(1991)
Mouse S.dublin S.typhimurium NA ND ++ Bao&Clements(1991)
Mouse S.typhimurium S.typhimurium Glucan-bindingdomainof ND ++ Jespersgaardetal.(2001)
glucosyltransferase,Streptococcusmutans
Mouse S.typhimurium S.typhimurium Haemagglutinin,Porphyromonasgingivalis ND ++ Kohleretal.(2000a,b)
Human S.typhiTy21a StyphiTy21a UreasesubunitsAandB,Helicobacterpylori Nochange ++ Metzgeretal.(2004)
Mouse S.typhimurium S.typhimurium Ovalbumin,G.gallus ++ +++ Saxenaetal.(2009)
Mouse S.typhimurium Salmonellaenterica Ovalbumin,G.gallus ++ ++ Saxenaetal.(2009)
serovarEnteritidis
Mouse S.dublin S.typhimurium FusionproteinofYersiniaouterproteinE ++ ND SevilDome`nechetal.(2008)
andp60fromL.monocytogenes
Mouse S.typhimurium S.dublin FusionproteinofYersiniaouterproteinE ++ ND SevilDome`nechetal.(2008)
andp60fromL.monocytogenes
Mouse S.dublin S.dublin Envelopeprotein,MurrayValley ND +++ Whittle&Verma(1997)
encephalitisvirus
Mouse S.stanley S.stanley FimbrialproteinK88,E.coli ND 222 Attridgeetal.(1997)
Mouse S.stanley Salmonellastrasbourg FimbrialproteinK88,E.coli ND 2 Attridgeetal.(1997)
Mouse S.typhimurium S.typhimurium Cfragmentoftetanustoxin, ND 22 Gahanetal.(2008)
Clostridiumtetani
Mouse S.typhimurium S.typhimurium Cfragmentoftetanustoxin,C.tetani ND 222 Robertsetal.(1999)
Mouse S.typhimurium S.dublin Cfragmentoftetanustoxin,C.tetani ND 22 Robertsetal.(1999)
Mouse S.typhimurium S.typhimurium FusionproteinofYersiniaouterproteinE 222 ND SevilDome`nechetal.(2007)
andp60fromL.monocytogenes
Mouse S.stanley S.stanley FimbrialproteinK88,E.coli ND 222 Vindurampulle&Attridge(2003b)
Mouse S.dublin S.stanley FimbrialproteinK88,E.coli ND 222 Vindurampulle&Attridge(2003b)
M
ic
ro
b
io
lo
g
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1
5
9
Pre-existingimmunityagainstvaccinevectors
120
100
%) 80
1 (
M-
ST 60
of
e
ak 40
pt
U
20
0
0 10 20 30 40 50 60 70 80
Time (min)
Fig.2.UptakeofSTM-1byJ774macrophages,relativetothehighestuptakepercentage.X,Opsonizedwithnaivesera;m,
opsonizedwithserumfrommiceexposedtoSalmonellaenteriditis;&,opsonizedwithserumfrommiceexposedtoSTM-1.
proteincandownregulateimmuneresponsesinmiceagainst responses in mice when exposed to a similar strain used
the delivered antigen (Attridge et al., 1997). Similar results as vector (Sevil Dome`nech et al., 2007). In contrast,
werereportedbyRobertsetal.(1999)andVindurampulle& another study by the same authors reported that animals
+
Attridge(2003a,b).However,thelatterauthorsfoundthat exposed to related vectors induce much higher CD8
the hypo-responsiveness could be largely eliminated by responseswhencomparedwithanimalswhichdonothave
exposing animals to the foreign antigen prior to vector- any pre-existing Salmonella immunity (Sevil Dome`nech
priming(Vindurampulle&Attridge,2003b).Unfortunately, et al., 2008). The difference between these two studies was
this would appear to be impractical for an immunization that in the first, the prime and boost were with identical
regimen! serovars,whileinthesecondstudy,differentserovarswere
used.Thismaypointtoawayofavoidingdownregulation
Astudy presentedbyGahan etal.(2008)immunized mice
of CD8 responses by pre-existing immunity. This is
with S. Typhimurium expressing C fragment of tetanus
important, as one of the advantages of using Salmonella
toxin antigen from an expression plasmid or as a DNA
(an intracellular pathogen) is that strong cellular immune
vaccine. Vaccinated mice developed humoral responses to
responses can be induced.
LPS and tetC (for the plasmid-bearing vaccines). Animals
from all groups (including a previously unvaccinated It must be noted that in the case of Salmonella vaccines,
group) were immunized on day 182 with Salmonella effects other than strictly immunological responses (par-
expressing tetC. At this time, the anti-LPS and tetC titres ticularly adaptive responses) should be considered. In the
were beginning to wane. Fourteen days after the second contextofinnateimmunity,itwasshownthatadministra-
immunization, the colonization of various mouse organs tion of non-virulent Salmonella to gnobiotic pigs elimi-
was assessed. The ability to colonize was found to be nated disease following challenge with a virulent strain
significantly reduced in groups that had been previously (Foster et al., 2003). Interestingly, protection was not by
vaccinated with Salmonella. In view of this finding, it was competitive exclusion, as the virulent strain was in high
perhaps not surprising that at day 210 the LPS titres were numbersinthegutbutdidnotdistributesystemically.The
not significantly different between groups receiving one or protectionwasproposedtobemediatedbytheinfiltration
two vaccinations. More interestingly, mice that had been of a large number of polymorphonuclear leukocytes into
primed with Salmonella alone, and then boosted with the gut, and although perhaps impractical as a general
Salmonella expressing tetC, induced much lower anti-tetC prophylactic (as the time between vaccination and
responsesthanmicethathadnotbeenprimed.Thisargues infection is short), this may be an option for short-term
strongly that prior immunological immunity to the vector or perhaps therapeutic vaccination (as reviewed by Foster
canseriouslydampensubsequentantigen-specifichumoral et al., 2012).
responses. Whether the same is true for cellular responses
Chickens (Gallus gallus) are a natural animal reservoir for
was not evaluated.
Salmonella, which makes them an important source of
Otherstudieshaveevaluatedcellularresponses.Astudyby Salmonella-associatedgastroenteritisinhumans.Theability
Sevil Dome`nech and colleagues reported that pre-existing to use oral Salmonella vaccines to immunize against
+
anti-vector immunity seriously compromises CD8 heterologous pathogens would be of enormous benefit to
http://mic.sgmjournals.org 5
M.Saxenaandothers
the poultry industry in both broiler and layer flocks. Both negative impact of vector-specific immune responses can
vertical and horizontal transmission is associated with alsobecounteredbyrepeatedimmunizationwiththesame
Salmonella in chickens (Liljebjelke et al., 2005). Vertical vaccine and dose; this in effect leads to higher priming of
transmissionviainovotransmissionisparticularlyimportant, naive T cells against the delivered antigen. Of course, such
because if there is prior exposure to the vaccine strain, repeated vaccination may not be practicable in real-world
subsequentvaccinationusinganoralSalmonellavectorcould situations.
be severely compromised. A considerable number of studies
oncross-protectiveimmunityandcompetitiveexclusionhave
Effects of prior immunological exposure to
been undertaken in chickens. Protective cross-reactive
vectors – viral vectors
immunity against Salmonella strains has been demonstrated
against both homologous and heterologous challenges (Beal Despitethemanyadvantageswhichviralvectoringcanoffer,
et al., 2006), although cross-serogroup protection was not pre-existing immunity is a major obstacle of many viral-
strong. Furthermore, a recent study reported that pre- vectored vaccines, such as Ad serotype 5 or herpes simplex
treatment of newly hatched chickens with different virus type 1 (HSV-1), where the rate of seroprevalence to
Salmonella strains could produce a complete invasion– thesevirusesisveryhigh[40–45%and70%(ormore)ofthe
inhibition effect on any subsequent exposure to both US population, respectively] (Hocknell et al., 2002; Pichla-
homologous and heterologous strains (Methner et al., Gollon etal., 2009).Vector-specific antibodiesmayimpede
2010). Pre-exposure with a highly invasive form of the induction ofimmuneresponsestothevaccine-encoded
Salmonella Enteritidis caused a largeinflux of heterophilsto antigens,astheymayreducethedoseandtimeofexposure
the caecal mucosa in 1-day-old chicks, and subsequent of the target cells to the vaccinated antigens (Pichla-Gollon
heterologouscaecalcolonizationwasinhibitedforaperiodof et al., 2009; Pine et al., 2011). In a large-scale clinical trial
48 h(Methneretal.,2010).Theimplicationsofthiskindof (STEP)ofanAdserotype5(AdHu5)-basedHIV-1vaccine,
colonization-inhibitionstudyontheimmunologicalstatusof thevaccinesshowedalackofefficacyandtendedtoincrease
theaffectedchickensareyettobefullyelucidated.Itshouldbe the risk of HIV-1 infection in vaccine recipients who had
notedthatthestudieslistedinTables1and2arecontrolled pre-existing neutralizing antibodies to AdHu5 (Buchbinder
laboratory studies, with the possibility of a competitive etal.,2008).ForanHSV-1-basedvectorvaccine,ithasbeen
exclusioncomponenttoimmunitynotdiscussed. demonstrated that pre-existing anti-HSV-1 immunity
reduced,butdidnotabolish,humoralandcellularimmune
SimilarlystudiesofL.monocytogenesandtheeffectsofpre- responses against the vaccine-encoded antigen (Hocknell
existing immune responses indicate conflicting results. A et al., 2002; Lauterbach et al., 2005). However, Brockman
study by Bouwer et al. (1999) indicates that pre-existing and Knipe found that the induction of durable antibody
immune responses against the Listeria vector do not responses and cellular proliferative responses to HSV-
diminish immune responses against the delivered hetero- encoded antigen were notaffected by prior HSV immunity
logous antigen, and a similar study by Starks et al. (2004) (Brockman& Knipe,2002).Similarly, pre-existingimmun-
also concluded that prior exposure of mice to the empty ity to poliovirus has little effect on vaccine efficacy in a
Listeria vector did not influence anti-cancer immune poliovirus-vectored vaccine (Mandl et al., 2001). Different
responses when a similar mutant was used as a carrier of effects of pre-existing immunity on the efficacy of recom-
amelanomacancerantigen.Similarfindingswerereported binant viral vaccine vectors are summarized in Table 2.
by Whitney et al. (2011) in rhesus macaques in which L. Thereareseveralapproachestoavoidingpre-existingvector
monocytyogens was used as a carrier of gag-HIV antigen. immunity, such as the use of vectors derived from non-
Conversely, studies by Stevens et al. (2005) in which L. humansources,usinghumanvirusesofrareserotypes(Kahl
monocytogens was used to deliver feline immunodeficiency etal.,2010;Lasaro&Ertl,2009),heterologousprime–boost
virus(FIV)gagproteinandasacarrierofDNAvaccinesto approaches (Liu et al., 2008), homologous reimmunization
vaccinatecatsagainstFIVenvelopeproteinindicatedlower (Steffensen et al., 2012) and removing key neutralizing
immune responses against the delivered antigen in cats epitopesonthesurfaceofviralcapsidproteins(Gabitzsch&
exposedtoemptyListeriavector incomparison withnaive Jones, 2011; Roberts et al., 2006). The inhibitory effect of
animals (Stevens et al., 2005). Similar findings have been pre-existing immunity can also be avoided by masking the
reported by Tvinnereim et al. (2002) and Leong et al. Ad vector inside dendritic cells (DCs) (Steffensen et al.,
(2009). However, taken together, these studies conclude 2012).Inaddition,mucosalvaccinationoradministrationof
that prior exposure of host animals to empty vector does higher vaccine doses can overcome pre-existing immunity
not abrogate immune responses to the vectored antigen, problems (Alexander et al., 2012; Belyakov et al., 1999;
but only reduces them somewhat. Only the study by Vijh Priddyetal.,2008;Xiangetal.,2003).
et al. (1999) indicated that exposure to the empty vector
may completely abrogate immune responses against the
Concluding remarks and perspective
delivered antigens (Vijh et al., 1999). However, these
studies also indicate that downregulation of antigen- As we search for new vaccine approaches for the array of
specific immune responses is highly dependent on dose pathogensforwhichnoneisyetavailable,revisitingproven
and time. Leong et al. (2009) also demonstrated that the vaccines and developing these further has gained
6 Microbiology159
Pre-existingimmunityagainstvaccinevectors
Table2.Different effects ofpre-existingimmunity on theefficacy ofrecombinant viralvaccine vectors
ND,Notdetermined.
Vaccine Vaccine Pre-existing Vectoredantigen CMIresponse Humoral Reference
recipient vector immunity response
organism
Mouse Poliovirus Poliovirus Chickenovabumin 2 Nochange Mandletal.(2001)
Mouse HSV HSV Chickenovabumin 222 222 Lauterbachetal.(2005)
Mouse HSV HSV E.colib-galactosidase Nochange Nochange Brockman&Knipe(2002)
Mouse Ad Ad HIV-1gag 222 ND Pichla-Gollonetal.(2009)
Human Ad Ad HIV-1gag/pol/nef 22 ND McElrathetal.(2008)
Mouse Ad Ad H5haemagglutinin 2 2 Alexanderetal.(2012)
Mouse Ad Ad Ovabumin/glycoproteinof 2 ND Steffensenetal.(2012)
lymphocytic
choriomeningitisvirus
Mouse Ad Ad H5haemagglutininand 22 22 Pandeyetal.(2012)
N1nucleoprotein
momentum. Hence, attenuated bacteria and viruses which
responses(Kohleretal.,2000b).Thisisinconflictwiththe
havealonghistoryofefficacyandsafetyarebeingbrought above result, although it should be mentioned that they
into use. While very attractive, a common theme in these used different Salmonella species. Vindurampulle and
experimentalapproacheshasbeenthelimitationsthatpre- Attridgealsoexamined theimpactoftheSalmonellastrain
existingimmunitytothevectormaypose.However,asthis and the nature of the antigens used. In their study, they
examination of the relevant literature shows, there is a used S. Dublin and Salmonella Stanley aroA mutants to
rather confusing picture, with some studies in fact deliver E. coli K88 and LT-B antigens, and concluded that
indicating that pre-existing immunity may be a friend, the effect of pre-existing immunity depends on both the
rather than foe. strainusedandthetypeofantigendelivered(Vindurampulle
&Attridge,2003b).
Few studies using viral vectors have reported on the
influence of pre-existing immunity on humoral responses. All these studies on the effect of pre-existing immunity
Generally speaking, for bacterial-delivered antigens, the discusstheimpact onhumoralresponses. SevilDomenech
humoral responses were influenced by pre-existing and colleagues reported that pre-exposing animals to the
immunity,withslightlymorestudiesfindingaugmentation homologous Salmonella vector leads to a significant
+
rather than diminution. Why is there variation? This may reduction in CD8 responses; however, exposure of
be due to several factors, including the type of Salmonella animals to a heterologous strain leads to significantly
used and its invasiveness. Dunstan and colleagues tested higher CD8+ responses (Sevil Dome`nech et al., 2007,
theabilityofsixisogenicSalmonellaserovarTyphimurium 2008). Saxena and colleagues also reported that antigen-
strains harbouring different mutations for their ability to specificTcell responses wereeither similar or significantly
induce immune responses against the C fragment of higher, with no downregulation in T cell responses
tetanus toxin and concluded that the strain which had observed after pre-exposing mice to either homologous
the least ability to colonize Peyer’s patches induced the or heterologous strains (Saxena et al., 2009).
lowest immune responses (Dunstan et al., 1998).
For viral vectors, the impact of cell-mediated immunity
Similarly,theboostingtimeandnatureoftheantigenused was more pronounced, and as depicted in Table 2, almost
might be important. Attridge and colleagues indicated the always resulted in a reduction in the subsequent immune
importance of boosting time. In one experiment, boosting response. Presumably this is because viruses will induce
mice at 10 weeks led to complete inhibition of antibody neutralizing antibody on the first dose, and in subsequent
responses against the delivered heterologous antigen; doses this antibody will limit the number of transduced
however, when the mice were boosted at 4 weeks, the cells,thereforelimitingtheresponses.Thisisparticularlya
downregulation of antibody responses was not so prom- problem with a common viral vector such as Ad, where a
inent (Attridge et al., 1997). A similar study conducted by large proportion of the population will have immuno-
Kohlersandcolleaguesshowsthatboostingat7 weeksafter logical memory against common serotypes (Lasaro & Ertl,
pre-exposing animals to empty vector leads to lower 2009). As these authors conclude, it will be possible to
antigen-specificIgGandsecretory IgAresponses; however, utilize such vectors only by developing vaccines from
boostingat14 weeksleadstohigherIgGandsecretoryIgA alternative serotypes. It may be that a vector such as
http://mic.sgmjournals.org 7
M.Saxenaandothers
attenuatedinfluenzavirus,withtheabilitytoeasilydevelop Beal,R.K.,Wigley,P.,Powers,C.,Barrow,P.A.&Smith,A.L.(2006).
reassortants, will be useful in this context. Cross-reactivecellularandhumoralimmuneresponsestoSalmonella
enterica serovars Typhimurium and Enteritidis are associated with
In addition, immunological memory in the form of protectiontoheterologousre-challenge.VetImmunolImmunopathol
opsonizing antibody certainly plays an important role in 114,84–93.
the early uptake of Salmonella by macrophages and DC. Belyakov, I. M., Moss, B., Strober, W. & Berzofsky, J. A. (1999).
Thismaybebeneficial,asthelivebacterialvectorusedfor Mucosal vaccination overcomes the barrier to recombinant vaccinia
delivery purposes harbours mutations in genes encoding immunization caused by preexisting poxvirus immunity. Proc Natl
AcadSciUSA96,4512–4517.
proteins responsible for their survival in the animal host.
This not only encumbers their ability to cause disease, Bermu´dez-Humara´n, L. G., Kharrat, P., Chatel, J. M. & Langella, P.
(2011). Lactococci and lactobacilli as mucosal delivery vectors for
making them safe livevectors, but also limitsthe number
therapeuticproteinsandDNAvaccines.MicrobCellFact10(Suppl.1),S4.
of replications. The presence of opsonizing antibodies
Beukema,E.L.,Brown,M.P.&Hayball,J.D.(2006).The potential
should mean a higher level of bacterial uptake, leading to
roleoffowlpoxvirusinrationalvaccinedesign.ExpertRevVaccines5,
higher presentation to the immune system and therefore
565–577.
a better immune response. We have previously shown
Bouwer,H.G.,Shen,H.,Fan,X.,Miller,J.F.,Barry,R.A.&Hinrichs,
that this is indeed the case (Saxena et al., 2009) (depicted
D. J. (1999). Existing antilisterial immunity does not inhibit the
in Fig. 2). It would be of great benefit to address these
development of a Listeria monocytogenes-specific primary cytotoxic
issues not only in mice but also in other organisms such T-lymphocyteresponse.InfectImmun67,253–258.
as chickens, which are the most likely host to be targeted Brockman,M.A.&Knipe,D.M.(2002).Herpessimplexvirusvectors
for the use of live Salmonella vectors, specifically where elicit durable immune responses in the presence of preexisting host
the vaccines are developed for use in livestock and immunity.JVirol76,3678–3687.
poultry. Brockstedt,D.G.,Giedlin,M.A.,Leong,M.L.,Bahjat,K.S.,Gao,Y.,
Luckett,W.,Liu,W.,Cook,D.N.,Portnoy,D.A.&Dubensky,T.W.,Jr
To summarize, bacterial vectors such as Salmonella and
(2004).Listeria-basedcancervaccinesthatsegregateimmunogenicity
viral vectors such as Ad show great promise as delivery fromtoxicity.ProcNatlAcadSciUSA101,13832–13837.
vehiclesforheterologousantigens;however,priorexposure
Buchbinder,S.P.,Mehrotra,D.V.,Duerr,A.,Fitzgerald,D.W.,Mogg,
tothevector mustbe considered.By judiciousselection of R., Li, D., Gilbert, P. B., Lama, J. R., Marmor, M. & other authors
the strain/serotype it will be possible to avoid the negative (2008). Efficacy assessment of a cell-mediated immunity HIV-1
effectsanditmayindeedbepossibletopositivelyinfluence vaccine (the Step Study): a double-blind, randomised, placebo-
the response, particularly for humoral immunity. controlled,test-of-concepttrial.Lancet372,1881–1893.
Chengalvala,M.V.,Bhat,B.M.,Bhat,R.,Lubeck,M.D.,Mizutani,S.,
Davis,A.R.&Hung,P.P.(1994).Immunogenicityofhighexpression
References adenovirus-hepatitis B virus recombinant vaccines in dogs. J Gen
Virol75,125–131.
Alderton,M.R.,Fahey,K.J.&Coloe,P.J.(1991).Humoralresponses Cossart, P. & Mengaud, J. (1989). Listeria monocytogenes. A model
and salmonellosis protection in chickens given a vitamin-dependent system for the molecular study of intracellular parasitism. Mol Biol
Salmonellatyphimuriummutant.AvianDis35,435–442. Med6,463–474.
Alexander, J., Ward, S., Mendy, J., Manayani, D. J., Farness, P., Dougan, G., Hormaeche, C. E. & Maskell, D. J. (1987). Live oral
Avanzini, J. B., Guenther, B., Garduno, F., Jow, L. & other authors Salmonellavaccines:potentialuseofattenuatedstrainsascarriersof
(2012).Pre-clinicalevaluationofareplication-competentrecombin- heterologous antigens to the immune system. Parasite Immunol 9,
ant adenovirus serotype 4 vaccine expressing influenza H5 hemag- 151–160.
glutinin.PLoSONE7,e31177.
Draper, S. J. & Heeney, J. L. (2010). Viruses as vaccine vectors for
Appaiahgari, M. B. & Vrati, S. (2010). IMOJEV(1): a Yellow fever infectiousdiseasesandcancer.NatRevMicrobiol8,62–73.
virus-based novel Japanese encephalitis vaccine. Expert Rev Vaccines
Dunstan,S.J.,Simmons,C.P.&Strugnell,R.A.(1998).Comparison
9,1371–1384.
oftheabilitiesofdifferentattenuatedSalmonellatyphimuriumstrains
Atkins,H.S.,Morton,M.,Griffin,K.F.,Stokes,M.G.,Nataro,J.P.& to elicit humoral immune responses against a heterologous antigen.
Titball,R.W.(2006).RecombinantSalmonellavaccinesforbiodefence. InfectImmun66,732–740.
Vaccine24,2710–2717.
Esteban,M.(2009).AttenuatedpoxvirusvectorsMVAandNYVAC
Attridge, S. R., Davies, R. & LaBrooy, J. T. (1997). Oral delivery of as promising vaccine candidates against HIV/AIDS. Hum Vaccin 5,
foreign antigens by attenuated Salmonella: consequences of prior 867–871.
exposuretothevectorstrain.Vaccine15,155–162.
Fitzgerald, J. C., Gao, G. P., Reyes-Sandoval, A., Pavlakis, G. N.,
Bahey-El-Din,M.,Casey,P.G.,Griffin,B.T.&Gahan,C.G.(2010). Xiang,Z.Q.,Wlazlo,A.P.,Giles-Davis,W.,Wilson,J.M.&Ertl,H.C.
ExpressionoftwoListeriamonocytogenesantigens(P60andLLO)in (2003). A simian replication-defective adenoviral recombinant
Lactococcus lactis and examination for use as live vaccine vectors. vaccinetoHIV-1gag.JImmunol170,1416–1422.
JMedMicrobiol59,904–912.
Foster, N., Lovell, M. A., Marston, K. L., Hulme, S. D., Frost, A. J.,
Bao, J. X. & Clements, J. D. (1991). Prior immunologic experience Bland,P.&Barrow,P.A.(2003).Rapidprotectionofgnotobioticpigs
potentiatesthesubsequentantibodyresponsewhenSalmonellastrains against experimental salmonellosis following induction of polymor-
areusedasvaccinecarriers.InfectImmun59,3841–3845. phonuclearleukocytesbyavirulentSalmonellaenterica.InfectImmun
Basso, H., Rohde, M. & Guzma´n, C. A. (2000). Vectors to achieve 71,2182–2191.
selectiveexpressionofvaccineantigenswithineukaryoticcellsusing Foster, N., Berndt, A., Lalmanach, A. C., Methner, U., Pasquali, P.,
Salmonellaspp.ascarrierstrains.FEMSMicrobiolLett182,219–223. Rychlik,I.,Velge,P.,Zhou,X.&Barrow,P.(2012). Emergency and
8 Microbiology159
Pre-existingimmunityagainstvaccinevectors
therapeuticvaccination–isstimulatinginnateimmunityanoption? Johnson,P.V.,Blair,B.M.,Zeller,S.,Kotton,C.N.&Hohmann,E.L.
ResVetSci93,7–12. (2011).AttenuatedListeriamonocytogenes vaccinevectorsexpressing
influenzaAnucleoprotein:preclinicalevaluationandoralinoculation
Gabitzsch,E.S.&Jones,F.R.(2011).NewrecombinantAd5vector
ofvolunteers.MicrobiolImmunol55,304–317.
overcomes Ad5 immunity allowing for multiple safe, homologous
immunizations.JClinCellImmunolS4,001. Kahl,C.A.,Bonnell,J.,Hiriyanna,S.,Fultz,M.,Nyberg-Hoffman,C.,
Chen,P.,King,C.R.&Gall,J.G.(2010).Potent immune responses
Gahan, M. E., Webster, D. E., Wijburg, O. L., Wesselingh, S. L. &
and in vitro pro-inflammatory cytokine suppression by a novel
Strugnell,R.A.(2008).Impactofpriorimmunologicalexposureon
adenovirusvaccinevectorbasedonrarehumanserotype28.Vaccine
vaccinedeliverybySalmonellaentericaserovarTyphimurium.Vaccine
28,5691–5702.
26,6212–6220.
Kaufmann,S.H.(1993).Immunitytointracellularbacteria.AnnuRev
Gao, W., Soloff, A. C., Lu, X., Montecalvo, A., Nguyen, D. C.,
Immunol11,129–163.
Matsuoka, Y., Robbins, P. D., Swayne, D. E., Donis, R. O. & other
authors (2006). Protection of mice and poultry from lethal H5N1 Killeen,K.&DiRita,V.(2000).Liveattenuatedbacterial vaccines.In
avianinfluenzavirusthroughadenovirus-basedimmunization.JVirol NewVaccineTechnologies.EditedbyR.Ellis.Georgetown,TX:Landes
80,1959–1964. Bioscience.
Gentschev,I.,Dietrich,G.,Spreng,S.,Kolb-Ma¨urer,A.,Brinkmann, Kirby, A. C., Sundquist, M. & Wick, M. J. (2004). In vivo
V., Grode, L., Hess, J., Kaufmann, S. H. & Goebel, W. (2001). compartmentalization of functionally distinct, rapidly responsive
Recombinantattenuatedbacteriaforthedeliveryofsubunitvaccines. antigen-specificT-cellpopulationsinDNA-immunizedorSalmonella
Vaccine19,2621–2628. entericaserovarTyphimurium-infectedmice.InfectImmun72,6390–
6400.
Go´mez, C. E., Na´jera, J. L., Krupa, M. & Esteban, M. (2008). The
poxvirus vectors MVA and NYVAC as gene delivery systems for Kohler,J.J.,Pathangey,L.,Hasona,A.,Progulske-Fox,A.&Brown,
vaccinationagainstinfectiousdiseasesandcancer.CurrGeneTher8, T. A. (2000a). Long-term immunological memory induced by
97–120. recombinant oral Salmonella vaccine vectors. Infect Immun 68,
4370–4373.
Guleria,I.,Teitelbaum,R.,McAdam,R.A.,Kalpana,G.,Jacobs,W.R.,
Jr&Bloom,B.R.(1996).Auxotrophicvaccinesfortuberculosis.Nat Kohler,J.J.,Pathangey,L.B.,Gillespie,S.R.&Brown,T.A.(2000b).
Med2,334–337. EffectofpreexistingimmunitytoSalmonellaontheimmuneresponse
torecombinantSalmonellaentericaserovarTyphimuriumexpressing
Hashimoto,M., Boyer,J. L., Hackett, N. R., Wilson,J. M. & Crystal,
a Porphyromonas gingivalis hemagglutinin. Infect Immun 68, 3116–
R.G.(2005).Inductionofprotectiveimmunitytoanthraxlethaltoxin
3120.
withanonhumanprimateadenovirus-basedvaccineinthepresence
of preexisting anti-human adenovirus immunity. Infect Immun 73, Lasaro, M. O. & Ertl, H. C. (2009). New insights on adenovirus as
6885–6891. vaccinevectors.MolTher17,1333–1339.
Hocknell, P. K., Wiley, R. D., Wang, X., Evans, T. G., Bowers, W. J., Lauterbach, H., Ried, C., Epstein, A. L., Marconi, P. & Brocker, T.
Hanke, T., Federoff, H. J. & Dewhurst, S. (2002). Expression of (2005). Reduced immune responses after vaccination with a
human immunodeficiency virus type 1 gp120 from herpes simplex recombinant herpes simplex virus type 1 vector in the presence of
virustype1-derivedampliconsresultsinpotent,specific,anddurable antiviralimmunity.JGenVirol86,2401–2410.
cellularandhumoralimmuneresponses.JVirol76,5565–5580. Leong,M.L.,Hampl,J.,Liu,W.,Mathur,S.,Bahjat,K.S.,Luckett,W.,
Hsu, K.-H., Lubeck, M. D., Davis, A. R., Bhat, R. A., Selling, B. H., Dubensky,T.W.,Jr&Brockstedt,D.G.(2009).Impactofpreexisting
Bhat,B.M.,Mizutani,S.,Murphy,B.R.,Collins,P.L.&otherauthors vector-specific immunity on vaccine potency: characterization of
(1992). Immunogenicity of recombinant adenovirus-respiratory Listeria monocytogenes-specific humoral and cellular immunity in
syncytial virus vaccines with adenovirus types 4, 5, and 7 vectors in humans and modeling studies using recombinant vaccines in mice.
dogsandachimpanzee.JInfectDis166,769–775. InfectImmun77,3958–3968.
Husseiny, M. I. & Hensel, M. (2008). Construction of highly Levine,M.M.,Galen,J.,Barry,E.,Noriega,F.,Tacket,C.,Sztein,M.,
attenuatedSalmonellaentericaserovarTyphimuriumlivevectorsfor Chatfield, S., Dougan, G., Losonsky, G. & Kotloff, K. (1997).
delivering heterologous antigens by chromosomal integration. AttenuatedSalmonellatyphiandShigellaasliveoralvaccinesandas
MicrobiolRes163,605–615. livevectors.BehringInstMitt98,120–123.
Innocentin,S.,Guimara˜es,V.,Miyoshi,A.,Azevedo,V.,Langella,P., Liljebjelke,K.A.,Hofacre,C.L.,Liu,T.,White,D.G.,Ayers,S.,Young,
Chatel,J.M.&Lefe`vre,F.(2009).Lactococcuslactisexpressingeither S. & Maurer, J. J. (2005). Vertical and horizontal transmission of
Staphylococcus aureus fibronectin-binding protein A or Listeria Salmonella within integrated broiler production system. Foodborne
monocytogenes internalin A can efficiently internalize and deliver PathogDis2,90–102.
DNAinhumanepithelialcells.ApplEnvironMicrobiol75,4870–4878. Limbach,K.J.&Richie,T.L.(2009).Viralvectorsinmalariavaccine
Jensen, E. R., Shen, H., Wettstein, F. O., Ahmed, R. & Miller, J. F. development.ParasiteImmunol31,501–519.
(1997).RecombinantListeriamonocytogenesasalivevaccinevehicle Liu,J.,Ewald,B.A.,Lynch,D.M.,Denholtz,M.,Abbink,P.,Lemckert,
andaprobeforstudyingcell-mediatedimmunity.ImmunolRev158, A.A.,Carville,A.,Mansfield,K.G.,Havenga,M.J.&otherauthors
147–157. (2008). Magnitude and phenotype of cellular immune responses
Jespersgaard, C., Zhang, P., Hajishengallis, G., Russell, M. W. & elicitedbyrecombinantadenovirusvectorsandheterologousprime-
Michalek, S. M. (2001). Effect of attenuated Salmonella enterica boostregimensinrhesusmonkeys.JVirol82,4844–4852.
serovar Typhimurium expressing a Streptococcus mutans antigen on Lo, W. F., Ong, H., Metcalf, E. S. & Soloski, M. J. (1999). T cell
secondary responses to the cloned protein. Infect Immun 69, 6604– responses to Gram-negative intracellular bacterial pathogens: a role
6611. for CD8+ T cells in immunity to Salmonella infection and the
Jiang,P.,Jiang,W.,Li,Y.,Wu,S.&Xu,J.(2004).Humoral immune involvementofMHCclassIbmolecules.JImmunol162,5398–5406.
responseinducedbyoraladministrationofS.typhimuriumcontain- Mandl, S., Hix, L. & Andino, R. (2001). Preexisting immunity to
ing a DNA vaccine against porcine reproductive and respiratory poliovirus does not impair the efficacy of recombinant poliovirus
syndromevirus.VetImmunolImmunopathol102,321–328. vaccinevectors.JVirol75,622–627.
http://mic.sgmjournals.org 9
M.Saxenaandothers
Mastroeni, P., Chabalgoity, J. A., Dunstan, S. J., Maskell, D. J. & andCD8T-cellepitopemappingandroleofgammainterferon.Infect
Dougan,G.(2001).Salmonella:immuneresponsesandvaccines.VetJ Immun75,4105–4115.
161,132–164.
Rimmelzwaan, G. F. & Sutter, G. (2009). Candidate influenza
McElrath,M.J.,DeRosa,S.C.,Moodie,Z.,Dubey,S.,Kierstead,L., vaccines based on recombinant modified vaccinia virus Ankara.
Janes, H., Defawe, O. D., Carter, D. K., Hural, J. & other authors ExpertRevVaccines8,447–454.
(2008).HIV-1vaccine-inducedimmunityinthetest-of-conceptStep Roberts,M.,Bacon,A.,Li,J.&Chatfield,S.(1999).Priorimmunityto
Study:acase-cohortanalysis.Lancet372,1894–1905. homologous and heterologous Salmonella serotypes suppresses local
Methner, U., Barrow, P. A. & Berndt, A. (2010). Induction of a and systemic anti-fragment C antibody responses and protection
homologous and heterologous invasion–inhibition effect after from tetanus toxin in mice immunized with Salmonella strains
administration of Salmonella strains to newly hatched chicks. expressingfragmentC.InfectImmun67,3810–3815.
Vaccine28,6958–6963. Roberts,D.M.,Nanda,A.,Havenga,M.J.,Abbink,P.,Lynch,D.M.,
Metzger, W. G., Mansouri, E., Kronawitter, M., Diescher, S., Ewald,B.A.,Liu,J.,Thorner,A.R.,Swanson,P.E.&otherauthors
Soerensen, M., Hurwitz, R., Bumann, D., Aebischer, T., Von (2006). Hexon-chimaeric adenovirus serotype 5 vectors circumvent
Specht, B. U. & Meyer, T. F. (2004). Impact of vector-priming on pre-existinganti-vectorimmunity.Nature441,239–243.
theimmunogenicityofaliverecombinantSalmonellaentericaserovar Rollier,C.S.,Reyes-Sandoval,A.,Cottingham,M.G.,Ewer,K.&Hill,
Typhi Ty21a vaccine expressing urease A and B from Helicobacter A.V.(2011).Viralvectorsasvaccineplatforms:deploymentinsight.
pyloriinhumanvolunteers.Vaccine22,2273–2277. CurrOpinImmunol23,377–382.
Minke, J. M., Audonnet, J. C. & Fischer, L. (2004). Equine viral Saxena, M., Coloe, P. J. & Smooker, P. M. (2009). Influence of
vaccines:thepast,presentandfuture.VetRes35,425–443. promoter,genecopynumber,andpreexistingimmunityonhumoral
Mittru¨cker, H. W. & Kaufmann, S. H. (2000). Immune response to andcellularresponsestoavectoredantigendeliveredbyaSalmonella
infectionwithSalmonellatyphimuriuminmice.JLeukocBiol67,457– entericavaccine.ClinVaccineImmunol16,78–87.
463. Schirrmacher, V. & Fournier, P. (2009). Newcastle disease virus: a
Mooij, P., Balla-Jhagjhoorsingh, S. S., Koopman, G., Beenhakker, promisingvectorforviraltherapy,immunetherapy,andgenetherapy
N.,vanHaaften,P.,Baak,I.,Nieuwenhuis,I.G.,Kondova,I.,Wagner, ofcancer.MethodsMolBiol542,565–605.
R. & other authors (2008). Differential CD4+ versus CD8+ T-cell Sevil Dome`nech, V. E., Panthel, K., Meinel, K. M., Winter, S. E. &
responses elicited by different poxvirus-based human immunodefi- Ru¨ssmann,H.(2007).Pre-existinganti-Salmonellavectorimmunity
ciency virus type 1vaccine candidates provide comparable efficacies prevents the development of protective antigen-specific CD8 T-cell
inprimates.JVirol82,2975–2988. frequenciesagainstmurinelisteriosis.MicrobesInfect9,1447–1453.
Nauciel, C. (1990). Role of CD4+ T cells and T-independent Sevil Dome`nech, V. E., Panthel, K., Winter, S. E. & Ru¨ssmann, H.
mechanisms in acquired resistance to Salmonella typhimurium (2008). Heterologous prime–boost immunizations with different
infection.JImmunol145,1265–1269. Salmonella serovars for enhanced antigen-specific CD8 T-cell
Pamer, E. G., Sijts, A. J., Villanueva, M. S., Busch, D. H. & Vijh, S. induction.Vaccine26,1879–1886.
(1997). MHC class I antigen processing of Listeria monocytogenes Shen, H., Slifka,M. K., Matloubian, M., Jensen, E. R., Ahmed, R. &
proteins: implications for dominant and subdominant CTL Miller, J. F. (1995). Recombinant Listeria monocytogenes as a live
responses.ImmunolRev158,129–136. vaccinevehiclefortheinductionofprotectiveanti-viralcell-mediated
Pandey,A.,Singh,N.,Vemula,S.V.,Coue¨til,L.,Katz,J.M.,Donis,R., immunity.ProcNatlAcadSciUSA92,3987–3991.
Sambhara,S.&Mittal,S.K.(2012).Impactofpreexistingadenovirus Shiver,J.W.,Fu,T.M.,Chen,L.,Casimiro,D.R.,Davies,M.E.,Evans,
vector immunity on immunogenicity and protection conferred with R.K.,Zhang,Z.Q.,Simon,A.J.,Trigona,W.L.&otherauthors(2002).
anadenovirus-basedH5N1influenzavaccine.PLoSONE7,e33428. Replication-incompetent adenoviral vaccine vector elicits effective
Peters,C.,Peng,X.,Douven,D.,Pan,Z.K.&Paterson,Y.(2003).The anti-immunodeficiency-virusimmunity.Nature415,331–335.
induction of HIV Gag-specific CD8+ T cells in the spleen and gut- Sirard,J.C.,Niedergang,F.&Kraehenbuhl,J.P.(1999).Liveattenuated
associated lymphoid tissue by parenteral or mucosal immunization Salmonella:aparadigmofmucosalvaccines.ImmunolRev171,5–26.
with recombinant Listeria monocytogenes HIV Gag. J Immunol 170,
Starks, H., Bruhn, K. W., Shen, H., Barry, R. A., Dubensky, T. W.,
5176–5187.
Brockstedt, D., Hinrichs, D. J., Higgins, D. E., Miller, J. F. & other
Pichla-Gollon, S. L., Lin, S. W., Hensley, S. E., Lasaro, M. O., authors(2004).Listeriamonocytogenesasavaccinevector:virulence
Herkenhoff-Haut,L.,Drinker,M.,Tatsis,N.,Gao,G.P.,Wilson,J.M. attenuation or existing antivector immunity does not diminish
& other authors (2009). Effect of preexisting immunity on an therapeuticefficacy.JImmunol173,420–427.
adenovirusvaccinevector:invitroneutralizationassaysfailtopredict
Steffensen, M. A., Jensen, B. A. H., Holst, P. J., Bassi, M. R.,
inhibitionbyantiviralantibodyinvivo.JVirol83,5567–5573.
Christensen, J. P. & Thomsen, A. R. (2012). Pre-existing vector
Pine,S.O.,Kublin,J.G.,Hammer,S.M.,Borgerding,J.,Huang,Y., immunity does not prevent replication deficient adenovirus from
Casimiro, D. R. & McElrath, M. J. (2011). Pre-existing adenovirus inducing efficient CD8 T-cell memory and recall responses. PLoS
immunitymodifiesacomplexmixedTh1andTh2cytokineresponse ONE7,e34884.
toanAd5/HIV-1vaccinecandidateinhumans.PLoSONE6,e18526.
Stevens, R., Lavoy, A., Nordone, S., Burkhard, M. & Dean, G. A.
Priddy, F. H., Brown, D., Kublin, J., Monahan, K., Wright, D. P., (2005). Pre-existing immunity to pathogenic Listeria monocytogenes
Lalezari, J., Santiago, S., Marmor, M., Lally, M. & other authors does not prevent induction of immune responses to feline
(2008). Safety and immunogenicity of a replication-incompetent immunodeficiency virus by a novel recombinant Listeria monocyto-
adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy genesvaccine.Vaccine23,1479–1490.
adults.ClinInfectDis46,1769–1781.
Stoyanov,C.T.,Boscardin,S.B.,Deroubaix,S.,Barba-Spaeth,G.,
Radosevic, K., Wieland, C. W., Rodriguez, A., Weverling, G. J., Franco, D., Nussenzweig, R. S., Nussenzweig, M. & Rice, C. M.
Mintardjo,R.,Gillissen,G.,Vogels,R.,Skeiky,Y.A.,Hone,D.M.& (2010). Immunogenicity and protective efficacy of a recombinant
otherauthors(2007).Protectiveimmuneresponsestoarecombinant yellowfevervaccineagainstthemurinemalarialparasitePlasmodium
adenovirus type 35 tuberculosis vaccine in two mouse strains: CD4 yoelii.Vaccine28,4644–4652.
10 Microbiology159