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0
Is it theoretically possible to generate a vaccine that is more
effective at inducing protective immunity than the infection
itself?
Immunity as evolutionary contest between pathogen and host
The ecological interaction between infectious pathogen and host is one where
the pathogens evolutionary goal is continued reproduction. Many infections result in
complete elimination of pathogen with subsequent lifelong immunity against
reinfection. Evolutionary considerations may suggest that natural immunity has been
optimized over long periods and artifcial vaccines are likely to be inferior. The second
category includes diseases and vaccines under consideration in this essay namely
those in which the immune system is either unable to fully eliminate primary
infection or is unable to prevent subsequent reinfection of the same species of
infectious agent through immunological memory. This limitation of protective
immunity allows a theoretical possibility of designing a vaccine to provide greater
e!cacy at inducing protective immunity than natural infection.
Epidemiological evidence
"ssessing natural immunity compared to vaccine#mediated immunity is by no
means simple. "side from challenge e$periments which are an ethical quagmire the
ne$t best estimates would come from epidemiological surveys. True estimates would
require large samples including adequate unvaccinated cases problematic for diseases
with widespread vaccine coverage in order to pick up rare cases of actual infection.
%urther detailed lifelong histories together with laboratory confrmed status of past
infection &including ideally molecular typing and serological correlates' would be
necessary to compare against vaccination histories if possible along with e$posure
histories. %or many diseases based on limited evidence there is a widespread
understanding that natural immunity is better than vaccine#mediated immunity
(
.
)nfortunately this is dependent on surveillance for repeat infections which is of a
di*erent quality in the pre#vaccination era compared to the present.
(
+%requently "sked ,uestions # -accination # Minist.re de /a 0ant1 et 2es 0ervices 0ociau$
https344www.msss.gouv.qc.ca4su5ets4santepub4vaccination4inde$.php6foire7au$7questions7en8q(9
:accessed ;< March =<(9>? +@eneral -accine 0afety Aoncerns B The Ahildrens Cospital of
Dhiladelphia http344www.chop.edu4service4vaccine#education#center4vaccine#safety4general#safety#
concerns.html8natural#infection :accessed ;< March =<(9>.
Tetanus may provide the strongest e$ample for the possibility of better vaccine#
mediated immunity than natural immunity using epidemiological evidence while
comparing to a well#described e$ample of where natural immunity is usually said to
be better than vaccine#mediated immunity namely varicella. %or tetanus received
wisdom is that E infection does not confer immunityF
=
. 0eries of repeated infections
have been reported
;
. Grreversible binding and rapid sequestration of the tetanus to$in
tetanospasmin into neurons may be responsible for the short e$posure of the to$in to
the immune system and thus minimizing time for generation of an adaptive immune
response. Together with the small doses required for a severe oHten fatal clinical
course few people develop antibodies as serosurveys in non#immunized populations
have shown
9
. Gn contrast the formaldehyde treated tetanus to$oid has a virtually
(<<I seroconversion rate and while EJeK!cacy of the to$oid has never been studied in
a vaccine trial. Gt can be inferred from protective antito$in levels that a complete
tetanus to$oid series has a clinical e!cacy of virtually (<<IF
L
. Measons for higher
vaccine#mediated than natural immunity in this case may include a higher dose of
antigen in the vaccine and a longer period of time in the bloodstream for generation of
an adaptive immune response.
Gn contrast taking varicella as typical of many other diseases where natural
immunity is taken to be superior to vaccine#mediated immunity clinical chickenpo$
aHter reinfection is considered e$tremely rare. There are only a handful of case reports
with serological correlates
N
. Aonsidering the historically widespread risk this
together with an upper estimate of a OI attack rate in an outbreak setting for children
with a clinical history of previous varicella
O
itself prone to misreporting
=
T. M. Aook M. T. Drotheroe and P. M. Candel +Tetanus3 " Meview of the /iterature British Journal
of Anaesthesia QO &=<<(' 9OORQO.
;
M /indley#Pones 2 /ewis and P/ 0outhgate +Mecurrent Tetanus The Lancet ;N; &=<<9' =<9Q.
9
C Matzkin and 0 Megev +Saturally "cquired Gmmunity to Tetanus To$in in an Gsolated
Aommunity Infection and immunity 9Q &(TQL' =NORNQ.
L
Aenters for 2isease Aontrol and Drevention Epidemiology and Prevention of Vaccine-Preventable
iseases ed. by U "tkinson 0 Uolfe and P Camborsky (=th ed. &Uashington 2A3 Dublic Cealth
%oundation =<(=' p. =TO.
N
Pennifer ". Pohnson Varen A. Wloch and Wich S. 2ang +-aricella Meinfection in a 0eropositive
Dhysician %ollowing Xccupational E$posure to /ocalized Yoster !linical Infectious iseases" An #$$icial
Publication of the Infectious iseases %ociety of America L= &=<((' T<ORT? "nne ". @ershon 0haron D.
0teinberg and /awrence @elb +Alinical Meinfection with -aricella#Yoster -irus Journal of Infectious
iseases (9T &(TQ9' (;OR9=.
O
" C Moss +Modifcation of Ahicken Do$ in %amily Aontacts by "dministration of @amma
@lobulin The &e' England (ournal of medicine =NO &(TN=' ;NTRON.
1
demonstrates the very high rate of natural immunity. Gn contrast clinical e!cacy of
the varicella vaccine has been reported in a meta#analysis at Q9.LI &TLI AG 99#(<<I'
and vaccine failures are constantly reported
Q
.
"s these contrasting e$amples may show evaluating natural vs vaccine#
mediated immunity from epidemiologic evidence alone is not without problems.
Cowever they also demonstrate that there does e$ist the possibility that vaccines can
lead to better immunity than natural infection.
Host-pathogen interaction with compromised immunity
Caving discussed epidemiologic evidence the rest of the essay will concentrate
on potential areas of impaired host immune response to pathogen where there is at
least a theoretical possibility of a vaccine performing better than natural infection in
protecting the host from clinical infection. Wroadly immune evasion will be discussed
in terms of a' host immune pathways evaded b' host life stage#dependent immune
status and c' vector and life#cycle issues. "spects of vaccine formulation will be
covered including quantity specifcity and presentation of antigen the use of
ad5uvants to enhance immune response and the route of vaccine delivery. "lso
e$amples from all three classes of infections in which compromised immunity is
prominent will be used namely multiple repeated infections chronic infections and
infections cycles with latent and reactivation phases.
Evasion of host immune pathways
)inimi*ing in$lammation
Cuman papillomavirus is typical of viruses that evades the immune system
through avoiding e$posure to the bloodstream reproducing in the epithelium without
causing inZammation so avoiding detection. -accines can induce better protective
immunity as administration is intramuscular thus in a conte$t permissive to immune
recognition virus#like particles &-/Ds' have capsids e$posed to the immune system
-/Ds are able to elicit high titres of neutralizing antibodies &two orders of magnitude
more than natural infection' and antigen dose e$ceeds that in natural infection
T
.
Q
Pane %. 0eward Mona Marin and Marietta -[zquez +-aricella -accine E*ectiveness in the )0
-accination Drogram3 " Meview The Journal of Infectious iseases (TO &=<<Q' 0Q=R0QT.
T
/uciano Mariani and "ldo -enuti +CD- -accine3 "n Xverview of Gmmune Mesponse Alinical
Drotection and Sew "pproaches for the %uture Journal of Translational )edicine Q &=<(<' (<L.
2
Th+ vs Th, responses
Xne classic e$ample of a pathogen biasing the TC(3TC= response ratio is in
leishmaniasis where di*use cutaneous leishmaniasis is one manifestation of a bias to
a A29 &Th=' dominated response with a lack of e!cient A2Q#mediated &Th(' killing of
parasites. Drotective immunity is thus limited in this more chronic form of infection.
"ttempts have been made to induce a Th( bias in the response when using vaccine
approaches including live attenuated killed and antigen#based methods by utilising
WA@ as an ad5uvant to enhance A2Q &ie TC(' response
(<
. Gn this case such a Th( bias can
lead to better protective immunity than natural infection within the constraints of the
model used.
Antigen variation
GnZuenza virus uses antigenic shiHt and antigenic driHt to evade host immune
response allowing for repeated infections
((
. To avoid lack of immune memory or
confounding e*ects of original antigenic sin one strategy is to use conserved epitopes
of the inZuenza virus to generate a universal vaccine
(=
.
Immune privilege
Gn chronic infections and those with a period of latency pathogens may enter
immune#privileged sites to reduce host immune response. -aricella zoster virus &-Y-'
aHter primary infection as varicella enters dorsal nerve root ganglia and is latent
reactivating sporadically as herpes zoster. 2uring the period of central nervous
system &AS0' latency minimal protective immunity is elicited due to immune
privilege. Wy introducing high antigen loads into the bloodstream with zoster
vaccination the immune system is stimulated above the level of natural infection to
generate protective immunity against the latent -0-
(;
. "nother e$ample of relative
immune privilege is the liver
(9
. Dlasmodia have a liver stage where they are relatively
protected from the immune system. -accine strategies have included using liver stage
(<
Ma5esh Mavindran and others +Aomparison of WA@ MD/ and Aationic /iposome "d5uvant
0ystems in /eishmanial "ntigen -accine %ormulations against Murine -isceral /eishmaniasis B)!
)icrobiology (< &=<(<' (Q(.
((
2erek P. 0mith and others +Mapping the "ntigenic and @enetic Evolution of GnZuenza -irus
%cience ;<L &=<<9' ;O(RON.
(=
Yuzana 0tanekov[ and Eva -are kov[ +Aonserved Epitopes of GnZuenza " -irus Gnducing
Drotective Gmmunity and Their Drospects for )niversal -accine 2evelopment Virology (ournal O
&=<(<' ;L(.
(;
"llison "bendroth and "nn M. "rvin +Gmmune Evasion as a Dathogenic Mechanism of -aricella
Yoster -irus %eminars in Immunology (; &=<<(' =OR;T.
3
antigen ( &/0"#(' the only P- falciparum antigen e$pressed e$clusively by hepatocytes in
vaccination strategies by presenting it outside the tolerogenic environment of the
liver in order to stimulate the immune system into acting against liver#stage parasites
over and above the level of protective immunity generated by natural infection
(L
.
.ranuloma formation
Xrganisms may subvert natural protective immunity through stimulating
immunopathologic responses that serve to evade host defences. @ranuloma formation
by pathogens in the )ycobacterium tuberculosis &)tb' comple$ demonstrates this. )pon
initial infection inZammatory reaction oHten leads to a granuloma containing
dormant mycobacteria that are inaccessible to elimination by the immune system
(N
. Gt
can be conceived that vaccines leading to sterile eradication of )tb can be designed
that overcome the suboptimal natural immunity leading to latent infection. Vaufmann
suggests a vaccine strategy of stimulating di*erent T cell populations that can in
concert eliminate latent )tb3 chemoattractant Th(O cells Th( cells that activate
macrophages cytoto$ic A2Q T cells that attack intracellular )tb and antibodies to
opsonize released )tb
(O
.
Host life stage-dependent immune status
/elative infantile immunode$iciency
" few infections are prominent in neonates and infants among them
0aemophilus in$luen*ae type W &0ib' which is encapsulated and for which immunity is
dependent on a thymus#independent polysaccharide antigen
(Q
. )nder = years of age
the immune system is not su!ciently matured to naturally resist invasive infection by
0ib thus causing high rates of morbidity and mortality in this age group
(T
. The recent
(9
Gan S. Arispe and others +Aellular and Molecular Mechanisms of /iver Tolerance Immunological
/evie's =(; &=<<N' (<(R(Q.
(L
2r "ndrew U. Taylor#Mobinson +Gmmunity to /iver 0tage Malaria Immunologic /esearch =O
&=<<;' L;RNT.
(N
/alita Mamakrishnan +Mevisiting the Mole of the @ranuloma in Tuberculosis &ature /evie's
Immunology (= &=<(=' ;L=RNN.
(O
0tefan C. E. Vaufmann +%uture -accination 0trategies against Tuberculosis3 Thinking Xutside
the Wo$ Immunity ;; &=<(<' LNOROO.
(Q
@. T. Mi5kers and others +Gnfant W Aell Mesponses to Dolysaccharide 2eterminants Vaccine
Gmmunity in Early /ife (N &(TTQ' (;TNR(9<<.
(T
Eugene 2. 0hapiro and Poel G. Uard +The Epidemiology and Drevention of 2isease Aaused by
Caemophilus GnZuenzae Type W Epidemiologic /evie's (; &(TT(' ((;R9=.
4
use of a con5ugated vaccine &with diphtheria or tetanus to$oid' enhances
immunogenicity in this age group over that of natural infection leading to protection
against invasive disease
=<
.
Immunosenescence
Gmmunosenescence constitutes a ma5or defciency of natural protective
immunity against infectious disease. Gn the older adult a whole array of changes to
innate and adaptive immune mechanisms contribute to a poorer protective response
than in younger adults. Uork on this phenomenon in the conte$t of inZuenza has been
active with demonstrable poor cellular immunity to natural infection in the elderly
=(
.
Uhile current inZuenza vaccination strategies in the elderly remain suboptimal
==

there is the potential to improve these potentially over the response to natural
infection by modulating the immunosenescent phenotype3 FAell#intrinsic changes
that impair the activation and di*erentiation of T cells and W cells are rather subtle
and may be overcome by temporally limited interventions at the time of vaccination.F
=;
.
Pathogen-vector and life-cycle infuences
Vector-associated immunomodulation
"part from the pathogen itself the arthropod vector may also contribute to
evading host immune protection. Alassically sandZy saliva inoculated
transcutaneously during transmission of Leishmania parasites increase infectivity
=9

by modulating host immune response including downregulation of TC( and
suppression of TS%#
25
. -accines have been tested which incorporate immunogenic
=<
Deter Vlein Vlouwenberg and /ouis Wont +Seonatal and Gnfantile Gmmune Mesponses to
Encapsulated Wacteria and Aon5ugate -accines Journal of Immunology /esearch =<<Q &=<<Q'.
=(
Sa Pia and others +/ower Aellular Gmmune Mesponses to GnZuenza " &C;S=' in the Elderly
Journal of )edical Virology Q( &=<<T' (9O(RON.
==
Sathaniel 2 /ambert and others +)nderstanding the Gmmune Mesponse to 0easonal GnZuenza
-accination in Xlder "dults3 " 0ystems Wiology "pproach E1pert revie' of vaccines (( &=<(=' TQLRT9.
=;
P\rg P. @oronzy and Aornelia M. Ueyand +)nderstanding Gmmunosenescence to Gmprove
Mesponses to -accines &ature Immunology (9 &=<(;' 9=QR;N.
=9
M @ Titus and P M Mibeiro +0alivary @land /ysates from the 0and %ly /utzomyia /ongipalpis
Enhance /eishmania Gnfectivity %cience 2&e' 3or45 &-3-' =;T &(TQQ' (;<NRQ.
=L
Megis @omes and %abiano Xliveira +The Gmmune Mesponse to 0and %ly 0alivary Droteins and Gts
GnZuence on /eishmania Gmmunity )icrobial Immunology ; &=<(=' ((<.
5
salivary antigens enhancing protective immunity over and above that of natural
infection
=N
.
Tissue-speci$ic life-stages
0chistosomes infect humans via the skin as cercarial larvae transiting through
the skin as schistosomlae before maturing to adult worms with associated
immunopathology. Mepeated infections are common which indicates that adaptive
immunity against larval forms is not e*ective. Xne mechanism by which cercariae
avoid stimulating the immune system is by secretion of immune modulators
including prostaglandins which inhibit antigen#presentation by /angerhans cells in
the skin
=O
. The increased e!cacy of irradiated cercariae in inducing protective
immune in mouse models
=Q
demonstrates how artifcial vaccine formulations focusing
on particular parasite life#stages may improve on natural immunity.
Conclusion
This essays aims to demonstrate that not only is it theoretically possible but
given defnitional constraints vaccine#mediated immunity has already surpassed
natural immunity in a few cases by epidemiologic and immunologic criteria. Woth
clinical endpoints and immune correlates such as seroconversion have been used in
the discussion. %urther theoretical e$tensions to the principle have been proposed
within a typology of compromised natural immune responses and suggestions of
potential vaccine strategies made.
=N
/ukasz Vedzierski +/eishmaniasis -accine3 Uhere "re Ue Today6 Journal of .lobal Infectious
iseases = &=<(<' (OORQL.
=O
0. P. PESVGS0 and others +Modulation of the Costs Gmmune Mesponse by 0chistosome /arvae
Parasite immunology =O &=<<L' ;QLRT;.
=Q
2. Michter 2. ". Carn and %#M. Matuschka +The Grradiated Aercariae -accine Model3 /ooking on
the Wright 0ide of Madiation Parasitology Today (( &(TTL' =QQRT;.
6
References
"bendroth "llison and "nn M. "rvin +Gmmune Evasion as a Dathogenic Mechanism of
-aricella Yoster -irus %eminars in Immunology (; &=<<(' =OR;T
Aenters for 2isease Aontrol and Drevention Epidemiology and Prevention of Vaccine-Preventable
iseases ed. by U "tkinson 0 Uolfe and P Camborsky (=th ed. &Uashington 2A3 Dublic Cealth
%oundation =<(='
Aook T. M. M. T. Drotheroe and P. M. Candel +Tetanus3 " Meview of the /iterature British
Journal of Anaesthesia QO &=<<(' 9OORQO
Arispe Gan S. Matthew @iannandrea Gngo Vlein Weena Pohn Wradford 0ampson and 0herry
Uuensch +Aellular and Molecular Mechanisms of /iver Tolerance Immunological /evie's =(;
&=<<N' (<(R(Q
+%requently "sked ,uestions # -accination # Minist.re de /a 0ant1 et 2es 0ervices 0ociau$
+@eneral -accine 0afety Aoncerns B The Ahildrens Cospital of Dhiladelphia
@ershon "nne ". 0haron D. 0teinberg and /awrence @elb +Alinical Meinfection with
-aricella#Yoster -irus Journal of Infectious iseases (9T &(TQ9' (;OR9=
@omes Megis and %abiano Xliveira +The Gmmune Mesponse to 0and %ly 0alivary Droteins and
Gts GnZuence on /eishmania Gmmunity )icrobial Immunology ; &=<(=' ((<
@oronzy P\rg P. and Aornelia M. Ueyand +)nderstanding Gmmunosenescence to Gmprove
Mesponses to -accines &ature Immunology (9 &=<(;' 9=QR;N
PESVGS0 0. P. P. D. CEUGT0XS @. M. Penkins and ". D. Mountford +Modulation of the Costs
Gmmune Mesponse by 0chistosome /arvae Parasite immunology =O &=<<L' ;QLRT;
Pia Sa Ahris /i ]un#^i /iu Pan C. Michardus 2an %eng Cong ]ang and others +/ower
Aellular Gmmune Mesponses to GnZuenza " &C;S=' in the Elderly Journal of )edical Virology Q(
&=<<T' (9O(RON
Pohnson Pennifer ". Varen A. Wloch and Wich S. 2ang +-aricella Meinfection in a 0eropositive
Dhysician %ollowing Xccupational E$posure to /ocalized Yoster !linical Infectious iseases" An
#$$icial Publication of the Infectious iseases %ociety of America L= &=<((' T<ORT
Vaufmann 0tefan C. E. +%uture -accination 0trategies against Tuberculosis3 Thinking Xutside
the Wo$ Immunity ;; &=<(<' LNOROO
Vedzierski /ukasz +/eishmaniasis -accine3 Uhere "re Ue Today6 Journal of .lobal Infectious
iseases = &=<(<' (OORQL
Vlein Vlouwenberg Deter and /ouis Wont +Seonatal and Gnfantile Gmmune Mesponses to
Encapsulated Wacteria and Aon5ugate -accines Journal of Immunology /esearch =<<Q &=<<Q'
/ambert Sathaniel 2 Gnna @ Xvsyannikova - 0hane Dankratz Mobert M Pacobson and
@regory " Doland +)nderstanding the Gmmune Mesponse to 0easonal GnZuenza -accination in
Xlder "dults3 " 0ystems Wiology "pproach E1pert revie' of vaccines (( &=<(=' TQLRT9
/indley#Pones M 2 /ewis and P/ 0outhgate +Mecurrent Tetanus The Lancet ;N; &=<<9' =<9Q
Mariani /uciano and "ldo -enuti +CD- -accine3 "n Xverview of Gmmune Mesponse Alinical
Drotection and Sew "pproaches for the %uture Journal of Translational )edicine Q &=<(<' (<L
Matzkin C and 0 Megev +Saturally "cquired Gmmunity to Tetanus To$in in an Gsolated
Aommunity Infection and immunity 9Q &(TQL' =NORNQ
Mamakrishnan /alita +Mevisiting the Mole of the @ranuloma in Tuberculosis &ature /evie's
Immunology (= &=<(=' ;L=RNN
7
Mavindran Ma5esh 0udipta Whowmick "mrita 2as and Sahid "li +Aomparison of WA@ MD/
and Aationic /iposome "d5uvant 0ystems in /eishmanial "ntigen -accine %ormulations
against Murine -isceral /eishmaniasis B)! )icrobiology (< &=<(<' (Q(
Michter 2. 2. ". Carn and %#M. Matuschka +The Grradiated Aercariae -accine Model3 /ooking
on the Wright 0ide of Madiation Parasitology Today (( &(TTL' =QQRT;
Mi5kers @. T. E. ". M. 0anders M. ". Wreukels and W. P. M. Yegers +Gnfant W Aell Mesponses to
Dolysaccharide 2eterminants Vaccine Gmmunity in Early /ife (N &(TTQ' (;TNR(9<<
Moss " C +Modifcation of Ahicken Do$ in %amily Aontacts by "dministration of @amma
@lobulin The &e' England (ournal of medicine =NO &(TN=' ;NTRON
0eward Pane %. Mona Marin and Marietta -[zquez +-aricella -accine E*ectiveness in the )0
-accination Drogram3 " Meview The Journal of Infectious iseases (TO &=<<Q' 0Q=R0QT
0hapiro Eugene 2. and Poel G. Uard +The Epidemiology and Drevention of 2isease Aaused by
Caemophilus GnZuenzae Type W Epidemiologic /evie's (; &(TT(' ((;R9=
0mith 2erek P. "lan 0. /apedes Pan A. de Pong Theo M. Westebroer @uus %. Mimmelzwaan
"lbert 2. M. E. Xsterhaus and others +Mapping the "ntigenic and @enetic Evolution of
GnZuenza -irus %cience ;<L &=<<9' ;O(RON
0tanekov[ Yuzana and Eva -are kov[ +Aonserved Epitopes of GnZuenza " -irus Gnducing
Drotective Gmmunity and Their Drospects for )niversal -accine 2evelopment Virology (ournal
O &=<(<' ;L(
Taylor#Mobinson 2r "ndrew U. +Gmmunity to /iver 0tage Malaria Immunologic /esearch =O
&=<<;' L;RNT
Titus M @ and P M Mibeiro +0alivary @land /ysates from the 0and %ly /utzomyia /ongipalpis
Enhance /eishmania Gnfectivity %cience 2&e' 3or45 &-3-6 =;T &(TQQ' (;<NRQ
8
9