VACCINES • CID 2008:47 (1 August) • 401
VA C C I N E S
Stanley A. Plotkin, Section Editor
Correlates of Vaccine-Induced Immunity
Stanley A. Plotkin
Sanofi Pasteur, Doylestown, and Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania
The immune system is redundant, and B and T cells collaborate. However, almost all current vaccines work
through induction of antibodies in serum or on mucosa that block infection or interfere with microbial
invasion of the bloodstream. To protect, antibodies must be functional in the sense of neutralization or
opsonophagocytosis. Correlates of protection after vaccination are sometimes absolute quantities but often
are relative, such that most infections are prevented at a particular level of response but some will occur above
that level because of a large challenge dose or deficient host factors. There may be 11 correlate of protection
for a disease, which we term “cocorrelates.” Either effector or central memory may correlate with protection.
Cell-mediated immunity also may operate as a correlate or cocorrelate of protection against disease, rather
than against infection. In situations where the true correlate of protection is unknown or difficult to measure,
surrogate tests (usually antibody measurements) must suffice as predictors of protection by vaccines. Examples
of each circumstance are given.
The ascertainment of correlates of immunity is one of
the most controversialareasofinfectiousdiseases.Aside
from its basic scientific interest, determination of a cor-
relate is often the first step in the development of strat-
egies of vaccination against a disease, it provides an
objective criterion for protection of individual vacci-
nees, and even more practically, it permits the licensure
of a vaccine without demonstration of field efficacy in
situations where clinical trials are dangerous or when
new combinations of existing vaccines are tested. Al-
though the literature is rich in attempts to define cor-
relates for particular vaccines, few synthetic analyses
have been published. In 2001, I attempted a descriptive
summary , and more recently, Qin et al.  reviewed
the subject of correlates from a statistical viewpoint.
They grouped correlates into 4 categories, several of
which were labeled “surrogates.” The dictionary defi-
nition of a correlate is “something that is closely and
mutually related,” whereas a surrogate is defined as a
Received 24 January 2008; accepted 1 May 2008; electronically published 16
Reprints or correspondence: Dr. Stanley A. Plotkin, Emeritus Professor, Dept. of
Pediatrics, University of Pennsylvania, 4650 Wismer Rd., Doylestown, PA 18902
Clinical Infectious Diseases2008;47:401–9
? 2008 by the Infectious Diseases Society of America. All rights reserved.
“substitute.” It appears that Qin et al.  use the term
“surrogate” to mean a substitute for clinical protection,
rather than a substitute for a protective immune
The definitions used in this article are shown in table
1, including 4 categories of immune functions that re-
late to protection: absolute correlates, relative corre-
lates, cocorrelates, and surrogates, with a surrogate be-
ing an immune function that is measured when the
true correlate is unknown or difficult to measure.
PRELIMINARY GENERAL POINTS
There are many adaptive immune responses that po-
tentially correlate with protection, listed in table 2. In
addition, it should be understood that each correlate
must be qualified as to the end point. Is it a correlate
of protection against infection, disease, hospitalization,
or death? These may be very different for the same
vaccine. For example, smallpox vaccine protects against
infection by antibody but against disseminated disease
by both antibody and responses mediated by CD4+and
CD8+T cells .
Another important point is that the challenge dose
influences the quality and quantity of a correlate. Sev-
eral examples can be given: a study done on inactivated
polio vaccine showed that intestinal excretion of an
attenuated poliovirus challenge was blocked in 80% of
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402 • CID 2008:47 (1 August) • VACCINES
Table 1. Definitions employed in this article.
CorrelateA specific immune response to a vaccine that is closely related to protection against infection, disease, or
other defined end point
A quantity of a specific immune response to a vaccine that always provides near 100% protection
A quantity of a specific immune response to a vaccine that usually (but not always) provides protection
A quantity of a specific immune response to a vaccine that is 1 of ?2 correlates of protection and that may
be synergistic with other correlates
A quantified specific immune response to a vaccine that is not in itself protective but that substitutes for the
true (perhaps unknown) correlate
Table 2. Potential protective adaptive immune responses induced by vaccination.
Type of antibody
Functionality (opsonophagocytosis, cytotoxicity, etc.)
IgA locally produced
IgG diffused from serum
B cell help
T cell help
vaccinees after low-dose challenge but in only 30% after high-
dose challenge, a study in which unattenuated cytomegalovirus
was injected in graded doses and in which protection against
low-dose challenge was equal for both natural and vaccine-
induced immunity  but in which high doses overcame the
latter , and the observation that higher amounts of pertussis
toxin antibody are necessary to protect vaccineesagainsthouse-
hold exposure than against nonhousehold exposure .
Lastly, it is crucial to understand that the correlate of pro-
tection induced by vaccination is not necessarily the same cor-
relate that operates to close off infection. An excellent example
of this principle is measles vaccine. Titers ?200 mIU/mL of
antibody after vaccination are protective against infection,
whereas titers between 120 and 200 mIU/mL protect against
clinical signs of disease but not against infection. Titers !120
mIU/mL are not protective at all . Nevertheless, the im-
portance of cellular immunity to measles in recovery from
disease and in terminating replication of the attenuated vaccine
virus is well established. In fact, B cell–deficient humans do
recover from measles, whereas T cell deficiency leads to serious
and fatal disease. Studies in monkeys confirm that antibodies
usually protect against infection, but if infection occurs, CD8+
cells are needed to control viremia and consequent infection
of organs [8–11].
ANTIBODIES AS CORRELATES OF PROTECTION
Most vaccines protect through induction of antibodies, because
many pathogens reach their target organs by passage through
the bloodstream in an extracellular state (table 3) . Other
pathogens exert their action through toxin production that can
be neutralized by antitoxin, still others replicate on mucosal
surfaces where locally produced antibodies or antibodies dif-
fused from the serum can protect, and in the special case of
rabies, there is a period before the virus enters the neuronal
axons when it is extracellular and susceptible to the action of
An important means of showing that antibodies are the cor-
relate of protection is to passively administer them by injection
or to observe a protective effect of maternal antibodies in the
newborn . Many diseases for which vaccines are effective
are in this category, including smallpox, diphtheria, tetanus,
pertussis, Haemophilus influenzae type b (Hib) infection, pneu-
mococcus infection, hepatitis A, hepatitis B, varicella, measles,
rubella, polio, and rabies. Table 4 lists antibody quantities that
correlate with protection against selected diseases [14–29].
However, it should be understood that a correlate of pro-
tection may be either absolute or relative. Examples of absolute
correlates (situations in which a certain level of response almost
guarantees protection) includediphtheria,tetanus,measles,and
rubella. In addition, the protective effect of immune globulin
on hepatitis A virus is well known. A level of 10 mIU/mL in
the serum is almost always protective against disease. Hepatitis
A vaccines induce average levels in the thousands of mIU/mL,
with excellent persistence, thereby providing high efficacy .
Another interesting example is the Lyme disease vaccine that
was briefly marketed in the late 1990s. The mechanism of pro-
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VACCINES • CID 2008:47 (1 August) • 403
Table 3.Major licensed viral and bacterial vaccines for humans, according to the mechanism of disease prevented by the vaccine.
Type of vaccine, mechanism preventedLicensed vaccine(s)
Viremia Smallpox, yellow fever, measles, mumps, rubella, polio, varicella, hepatitis A,
hepatitis B, Japanese encephalitis, tickborne encephalitis
Mucosal and skin invasion
Reactivation in neurons
Haemophilus influenzae type b meningococcal, pneumococcal, typhoid (Vi)
Pertussis, typhoid (Ty21a)
Diphtheria, tetanus, pertussis, cholera, anthrax
Table 4.Some quantitative correlates of protection after vaccination.
Vaccine Test Correlate of protectionReference(s)
1100 EIA U/mL
0.20–0.35 mcg/mL (for children); 1/8 dilution
?1/64 dilution; ?5 IU/mL
gp, glycoprotein; HAI, hemagglutination inhibition; Hib, Haemophilus influenzae type b; SN, serum neutralization.
tection was induction of antibodies against the OspA surface
protein that neutralize Borrelia burgdorferi in infected ticks tak-
ing blood meals from vaccinees and thus prevent regurgitation
of the spirochete. During one of the efficacy trials, it was es-
tablished that infected vaccinees (vaccine failure) always had
antibodies significantly less than 1100 EIA U/mL, which was
the average titer in vaccinated non–case patients . There-
fore, 1100 EIA U/mL was an absolute correlate of protection.
unfortunately, many correlates are relative—that is, protection
is usually achieved at a certain level of response, but break-
throughs occur even at nominally protective levels. In animal
models testing anthrax vaccines based on the protective antigen
component of the toxic complex, an antitoxin level of 1/1000
gave complete protection, whereas titers of 1/500–1/800 gave
only partial protection [31–33]. An example more relevant to
routine human vaccination is provided by a recent analysis of
protection after influenza vaccination (L. Coudeville, F. Bail-
leux, F. Megas, and P. Andre ´, personal communication). One
of the criteria often used to judge the acceptability of an in-
fluenza vaccine is a hemagglutination-inhibition antibody titer
of 1/40 . As shown in a model based on published efficacy
data, at that titer, 70% of subjects were indeed protected, but
protection increased gradually to 90% with higher titers (figure
1). The model suggests that the relationship of titer to protec-
tion is described by a curve, rather than by a threshold.
ALL ANTIBODIES ARE NOT EQUAL
Assays for antibodies are often based on binding of antigen,
formulated in ELISA tests for convenience and rapidity. How-
ever, binding antibodies do not necessarily have functions, such
as opsonophagocytosis for bacteria and neutralization for vi-
ruses. The subclass of IgG may also be important for protection
Meningococcal polysaccharide vaccines give notoriously
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404 • CID 2008:47 (1 August) • VACCINES
correlation is relative and not absolute (L. Coudeville, F. Bailleux, F. Megas, and P. Andre ´, personal communication).
Relationship between hemagglutination-inhibiting (HI) antibodies and protection of a population against influenza, illustrating that the
mococcal polysaccharide . Only the youngest age group makes high levels of opsonophagocytic antibodies, with corresponding high protection
against invasive pneumococcal disease. GMT, geometric mean titer.
Opsonophagocytic antibodies against 5 pneumococcal serotypes measured in subjects of varying ages who were vaccinated with pneu-
poor protection in young children, although children do have
significant ELISA antibody responses. In contrast, bactericidal
assays show low responses in children, gradually improving
with age and correlating with increased protection . The
decreased efficacy of Hib vaccine that has been observed in
combination with acellular pertussis vaccine may be the result
of lower avidity maturation . Another striking example is
that of the pneumococcal polysaccharide vaccine. Although
shown to be highly effective in young adults, attempts to prove
efficacy in elderly persons have yielded conflicting and often
negative estimates. An explanation of this disparity is found in
studies of opsonophagocytic antibodies, which reveal that
adults aged !46 years respond much better than older adults
(figure 2) .
An example from virology is taken from a comparative study
of rubella vaccine strains. Although both the HPV-77 and RA
27/3 strains induced hemagglutinin antibodies, titers of neu-
tralizing antibodies were considerably higher after vaccination
with the latter strain, which corresponded with greater protec-
tion against superinfection by wild rubella virus [38, 39].
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VACCINES • CID 2008:47 (1 August) • 405
vaccine under conditions of artificial challenge in children.
Correlates of immune protection after live influenza
antibody Nasal IgAShedding, %
HAI, hemagglutination-inhibiting. Data are from .
MUCOSAL ANTIBODIES AS COCORRELATES
Antibodies on the mucosal surfaces, either locally secreted IgA
or transocytosed IgG, may protect against organisms that exert
pathology on those surfaces and againstorganismsthatcolonize
the mucosa before invading systemically. Examples of the for-
mer organisms include respiratory viruses, whereas examples
of the latter include the encapsulated bacterial pathogens that
frequently cause bacteremia in children.
A clear demonstration of mucosal antibodies as cocorrelates
of protection was made during the development of intranasally
administered live influenza vaccine . Children who had
been previously vaccinated and placebo control individuals
were challenged intranasally with the live vaccine under cir-
cumstances in which some children lacked both serum and
nasal antibody, some had one but not the other, and some had
both antibodies (table 5) . The doubly antibody-negative
control children shed virus 63% of the time, in contrast to the
doubly antibody-positive vaccinated children, of whom only
3% shed virus. Those with serum IgG antibody alone shed
virus 15% of the time and those with nasal IgA antibody alone
shed virus 19% of the time. Thus, there were 2 correlates of
protection against infection, which were synergistic.
Protection against encapsulated bacterial pathogens consists
of either prevention of bacteremia or prevention of coloniza-
tion. The latter does not refer to prevention of colonization
through herd immunity, which has been strikingly demon-
strated in adults whose child contacts have received pneumo-
coccal conjugate vaccine , but rather to direct effects on
colonization. Figure 3  shows the cumulative curves of
serum antibody against Hib in colonized and uncolonized vac-
cinees. Almost all the vaccinees have sufficient antibody to be
protected against invasion (10.15 mcg/mL) (table 4), but the
uncolonized vaccinees have serum antibody levels 15 mcg/mL,
indicating that higher levels are needed to diffuse into the phar-
ynx and to prevent carriage of Hib . The same principle
also appears to betrueforatleastsomepneumococcalserotypes
A remark in passing: it has become cliche ´ to say that vaccines
prevent only disease, not infection. Although that may be often
the case, it is not a general truth. If the presence of antibodies
is sufficient to prevent colonization of mucosal surfaces, vac-
cines can produce “sterile” immunity. Vaccines against polio,
measles, rubella, Hib, pneumococcus, meningococcus, and
probably human papillomavirus are all capable of preventing
infection as well as disease.
An emerging area of research concerns correlates of protection
that are organ specific. From experimental studies, it appears
that CD4+cells are key to the prevention of brain pathology
after measles  and in helping CD8+cells to close off West
Nile virus CNS infection . Although vaccination will nor-
mally prevent microbes from reaching targetorgans,morework
is needed to define correlates that are organ specific.
ANTIBODIES AS SURROGATES
To repeat, surrogates are immunological measurementsthatare
feasible to make but that are only indirectly related to the true
correlate of protection. A recent example of the use of a sur-
rogate concerns rotavirus vaccine. The generally accepted sur-
rogates of protection from rotavirus disease are serum IgA or
total neutralizing antibodies against each G or P serotype, cor-
responding to the vp7 and vp4 surface proteins, respectively
. However, although rotavirus vaccines are efficient in pro-
tecting against disease, they do not always prevent intestinal
infection with wild virus (although they may reduce the quan-
tity shed). Antibodies to vp7 are more able to protect against
infection and disease, whereas antibodies to vp4 modify disease
but not infection . In addition, antibodies against at least
one protein without neutralizing epitopes (vp6) protect mice,
and both helper T cell and CD8+cell functions at the intestinal
level have been proposed as effectors of immunity [47–49].
Thus, in the absence of an agreed correlate, serum IgAantibody
is a useful surrogate.
Varicella vaccine provides another example of antibody sur-
rogate. During the development of the vaccine, a test was de-
veloped to measure binding antibodies to varicella glycopro-
teins, the so-called gpELISA. Seroconversion to the vaccine was
190% by this technique, and there was a relative correlation
with protection and with a neutralizationtest.Theputative
protective titer was 15 gpELISA units . However, another
test, the fluorescent antimembrane antigenstest,althoughmore
labor intensive to perform, shows better correlation with the
protection observed after 1 dose (∼75%) . Moreover, sev-
eral studies reported that antibodies to varicella fade after vac-
cination and that CD4+cell responses to varicella antigens were
closer correlates of protection [51, 52], although the presence
of varicella-specific CD4+cells may simply reflect the ability to
respond with antibodies when exposed to the virus. Neverthe-
less, these ideas remain to be confirmed, and antibodies and
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406 • CID 2008:47 (1 August) • VACCINES
colonized or not colonized by the organism . The level necessary to prevent colonization is higher than that necessary to prevent systemic infection.
Levels of ELISA antibodies to Haemophilus influenzae type b polysaccharide (prp) in the sera of children whose nasopharynges are
cell-mediated immunity both may be important to protection
Lastly, there is the vexing question of correlates of protection
against pertussis, in which Bordetella pertussis causes a mucosal
infection and a toxic disease due to pertussis toxin. Much ink
has been spilled about which components of pertussis vaccines
are protective and whether antibodies against them are suffi-
cient correlates. In my opinion, the problem is not lack of
correlates but its opposite;thereappeartobemultipleresponses
that reduce the risk of disease. Antibodies to pertussis toxin,
pertactin, and agglutinogens, as well as cellular responses, have
all been proposed as correlates on the basis of evidence from
trials in humans and in animals [6, 53, 54]. Whether they are
surrogates or cocorrelates is difficult to judge, but antibodies
to several different components have been associated with pro-
tection by vaccines, probably because protection can be me-
diated both by antitoxin to pertussis toxin and by antibody to
attachment factors. In any case, the example of pertussis shows
that correlates of protection may act synergistically.
ANAMNESIS AS A SURROGATE
Immunological memory, either effector or central, is necessary
for long-term protection against infection [55, 56] unless ex-
posure to a microbe is frequent enough to maintain the pres-
ence of antibodies . The utility of passive antibodies against
hepatitis B virus is proof of the importance of antibodies in
hepatitis B, as well as the observation that antibody levels 110
mIU/mL after vaccination are protective . Nevertheless,
antibodies decline rapidly, and half of vaccinees may be sero-
negative at 5 years after vaccination . Despite the loss of
antibodies, B cell central memory is prolonged and protective
efficacy is maintained at a high level [59, 60]. B cell memory
to hepatitis B virus acts as a surrogate of protection, which is
actually mediated through the antibodies evoked by antigenic
stimulation of memory cells. Revaccinationinducesanamnestic
can also induce an anamnestic response and that the long in-
cubation period of hepatitis B virus allows antibodies to close
off or modify the course of infection to protect the liver.
The opposite case was seen in the United Kingdom when
Hib vaccine was introduced using a vaccine schedule of 3 doses
at age !1 year, without a booster . Anamnestic responses
to Hib polysaccharide were demonstrable in vaccinees who had
lost effector memory and thus circulating antibodies [62, 63],
but the extremely high effectiveness of the vaccine in countries
that use a booster was reproduced in the United Kingdom only
during the period when catch-up vaccination of older children
was also employed. In the absence of herd immunityfromcatch
up, infants who were not boosted becamesusceptibletodisease.
The rapid invasion of vaccinees by the organism moved faster
than the antibody recall, which also appears to be true after
natural Hib infection .
CELLULAR RESPONSES AS CORRELATES
In recent years, immunologists have devoted much of their
attention to cellular responses, but it is obvious from the above
discussion that, in the case of vaccines, antibodies in sufficient
quantity are the predominantprotectivecorrelate.Nevertheless,
it is also obvious that cell-mediated immune functions are crit-
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VACCINES • CID 2008:47 (1 August) • 407
ical in protection against intracellular infections, and in almost
all diseases, CD4+cells are necessary to help B celldevelopment.
The best case for the importance of cellular immunity is the
bacille Calmette-Gue ´rin (BCG) vaccine against tuberculosis.
Production of IFN-g by CD4+cells is necessary to prevent
disease after exposure but apparently is not an adequate cor-
relate of BCG vaccine–induced protection . CD8+cells
maintain the tubercle bacilli in a latent state . Almost all
current attempts to develop better protection against tuber-
culosis are based on improving cellular responses to BCG vac-
cine, but at the moment, no true correlateisknown.Zoster
vaccine induces both antibody and cellular immune responses,
but no quantitative correlate of protection emerged from the
efficacy trial . However, because the duration of cellular
responses, rather than that of antibody responses, paralleled
clinical efficacy and because the waning of cellular immunity
with age is responsible for herpes zoster, it appears likely that
it is the boost in cellular responsethatcorrelateswithprotection
As mentioned above, antibodies that are presentintheserum
and on mucosal surfaces are good correlates of immunity to
influenza, but this may be true only for children and young
adults. McElhaney et al.  found that cytokine production
and proliferation of T cells in the presence of influenza antigen
correlated with protection of elderly adults. Thus, whereas an-
tibody production is critical in the young to prevent primary
influenza infection, CD4+cells may be more important in im-
munologically experienced individuals undergoing heterosub-
The interplay between antibody- and cell-mediated immu-
nity is well exemplified by the case of cytomegalovirus. Pro-
tection by vaccination has been demonstrated with both live-
attenuated and glycoprotein vaccines, and passive antibodies
also have been shown to protect . Nevertheless, once latent
infection has been established, good T cell function is necessary
to control reactivation and disease. Thus, one could say that
antibodies are a correlate of protection against infection,
whereas T cell immunity is a correlate of protection against
disease [1, 72].
Another apposite example is protection against poxviruses,
such as smallpox and monkeypox. For monkeypox, it has been
demonstrated that antibodies are necessary for prevention of
infection and that CD4+cells must be presentto helpantibodies
to develop, but that once antibodies are present no cellular
functions are necessary [73–75]. Immunity against smallpox
due to vaccinia induces lifelong persistence of antibodies, and
although infection and even disease may nevertheless occur
many years after vaccination, the patient is likely to have mod-
ified disease and to survive [3, 76]. This resistance to clinically
typical smallpox depends on T cell memory, which declines
with time. Thus, antibody alone prevents infection and severe
disease, but the combination of antibody andcellularimmunity
is required for infection to be asymptomatic .
For the most part, it is the production of antibodies by B cells
that protect vaccinees exposed to the pathogen concerned,
whereas aside from their help to B cells, cellular immune re-
sponses are more important in the control of established in-
fection. This paradigm is not strict, but rather a relative and
statistical truth, subject to variation from one infection to
Potential conflicts of interest.
is a consultant for Merck, and is a board member for Dynarex.
S.A.P. is an employee of Sanofi Pasteur,
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