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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