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Correlates of
Vaccine-induced
Immunity
by
Stanley A. Plotkin
Annecy Correlates 2010
9/22/2010 10:42 AM
References:
1) Plotkin SA. 2001. Immunologic correlates of
protection induced by vaccination. Ped. Inf. Dis. J.
20:63-75.
2) Qin L, et al. 2007. A framework for assessing
immunological correlates of protection in vaccine
trials. J Inf Dis 196:1279-1281.
3) Plotkin SA. 2008. Vaccines: correlates of
vaccine-induced immunity. Clin. Inf. Dis. 47:401409.
2
4) Plotkin SA. 2010. Correlates of protection
induced by vaccination. Clin. Vacc. Immun.
17:1055-1065.
Potential Protective Adaptive Immune
Mechanisms Induced by Vaccination
Serum Antibody
Neutralizing
Non-neutralizing
Functionality (opsonsphagocytosis)
Avidity (cytotoxicity, etc.)
Mucosal Antibody
IgA locally produced
IgG diffused from serum
3
CD4+ T cells
B cell help (Th2)
T cell help (Th1)
Help to inflammation (Th17)
Cytokines
Lysis
CD8+ T cells
Lysis
Avidity
3
My Definitions:
Correlate: An immune response that is responsible for and
statistically interrelated with protection
Absolute Correlate: A specific level of response highly
correlated with protection: a threshold
Relative Correlate: Level of response variably correlated
with protection
Co-Correlate: One of two or more factors that
correlate with protection in alternative, additive, or
synergistic ways.
Surrogate: An immune response that substitutes for the true
immunologic correlate of protection, which may be unknown
or not easily measurable
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How Correlates Are Determined
1. Levels of passively administered or maternal antibody
that protect
2. Analysis of immune responses in protected and
unprotected subjects in efficacy trials
3. Observations made on vaccine failures,
e.g. immunosuppressed individuals
4. Human challenge studies
5. Extrapolation from animal challenge studies
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Principle 1
Must Define Protection
Against what ?
6
Infection ?
(Local or Disseminated)
Disease ?
(Mild or severe)
Correlates of Protection Against
Pneumococcal Disease
Bacteremia
Pneumonia
Otitis
NP Carriage
7
ELISA Units
0.2 – 2.3
2.5
2.0 – 3.5
5.0
Goldblatt D, WHO Banako meeting
Principle 2
The Mechanism of
Protection by
Vaccination is NOT
Necessarily the Same
Mechanism as Recovery
From Infection
8
Antibodies produced by measles
vaccination correlate with protection
against infection and rash
but CD8+ T cells are needed to control
viremia if infection occurs.
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Principle 3
A Large Challenge Dose
Can Overcome Immunity
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“Challenge” of Poliovaccine by OPV
% Infected 7 days after challenge
Low dose
High Dose
OPV Vaccinees
3%
15%
IPV Vaccinees
30%
70%
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Principle 4
Most Current Vaccines
Protect Through Antibodies
12
Most vaccine preventable infections
spread through the blood,
produce toxemia, or replicate
on mucosa.
13
Principle 5
Correlates may
be relative
14
Protection Against Influenza and Anti-HA Antibodies
Influenza
15
Coudeville, L Personal communication
Principle 6
Antibodies must be
FUNCTIONAL
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Opsonophagocytic Antibodies
Romero-Steiner, CID, 1999
Response to Pneumococcal Vaccine with Age
400
352
304
Opsonophagocytic GMT
300
20-45
60-79
200
152
80-89
152
>90
104 106
100
72
49
37
31
48
39
32
19
12
14
24
17
21
29
0
4
6B
14
Serotype
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19F
23F
Principle 7
Mucosal Antibodies
Also Protect as
Co-Correlates
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Correlates of Immune Protection After
Live Influenza Vaccine or Natural Infection
(Artificial Challenge in Children)
Serum
HAI
+
+
19
Belshe, JID, 2000
Nasal
lgA
+
+
Shedding
63%
19%
15%
3%
Principle 8
Memory may be
a Surrogate
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Effector vs. Central Memory
Effector Memory important
in short incubation infections like
H. influenzae type b
Central Memory important for long incubation
infections and long-term memory
(long-lived plasma cells)
21
Memory B Cells are demonstrable
by ELISPOT in Hepatitis B
vaccinees and convalescents despite
non-protective serum antibody levels
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Smallpox
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Pathogenesis of Mousepox in Vaccinated Mice
CD8+ cell depletion = No CTL, No IFN
but still protection
CD4+ cell depletion = Poor CTL, low Ab
but still protection
B cell depletion = No protection
B cell depletion but passive antibody = protection
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Persistence of Immunity after Vaccinia
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Antibody:
 75 years
CD8+ T-cell Memory:
20 years
CD4 + T-cell Memory:
50 years
Immunity Against Poxviruses
Primary Infection and recovery from Vaccination:
Both B cells and T cells necessary for survival
Secondary Exposure to Infection in vaccinees:
Only B cells necessary for protection, although
T cells may give partial protection.
Low titer antibodies (ca. 1/20- 1/32) are protective
(5 proteins elicit SNAb)
However, susceptibility to nonfatal smallpox
returns at about 20 years postvaccination
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Panchanathan, J. Virol. 2006, Sarkas J, Bull WHO, 1975
Liu, Nat Med, 2000
Meningococcal
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Efficacy of Meningococcal Group C
Vaccine Correlates with hSBA of 1/4 - 1/8
However, retrospective analysis of
vaccine failures revealed T helper cell
deficiency manifested by low T cell
proliferation, low B cell activation
in the presence of T cells.
28
Foster RA, CVI, 2010
Influenza
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 HAI antibodies in serum and on mucosa
correlate with protection
 However, in elderly antibody responses
are poor. CD8+ responses, rather than
CD4+ responses correlate with
antibody rises, and CD8+ CTL
independently correlates with protection
30
Goronay, J Virol, 2001
Granzyme B in CTL after
Influenza Vaccination of Elderly
Prior flu in
previous season
0
4
10
Weeks Post-vaccination
31
McElhaney JE, et al. Vaccine 27:2418, 2009
HPV
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Mucosal Antibody Protects Against HPV
 Passive antibody protects in animal models
 Microtrauma allow access of virions to epidermal
basement membrane
 IgG antibodies in serum transudate into cervical
mucus and exudate at trauma site.
 Antibodies to L1 prevent binding to membrane cells
and also form immune complexes with viral particles
33
Schiller J, personal communication. Journal Vaccine, 2008
Ebola
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Assessment of antigen-specific
Immunoglobulin G (IgG) in Ebola Vaccinated Monkeys
35
Sullivan NJ, et al. Nature Rev. Microbiology 7:393, 2009.
However, antibodies do not protect
monkeys and the presence of antibodies
may simply reflect CD4+ cell function,
particularly as antibodies do not neutralize.
T cell depletion studies in monkeys
show that T cells are necessary for protection
Therefore, antibodies are a surrogate,
not a correlate.
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Zoster
37
Zoster Vaccine
• Vaccine contains large amounts of infectious
and non-infectious varicella virus
• Inactivated virus also protects
• VZ antigen stimulates flagging cellular immunity
in the elderly
38
• Correlate of protection is VZ-specific
CD4+ lymphocyte proliferation stimulation index
≥ 5.0, but VZ antibody response is used as surrogate
Hata et al. NEJM 2002
Plague
39
Yersinia pestis inactivates neutrophils
• Type 3 secretion system and LcrV protein translocates
outer membrane proteins (Yops) into
host cells, also reduces innate immunity
• LcrV antibodies protect against macrophage cytotoxicity
• F1 capsule antibodies and LcrV antibodies protect monkeys
• Antibody-deficient mice protected by T cells directed
against other antigens
• Exact correlate remains elusive.
40
Williamson BD, Microbe. Path. 2007
Zanberman S. Vaccine, 2008
Tularemia
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Synergy of Antibody and Cellular Immunity in Tularemia
GC Glycoprotein
Ft.LVS: wbtA-Live strain
Combination
Adjuvant Control
42
Sebastian S, et al. Vaccine 27:507-605, 2009, Krimanjerwara G, Immol. Rev. 2008
Pertussis
43
No Pertussis
Pertussis
Pertussis
long ago
44
Storsaeter J, et al. Vaccine 21:3542-3549, 2003
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Storsaeter J, et al. Vaccine 21:3542-3549, 2003
46
Storsaeter J, et al. Vaccine 21:3542-3549, 2003
Malaria
47
• Antibody to CSP definitely correlates
with protection, but probably cellular
immunity also important
• In challenge studies of individuals given
adjuvanted RTS, S vaccine, genes that make
immunoproteasomes are upregulated in
protected subjects. They degrade proteins
into peptides that bind to MHC Class I HLA
for CTL stimulation
48
Kester K. JID 2009,
Joos C, PLOS One, 2010
49
Vahey MT. et al.
JID 201:580, 2010
Mucosal Carriage
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Is Cell-Mediated Immunity Responsible
for Protection Against Mucosal Carriage?
 Pneumococcal conjugate vaccines reduce nasopharyngeal
carriage of pneumonia
 In humans, antibodies to pneumococcal surface
proteins A (PspA) correlate with prevention of carriage.
 Diffusion of serum antibody into the nasopharynx
may play a role, but
 In mice prevention of pneumococcal carriage depends
on a Th17 cellular response!
 Th17 cells also important in protection against TB
51
Casal J, Curr OP Inf Dis 2003; Zhang Z, JCI, 2009
Zyment J Immuni. 2009
Rotavirus Vaccines
Neutralizing antibodies are serotype-specific, directed against
vp4(P) and vp 7(G) surface proteins.
Oral IgG can be protective.
Neutralizing antibodies protect against P and G serotypes.
Non-neutralizing antibodies can inactivate intracellular virus
B cells in intestine (IgA and IgG) are associated with protection
Cellular immunity against VP6 gives partial heterotypic immunity,
CD4 (IFN) mediated, and contributes to long-term immunity
Protection is much stronger against disease than infection.
However, surrogate measurement of anti-rotavirus
serum IgA gives good idea of protection
52
Blutt et al, J Virol. 2008, Franc M, Vaccine, 2006, Yuan L, Immunology 2001
HIV
53
• Recent data in NHP challenged with
SHIV suggest that even low titers
of neutralizing antibodies protect.
• RV 144 vaccine trial in Thailand suggested
that antibodies, probably non-neutralizing,
may be protective.
54
Hessell AJ. Nat. Med. 2009
Can cellular immunity confer sterile immunity ?
Perhaps, if effector T cells present: experience of
L. Picker lab with responses to Rhesus CMV
carrying HIV gag; probable presence of mucosal
CTL in uninfected sex workers; and data
that cellular responses prevent fetal infection
in monkeys.
55
Piacentini, Vaccine 2008; Appay. Nat. Med, 2008; Rasmusson R, Vaccine 2010
Acquisition of HIV by Kenyan Sex Workers Prevented
by Genital IgA and Systemic T Cell Proliferation
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Hirbod T, et al. AIDS 2008, 22:727-735.
Correlates of Protection
Anthrax
Zoster
Antibody
Response
Cellular
Response
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