Correlates of Vaccine-induced Immunity by 9/22/2010 10:42 AM Annecy Correlates 2010 Stanley A. Plotkin
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. 47:401-409. 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.) CD4+ T cells B cell help (Th2) T cell help (Th1) Help to inflammation (Th17) Cytokines Lysis Mucosal Antibody IgA locally produced IgG diffused from serum 3 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 4 not easily measurable
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 5
Principle 1 Must Define Protection Against what? Infection? (Local or Disseminated) Disease? (Mild or severe) 6
Correlates of Protection Against Pneumococcal Disease ELISA Units Bacteremia 0.2 2.3 Pneumonia 2.5 Otitis 2.0 3.5 NP Carriage 5.0 7 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. 9
Principle 3 A Large Challenge Dose Can Overcome Immunity 10
Challenge of Poliovaccine by OPV % Infected 7 days after challenge Low dose High Dose OPV Vaccinees 3% 15% IPV Vaccinees 30% 70% 11
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 16
Opsonophagocytic GMT Opsonophagocytic Antibodies Response to Pneumococcal Vaccine with Age Romero-Steiner, CID, 1999 400 352 300 304 20-45 200 152 152 60-79 80-89 >90 104 106 100 72 37 31 12 49 39 19 32 48 24 29 14 17 21 0 4 6B 14 19F 23F Serotype 17
Principle 7 Mucosal Antibodies Also Protect as Co-Correlates 18
Correlates of Immune Protection After Live Influenza Vaccine or Natural Infection (Artificial Challenge in Children) Serum HAI - - + + Nasal lga - + - + Shedding 63% 19% 15% 3% 19 Belshe, JID, 2000
Principle 8 Memory may be a Surrogate 20
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 22
23 Smallpox
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 24
Persistence of Immunity after Vaccinia Antibody: 75 years CD8+ T-cell Memory: CD4 + T-cell Memory: 20 years 50 years 25
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. 26 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 Panchanathan, J. Virol. 2006, Sarkas J, Bull WHO, 1975 Liu, Nat Med, 2000
27 Meningococcal
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
29 Influenza
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
32 HPV
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
34 Ebola
Sullivan NJ, et al. Nature Rev. Microbiology 7:393, 2009. Assessment of antigen-specific Immunoglobulin G (IgG) in Ebola Vaccinated Monkeys 35
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. 36
37 Zoster
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
39 Plague
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
41 Tularemia
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
43 Pertussis
No Pertussis Pertussis Pertussis long ago 44 Storsaeter J, et al. Vaccine 21:3542-3549, 2003
45 Storsaeter J, et al. Vaccine 21:3542-3549, 2003
46 Storsaeter J, et al. Vaccine 21:3542-3549, 2003
47 Malaria
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
50 Mucosal Carriage
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
53 HIV
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 56 Hirbod T, et al. AIDS 2008, 22:727-735.
Correlates of Protection Anthrax Zoster Antibody Response 57 Cellular Response
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