Correlates of Protection
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Correlates of Protection
Correlates of Protection (CoP) | An immune response statistically correlated with protection |
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Mechanistic CoP (mCoP) | An immune response responsible for protection |
Non-mechanistic CoP (nCoP) | An immune response surrogating mCoP and easily measured |
Identifying method of CoP (mCoP)
- Theoretically
- To measure immune responses at the time of exposure to the infection and compare them between those who get infection and not
- might be feasible by detecting immune responses of bloods donated just before an outbreak
- To measure immune responses at the time of exposure to the infection and compare them between those who get infection and not
- Practically
- To measure immune responses after the vaccination and compare them between those who get infection and not
- usually done in vaccine clinical trial phase 3
- To measure immune responses at the time of challenging exposure of vaccinated volunteers
- would be ethically approved only for milder and/or treatable infections such as seasonal influenza, cholera, dengue or cytomegalovirus
- To extrapolate vaccinated animal challenge model
- To extrapolate protective level of dosing of passive immunization (antibody treatment)
- To measure immune responses after the vaccination and compare them between those who get infection and not
Be careful
- "Immune reseponses" contain various kinds of immunological functions, thus a single immune biomarker cannot necessarily be CoP
- Serum antibodies with multiple isotypes and multiple functions
- Mucosal antibodies with multiple isotypes and multiple functions
- Helper T cells
- Killer T cells
- Regulatory T cells
- Natural killer cells
- Phagocytes and antigen-presenting cells
- etc.
- Protection against infection is generally different from protection against disease
- You should focus on which type of protection you expect
Protection against infection | Protection against disease | |
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Polio | Infection is prevented by mucosal antibodies at nasopharynx and intestine (IgA + diffused IgG) | Disease (paralysis) is prevented by serum antibodies before entering CNS via blood |
Pneumococcus | Infection (bacteremia) is prevented by 0.20-0.35 µg/mL (ELISA) of serum antibodies | Disease (pneumonia, otitis media, nasopharynx carriage) is prevented by >10 times higher serum antibodies |
An example of measles
Chen, R. T., Markowitz, L. E., Albrecht, P., Stewart, J. A., Mofenson, L. M., Preblud, S. R., & Orenstein, W. A. (1990). Measles Antibody: Reevaluation of Protective Titers. In The Journal of Infectious Diseases (Vol. 162). https://doi.org/10.1093/infdis/162.5.1036
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Pre-exposure PRN ≤120 (GMT) |
Pre-exposure PRN >120 (GMT) | |
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Cases | 8 cases (63) |
0 case |
Non-cases | 1 non-case (56) |
71 non-cases (1157) |
- *PRN = Plaque Reduction Neutralization
- t test p<0.001
Pre-exposure PRN 216-874 |
Pre-exposure PRN ≥1052 | |
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Post-exposure PRN boosted† |
7 non-cases | 0 non-case |
Post-exposure PRN unchanged |
4 non-cases | 7 non-cases |
- †suggestive of subclinical infection
- Fisher's exact test p<0.001
Pre-exposure PRN <1052 |
Pre-exposure PRN ≥1052 | |
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Non-cases with ≥1 symptom‡ |
26 non-cases | 11 non-cases |
Non-cases with no symptom |
11 non-cases | 24 non-cases |
- ‡suggestive of subclinical infection
- χ2 test p<0.002
Pre-exposure PRN ≤120 |
Pre-exposure PRN 121-1051 |
Pre-exposure PRN ≥1052 | |
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Cases with no vaccine |
1 unvaccinated case | ||
Cases with 1 vaccine |
7 unvaccinated case | ||
Non-cases with no vaccine |
0 unvaccinated non-case | 0 unvaccinated non-case | |
Non-cases with 1 vaccine |
36 vaccinated non-cases | 35 vaccinated non-cases |
- Single definitive cut-off of CoP is not commonly available and CoP is generally relative
- Generally speaking, the higher a CoP biomarker is, the more highly the subject is protected from infection or disease
- In other words, a certain proportion of subjects with a certain level of CoP biomarker can be protected from infection/disease
- The proportion of protected subjects increases as the level of CoP biomarker rises