Correlates of Protection

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Correlates of Protection

Definitions of terms
Correlates of Protection (CoP) An immune response statistically correlated with protection
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
  • 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)

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
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
Comparison between Cases and Non-cases; serologically confirmed
Pre-exposure PRN ≤120
(GMT)
Pre-exposure PRN >120
(GMT)
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
Comparison among serologically discarded Non-cases
Pre-exposure PRN
216-874
Pre-exposure PRN
≥1052
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
Comparison among serologically discarded Non-cases
Pre-exposure PRN
<1052
Pre-exposure PRN
≥1052
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
Comparison between Cases and Non-cases; serologically confirmed
Pre-exposure PRN
≤120
Pre-exposure PRN
121-1051
Pre-exposure PRN
≥1052
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