Correlates of Protection

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