Immune surveillance for vaccine-preventable diseases

Figures & data

Table 1. Definitions.

Correlate of protection	An indicator or marker that is associated (statistically or mechanistically/causally) with the protection of an individual against a specific infection or disease*
Surrogate of protection	Statistically, but not causally related with protection against disease or infection
Mechanistic correlate of protection	An indicator or marker that is mechanistically (causally) associated with the protection of an individual against a specific infection
Vaccine efficacy	The ability of a vaccine to reduce disease incidence (% reduction)
Herd immunity	The degree of immunity that need to be reached in the community to protect those who are not immune
Immune surveillance	Monitoring infection- or vaccine-acquired immune protection at the population level
Immunity	Immune-mediated protection against a specific infectious agent
Immunogenicity	The ability to provoke an immune response by a vaccine, pathogen or antigen
Seroconversion	The detectable increase of antibodies in the blood following vaccination or infection

*See ref [7].

Table 2. Immunogenicity correlates of protection for vaccines.

Vaccine	Assay	Protective cutoff	Evidence/status of the cutoff	Refs.
Diphtheria	toxin neutralization (ToBI)/ELISA/MIA	0.01–0.1 IU/mL	Established	[35]
Tetanus	ELISA/ToBI/MIA	0.01–0.1 IU/mL	Established	[36]
B. pertussis	ELISA/MIA		TBD
		20 IU/ml for PT	arbitrarily	[37]
S. pneumoniae	ELISA/MIA (OPA?)	0.35 μg/mL* (0.20 µg/ml GSK) for IPD	Is widely used but with limited evidence, not suited for serotypes individually	[38,39]
		1.0 µg/mL for pneumonia
		5.0 µg/mL for otitis media
Hib	ELISA/MIA	0.15/1.0 μg/mL	Established	[40]
N. meningitidis ABCWY	SBA (rabbit or human SBA)	1:8/1:4 rSBA/hSBA titer for IMD	Established
	SBA	1:128 titer carriage/long term		[41,108]
	ELISA/MIA	2.0 µg/mL	Good correlation with SBA
Measles	Virus neutralization ELISA/MIA	0.12–2.0 IU/mL	Proposed in various studies. Infections have been reported up to 2.0 IU/ml	[27,42,43]
Mumps	Virus neutralization ELISA/MIA	34 (PRNT titer) 45–102 U/ml (RIVM, NL)	arbitrary units	[25,44,45]
Rubella	ELISA/MIA	10 IU/mL	arbitrarily	[44]
Varicella	MIA/ELISA	0.26 µg/ml	arbitrarily	[46]
Poliovirus	viral neut.	1:8 titer	Established, WHO	[47]
HPV	cLIA/MIA/ELISA		TBD
HepB	ELISA/MIA	10 mIU/mL	Established	[48]
HepA	ELISA	10 mIU/mL	Established	[49]
HepC	MIA/ELISA		TBD
Rotavirus	ELISA/MIA(?)		TBD
RSV	Virus neutralization/
ELISA/MIA		TBD

ELISA: enzyme-linked immunosorbent assay; IPD: invasive pneumococcal disease; IMD: invasive meningococcal disease; IPD: invasive pneumococcal disease; MIA: multiplex immune assay; OPA: opsonophagocytosis assay; PT: pertussis toxin; TBD: to be determined; ToBi: toxin-binding inhibition; SBA: serum bactericidal assay.

Figure 1. Illustration of different stages of B cell differentiation at various stages of infection or vaccination and re-infection or booster vaccination. The initial response is dominated by IgM which following class switching is taken over by IgG. The secondary response following booster vaccination or re-infection is dominated by IgG and is characterized by higher antibody levels. Mucosal vaccination or infection will also induce IgA (not depicted).

Table 3. Serosurveillance purposes.

Purpose		Antigen in assay	Application
Vaccination response	Vaccine potency	Vaccine-derived	Evaluate the magnitude/strength of the response; estimates can be seroconversion rates, GMCs/serum-titers, significant titer rises, etc.
	Vaccine efficacy	Vaccine-derived	Evaluate immune protection; estimates can be GMCs or seroprevalence, related to an estimated/predetermined cutoff for immune protection
	Vaccine waning	Vaccine-derived	Evaluate the duration of vaccine-acquired immune protection; estimates can be concentration/titer changes in time
Exposure or infection	Infection	Pathogen-derived	Define persons in the population with previous/recent infection
	Breakthrough infection (re-infection)	Pathogen-derived, not part of the vaccine	Discriminate persons with infection history in the background of vaccination
	Emergence	Immunogenic unique, quantitative/qualitative discrimination	(Re-)Emerging pathogens, related to zoonoses and migration cq, international spread
	Evolution	Vaccine and non-vaccine (evolved/adapted trains)	Changes in pathogens related to antigenic drift/shift, or immunity/vaccine escape

Table 4. Type of antibodies related to vaccination and exposure/infection.

Vaccine	composition	Antibodies	Unique infection-induced antibodies	refs
Diphtheria	toxin	IgG		[35]
Tetanus	toxin	IgG		[36]
B. pertussis aP	1–5 proteins	IgG	Non-vaccine proteins, IgA
B. pertussis wP	Inactivated	IgG, IgA	Unknown?
S. pneumoniae	polysaccharides	IgG, some IgA	Proteins, IgA
Hib	polysaccharides	IgG, some IgM and IgA	Proteins	[61,62]
N. meningitidis ACWY
B	Polysaccharides 3 proteins and 1 OMV	IgG, some IgM, IgA	Proteins Non-vaccine proteins
Measles	Live attenuated	IgG, some IgM, IgA	IgA	[63,102]
Mumps	Live attenuated	IgG	IgA	[26,64]
Rubella	Live attenuated			[63]
Poliovirus IPV	Inactivated	IgG	IgA
Poliovirus OPV	live attenuated (oral)	IgG and IgA	-	[65,66]
HPV	L1 Protein VLP	IgG	Much lower levels
HepB	Surface protein VLP	IgG	Core protein
Rotavirus	Live attenuated virus

aP: acellular pertussis; OMV: outer-membrane vesicle; VLP: virus-like particle; wP: whole cellular pertussis.

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