ImmunologyTier 2Medical Sciences concept

Conjugate vs polysaccharide vaccine immunology (T-dependent vs T-independent response)

Core concept

Two ways to activate a B cell

	T-INDEPENDENT	T-DEPENDENT
Antigen	Capsular polysaccharide (TI-2, repetitive epitopes cross-linking the BCR); LPS (TI-1, polyclonal mitogen)	Protein, or polysaccharide conjugated to a protein carrier
Help	None - extensive BCR cross-linking alone	BCR + CD40-CD40L + cytokines from a cognate Tfh cell, in a germinal centre
Isotype	IgM predominantly (limited switching to IgG2)	Full class switching
Affinity maturation	No	Yes - somatic hypermutation
Memory	No	Yes
Booster effect	None - repeat doses can cause HYPORESPONSIVENESS	Yes - anamnestic
Works under age 2?	No - the marginal zone B cell compartment is immature	Yes, from 6-8 weeks
Responding cell	Marginal zone and B1 B cells - spleen-dependent	Follicular B2 cells

Conjugating the polysaccharide to a protein carrier converts a T-independent into a T-DEPENDENT response
- Carrier proteins: CRM197 (diphtheria toxoid mutant), tetanus toxoid, meningococcal outer membrane protein
- The B cell binds polysaccharide via its BCR, internalises the whole conjugate, and presents CARRIER peptides on MHC II to carrier-specific T cells -> linked recognition -> full help
- -> memory, boosting, high-avidity IgG, immunogenicity in infants, and *mucosal IgA -> reduced nasopharyngeal carriage -> HERD IMMUNITY*

	Conjugate	Polysaccharide
Pneumococcal	PCV13, PCV15, PCV20, PCV21	23vPPV (Pneumovax 23)
Meningococcal	MenACWY (Nimenrix, Menveo); MenB is protein-based (Bexsero, Trumenba)	Old MenACWY polysaccharide (obsolete)
Haemophilus	Hib conjugate	-
Typhoid	Vi conjugate	Vi polysaccharide

*The polysaccharide vaccine still has a role - 23vPPV covers more serotypes* than any conjugate, so it is added after a conjugate in the at-risk adult
Sequence matters: CONJUGATE FIRST, then polysaccharide at least 8 weeks later
- Polysaccharide-first blunts the subsequent conjugate response (hyporesponsiveness - depletion of the memory B-cell pool without replacement)
*Vaccinate at least 2 weeks BEFORE elective splenectomy, chemotherapy, or a complement inhibitor* - and if that is not possible, wait until the acute illness or the immunosuppressive nadir has passed
The polysaccharide response is what is selectively lost in
- Children under 2
- Asplenia and hyposplenism - marginal zone B cells live in the spleen
- Specific antibody deficiency - normal total IgG, absent polysaccharide response
- IgG2 subclass deficiency
- CVID, Wiskott-Aldrich, HIV, myeloma, CLL

The pneumococcal conjugate vaccine programme is the proof of concept - childhood PCV7/13 reduced invasive disease in unvaccinated adults through reduced carriage; serotype replacement then drove the move to higher-valency vaccines
Test immunisation is a diagnostic tool - measure pneumococcal serotype-specific IgG, give 23vPPV, remeasure at 4 weeks
- Normal = >=4-fold rise, or protective titres to >=70% of serotypes
- Cannot be interpreted in children under 2, or once immunoglobulin replacement has started
Conjugate vaccines are inactivated - safe in immunosuppression, though the response may be blunted
- Rituximab abolishes responses for 6-12 months - vaccinate >=4 weeks before, or defer to >=6 months after the last dose
- Methotrexate blunts responses; a 2-week hold around vaccination improves them
Timing in asplenia - conjugate pneumococcal, MenACWY, MenB and Hib, plus annual influenza and COVID-19; boosters at defined intervals; standby antibiotics, a medical alert device and written advice about febrile illness and animal bites
A vaccine failure in an adult with invasive pneumococcal disease should prompt measurement of immunoglobulins and a specific antibody response, and consideration of hyposplenism

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