Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines

Figures & data

Figure 1. T-cell-independent and T-cell-dependent responses to polysaccharide and glycoconjugate vaccines.

(A) B cells directly recognize vaccine polysaccharides. No interaction occurs between Th and B cells (B) B cells recognize the polysaccharide–protein conjugate of the vaccine. The protein carrier is processed and presented to Th cells in the context of the MHC, which induces T-cell activation. In turn, T cells stimulate the specific B cells to produce antibodies against the conjugate.

Th: T helper.

Figure 2. Contrasting responses following repeated meningococcal C or A polysaccharide vaccine.

SBA (rabbit complement) GMTs against serogroup A (A) and C (B) in Gambian infants post-vaccination with MenAC-PS vaccine at 19.7 months or 5 years of age [55,62]. Group MenAC-PS had received prior MenAC-PS at 3 and 6 months; group MenAC-CV+PS had received 1, 2 or 3 prior MenAC-CV doses and MenAC-PS at age 2 years; group MenAC-CV had received 1, 2 or 3 prior MenAC-CV doses and MenAC-PS at year 5. (C) SBA (rabbit complement) GMTs against serogroups A and C in Saudi Arabian 10–29-year olds post MenAC-PS in naive versus previously MenAC-PS-immunized subjects [54]. (D) Percentage of toddlers (from a study conducted in Canada) with serogroup C SBAs ≥1:8 (human complement) after MenACWY-PS [24]. Group MenACWY-PS received MenACWY-PS at study months 0, 2 and 14. Vaccine-naive subjects received MenACWY-PS at month 14. (E) SBA (human complement) GMTs against serogroup C after MenC-PS challenge in naive, MenC-PS or MenC-CV immunized adults [53].

CV: Conjugate vaccine; GMT: Geometric mean antibody titer; MenAC: Meningococcal serogroups A and C; MenACYW: Meningococcal serogroup A, C, W-135 and Y; MenC: Meningococcal serogroup C; PS: Polysaccharide; SBA: Serum bactericidal antibodies.

Data taken from [24,53–55,62].

Figure 3. Effect of prior meningococcal polysaccharide vaccination on responses to meningococcal conjugate vaccine in adolescents.

SBA (rabbit complement) GMTs before and after initial meningococcal serogroup A, C, W-135 and Y (MenACWY)-PS vaccination at 14 years of age, and before and after MenACWY-CV booster 3 years later (squares); SBA (rabbit complement) GMTs in vaccine naive subjects after MenACWY-CV at 17 years of age (circles).

Error bars represent the 95% CIs.

GMT: Geometric mean antibody titer; SBA: Serum bactericidal antibody.

Data taken from [56].

Figure 4. Antipneumococcal antibody GMCs (A) and opsonophagocytic activity GMTs (B) in adults ≥70 years of age administered PCV-7 (n = 110) or 23vPn-PS followed 1 year later by PCV-7 (n = 78).

Error bars represent the 95% CIs. Differences between the groups were statistically significant (p < 0.01) for all serotypes except OPA titers for serotype 19F.

GMC: Geometric mean antibody concentration; GMT: Geometric mean antibody titer; OPA: Opsonophagocytic assay: Pn: Pneumococcal; PS: Polysaccharide.

Data taken from [86].

Figure 5. Anti-pneumococcal antibody concentrations (non-22F ELISA) against serotype 3 following 11Pn-PD vaccination in infants.

Triangles represent vaccine-naive subjects vaccinated at month 12–15 with 23vPn-PS; Subjects were vaccinated at 2, 4 and 6 months with 11Pn-PD and then boosted at 12–15 months with either 11Pn-PD (represented by circles) or with 23vPn-PS (represented by squares).

GMC: Geometric mean antibody concentration.

Data taken from [95].

Figure 6. Schematic outlining the kinetics of the immune response on exposure to infection.

Table 1. Immune responses to pneumococcal serotypes in different populations illustrating hyporesponsiveness.

Population	µg per each PS (dose one/dose two)	Serotype	GMC (95% CI)^†				Ref.
			Pre-dose one	Post-dose one	Pre-dose two	Post-dose two
Adults who received two doses of 23vPn-PS 5.3 years apart	25/25	1, 4, 7F, 14, 18C, 19F^‡	6.97	19.06	4.06	7.47	[72]
Elderly adults who received 14vPn-PS then 23vPn-PS 6 years later	50/25	1	572	1857	859	1119^§	[71]
		14	499	1956	859	1143^§
		19F	715	2087	1064	1173^§
		23F	1337	2338	1295	2212^§
Healthy adults who received a first dose of 23vPn-PS, or a second dose after ≥5 years	25/25	4	2.4 (1.7–3.4)	3.8 (2.8–5.3)	2.9 (2.3–3.6)	3.4 (2.6–4.4)	[76]
		14	4.5 (2.9–7.1)	20.7 (13.3–32.3)^¶	9.3 (6.8–12.8)	11.6 (8.1–16.7)
		23	2.7 (1.9–3.8)	6.6 (4.4–9.7)	5.0 (3.8–6.6)	6.4 (4.6–8.8)
PCV-7-primed infants who did or did not receive 23Pn-PS at 12 months and 23Pn-PS at 17 months	0/25	4			∼0.3	∼3.3	[78]^#
	25/25	4			∼2.1	∼2.2
	0/25	6B			∼0.6	∼3.9
	25/25	6B			∼1.9	∼2.0
	0/25	19F			∼0.9	∼9.1
	25/25	19F			∼4.0	∼4.2

^†95% CI if available.

^‡Combined GMCs.

^§Antibody level after re-vaccination with 23v-PS was not statistically significantly higher compared with pre-revaccination levels.

^¶p = 0.05 compared with post-vaccination levels in subjects receiving their second dose.

^#GMC values are estimated from a graphical presentation.

14v: 14-valent; 23v: 23-valent; GMC: Geometric mean antibody concentration; Pn: Pneumococcal; PS: Polysaccharide.

Table 2. Immune responses to pneumococcal serotype 3.

Population	Primary/booster vaccine	Schedule (months)	(n)	GMC (95% CI) post-primary	(n)	GMC (95% CI) post-booster	Ref.
Infants (Czech Republic)	11Pn-PD/11Pn-PD	3, 4, 5 12–15	146	3.78 (3.32–4.31)	144	2.84 (2.49–3.24)	[94]
Children (Czech Republic)	11Pn-PD/23vPn-PS	43			51	7.88 (6.14–10.13)	[116]
	23vPn-PS	44			49	5.01 (4.01–6.26)	[116]
Infants (Finland)	11Pn-PD/11Pn-PD	2, 4, 6, 12–15	51	2.06 (1.67–2.54)	24	1.60 (1.26–2.03)	[95]
Toddlers (Finland)	11Pn-PD	12–15			25	4.64 (3.30–6.53)	[95]
Infants (Germany)	PCV-13/PCV-13	2, 3, 4, 11–12	285	1.55 (1.41–1.72)	279	∼1.0	[117]
Infants (USA)	PCV-13/PCV-13	2, 4, 6, 12–15	122	1.39	86	1.11	[118,119]
Infants (Poland)	PCV-13/PCV-13 (P80)	2, 3, 4, 12	238	1.5 (1.38–1.63)	213	1.09 (0.99–1.20)	[120]
	PCV-13/PCV-13	2, 3, 4, 12	∼238	1.62 (0.49–1.75)	∼226	1.16 (1.05–1.29)	[120]
Infants (Spain)	PCV-13/PCV-13	2, 4, 6, 15	∼268	0.97 (0.87–1.08)	∼211	1.07 (0.95–1.20)	[121]
Infants (Italy)	PCV-13/PCV-13	3, 5, 11	∼155	1.15 (1.04–1.28)	∼125	1.22 (1.09–1.75)	[122]
Infants (France)	PCV-13/PCV-13	2, 3, 4, 12	242	1.25 (1.13–1.37)	86	∼1.0	[96]
Toddlers (France)	PCV-13	12	NA		89	∼1.4	[123]
Infants (Finland)	8vPCV-DT	2, 4, 6, 15	25	3.87 (3.17–4.72)	24	2.89 (2.33–3.59)	[124]
	8vPCV-TT	2, 4, 6, 15	25	2.08 (1.58–2.74)	25	2.3 (1.56–3.41)	[124]
Infants (Philippines)	11vPCV-DT/TT^†	1.5, 2.5, 3.5, 9	47	4.87	45	3.59	[125]
Infants (Finland)	11vPCV-DT/TT^†	2, 4, 6, 12	60	1.62	56	2.69	[125]
Infants (Israel)	11vPCV-DT/TT^†	2, 4, 6, 12	63	2.43	51	4.35	[125]
Infants (Israel)	11vPCV-DT/TT^†	2, 4, 6, 12	59	1.58 (1.25–2.00)	57	3.42 (2.56–4.56)	[127]
	11vPCV-DT/TT^†	2, 4, 6, 12	64–69	2.61 (2.20–3.11)	64–67	4.25 (3.74–4.83)	[127]
	11vPCV-DT/TT^†	2, 4, 6, 12	41–47	2.33 (1.83–2.99)	46	2.92 (2.29–3.71)	[127]
Infants (Finland)	11vPCV-DT/TT^†‡	2, 4, 6, 12	91	1.37 (1.14–1.64)	101	1.91 (1.66–2.20)	[126]
Infants (Israel)	11vPCV-DT/TT^†‡	2, 4, 6, 12	125	2.04 (1.75–2.38)	111	3.77 (3.22–4.41)	[126]

^†Serotype 3 conjugated to DT.

^‡Vaccine co-administered with whole-cell pertussis vaccine.

8v: 8-valent; 11v: 11-valent; 23v: 23-valent; DT: Diptheria toxoid; GMC: Geometric mean antibody concentration; NA: Not available; PCV: Pneumococcal conjugate vaccine; PD: Protein D; Pn: Pneumococcal; PS: Polysaccharide; TT: Tetanus toxoid.

Jokhdar H, Borrow R, Sultan A et al. Immunologic hyporesponsiveness to serogroup C but not serogroup A following repeated meningococcal A/C polysaccharide vaccination in Saudi Arabia. Clin. Diagn. Lab. Immunol.11(1), 83–88 (2004).

 PubMedGoogle Scholar

MacDonald NE, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial. JAMA280(19), 1685–1689 (1998).

 PubMed Web of Science ®Google Scholar

Granoff DM, Gupta RK, Belshe RB, Anderson EL. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination. J. Infect. Dis.178(3), 870–748 (1998).

 PubMed Web of Science ®Google Scholar

Keyserling H, Papa T, Koranyi K et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch. Pediatr. Adolesc. Med.159(10), 907–913 (2005).

 PubMed Web of Science ®Google Scholar

de Roux A, Schmöle-Thoma B, Siber GR et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin. Infect. Dis.46(7), 1015–1023 (2008).

 PubMed Web of Science ®Google Scholar

Nurkka A, Joensuu J, Henckaerts I et al. Immunogenicity and safety of the eleven valent pneumococcal polysaccharide-PD conjugate vaccine in infants. Pediatr. Infect. Dis. J23(11), 1008–1014 (2004).

 PubMed Web of Science ®Google Scholar

Törling J, Hedlund J, Konradsen HB, Örtqvist Å. Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons previously treated for pneumonia. Vaccine22(1), 96–103 (2003).

 PubMed Web of Science ®Google Scholar

Mufson MA, Hughey DF, Turner CE, Schiffman G. Revaccination with pneumococcal vaccine of elderly persons 6 years after primary vaccination. Vaccine9(6), 403–407 (1991).

 PubMedGoogle Scholar

Jackson LA, Benson P, Sneller VP et al. Safety of revaccination with pneumococcal polysaccharide vaccine. JAMA281(3), 243–248 (1999).

 PubMed Web of Science ®Google Scholar

Russell FM, Carapetis JR, Balloch A et al. Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide at 12 months of age in a randomised controlled trial. Vaccine28(19), 3341–3349 (2010).

 PubMed Web of Science ®Google Scholar

Prymula R, Peeters P, Chrobok V et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet367(9512), 740–748 (2006).

 PubMed Web of Science ®Google Scholar

Schuerman L, Prymula R, Chrobok V, Dieussaert I, Poolman J. Kinetics of the immune response following pneumococcal PD conjugate vaccination. Vaccine25(11), 1953–1961 (2007).

 PubMed Web of Science ®Google Scholar

Kieninger DM, Kueper K, Steul K et al. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine28(25), 4192–4203 (2010).

 PubMed Web of Science ®Google Scholar

Gadzinowski J, Daniels ED, Giardina P et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine manufactured with and without polysorbate 80 in healthy infants given a 2, 3, 4 and 12 months of age. Presented at: 27th Annual Meeting of the European Society for Paediatric Infectious Diseases. Brussels, Belgium, 9–13 June 2009.

 Google Scholar

Diez-Domingo J, Gurtman A, Bernaola E et al. Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers receiving routine vaccinations in Spain. Presented at: 27th Annual Meeting of the European Society for Paediatric Infectious Diseases. Brussels, Belgium, 9–13 June 2009.

 Google Scholar

Esposito S, Tansey S, Thompson A et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin. Vaccine Immunol.17(6), 1017–1026 (2010).

 PubMed Web of Science ®Google Scholar

Grimprel E, Scott D, Laudat F, Baker S, Gruber W. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccination to healthy infants in France. Presented at: 48th Annual ICAAC. Washington DC, USA, 25–28 October 2008.

 Google Scholar

Grimprel E, Laudat F, Baker SA et al. Safety and immunogenicity of a 13–valent pneumococcal conjugate vaccine given with routine pediatric vaccination to healthy infants in France. Presented at: 27th Annual Meeting of the European Society for Paediatric Infectious Diseases. Brussels, Belgium, 9–13 June 2009.

 Google Scholar

Nurkka A, Ahman H, Yaich M, Eskola J, Käyhty H. Serum and salivary anti-capsular antibodies in infants and children vaccinated with octavalent pneumococcal conjugate vaccines, PncD and PncT. Vaccine20(1–2), 194–201 (2002).

 Web of Science ®Google Scholar

Puumalainen T, Dagan R, Wuorimaa T et al. Greater antibody responses to an eleven valent mixed carrier diphtheria- or tetanus-conjugated pneumococcal vaccine in Filipino than in Finnish or Israeli infants. Pediatr. Infect. Dis. J.22(2), 141–149 (2003).

 PubMed Web of Science ®Google Scholar

Dagan R, Goldblatt D, Maleckar JR, Yaïch M, Eskola J. Reduction of antibody response to an 11-valent pneumococcal vaccine coadministered with a vaccine containing acellular pertussis components. Infect. Immun.72(9), 5383–5391 (2004).

 PubMed Web of Science ®Google Scholar

Dagan R, Käyhty H, Wuorimaa T et al. Tolerability and immunogenicity of an eleven valent mixed carrier Streptococcus pneumoniae capsular polysaccharide–diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants. Pediatr. Infect. Dis. J.23(2), 91–98 (2004).

 PubMed Web of Science ®Google Scholar