PCVs in individuals at increased risk of pneumococcal disease: a literature review

Figures & data

Figure 1. Results of literature search and evaluation of identified studies.

Table 1. Summary of trials: immunocompromised, asplenic, and immunocompetent individuals.

Risk group Study (year) (location)	Primary aim/outcome Population Age range (median) of study individuals	Immunization schedule (dosing interval) n, PCV group n, comparator group	Timing of measurements Immune response measured	Ref.
Immunocompromised children
HIV infection Abzug et al. (2006) (USA)	Immunogenicity of PCV7 in high-risk children with HIV receiving HAART and not vaccinated in infancy Children with HIV receiving HAART (defined by route of infection, CD4%, HIV RNA PCR copies/ml) Median age: 9.6 years	PCV7/PCV7/PPV23 (0, 8, 16 weeks) n = 225	At study entry; week 8, 16, 24, 48 and 96. ELISA – threshold Responders, %: GMC ≥0.5 µg/ml GMC ≥1.0 µg/ml	[71]
HIV infection Costa Ide et al. (2008) (Brazil)	Immunogenicity to PCV7 in HIV-infected children Children AR: NR	PCV7 (two doses, 0, 2 months) n = 40	Pre-vaccination; 1–3 months after second dose of PCV7 ELISA – threshold and fold-rise Responders, %: ≥fourfold increase in titer ≥1.3 µg/ml for ≥4 serotypes	[67]
HIV infection Madhi et al. (2005) (South Africa)	Immunogenicity of PCV9 in HIV+ children untreated with ART and HIV-exposed but uninfected children HIV+ children untreated with ART and HIV-exposed but uninfected children Mean age ± SD: 1.6 ± 0.3 months (at vaccination)	PCV9 or PLA (three doses; age: 6, 10, 14 weeks) n = 193	21–42 days after third dose ELISA – threshold Responders, %: Ab conc ≥0.35 µg/ml OPA OPA GMT ≥ 1:8	[30]
HIV infection Madhi et al. (2009) (South Africa)	Immunogenicity to PCV7 5 years after a primary vaccination series Children with HIV Mean age: 5.6–5.8 years	PCV7, n = 120 or PLA, n = 155 (1 dose ∼5 years following primary series of PCV9 or PLA (3 doses; 6, 10, 14 weeks) n = 275	Pre-vaccination; 4 weeks after vaccination ELISA – threshold Responders, %: Ab conc ≥0.35 µg/ml OPA OPA GMT ≥1:8	[41]
HIV infection (CD4^+ T lymphocyte cells ≥25%) Madhi et al. (2010) (South Africa)	Effect of HIV infection status and ART on Ab responses to PCV in infants Infants Mean age: 7.0–7.5 weeks	PCV7 (three doses; age: 6–12 weeks, 9–18 weeks and 12–24 weeks) n = 483	3–6 weeks after the third dose ELISA – threshold Responders, %: Ab conc ≥0.35 µg/ml OPA OPA titer ≥8	[68]
HIV infection (CD4^+ T lymphocyte cells ≥25%) Madhi (2013) (South Africa) Secondary endpoints from Madhi et al. (2010)	Effect of HIV infection status and ART on Ab responses to PCV in infants Infants Mean age: 7.0–7.5 weeks	PCV7 (three doses; age: 6–12 weeks, 9–18 weeks, 12–24 weeks) n = 552	Pre-vaccination; 1 months following doses 1, 2, and 3 ELISA – threshold Responders, %: Ab conc ≥0.35 µg/ml OPA OPA titer ≥8	[69] [68]
HIV infection Nachman et al. (2003) (USA)	Safety and immunogenicity of 3-dose PCV7 plus booster dose in infants with HIV Infants Median age: 157 days	PCV7, n = 30 or PLA, n = 15 (3 doses, 8-week dosing interval + booster dose, age: 15 months [≥6 months post-dose 3]) + PPV23 (age: 24 months) n = 45	Pre-vaccination; 4 weeks after third dose; immediately before and 1 months after the booster dose; immediately before PPV ELISA – fold-rise Responders, %: fourfold rise in GMC	[42]
HIV infection, immunosuppressive therapy Rivera-Olivero et al. (2014) (Venezuela)	Immunogenicity of PCV7 in children at risk of IPD Children AR: 2–59 months HIV (n = 12) Immunosuppressive therapy (n = 11)	Aged: 2–6 months: PCV7 (3 doses, 6–8 weeks apart) Aged: 7–23 months: PCV7 (2 doses, 6–8 weeks apart) Aged: ≥24 months with 1–3 previous PCV7 doses: PCV7 (one dose); without previous PCV7 doses: PCV7 (two doses, 6–8 weeks apart)	Pre-vaccination; 2 months after last dose ELISA – threshold Responders, %: GMC ≥0.35 µg/ml	[89]
HIV infection Spoulou et al. (2005) (Greece)	Immunogenicity of PCV7 in children with HIV Children AR: 20–163 (128) months HC AR: 32–175 (95) months	HIV group: PCV7 (2 + booster dose; 0, 1, 12 months), n = 14 HC: PCV7 (2 doses; 0, 12 months), n = 21	Before and 4–6 weeks after each dose ELISA – fold-rise >twofold rise in IgG	[70]
SCT Meisel et al. (2007) (Germany)	Immunogenicity and tolerability of PCV7 in children undergoing allogeneic SCT Children AR: 1.4–16.9 (8.3) years	PCV7 (three doses, monthly intervals, 6–9 months post-transplantation) n = 53	Pre-vaccination; 4–6 weeks after second and third doses of PCV7 ELISA – threshold Seroconversion, %: GMC ≥0.5 µg/ml Responders, %: GMC ≥0.5 µg/ml	[50]
Solid organ transplantation (≥4 months post-transplantation) Barton et al. (2009) (Canada)	Safety and immunogenicity of PCV7 in pediatric solid organ transplant Children AR: Overall: 0.6–17.5 (7.0) years; Heart: 0.6–17.5 (3.9) years; Liver: 1.25–12 (4.6) years; Kidney: 6.6–17.8 (13.8) years; Lung: 11.6–16.9 (14.7) years	PCV7/PCV7/PCV7/PPV23 (8-week dosing intervals) Heart, n = 31 Liver, n = 18 Kidney, n = 27 Lung, n = 5 n = 82	Baseline; 8 weeks after second and third doses of PCV7; 8–12 weeks after PPV23 ELISA – threshold Seroprotection: GMC ≥0.2 µg/ml GMC ≥0.15 µg/ml	[73]
Solid organ transplantation(heart, liver, or small bowel – ≥6 month post-transplantation) Lin et al. (2005) (USA)	Immunogenicity of 2 doses of PCV7 followed by PPV23 in children receiving solid organ transplant Children receiving solid organ transplant AR: 2–18 years	Patients PCV7/PCV7/PPV23 (6- to 8-week dosing intervals), n = 25 HC PCV7/PPV23 (6- to 8-week dosing intervals), n = 23	Baseline; 6–8 weeks after each PCV7 dose; 4–8 weeks and 5–7 months after PPV23 ELISA – threshold Responders, %: GMC >0.5 µg/ml GMC ≥1.0 µg/ml	[55]
Arthritis (JIA) Farmaki et al. (2010) (Greece)	Effects of anti-TNF treatment on the immunogenicity of PCV7 in patients with JIA Children AR: 4–18 years	PCV7 (two doses; 0, 6–8 weeks) Anti-TNF group, n = 31 Control (no anti-TNF), n = 32	Before first PCV7 dose; 41.5 ± 3.3 days after first dose (immediately prior to second dose) ELISA – threshold and fold-rise Adequate serotype-specific Ab response: GMT ≥fourfold increase from baseline + GMT >0.35 µg/ml Adequate vaccine response: ≥fourfold increase from baseline in ≥5 serotypes	[74]
Defective immune response (recurrent infections) Uddin et al. (2006) (UK)	Immune response to PCV7 and PPV23 booster in children with a history of recurrent infections, including those diagnosed as having defective Ab immunity Children AR: 2–13 years	PCV7/PCV7/PPV23 (0, 1, 2 months) n = 145	Pre-vaccination; post-vaccination (1–8 months; >8 months after vaccination, exact timing not specified) ELISA – threshold Responders, %: IgG levels >0.2 µg/ml	[90]
Oncology (recipients of intensive chemotherapy for hematological malignancies or solid tumors [completed ≥3 and <12 months before vaccination], or children with acute lymphoblastic leukemia receiving maintenance chemotherapy) Cheng et al. (2012) (Hong Kong)	Seroprotection rates after PCV7 Children AR: 1.4–18.2 (9.5) years	PCV7 (two doses; 0, 1 months) Children with hematological cancer, n = 29 Children with solid tumors, n = 15	Baseline; 4 weeks after second dose of PCV7 ELISA – threshold Seroprotection, %: GMC ≥0.35 µg/ml ≥twofold increase in GMC from pre-vaccination (in patients with protective Ab levels pre-vaccination)	[81]
CKD (INS in remission) Liakou et al. (2011) (Greece)	Immunogenicity of PCV7 in children with INS in remission Children Mean age ± SD: Group A: 8.1 ± 2.2 years Group B: 11.4 ± 3.6 years	PCV7 (one dose) Group A: INS in remission taking low-dose prednisone (<1 mg/kg every other day) or no therapy, n = 15 Group B: prednisone + MMF and/or cyclosporine A for ≥6 months, n = 18 HC: healthy siblings of the patients, n = 16	Pre-vaccination; 1 and 12–14 months after vaccination ELISA – threshold Patients above protective threshold for ≥5 serotypes, %: Ab levels ≥0.35 µg/ml	[77]
CKD (INS in remission) Liakou et al. (2014) (Greece) Follow-up study of Liakou 2011	Immunogenicity of PCV7 in children with INS in remission Children Mean age ± SD: Group A: 8.8 ± 1.8 years Group B: 12.4 ± 3.7 years	PCV7 (booster dose, 12–14 months following primary dose in previous trial) Group A: INS in remission taking low-dose prednisone (<1 mg/kg every other day) or no therapy, n = 14 Group B: prednisone + MMF and/or cyclosporine A for ≥6 months, n = 15	Baseline; 28–32 days after vaccination ELISA – threshold Responders, %: GMC ≥0.35 µg/ml	[78] [77]
LBW Shinefield et al. (2002) (USA)	Immunogenicity of PCV7 in premature infants or those with LBW Infants Mean age at doses 1–4: LBW: 64.6, 130.3, 198.8, 420.6 days NBW: 64.3, 130.1, 197.8, 419.5 days	PCV7 (4 doses) n for doses 1–4: LBW: 875, 845, 816, 745 NBW: 16178, 15609, 15095, 13888	Pre-vaccination; 1 month following dose 3 ELISA – threshold Responders, %: IgG levels ≥0.15 µg/ml	[85]
LBW Szynczewska et al. (2014) (Poland)	Immunogenicity of PCV7 in infants with LBW Infants AR: NR Group 1 (birth weight <1000 g); gestational AR 24–29 weeks Group 2 (birth weight ≥1000 g); gestational AR 30–34 weeks	PCV7 (three doses at ages 2, 4, 6 months + booster dose at 16 months)	Pre-vaccination; 4 weeks after dose 3; prior to and 4 weeks following booster dose ELISA – threshold Seroprotection, %: GMC ≥0.35 µg/ml	[83]
Immunocompromised adults
HIV infection (asymptomatic) Chen et al. (2008) (Uganda)	Whether immunization with PCV followed by PPV23 could increase Ab and OPK titers in patients with HIV before introduction of ART Adults Mean age ± SD: Group 1: 36.8 ± 7.45 years Group 2: 37.1 ± 7.63 years Group 3: 26.8 ± 7.70 years	PCV7/PPV23 (0, 2 months) Group 1: HIV+ with CD4 count 200–499 µl^−1, n = 30 Group 2: HIV+ with CD4 count ≥500 µl^−1, n = 28 Group 3: HIV−, n = 29	Pre-vaccination; 2, 3, 8 months after PCV7 ELISA – threshold Seroprotection, %: GMC ≥0.35 µg/ml OPA OPK titer ≥8	[61]
HIV infection Crum-Cianflone et al. (2010) (USA)	Immunogenicity of revaccination with PCV or PPV23 in HIV-infected adults previously vaccinated with PPV 3–8 years earlier Adults AR: 36–47 (42) years	PCV7 (one dose) vs PPV23 (one dose) HIV+, n = 204 HIV−, n = 25 (received PCV7 only)	Pre-vaccination; 14, 60, 180 days after PCV7 ELISA – fold-rise ≥twofold increase in IgG level, with post-vaccination level ≥1000 ng/ml	[91]
HIV infection (CD4^+ lymphocyte count ≥200 cells/l) Deloria-Knoll et al. (2006) (USA)	The effects of vitamin A or zinc supplementation on PCV7 immunogenicity in HIV-infected drug users HIV-infected drug users Mean age ± SD: 41.5 ± 6.0 years PLA group Mean age ± SD: 43.3 (6.4) years	PCV7/PPV23 (0, 6 months), n = 118; PLA group, n = 29	Day 0, at each immunization, and 30 days after each immunization ELISA – fold-rise Geometric mean fold change	[62]
HIV infection (CD4 counts ≥200 cells/l within past 3 months) Feikin et al. (2001) (USA)	Immunogenicity of various PCV7 and PPV23 vaccine regimens in adults with HIV Adults Mean age: PCV7/PCV7, 45 years PCV7/PPV23, 42 years PLA/PPV23, 41 years PLA/PLA, 44 years	PCV7/PCV7 (0, 8 weeks), n = 15 vs PCV7/PPV23 (0, 8 weeks), n = 18 vs PLA/PPV23 (0, 8 weeks), n = 16 vs PLA/PLA (0, 8 weeks), n = 18	Pre-dose 1; 8-week post-dose 1; 8-week post-dose 2 ELISA – fold-rise Responder, %: >twofold increase in IgG conc OPA >fourfold increase in OPA titer	[34]
HIV infection Gordon et al. (2007) (Malawi)	Pulmonary immune responses in patients with HIV Adults AR: NR	PCV7 or PLA (1 dose) HIV+ PLA group, n = 9 PCV7 group, n = 10 HIV− PLA group, n = 12 PCV7 group, n = 10 n = 41	Baseline, 1 and 6 months ELISA GMC	[40]
HIV infection (CD4 cell counts 200–500 cells/ml and plasma HIV RNA <50,000 copies/ml) Lespirit et al. (2007) (France)	Immunogenicity of PCV with a PPV23 booster dose compared with PPV23 alone in patients with HIV Adults Mean age ± SD: 44 ± 10 years	PCV/PPV23 (0, 4 weeks), n = 105 vs PPV23 (1 dose at 4 weeks), n = 103 n = 208	Week 0, 4, 8, 24 ELISA – threshold and fold-rise Responders, %: twofold increase in Ab and GMC ≥1.0 µg/ml	[35]
HIV infection Miiro et al. (2005) (Uganda)	Immunogenicity of PCV7 in HIV-infected adults previously vaccinated with PPV23 Adults AR: 24–56 (37) years	PCV7 (2 doses; 0, 4 weeks) n = 109	Baseline; time of second dose; 4 weeks after second dose ELISA GMC	[66]
HIV infection (on ART for >6 months with HIV RNA ≤50 copies/ml and CD4^+ cell count ≥200 cells/ml) Søgaard et al. (2010) (Denmark)	Safety and immunogenicity following addition of a TLR9 agonist to PCV7 and PPV23 booster vaccination in patients with HIV Adults Controls (not receiving TLR9 agonist) AR: 42.0–59.0 (48.9) years	PCV7/PCV7/PPV23 (0, 3, 9, months) PCV7: double-doses (1 ml) Controls, n = 49	0, 3, 4, 9, and 10 months ELISA – threshold and fold-rise High responders, %: twofold increase in GMC and ≥1 µg/ml for at least 5 PCV7 serotypes OPA	[64]
SCT Meerveld-Eggink et al. (2009) (The Netherlands)	Reconstitution of humoral immunity following allogeneic SCT determined by measuring Ab responses to vaccination with pneumococcal, Hib and tetanus-toxic-containing vaccines 1 year post-transplantation Adults AR: 44–67 (56.5) years	PCV7/PCV7/PPV23 (1 year, 2 weeks; 1 year, 3 months; 1 year, 6 months post-transplantation) n = 26	Pre-vaccination: 3 weeks after second dose of PCV7 ELISA – threshold and fold-rise Seroconversion, %: ≥fourfold increase in Ab titer Responders, %: IgG conc ≥0.35 µg/ml IgG conc ≥1.0 µg/ml	[52]
Solid organ transplantation (heart or lung) Gattringer et al. (2011) (Austria)	Immunogenicity of PCV7 followed by PPV23 in adult recipients of heart or lung transplants Adults AR: 31–76 (59) years	PCV7/PPV23 (8-week dosing interval) n = 26	Before each vaccination; median 108 days (min: 50 days; max: 160 days) after PPV23 ELISA – threshold Responders, %: ≥twofold increase in GMT	[54]
Solid organ transplantation (renal transplant recipients –stable allograft function 3 months–3 year post-transplantation) Kumar et al. (2003) (Canada)	Immunogenicity of single-dose PCV7 compared with PPV23 in adult renal transplant recipients Adult Mean age ± SD: PCV7 group, 47.5 ± 13.7 years PPV23 group, 47.7 ± 12.7 years	PCV7 (one dose), n = 30 vs PPV23 (one dose), n = 30	Baseline; 8 weeks after vaccination ELISA – threshold and fold-rise Responders, %: twofold increase in GMT and ≥1.0 µg/ml OPA fourfold increase in titer and absolute value >1:8	[60]
Solid organ transplantation (liver – ≥3 months post-transplantation) Kumar et al. (2008) (Canada)	Immunogenicity of a prime–boost vaccination strategy with PCV7 and PPV23 compared with PPV23 alone in liver transplant recipients Adults Mean age ± SD: Primed group, 51.9 ± 12.2 years Unprimed group, 50.4 ± 11.3 years	Primed group: PCV7/PPV23 (0, 8 weeks), n = 56 Unprimed group: PLA/PPV23 (0, 8 weeks), n = 57	Baseline; 8 weeks after PCV7; 8 weeks after PPV23 ELISA – threshold & fold-rise Responders, %: ≥twofold increase in GMT and ≥0.35 µg/ml OPA ≥fourfold increase in OPA activity	[53]
Solid organ transplantation (renal transplant recipients –≥6 months post-transplantation) Tobudic et al. (2012) (Austria)	Immunogenicity of PCV7/PPV23 compared with PPV23 in adult renal recipients Adults Mean age ± SD: PCV7/PPV23 group, 54.1 ± 12.0 years PPV23 group, 50.5 ± 12.8 years	PCV7/PPV23 (0, 12 months), n = 33 vs PPV23 (0 months) n = 40 (of whom 29 recipients received PPV23 at 12 months)	Baseline; 8 weeks after dose 1; before and 8 weeks after dose 2 ELISA – threshold and fold-rise Responders, %: twofold increase in IgG conc and ≥1.0 µg/ml	[36]
Arthritis (established arthritis) Kapetanovic et al. (2011) (Sweden)	Impact of different immunosuppressive treatments on Ab response following PCV7 in patients with established arthritis Adults AR: 22–86 years	PCV7 (one dose) RA Group 1 (n = 85): MTX or other DMT Group 2 (n = 89): anti-TNF + MTX + other DMT Group 3 (n = 79): anti-TNF monotherapy SpA Group 4 (n = 83): anti-TNF + MTX Group 5 (n = 83): anti-TNF Group 6 (n = 86): NSAID and/or analgesics	Immediately prior to vaccination; 4- to 6-week post-vaccination ELISA – fold-rise Positive antibody response: ≥twofold increase in Ab levels for serotypes 6B and 23F Responders, %: ≥fourfold increase in Ab levels for serotypes 6B and 23F	[75]
Arthritis (established arthritis) Kapetanovic et al. (2013) (Sweden) Extension study of Kapetanovic 2011	Impact of non-TNF inhibitor biologics on Ab response following PCV7 in patients with established arthritis Adults: AR: 41–85 (mean: 60.2) years	PCV7 (one dose) n = 88	Immediately prior to vaccination; 4- to 6-week post-vaccination ELISA – fold-rise Positive antibody response: ≥twofold increase in Ab levels for serotypes 6B and 23F	[76] [75]
Defective immune response (specific Ab deficiency – failure to respond to PPV23 but able to respond to tetanus toxoid) Shrimpton et al. (2006) (UK)	Immune response to pneumococcal vaccination in patients with specific antibody deficiency Adults Patients, AR: 28–67 (average: 47) years Controls, average age: 42 years	PCV7 (one to two doses) n = 7 (six of seven patients received a second dose 10–21 months following the first) PPV23 (two doses prior to PCV7) Controls, n = 4	Pre-vaccination; 4-week after vaccination ELISA Individual patient data	[92]
Oncology (CLL) Sinisalo et al. (2007) (Finland)	Immunogenicity of PCV7 in patients with CLL compared with non-CLL subjects Adults AR: 43–84 (65) years Non-CLL controls AR: 52–77 (66) years	PCV7 (one dose) Adults with CLL, n = 52 Non-CLL controls, n = 25	Pre-vaccination; 4 weeks after vaccination ELISA – threshold and fold-rise Seroprotection, %: GMC ≥0.35 µg/ml Responders: ≥twofold increase in GMC and ≥0.35 µg/ml	[80]
Immunocompromised children and adults
HIV infection Abzug et al. (2013) (USA) Sub-study of Abzug 2006	Immunological memory following revaccination with PCV7 or PPV23 in high-risk children with HIV receiving HAART Children and adults PCV7 AR: 8.3–21.8 (13.8) years PPV23 AR: 8.5–21.9 (14.6) years	Revaccination 4–5 years after PCV7/PCV7/PPV23: PCV7 (one dose), n = 36 PPV23 (one dose), n = 31	Prior to revaccination; week 1 and 4 after revaccination ELISA – threshold and fold-rise Combined immune response (memory or primary response): GMC ≥0.5 µg/ml or ≥fourfold rise between days 0 and week 1 or 4	[72] [71]
SCT (autologous SCT for hematologic cancer) Antin et al. (2005) (USA)	Ab conc for each PCV7 serotype for pre- vs non-immunized group in patients undergoing autologous hematopoietic SCT Adults and children Pre-immunized group: AR: 4–69 (44) years Non-immunized group: AR: 13–69 (46) years	Pre-immunized group: PCV7 (four doses; 7–10 days pre-stem cell collection; 3, 6, 12 months post-transplant), n = 25 Non-immunized group: PCV7 (three doses; 3, 6, 12-month post-transplant), n = 20	Pre-immunized group: day of each dose; day of stem cell collection; mean 5 weeks after 12-month dose Non-immunized group: pre-stem cell collection; day of each dose; mean 5 weeks after 12-month dose ELISA – threshold IgG levels ≥0.35 µg/ml to all seven vaccine serotypes	[48]
SCT Cordonnier et al. (2009) (Europe)	Immunogenicity of PCV7 following early compared with late vaccination in recipients of SCT Adults and children AR: 7–59 (mean: 37) years	Early group: PCV7/PCV7/PCV7/PPV23 (3, 4, 5, 12-month post-transplant), n = 75 Late group: PCV7/PCV7/PCV7/PPV23 (9, 10, 11, 18 months post-transplant), n = 83 n = 158	Pre-vaccination; 1 month after dose 3 of PCV7; 1 month after PPV23 ELISA – threshold Response rate, %: ≥0.15 µg/ml to all PCV7 serotypes ≥0.5 µg/ml to all PCV7 serotypes	[49]
SCT Cordonnier et al. (2010) (Europe) Sub-analysis of Cordonnier (2009) showing OPA results for responders to 3 doses of PCV	OPA results in hematopoietic SCT recipients from the Cordonnier 2009 trial Adults and children AR: 10–56 [mean: 37] years	Early group: PCV7 (three doses; 3, 4, 5 month post-transplant), n = 14 Late group: PCV7 (three doses; 9, 10, 11 months post-transplant), n = 14 n = 28	1 month after dose 3 of PCV7 OPA GMT	[93] [49]
SCT Molrine et al. (2003) (USA)	Whether PCV7 would be immunogenic in patients undergoing allogeneic SCT and the impact of donor immunization Adults and children AR: 2–66 (40) years	Immunized group: PCV7 (4 doses, 7–10 days prior to; 3, 6, 12 months post-transplantation), n = 30 Non-immunized group: PCV7 (3 doses, 3, 6, 12 month post-transplantation), n = 35 n = 65	Prior to each post-transplantation dose; 4 weeks after third dose ELISA – threshold Seroprotection, %: GMC ≥0.5 µg/ml	[51]
A-T Sanal et al. (2004) (Turkey)	Immune responses to PCV7 in patients with A-T Adults and children AR: 7–20 (13) years	PCV7 (one dose; 12 patients had received PPV23 in a previous study), n = 14 Controls, n = 40	Pre-vaccination; 4 weeks after PCV7 ELISA – threshold Antibody titer >10 U/ml	[56]
A-T Schubert et al. (2004) (Germany)	Immune responses to PCV7 in patients with A-T Adults and children AR: 4–25 (11) years	PCV7 (two doses; 0, 4 weeks) patients, n = 10 Age-matched controls, n = NR	Pre-immunization; post-immunization, specific assessment times not specified ELISA – GMC and fold-rise	[79]
Down syndrome Kusters et al. (2013) (The Netherlands)	Immunogenicity of PCV7 in individuals with Down syndrome Children and adults: AR: 6–24 (12) years	PCV7/PCV7/PPV23 (0, 4, 12 weeks)	Pre-vaccination; 4 weeks after last vaccination ELISA – threshold Responders, %: IgG levels ≥1.0 µg/ml OPA GMT	[82]
Asplenic children
Asplenia (congenital asplenia or splenectomy) Mikoluc et al. (2008) (Poland)	Immunogenicity of one dose of PCV7 in children with asplenia Children AR: 4.5 months–19.5 (mean: 12) years	PCV7 (one dose) n = 30	Pre- and post-vaccination, exact timepoint not specified ELISA – threshold and fold-rise Responders, %: GMC ≥0.35 µg/ml ≥twofold increase in Ab conc	[94]
Asplenia Smets et al. (2007) (Belgium)	Safety and immunogenicity of revaccination with either PCV7 or PPV23 in asplenic children previously vaccinated with PPV23 Children Mean age ± SD: PCV7 group, 2.6 ± 4.7 years PPV23 group, 11.7 ± 3.4 years	PCV7, n = 11 vs PPV23, n = 8 (one dose as secondary vaccination following previous [≥3 years ago] PPV23)	Baseline; 1, 6 months after revaccination ELISA – threshold and fold-rise Responders, %: GMC ≥1 µg/ml fourfold increase in GMC from baseline	[95]
Asplenia (splenectomized for hereditary spherocytosis) Stoehr et al. (2006) (Germany)	Immune response to PCV7 and PPV23 booster in children splenectomized for hereditary spherocytosis Children AR: 5.3–26.7 years	PCV7/PPV23 (0, 2 months) Group A, completely splenectomized, n = 16 Group B, near total splenectomy, n = 23 Group C, HC splenectomized after trauma, n = 3	Prior to vaccination; 8 weeks after PCV7; weeks after PPV23 ELISA – threshold Responders, %: GMC ≥1 µg/ml	[96]
SCD Nowak-Wegrzyn et al. (2000) (USA)	OPA activity of pneumococcal serotypes following PCV7 vaccination of infants with SCD Children 2 or 12 months	2-month age group: PCV7/PCV7/PCV7/PPV23 (age: 2, 4, 6, 24 months), n = 28 12-month age group: PCV7/PPV23 (age: 12, 24 months), n = 10	2-month age group: 2, 4, 6, 7, 12, 24, 25 months of age 12-months age group: 12, 13, 24, 25 months of age ELISA GMC OPA Median opsonic activity (%)	[45]
SCD O’Brien et al. (2000) (USA)	Immunogenicity of PCV7 in children with SCD Children AR: 1.3–14.6 months	Schedule A (n = 34): PCV7/PCV7/PCV7/PPV23 (age: 2, 4, 6, 24 months) Schedule B (n = 13): PCV7/PPV23 (age: 12, 24 months) Controls received Schedule A or B without PPV23, n = 14	Schedule A: Before and after each PCV7 dose; 12 and 24 months of age; 1 month after PPV23 Schedule B: Before and after PCV dose; 24 months of age; 1 month after PPV23 ELISA – threshold Responders, %: GMC ≥0.15 µg/ml GMC ≥1.0 µg/ml	[46]
SCD Reinert et al. (2007) (France)	Immunogenicity and tolerability of PCV7 in young infants with SCD Infants AR: 53–119 (mean: 81.4) days	PCV7/PCV7/PCV7/PPV23 (age: 2, 3, 4, 15–18 months) n = 51	ELISA: Pre-vaccination; 1 month after primary vaccination; pre-booster dose; 1 month after booster dose OPA: 1 month after primary vaccination ELISA – threshold Responders, %: GMC ≥0.15 µg/ml GMC ≥0.35 µg/ml GMC ≥1.0 µg/ml OPA Titer ≥8	[47]
SCD Rivera-Olivero et al. (2014) (Venezuela)	Immunogenicity of PCV7 in children at risk of IPD Children AR: 2–59 months SCD, n = 22	Aged: 2–6 months: PCV7 (3 doses, 6–8 weeks apart) Aged: 7–23 months: PCV7 (2 doses, 6–8 weeks apart) Aged: ≥24 months with 1–3 previous PCV7 doses: PCV7 (one dose); without previous PCV7 doses: PCV7 (two doses, 6–8 weeks apart)	Pre-vaccination; 2 months after last dose ELISA – threshold Responders, %: GMC ≥0.35 µg/ml	[89]
Asplenic adults
Asplenia (anatomical or functional asplenia) Meerveld-Eggink et al. (2011) (The Netherlands)	Immunogenicity of PCV7 and Hib vaccination in asplenic patients Adults AR: 23–77 (mean: 51.5) years	PCV7/PCV7/PPV23 (0, 6 weeks, 6 months) n = 54	Prior to vaccination; 3 weeks after each vaccination ELISA – threshold Responders, %: GMC ≥0.35 µg/ml GMC ≥1.0 µg/ml	[43]
Asplenia (individuals with β-thalassemia) Papadatou et al. (2014) (Greece)	Immunogenicity of 1 dose of PCV13 in asplenic males with β-thalassemia (previously vaccinated with PCV7/PPV23) Adults AR: 19–48 (mean: 36.5) years	PCV13 (one dose) n = 21	Prior to vaccination; 1 and 4 weeks after vaccination ELISA – threshold Responders, %: GMC ≥0.35 µg/ml (baseline only) No specific definition of response; pre- and post-vaccination GMCs compared	[31]
Asplenia (splenectomized) Stanford et al. (2009) (UK)	Immunogenicity of PCV7 in splenectomized individuals, including the effect of PPV23 on PCV7 Ab responses Adults AR: 18.1–81.8 (54.8) years	PCV7 (1 dose)/PPV23 (6 months), if not received within previous 5 years n = 111	Pre-vaccination; 3–6 weeks following PCV7; 3–6 weeks following PPV23 in those receiving PPV23 ELISA – threshold and fold-rise Responders, %: ≥twofold increase in GMC GMC ≥0.35 µg/ml GMC ≥1.00 µg/ml	[44]
Asplenic children and adults
Asplenia (individuals with β-thalassemia) Orthopoulos et al. (2009) (Greece)	Effect of combined PCV7 and PPV23 on PCV-induced immunologic priming in asplenic males with β-thalassemia Patients: asplenic males with β-thalassemia, AR:12–41 (30) years Controls: non-splenectomized β-thalassemia males and females, AR: 13–40 (30) years	PCV7/PCV7/PPV23 (0, 1, 12 months), n = 18 vs. PCV7/PPV23/PPV23 (0, 1, 12 months), n = 17 Non-splenectomized β-thalassemic controls: PCV7/PPV23 (0, 12 months), n = 23	Before each vaccination; 4–6 weeks after each vaccination ELISA – fold-rise No specific definition of response; pre- and post-vaccination GMCs compared	[32]
SCD Vernacchio et al. (2000) (USA)	Measurement of functional Ab activity in patients with SCD randomized to either PCV7 or PPV23 Children and adults with SCD Median age: 13–14 years	PCV7/PCV7/PPV23 (0, 8, 16 weeks), n = 11 vs PPV23 (one dose), n = 12	Prior to each dose; 3–6 weeks after PPV23 ELISA GMC OPA GMT	[33]
Immunocompetent children
Asthma (≥3 episodes of wheeze, including intermittent, mild persistent, and moderate persistent asthma) Rose et al. (2006) (Germany)	Immunogenicity of pneumococcal vaccination in 2- to 5-year-olds with asthma Children PCV7 group, AR: 24–61 (36) months PPV23 group, AR: 24–71 (45) months	PCV7 (one dose), n = 23 vs PPV23 (one dose), n = 38	Pre-vaccination; 4 weeks after vaccination ELISA – threshold Responders, %: GMC ≥1.0 µg/ml GMC ≥0.35 µg/ml	[57]
Asthma (pre-school mild-to-moderate asthma; >3 separate asthma episodes in last 12 months, requiring β2-bronchodilator treatment for ≥3 days or systemic steroids) Rose et al. (2009) (Germany)	Safety and immunogenicity of sequential PCV7 and PPV23 in children with asthma Children AR: 39.5–46.5 (41) months	PCV7/PPV23 (0 + 2 or 10 months) Group A, 2-month dosing interval, n = 36 Group B, 10-month dosing interval, n = 34 n = 70	Pre-vaccination; 2 months after PCV7; 12 months after PCV7 (10 months after PPV23 in Group A); 10 months after PPV23 (Group B only) ELISA – threshold Responders, %: GMC ≥0.35 µg/ml	[39]
CLD (recurrent pneumonia, bronchiectasis, and/or atelectasis; bronchial hyper-reactivity and asthma; cystic fibrosis; recurrent URTI; bronchial tree malformations; pulmonary bronchodysplasia; ciliary dyskinesia; bronchiolitis obliterans) Navarro et al. (2006) (Spain)	Longitudinal analysis of immunogenicity to PCV7 in children with chronic or recurrent lung diseases Children AR: 7 months–15 (mean 4.6) years	Aged <2 years: PCV7 (3 + booster doses; 2, 4, 6, 12–24 motnhs) Aged >2 years: PCV7 (1 dose) n = 163 PCV7 (vaccinated at study entry), n = 14	Baseline and sequentially during follow up; exact timing of assessments not provided ELISA – threshold Not protected, %: IgG levels <0.2 µg/ml	[38]
CLD CHD CKD Rivera-Olivero et al. (2014) (Venezuela)	Immunogenicity of PCV7 in children at risk of IPD Children AR: 2–59 months	Aged: 2–6 months: PCV7 (3 doses, 6–8 weeks apart) Aged: 7–23 months: PCV7 (2 doses, 6–8 weeks apart) Aged: ≥24 months with 1–3 previous PCV7 doses: PCV7 (one dose); without previous PCV7 doses: PCV7 (two doses, 6–8 weeks apart) CHD, n = 19 CLD, n = 9 CKD, n = 9	Pre-vaccination; 2 months after last dose ELISA – threshold Responders, %: GMC ≥0.35 µg/ml	[89]
CKD (glomerular filtration rate ≤70 ml/min per 1.73 m^2) Vieira et al. (2009) (Brazil)	Immune response to PCV7 in children with CKD undergoing conservative treatment or dialysis Children AR: 1.0–9.9 years	PCV7 (two doses; 0, 2 months) PCV7 + conservative kidney disease treatment, n = 24 PCV7 + dialysis, n = 24	Pre-vaccination; 60 days after second PCV7 dose ELISA – threshold and fold-rise IgG level ≥0.35 µg/ml Adequate response, %: IgG level ≥0.35 µg/ml or ≥fourfold increase	[37]
Cochlear implantation Rose et al. (2004) (Germany)	Immunogenicity of PCV7 and PPV23 in patients with cochlear implants Children AR: 14 months–27 years	PCV7 (one dose) vs PPV23 (one dose) n = 168	Pre-vaccination; 4–6 weeks after vaccination ELISA – threshold Responders, %: GMC ≥1.0 µg/ml GMC ≥0.2 µg/ml	[59]
Immunocompetent adults
CLD (≥10 pack/years cigarette smoking and clinical diagnosis of moderate-to-very severe COPD, as defined by post-bronchodilator–FEV1/FVC <70% and FEV1 <70% predicted) Dransfield et al. (2012) (USA) (final analysis: complete recruitment)	Immunogenicity at 1–2 years of PCV7 and PPV23 vaccination in patients with COPD Adults Mean age ± SD: PCV7 group, 63 ± 9 years PPV23 group, 64 ± 10 years	PCV7 (one dose), n = 91 vs PPV23 (one dose), n = 90	Pre-vaccination; 1 month, 1 year, 2 years after vaccination Ratio of OPK for PCV7 and PPV23 groups	[58]

Ab: Antibody; AR: Age range; ART: Antiretroviral therapy; A-T: Ataxia telangiectasia; CHD: Chronic heart disease; CKD: Chronic kidney disease; CLD: Chronic lung disease; CLL: Chronic lymphocytic leukemia; conc: Concentration(s); COPD: Chronic obstructive pulmonary disease; DMT: Disease modifying therapy; FEV₁: Forced expiratory volume in 1 second; FVC: Forced vital capacity; GMC: Geometric mean concentration(s); GMT: Geometric mean titer(s); HAART: Highly active antiretroviral therapy; HC: Healthy controls; Hib: Haemophilus influenzae type b; HIV+/−: HIV-positive/-negative; INS: Idiopathic nephrotic syndrome; JIA: Juvenile idiopathic arthritis; LBW: Low birth weight; MMF: Mycophenolate mofetil; MTX: Methotrexate; NBW: Normal birth weight; NR: Not reported; OPA: Opsonophagocytosis assay; OPK: Opsonophagocytosis killing; PLA: Placebo; PPV23: 23-valent pneumococcal polysaccharide vaccine; SCD: Sickle cell disease; SD: Standard deviation; SCT: Stem cell transplantation; SpA: Spondylarthropathy; TLR9: Toll-like receptor 9; URTI: Upper respiratory tract infection.

Table 2. Summary of immunologic assessments and responder criteria utilized in the 58 separate studies summarized in this review.

Assay^†	Number of studies in immunocompromised individuals Total, n = 39		Number of studies in asplenic individuals Total, n = 12		Number of studies in immunocompetent individuals Total, n = 9
ELISA
ELISA protocol
Referenced WHO standard  Compatible with WHO standard^‡  Other/unspecified protocol		12 9 18		4 2 6		5 3 1
Threshold or fold-rise
Threshold^§	n = 25		n = 14		n = 10
≥0.15 µg/ml  ≥0.2 µg/ml  ≥0.35 µg/ml  ≥0.5 µg/ml  ≥1.0 µg/ml  ≥1.3 µg/ml  >10 U/ml^¶		3 2 9 5 4 1 1		2 0 6 0 6 0 0		0 2 6 0 2 0 0
Fold-rise	n = 10		n = 3		n = 0
≥2-fold-rise  ≥4-fold-rise		5 5		2 1		0 0
Threshold and/or fold-rise	n = 10		n = 0		n = 0
≥2-fold increase + ≥0.35 µg/ml  ≥2-fold increase + ≥1 µg/ml  ≥4-fold increase + ≥0.35 µg/ml  ≥4-fold increase or ≥0.5 µg/ml		3 5 1 1		0 0 0 0		0 0 0 0
ELISA response by serotypes
In ≥1 serotype	n = 1		n = 0		n = 0
≥2-fold increase + ≥0.35 µg/ml		1		0		0
In ≥2 serotypes	n = 3		n = 0		n = 0
≥2-fold increase  ≥2-fold increase + ≥1 µg/ml		2 1		0 0		0 0
In ≥4 serotypes	n = 1		n = 0		n = 0
≥1.3 µg/ml		1		0		0
In ≥5 serotypes^§:	n = 3		n = 0		n = 2
≥0.35 µg/ml  2-fold increase + ≥1 µg/ml  4-fold increase		0 2 1		0 0 0		2 0 1
In seven serotypes	n = 5		n = 1		n = 0
≥0.15 µg/ml  ≥0.35 µg/ml  ≥0.5 µg/ml  ≥1 µg/ml  ≥2-fold increase or ≥0.5 µg/ml  4-fold increase		1 1 1 0 1 1		0 0 0 1 0 0		0 0 0 0 0 0
OPA
OPA response by serotype
Threshold	n = 9		n = 3		n = 1
OPA ≥1:8  Other		4 5		1 2		0 1

^†One study [89] included individuals from all three categories. Some studies had more than one response criterion and thus the number of trials in each category may not add up to the total number of trials summarized in the table.

^‡Protocol utilized absorbent containing C-polysaccharide and/or 22F capsular polysaccharide, and standard human antipneumococcal reference serum (i.e., 89-SF or 007sp).

^§Studies may have had more than one threshold.

^¶Antibody level as determined by ELISA >10% of the reference plasma pool level.

GMC: Geometric mean concentration(s); GMT: Geometric mean titer(s); OPA: Opsonophagocytosis.

Table 3. Immunologic findings following primary and secondary pneumococcal vaccination (comparative and non-comparative studies).

Risk group Study (year) (location) Study type Vaccine schedule	Assay type (units)	Timepoint		Pneumococcal serotypes								Additional serotypes				Notes	Ref.
			n	4	6B	9V	14	18C	19F	23F	All PCV7	1	3	5	7
Immunocompromised children
HIV Abzug et al. (2006) (USA) NC, RV PCV7/PCV7/PPV23 (0, 8 weeks, 16 weeks)	ELISA GMC (µg/ml)	Pre-vac	225	–	0.73	–	0.37	–	1.55	0.25	–	0.30	–	–	–	^aSignificant difference compared with previous timepoint (p ≤ 0.02)	[71]
		Post-dose 1	224	–	1.76^a	–	1.91^a	–	2.59^a	0.92^a	–	0.33	–	–	–
		Post-dose 2	219	–	2.90^a	–	3.08^a	–	3.12^a	1.44^a	–	0.33	–	–	–
		Post-PPV23	225	–	3.23	–	3.55^a	–	4.25^a	1.44	–	1.61	–	–	–
HIV Costa Ide et al. (2008) (Brazil) NC, PV PCV7/PCV7 (0, 2 months)	ELISA	Pre-vac	40	0.34	0.75	0.45	0.94	0.51	1.51	0.52	–	–	–	–	–	p < 0.001 for all comparisons (pre-vac vs post-dose 2) *Assessments conducted outside 8-week cut-off	[67]
	GMT (µg/ml)	Post-dose 2*	40	1.22	1.65	1.79	4.53	2.05	3.1	1.48	–	–	–	–	–
HIV Madhi et al. (2005) (South Africa) NC, PV PCV9 or PLA (3 doses; age: 6, 10, 14 weeks)	ELISA	Primary series														^ap = 0.02 for PCV9 in HIV+ vs HIV− groups for serotypes 1 and 18C; p ≤ 0.05 for serotypes 1, 4, 6B, 14, 18C, 19F, and 23F in PLA in HIVinus;+ vs HIV− groups	[30]
	GMC^a(µg/ml)	Post-dose 3
		HIV+
		PCV9	30	2.77	1.21	2.36	2.23	1.87	3.59	1.78	–	3.45	–	3.32	–
		PLA	36	0.20	0.20	0.11	0.35	0.09	0.74	0.16	–	0.18	–	0.22	–
		HIV−
		PCV9	63	4.09	1.76	3.35	3.62	4.55	6.02	3.15	–	7.55	–	5.79	–
		PLA	64	0.08	0.10	0.08	0.24	0.06	0.29	0.09	–	0.09	–	0.15	–
HIV Madhi et al. (2009) (South Africa) NC, PV PCV7 (1 dose ~5 years following primary series of PCV9 or PLA)	ELISA GMC (µg/ml)	Booster dose														ELISA (GMC): significantly different (p < 0.05) for all groups between pre-vac (before PCV7 at 5 years) and post-vac (1 month following PCV7 at 5 years) except HIV-infected control subjects (serotypes 6B and 14) and HIV-infected previous vaccinees (serotype 19F). Also significant for comparison for most serotypes between previous vaccinees and control subjects at the same visit, and between HIV+ and HIV− previous vaccinees and control subjects	[41]
		HIV+	31
		Vaccinees
		Pre-vac		0.30	0.64	0.25	1.02	0.18	0.90	0.30	–	–	–	–	–
		Post-vac		1.07	3.9	0.64	2.47	1.10	1.26	0.61	–	–	–	–	–
		Controls	45
		Pre-vac		0.20	0.16	0.18	0.53	0.15	0.52	0.21	–	–	–	–	–
		Post-vac		0.50	0.20	0.54	0.64	0.69	1.13	0.39	–	–	–	–	–
		HIV−	89
		Vaccinees
		Pre-vac		0.44	1.42	0.88	1.90	0.48	2.00	1.10	–	–	–	–	–
		Post-vac		11.11	31.1	7.39	26.8	11.4	6.27	11.62	–	–	–	–	–
		Controls	110
		Pre-vac		0.24	0.21	0.36	0.66	0.27	0.76	0.31	–	–	–	–	–
		Post-vac		2.79	1.57	3.17	5.51	3.60	4.61	3.90	–	–	–	–	–
	OPA GMT	HIV+
		Vaccinees Controls	31 44	– –	281 101	151 150	– –	– –	42 76	– –	– –	– –	– –	– –	– –
		HIV−
		Vaccinees Controls	51 51	– –	1075 301	498 588	– –	– –	71 170	– –	– –	– –	– –	– –	– –
HIV Madhi et al. (2010) (South Africa) NC, PV PCV7 (3 doses; age: 6–12 weeks, 9–18 weeks, and 12–24 weeks)	ELISA GMC (µg/ml)	Post-dose 3														^ap = 0.027 vs HIV+/ART+; ^bp = 0.04 vs HIV+/ART+; ^cp = 0.025 vs M+/I−; ^dp = 0.003 vs M+/I−; ^ep < 0.001 vs HIV+/ART− ^Ap < 0.001 vs HIV+/ART+; ^Bp = 0.002 vs HIV+/ART−; ^Cp < 0.001 vs HIV+/ART−; ^Dp = 0.015 vs HIV+/ART+	[68]
		HIV+/ART+	172	5.74	2.25	5.48	4.81	6.06	7.55	4.83	–	–	–	–	–
		HIV+/ART−	77	5.94	3.52^a	4.85	6.33^b	5.20	6.19	5.38	–	–	–	–	–
		M+/I−	120	7.99	2.60	6.45	4.47	7.46	8.47	6.91	–	–	–	–	–
		M−/I−	114	6.45	1.43^c,e	5.12	3.60^e	6.02	6.97	4.10^d	–	–	–	–	–
	OPA	Post-dose 3
	GMT	HIV+/ART+	172	–	–	725	–	–	312	1309	–	–	–	–	–
		HIV+/ART−	77	–	–	331^A	–	–	149^A	758^D	–	–	–	–	–
		M+/I−	120	–	–	610	–	–	283	2678	–	–	–	–	–
		M−/I−	114	–	–	566^B	–	–	365^C	1755^C	–	–	–	–	–
HIV Madhi et al. (2013) (South Africa) NC, PV PCV7 (3 doses; age: 6–12 weeks, 9–18 weeks, and 12–24 weeks)	ELISA GMC (µg/ml)	HIV+/ART+														*1-month post-dose ^ap = 0.002 vs M−/I−; ^bp < 0.001 vs M−/I−; ^cp = 0.037 vs M−/I−; ^dp = 0.004 vs M−/I−; ^ep = 0.003 vs M−/I−; ^fp = 0.038 vs M−/I−; ^gp = 0.001 vs M−/I−; ^hp = 0.016 vs M−/I−; ^ip = 0.014 vs M−/I−; ^jp = 0.043 vs M−/I−; ^kp = 0.024 vs M−/I−; ^lp = 0.023 vs M−/I−; ^mp = 0.006 vs M−/I−; ^np = 0.033 vs M−/I−; ^Ap < 0.001 post-dose 2 vs post-dose 1; ^Bp < 0.05 post-dose 2 vs post-dose 1	[69]
		Pre-vac	204–205	0.13	0.17	0.13^a	0.86	0.12^b	0.48^c	0.18^d	–	–	–	–	–
		Post-dose 1*	196	0.48	0.12^e	0.23^f	0.52^g	0.36	0.62^h	0.20	–	–	–	–	–
		Post-dose 2*	191	4.79	0.38^i	4.29	1.83	3.90	4.80	1.23	–	–	–	–	–
		Post-dose 3*	169–171	5.75	2.26^A	5.46^B	4.83^A	6.06^A	7.56^A	4.81^A	–	–	–	–	–
		HIV+/ART−
		Pre-vac	104	0.15	0.22	0.15^j	1.05	0.11^b	0.57	0.19^k	–	–	–	–	–
		Post-dose 1*	91	0.61	0.15	0.31	0.67	0.46	0.75	0.23	–	–	–	–	–
		Post-dose 2*	84	4.95	0.52^g	2.94	2.03	3.92	5.05	1.46^l	–	–	–	–	–
		Post-dose 3*	77	5.94	3.52^A	4.85^B	6.33^A	5.2	6.19	5.38^A	–	–	–	–	–
		M+/I–
		Pre-vac Post-dose 1* Post-dose 2* Post-dose 3*	124 122 121 120	0.08^m 0.42 6.21^n 7.99^B	0.09^e 0.08^b 0.24 2.60^A	0.09^b 0.21 5.01 6.45^B	0.42^b 0.39^g 1.76 4.47^A	0.10^b 0.33 4.06 7.46^A	0.23^b 0.44^a 4.96 8.47^A	0.12^b 0.12^e 1.15 6.91^A	– – – –	– – – –	– – – –	– – – –	– – – –
		M–/I–
		M–/I– Pre-vac Post-dose 1* Post-dose 2* Post-dose 3*	119 117 116 114	0.12 0.45 4.43 6.45^A	0.15 0.16 0.24 1.43^A	0.20 0.31 3.84 5.12^B	1.00 0.82 1.78 3.6^A	0.21 0.44 3.29 6.02^A	0.62 0.81 4.04 6.97^A	0.25 0.25 0.83 4.09^A	– – – –	– – – –	– – – –	– – – –	– – – –
	OPA GMT	HIV+/ART+														*1-month post-dose ^ap = 0.09 vs M−/I−; ^bp < 0.001 vs M−/I−;^cp = 0.012 vs M−/I−; ^dp = 0.007 vs M−/I−; ^Ap < 0.001 post-dose 2 vs post-dose 1; ^Bp < 0.05 post-dose 2 vs post-dose 1; ^Cp < 0.01 post-dose 2 vs post-dose 1
		Post-dose 2* Post-dose 3*		– –	– –	246 724^Aa	– –	– –	85 312^A	98 1309^Ab	– –	– –	– –	– –	– –
		HIV+/ART−
		Post-dose 2* Post-dose 3*		– –	– –	178 331^Bc	– –	– –	69 149^A	67 758^Ad	– –	– –	– –	– –	– –
		M+/I−
		Post-dose 2* Post-dose 3*		– –	– –	581 610	– –	– –	97 283^A	97 2678^Ab	– –	– –	– –	– –	– –
		M−/I−
		Post-dose 2* Post-dose 3*		– –	– –	362 566^C	– –	– –	73 365^A	35 1755^A	– –	– –	– –	– –	– –
HIV Nachman et al. (2003) (USA) NC, PV PCV7 or PLA (3 doses, 8-weeks dosing interval + booster dose, age: 15 months [≥6 months post-dose 3]) + PPV23 (age: 24 months)	ELISA GMC (µg/ml)	PCV7															[42]
		Pre-vac Post-dose 3 Pre-booster Post-booster	24 24 21 19	0.02 2.8 0.4 3.4	0.05 5.4 1.2 11.4	0.03 1.6 0.4 2.3	0.05 8.5 2.2 10.4	0.03 2.6 0.4 3.3	0.07 4.7 0.7 6.5	0.03 3.3 1 7.7	– – – –	– – – –	– – – –	– – – –	– – – –
HIV Rivera-Olivero et al. (2014) (Venezuela) NC, PV PCV7: Aged: 2–6 months: 3 doses, 6–8 weeks apart Aged: 7–23 months: two doses, 6–8 weeks apart Aged: ≥24 months (one to three previous doses): one dose; no previous doses: two doses , 6–8 weeks apart	ELISA GMC (µg/ml)	Pre-vac Post-vac	12	0.99 4.84	2.28 2.68	0.73 3.42	2.48 9.46	0.56 1.83	2.60 6.62	0.76 1.76	– –	– –	– –	– –	– –		[89]
HIV Spoulou et al. (2005) (Greece) NC, RV HIV group: PCV7 (2 + booster dose; 0, 1, 12 months) HC: PCV7 (two doses; 0, 12 months)	ELISA GMC (µg/ml)	HIV+	14													^ap < 0.05 post-dose 1 for controls vs baseline values	[70]
		Pre-vac		–	0.80	–	2.50	–	2.14	0.40	–	–	–	–	–
		Post-dose 2 (+1 month)		–	1.10	–	3.90	–	3.40	1.80	–	–	–	–	–
		Controls	21
		Pre-vac Post-dose 1 (+1 month)		– –	2.06 6.00^a	– –	2.20 5.50	– –	0.90 4.20^a	0.40 1.30	– –	– –	– –	– –	– –
Solid organ transplantation Barton et al. (2009) (Canada) NC, PV PCV7/PCV7/PCV7/PPV23 (8-weeks dosing intervals)	ELISA GMC (µg/ml)	After PCV7 dose 3	NR	0.96	–	–	–	–	4.84	–	–	–	–	–	–	GMC increases significant for serotypes 19F, 14, 6B, 23F, and 9V (p < 0.05) After PPV23, the only PCV7 serotype to increase was 19F	[73]
Solid organ transplantation Lin et al. (2005) (USA) NC, PV Patients: PCV7/PCV7/PPV23 (6–8 weeks dosing intervals)	ELISA GMC (µg/ml)	HCs														^ap ≤ 0.05 between heart and liver transplant within the same timepoint	[55]
		Pre-vac	23	0.14	0.65	0.31	0.46	0.17	2.01	0.14	–	0.43	–	0.88	–
		6–8 weeks	22	2.38	8.13	4.43	17.22	3.84	9.19	7.76	–	0.25	–	1.08	–
		after PCV7
		4–8 weeks	21	2.69	6.84	4.10	16.71	3.30	10.50	5.95	–	3.01	–	3.56	–
		after PPV23
		Heart transplant
		Pre-vac	11	0.11	0.37^a	0.11^a	0.16	0.10^a	2.03	0.06	–	0.12^a	–	0.66	–
		6–8 weeks after first PCV7	11	0.96	1.46	0.46^a	2.88	0.95^a	2.68^a	0.61	–	0.14^a	–	0.89	–
		6–8 weeks after	11	1.28	2.09^a	0.45^a	4.23	0.79^a	3.20^a	0.97	–	0.14^a	–	0.81^a	–
		second PCV7
		4–8 weeks after PPV23	11	1.02	1.62	0.44^a	2.99	0.68^a	3.13^a	0.73	–	0.30a	–	1.21^a	–
		Liver transplant Pre-vac	13	0.20	1.12	0.32	0.60	0.31	5.18	0.24	–	0.24	–	1.54	–
		6–8 weeks after	13	1.57	6.23	4.26	11.85	4.63	10.14	3.66	–	0.25	–	1.74	–
		first PCV7
		6–8 weeks after	12	1.81	9.59	3.55	11.91	3.23	11.01	3.52	–	0.28	–	2.1	–
		second PCV7
		4–8 weeks after PPV23	11	1.55	6.48	2.85	11.8	2.92	9.13	2.38	–	0.99	–	4.17	–
Arthritis Farmaki et al. (2010) (Greece) NC, PV PCV7 (two doses; 0, 6–8 weeks)	ELISA GMT (µg/ml)	Anti-TNF	31													*Immediately before second PCV dose. Assessments not available for post-second PCV dose timepoints. ^ap = 0.0041 vs no anti-TNF group; ^bp = 0.0136 vs no anti-TNF group; ^cp = 0.015 vs no anti-TNF group	[74]
		Pre-vac		0.13	0.19	0.46	0.42	0.57	0.51	0.27	–	–	–	–	–
		Post-vac*		1.80^a	2.12	2.75	5.52^b	6.37	3.75	4.45^c	–	–	–	–	–
		No anti-TNF	32
		Pre-vac		0.11	0.31	0.54	0.35	0.56	0.74	0.38	–	–	–	–	–
		Post-vac*		5.04	5.02	4.44	10.28	7.03	4.27	11.21	–	–	–	–	–
Oncology Cheng et al. (2012) (Hong Kong) NC, PV PCV7 (two doses; 0, 1 months)	ELISA GMC (µg/ml)	Pre-vac														^ap < 0.01	[81]
		Solid tumor	15	0.10	0.39	0.12	0.23	0.41	0.99	0.19	–	–	–	–	–
		Hematologic	29	0.11	0.69	0.14	0.38	0.41	0.81	0.24	–	–	–	–	–
		+2 months
		Solid tumor	15	8.08^a	6.12^a	7.53^a	24.52^a	15.12^a	4.89^a	16.96^a	–	–	–	–	–
		Hematologic	29	3.44^a	2.94^a	1.21^a	16.02^a	5.16^a	2.22^a	8.23^a	–	–	–	–	–
Immuno-suppressive therapy Rivera-Olivero et al. (2014) (Venezuela) PV, NC Vaccine schedule as above	ELISA GMC (µg/ml)	Pre-vac Post-vac	11	ND ND	1.37 4.38	0.77 3.07	2.41 11.18	0.8 2.99	1.63 6.00	0.82 2.17	– –	– –	– –	– –	– –		[89]
Chronic kidney disease Liakou et al. (2011) (Greece) NC, PV PCV7 (one dose)	ELISA GMC (µg/ml)	Group A	15													^ap < 0.01 for all serotypes compared with baseline; ^bp < 0.01 vs control; ^cp = 0.036 vs Group B	[77]
		Pre-vac		0.02	0.05	0.18	0.18	0.17	0.93	0.21	–	–	–	–	–
		+1 month^a		2.3	4.9	6.02	11.5	5.11^b,c	4.35	12.24	–	–	–	–	–
		Group B	18
		Pre-vac		0.009	0.02	0.28	0.09	0.17	0.61	0.17	–	–	–	–	–
		+1 month^a		2.17^b	2.85	3.98^b	4.37	1.70^b	3.32	4.92	–	–	–	–	–
		HC	16
		Pre-vac		0.06	0.42	0.52	0.51	0.17	0.61	0.44	–	–	–	–	–
		+1 month^a		6.89	9.22	13.13	11.64	8.55	5.72	10.09	–	–	–	–	–
Chronic kidney disease Liakou et al. (2014) (Greece) NC, RV PCV7 (booster dose 12–14 months following primary dose in previous study)	ELISA GMC (µg/ml)	Group A	14														[78] [77]
		Baseline +1 month		0.19 2.10	1.26 7.66	1.36 5.37	3.50 12.49	0.73 1.90	2.29 5.84	3.56 13.0	– –	– –	– –	– –	– –
		Group B	15
		Baseline +1 month		0.51 1.34	1.20 3.86	2.00 3.17	2.84 6.71	0.88 1.37	2.27 3.87	2.89 9.11	– –	– –	– –	– –	– –
LBW Shinefield (USA) NC, PV PCV7 (four doses)	ELISA GMT (µg/ml)	LBW	6														[85]
		+1 month post-dose 3		0.52	4.2	2.37	5.04	2.66	2.37	1.52	–	–	–	–	–
		NBW	146
		+1 month post-dose 3		1.35	3.3	1.63	4.7	2.01	1.4	1.5	–	–	–	–	–
LBW Szynczewski et al. (2014) (Poland) NC, PV PCV7 (three doses at ages 2, 4, 6 months + booster dose at 16 months)	ELISA GMC (µg/ml)	Birth weight <1000 g	23														[83]
		Pre-vac Dose 3 Booster		0.08 2.14 2.84	0.26 1.16 6.49	0.08 2.27 4.70	0.32 5.37 15.26	0.09 1.85 3.83	0.18 2.56 3.53	0.13 1.22 4.99	– – –	– – –	– – –	– – –	– – –
		Birth weight ≥1000 g	37
		Pre-vac Dose 3 Booster		0.09 1.59 2.66	0.44 0.92 10.79	0.13 1.57 4.71	0.49 3.56 14.86	0.08 1.56 3.13	0.26 2.43 5.75	0.16 0.89 6.23	– – –	– – –	– – –	– – –	– – –
Immunocompromised adults
HIV Chen et al. (2008) (Uganda) NC, PV PCV7/PPV23 (0, 2 months)	ELISA GMC (µg/ml)	Group 1	30													Group 1: HIV+ with CD4 200–499 µL-1; Group 2: HIV+, with CD4 ≥500 µL-1; Group 3: HIV- ^ap < 0.01 (vs pre-vac); ^bp < 0.05 (vs group 3); ^cp < 0.01 (vs group 3)	[61]
		Pre-PCV7		1.55	–	–	5.27	–	–	–	–	–	–	–	–
		Post-PCV7		4.17^a	–	–	25.31^a,b	–	–	–	–	–	–	–	–
		Post-PPV23		4.56^a	–	–	23.14^a,c	–	–	–	–	–	–	–	–
		Group 2	28
		Pre-PCV7		0.82	–	–	5.10	–	–	–	–	–	–	–	–
		Post-PCV7		4.00^a	–	–	42.44^a	–	–	–	–	–	–	–	–
		Post-PPV23		3.88^a	–	–	42.76^a	–	–	–	–	–	–	–	–
		Group 3	29
		Pre-PCV7		0.83	–	–	4.67	–	–	–	–	–	–	–	–
		Post-PCV7		6.75^a	–	–	52.11^a	–	–	–	–	–	–	–	–
		Post-PPV23		6.87^a	–	–	53.86^a	–	–	–	–	–	–	–	–
Chen et al. (2008) [continued]	OPA GMT	Group 1	30													^ap < 0.01 (vs pre-vac); ^bp < 0.01 vs group 3; ^cp < 0.05 vs group 3; ^dp < 0.05 vs group 2	[61]
		Pre-PCV7		4.29	–	–	7.29	–	–	–	–	–	–	–	–
		Post-PCV7		13.93^a,b	–	–	41.26^a,c	–	–	–	–	–	–	–	–
		Post-PPV23		13.61^a,b,d	–	–	43.21^a,b	–	–	–	–	–	–	–	–
		Group 2	28
		Pre-PCV7		4.00	–	–	12.80	–	–	–	–	–	–	–	–
		Post-PCV7		32.0^a,c	–	–	107.63^a	–	–	–	–	–	–	–	–
		Post-PPV23		37.12^a	–	–	118.84^a	–	–	–	–	–	–	–	–
		Group 3	29
		Pre-PCV7		4.62	–	–	12.01	–	–	–	–	–	–	–	–
		Post-PCV7		75.66^a	–	–	275.03^a	–	–	–	–	–	–	–	–
		Post-PPV23		73.87^a	–	–	281.68^a	–	–	–	–	–	–	–	–
HIV Deloria-Knoll et al. (2006) (USA) NC, PV PCV7/PPV23 (0, 6 months)	ELISA GMC (µg/ml)	PLA	22														[62]
		Pre-vac		0.51	1.47	0.82	1.67	0.89	2.20	0.84	–	–	–	–	–
		Post-PCV7		0.88	2.77	2.05	6.19	2.43	2.97	2.03	–	–	–	–	–
HIV Feikin et al. (2001) (USA) C, PV PCV7/PCV7 (0, 8 weeks) PCV7/PPV23 (0, 8 weeks) PLA/PPV23 (0, 8 weeks) PLA/PLA (0, 8 weeks)	ELISA GMC (µg/ml)	PCV/PCV	15													^ap < 0.001 vs pre-vac for the same group; ^bp < 0.01 vs pre-vac for the same group; ^cp < 0.05 vs pre-vac for the same group	[34]
		Pre-vac		0.65	0.99	0.8	5	–	–	0.77	–	–	–	–	–
		Post-dose 1		1.2^a	1.7^a	2.0^a	9.8^a	–	–	1.4^a	–	–	–	–	–
		Post-dose 2		1.2^a	2.0^a	1.8^b	10.3^b	–	–	1.5^a	–	–	–	–	–
		PCV/PPV	18
		Pre-vac		0.77	1.2	0.93	5	–	–	1.2	–	–	–	–	–
		Post-dose 1		1.6^a	2.0^a	2.4^a	10.7^a	–	–	2.0^a	–	–	–	–	–
		Post-dose 2		1.5^a	2.2^a	2.6^a	11.4^a	–	–	1.8^b	–	–	–	–	–
		PLA/PPV	16
		Pre-vac		0.81	1.2	0.92	7.3	–	–	1.2	–	–	–	–	–
		Post-dose 1		0.83	1.2	0.91	7.8	–	–	1.1	–	–	–	–	–
		Post-dose 2		1.1	1.6	1.5^c	15.4^a	–	–	1.4	–	–	–	–	–
		PLA/PLA	18
		Pre-vac		0.7	1.0	0.67	3.8	–	–	0.92	–	–	–	–	–
		Post-dose 1		0.72	1.1	0.66	3.9	–	–	0.99	–	–	–	–	–
		Post-dose 2		0.7	1.0	0.59	3.9	–	–	1.0	–	–	–	–	–
	OPA GMT	PCV/PCV Pre-vac	15													^cp < 0.001 vs pre- vac for the same group; ^dp < 0.01 vs pre-vac for the same group; ^ep < 0.05 vs pre-vac for the same group; ^fp < 0.05 vs pre-vac for the PCV/PCV and PLA/PLA groups
				16	64	30.5	36.8	–	–	24.3	–	–	–	–	–
		Post-dose 1		40.2^c	116^c	38.5	61.1^e	–	–	40.3^d	–	–	–	–	–
		Post-dose 2		46.2^c	169^c	46.3	64.0^e	–	–	38.5	–	–	–	–	–
		PCV/PPV	18
		Pre-vac		8.0	33.3	16.7	18.1	–	–	10.2^f	–	–	–	–	–
		Post-dose 1		20.4^c	48.1^e	24.1^e	61.4^c	–	–	19.6^c	–	–	–	–	–
		Post-dose 2		16.0^d	56.6^e	23.1	50.1^c	–	–	18.8^d	–	–	–	–	–
		PLA/PPV	16
		Pre-vac		13.3	36.8	19.2	38.5	–	–	16.8	–	–	–	–	–
		Post-dose 1		15.3	45.2	17.4	45.2	–	–	18.2	–	–	–	–	–
		Post-dose 2		18.2	49.3	19.9	83.0^e	–	–	19.0	–	–	–	–	–
		PLA/PLA	18
		Pre-vac Post-dose 1 Post-dose 2		16.0 12.7 11.8	52.7 48.8 48.9	22.6 17.2 16.6	16.0 16.0 14.3	– – –	– – –	21.0 20.2 16.0	– – –	– – –	– – –	– – –	– – –
HIV Gordon et al. (2007) (Malawi) NC, PV PCV7 or placebo (one dose)	ELISA GMC (µg/ml)	HIV− PLA	12													No significant differences between groups pre-vac Pre-vac vs +1 mo: ^ap<0.0001; ^bp = 0.0001; ^cp = 0.002; ^dp = 0.004; ^ep = 0.01; ^fp = 0.0004	[40]
		Pre-vac		–	0.52	–	1.9	–	0.88	0.5	–	–	–	–	–
		+1 month		–	0.46	–	1.9	–	1.06	0.65	–	–	–	–	–
		HIV− PCV7	10
		Pre-vac		–	0.24	–	0.75	–	0.65	0.34	–	–	–	–	–
		+1 month		–	4.68^a	–	39.0^b	–	8.30^c	13.2^a	–	–	–	–	–
		HIV+ PLA	9
		Pre-vac		–	0.26	–	1.28	–	0.69	0.19	–	–	–	–	–
		+1 month		–	0.41	–	2.02	–	0.92	0.26	–	–	–	–	–
		HIV+ PCV7	10
		Pre-vac		–	0.25	–	0.71	–	0.79	0.49	–	–	–	–	–
		+1 month		–	1.89^d	–	18.9^a	–	5.76^e	8.9^f	–	–	–	–	–
HIV Lespirit et al. (2007) (France) C, PV PCV7/PPV23 (0, 4 weeks) PPV23 (1 dose at 4 weeks)	ELISA GMC (µg/ml)	PCV/PPV	105													^ap = 0.02; ^bp = 0.04; ^cp = 0.03; ^dp < 0.01 vs PPV alone	[35]
		Pre-vac		0.11	0.47	0.48	1.68^a	0.4	0.81	0.24	–	0.17		0.55
		Post-PCV/PPV		1.46^b	2.18	2.71^c	9.34^b	3.18^d	2.92^c	1.92^d	–	1.66		2.18
		PPV alone	103
		Pre-vac		0.13	0.47	0.48	1.07	0.38	0.74	0.25	–	0.16		0.55
		Post-PPV		0.96	1.55	1.86	5.88	1.58	1.99	0.86	–	1.35		1.97
HIV Miiro et al. (2005) (Uganda) NC, RV PCV7 (2 doses; 0, 4 weeks)	ELISA GMC (µg/ml)	Past PPV23														95%CIs only reported for ‘All’ group No significant differences according to past vaccination status (PPV or PLA) p < 0.01 for all serotypes post-dose 1 and for all except 9V (NS), 14 (NS), and 18C (p = 0.03) for post-dose 2 in all patients when comparing with the previous timepoint	[66]
		Pre-PCV7	54	0.29	0.43	0.64	2.97	0.60	1.35	0.51	–	–	–	–	–
		Post-dose 1	53	1.45	1.18	2.59	6.9	2.97	4.19	2.78	–	–	–	–	–
		Post-dose 2	49	1.59	2.25	2.61	6.45	2.82	5.98	4.92	–	–	–	–	–
		Past PLA
		Pre-PCV7	55	0.17	0.27	0.47	1.84	0.41	1.09	0.37	–	–	–	–	–
		Post-dose 1	55	0.91	1.17	2.8	7.36	2.77	4.62	2.10	–	–	–	–	–
		Post-dose 2	51	1.32	2.53	2.82	6.66	2.58	6.84	3.68	–	–	–	–	–
HIV Søgaard et al. (2010) (Denmark) NC, PV PCV7/PCV7/PPV23 (0, 3, 9 months)	ELISA GMC IgG (µg/ml)	Controls	49														[64]
		Pre-vac		0.39	1.23	0.7	2.38	1.00	2.09	0.75	–	–	–	–	–
		Post-dose 2 (+1 month)		1.48	5.00	2.71	11.2	4.88	5.24	5.88	–	–	–	–	–
		Post-dose 3 (+1 month)		1.45	4.07	2.63	10.1	3.91	6.30	4.09	–	–	–	–	–
	OPA GMT	Controls Pre-vac	49	–	8	–	32	–	20	11	–	–	–	–	–
		Post-dose 2 (+1 month)		–	184	–	318	–	242	173	–	–	–	–	–
		Post-dose 3 (+1 month)		–	505	–	339	–	551	245	–	–	–	–	–
Solid organ transplantation Gattringer et al. (2011) (Austria) NC, PV PCV7/PPV23 (8-weeks dosing interval)	ELISA GMC (µg/ml)	Pre-vac	26	0.11	0.56	0.14	0.72	0.36	0.38	0.23	–	0.57	–	0.93	0.57	^ap < 0.05 vs pre-vac	[54]
		Post-PCV7	26	0.30^a	1.27^a	0.40^a	1.43^a	1.10^a	0.62	0.64^a	–	0.51	–	0.92	0.53
		Post-PPV23	26	0.26	1.06	0.48	1.48	1.20	0.68	0.65	–	1.40^a	–	1.18	1.44^a
Solid organ transplantation Kumar et al. (2003) (Canada) C, PV PCV7 or PPV23 (one dose)	ELISA GMC (µg/ml)	PCV7	30													^ap = 0.09 for fold-rise at 8 weeks vs PPV23; ^bp = 0.046 for fold-rise at 8 weeks vs PPV23	[60]
		Pre-vac		1.00	2.43	0.84	12.1	1.20	4.61	0.45	–	–	–	–	–
		+8 weeks		2.16	4.55	2.86^a	18.1	3.93	7.20	1.49^b	–	–	–	–	–
		PPV23	30
		Pre-vac		0.98	2.97	1.06	14.1	1.33	5.98	0.83	–	–	–	–	–
		+8 weeks		1.71	3.91	1.70	19.9	2.71	6.96	1.15	–	–	–	–	–
	OPA GMT	PCV7	30
		Pre-vac		45.3	70.2	16.0	111.4	19.7	58.4	16.8	–	–	–	–	–
		+8 weeks		207.9	294.1	82.5	238.9	119.4	147.0	64.0	–	–	–	–	–
		PPV23	30
		Pre-vac		49.6	70.2	14.3	70.2	30.6	49.6	12.4	–	–	–	–	–
		+8 weeks		172.8	198.6	78.8	203.3	86.4	111.4	28.5	–	–	–	–	–
Solid organ transplantation Kumar et al. (2008) (Canada) NC, PV Primed group: PCV7/PPV23 (0, 8 weeks) Unprimed group: PLA/PPV23 (0, 8 weeks)	ELISA GMT (µg/ml)	Primed group	56													No significant differences between groups at 16 weeks (8 weeks following booster injection with PPV23) GMTs were significantly increased for PCV7 recipients (primed group) compared with PLA (unprimed group) but remained at similar levels in the primed group following booster vaccination with PPV23 *Assessments undertaken outside the 8-week cut-off	[53]
		Post-PPV23*		0.67	1.8	2.37	12.42	4.35	4.95	1.54	–	–	–	–	–
		Unprimed group	57
		Post-PPV23*		1.24	2.63	1.96	15.49	3.79	5.1	2.57	–	–	–	–	–
Solid organ transplantation Tobudic 2012 (Austria) C, PV PCV7/PPV23 or PPV23/PPV23 (0, 12 months)	ELISA GMC (µg/ml)	PCV7/PPV23	33													*8 weeks post-vac ^ap < 0.001 for fold-rise at 8 weeks vs PCV7; ^bp < 0.01 for fold-rise at 8 weeks vs PCV7; ^cp = 0.049 for fold-rise at 8 weeks vs PCV7; ^dp = 0.004 for fold-rise at 8 weeks vs PCV7	[36]
		Pre-vac Post-dose 1* Post-dose 2*		1.02 3.61 3.01	2.13 8.01 8.11	1.69 5.38 4.93	8.92 30.58 37.47	1.77 7.08 5.74	5.70 9.31 11.83	3.57 9.52 8.10	– – –	2.01 2.11 3.41	– – –	2.03 2.18 2.71	2.95 3.10 5.19
		PPV23/PPV23	40
		Pre-vac Post-dose 1* Post-dose 2*	29	1.21 3.31 3.19	3.57 7.11 4.01	1.94 6.57 8.85	9.82 32.4 35.64	2.43 6.58 6.41	5.33 11.81 17.26^c	4.24 8.77 12.63	– – –	2.44 6.93^a 6.62	– – –	2.08 5.09^b 3.84	2.64 7.91^a 8.32^d
Arthritis Kapetanovic et al. (2011) (Sweden) NC, PV PCV7 (one dose)	ELISA GMT (mg/l)	RA														p values for serotype 6B between p < 0.001 and p = 0.035 compared with pre-vac levels p values for serotype 23F between p < 0.001 and p = 0.0007 compared with pre-vac levels	[75]
		MTX	85
		Pre-vac		–	2.0	–	–	–	–	0.7	–	–	–	–	–
		+4–6 weeks		–	3.5	–	–	–	–	1.9	–	–	–	–	–
		Anti-TNF + MTX	89
		Pre-vac		–	1.5	–	–	–	–	0.7	–	–	–	–	–
		+4–6 weeks		–	2.3	–	–	–	–	1.4	–	–	–	–	–
		Anti-TNF alone	79
		Pre-vac		–	1.4	–	–	–	–	0.6	–	–	–	–	–
		+4–6 weeks		–	3.6	–	–	–	–	1.9	–	–	–	–	–
		SpA Anti-TNF + MTX	83
		Pre-vac +4–6 weeks		– –	1.7 3.0	– –	– –	– –	– –	0.8 2.5	– –	– –	– –	– –	– –
		Anti-TNF alone	83
		Pre-vac +4–6 weeks		– –	1.5 4.8	– –	– –	– –	– –	0.7 3.1	– –	– –	– –	– –	– –
		NSAID	85
		Pre-vac +4–6 weeks		– –	2.9 9.5	– –	– –	– –	– –	0.97 6.4	– –	– –	– –	– –	– –
Arthritis Kapetanovic et al. (2013) (Sweden) NC, PV PCV7 (one dose)	ELISA GMC (µg/ml)	Rituximab	29													Data for MTX and control groups from previous trial [75]	[76]
		Pre-vac +4–6 weeks		– –	0.3 0.4	– –	– –	– –	– –	0.2 0.3	– –	– –	– –	– –	– –
		Rituximab +MTX	26
		Pre-vac +4–6 weeks		– –	0.4 0.4	– –	– –	– –	– –	0.3 0.4	– –	– –	– –	– –	– –
		Abatacept	17
		Pre-vac +4–6 weeks		– –	0.6 1.1	– –	– –	– –	– –	0.4 1.1	– –	– –	– –	– –	– –
		Tocilizumab	16
		Pre-vac +4–6 weeks		– –	0.4 1.7	– –	– –	– –	– –	0.2 2.2	– –	– –	– –	– –	– –
		MTX	85
		Pre-vac +4–6 weeks		– –	2.0 3.5	– –	– –	– –	– –	0.7 1.9	– –	– –	– –	– –	– –
		Controls	86
		Pre-vac		–	2.9	–	–	–	–	0.97	–	–	–	–	–
		+4–6 weeks		–	9.5	–	–	–	–	6.4	–	–	–	–	–
Defective immune response Shrimpton et al. (2006) (UK) PCV7 (one to two doses) (6 patients received a second dose 10–21 months following the first) PPV23 (two doses prior to PCV7)	ELISA GMC* (µg/ml)	Patients	6													*GMCs calculated from individual IgG levels in publication Patients were tested before and 4 weeks after secondary vaccination with PCV7 and controls were tested before and 4 weeks after primary vaccination with PCV7	[92]
		Pre-PCV7 Post-PCV7		0.12 0.23	0.39 0.74	0.24 1.22	5.30 12.57	0.37 1.55	0.56 1.96	0.36 1.74	– –	0.20 0.17	– –	0.39 0.29	– –
		Controls	4
		Pre-PCV7 Post-PCV7		0.48 4.68	1.01 15.75	0.81 29.60	2.97 33.76	0.68 34.84	3.66 23.69	0.61 25.61	– –	0.12 0.18	– –	0.74 0.87	– –
Oncology Sinisalo et al. (2007) (Finland) NC, PV PCV7 (one dose)	ELISA GMC (µg/ml)	CLL	49													p ≤ 0.001 for all post-vac values (CLL vs controls) No significant differences between groups for pre-vac values	[80]
		Pre-vac		0.13	0.3	0.37	0.67	0.88	1.1	0.58	–	–	–	–	–
		Post-vac		0.32	0.63	1.12	1.12	2.42	2.41	2.02	–	–	–	–	–
		Controls	24
		Pre-vac		0.11	0.35	0.33	0.77	1.31	0.70	0.71	–	–	–	–	–
		Post-vac		1.64	4.44	7.63	6.34	15.73	7.66	9.29	–	–	–	–	–
Immunocompromised children and adults
HIV Abzug et al. (2013) (USA) C, RV PCV7 or PPV23 (one dose)	ELISA GMC (µg/ml)	PCV7	36														[72]
		Pre-vac +4 weeks		– –	1.1 6.9	– –	1.6 10.3	– –	– –	– –	– –	0.5 0.6	– –	– –	– –
		PPV23	31												–
		Pre-vac +4 weeks		– –	1.6 4.9	– –	1.3 5.9	– –	– –	– –	– –	0.4 1.5	– –	– –	–
Stem cell transplantation Antin et al. (2005) (USA) NC, PV Non-immunized group: PCV7 (three doses; 3, 6, and 12 months post-transplant) Pre-immunized group: PCV7 (four doses; 7–10 days pre-stem cell collection; 3, 6 and 12 months post-transplant)	ELISA GMC (µg/ml)	Non-immunized group														^ap = 0.002 vs pre-immunized group; ^bp = 0.028 vs pre-immunized group; ^cp = 0.013 vs pre-immunized group	[48]
		Post vac (last dose)	NR	1.06	2.36	1.08	3.35	0.81^a	2.16^b	1.23^c	–	–	–	–	–
		Pre-immunized group
		Post vac (last dose)	NR	2.85	8.09	2.77	6.54	3.27	7.61	6.66	–	–	–	–	–
Stem cell transplantation Cordonnier et al. (2009) (Europe) NC, PV Early group: PCV7/PCV7/PCV7/PPV23 (3, 4, 5, 12 months post-transplant)	ELISA GMC (µg/ml)	Early group														No significant differences for late vs early comparisons	[49]
		Pre-vac	74	0.13	0.73	0.58	1.90	0.46	0.72	0.55	–	–	–	–	–
		Post-dose 3	57	0.98	2.69	1.57	4.65	1.90	2.11	2.81	–	–	–	–	–
		Pre-PPV23	56	0.39	1.10	0.79	2.85	0.96	1.12	1.36	–	–	–	–	–
		1-month post-PPV23	54	1.18	1.71	1.61	5.44	1.55	3.00	1.85	–	–	–	–	–
Late group: PCV7/PCV7/PCV7/PPV23 (9, 10, 11, 18 months post-transplant)		Late group
		Pre-vac Post-dose 3 Pre-PPV23 1 month post-PPV23	64 57 53 48	0.04 2.03 0.72 4.48	0.33 3.08 1.71 3.72	0.23 2.03 1.05 3.52	0.80 5.83 3.23 7.71	0.23 3.26 1.67 4.33	0.31 3.24 1.45 11.49	0.19 3.34 1.56 4.08	– – – –	– – – –	– – – –	– – – –	– – – –
Ataxia-telangiectasia Sanal et al. (2004) (Turkey) C, RV PCV7 or PPV23 (1 dose) (PPV23 and control values reported in previous study)	ELISA GMC (µg/ml)	PCV7	14														[56]
		Pre-vac		–	0.26	–	0.26	–	0.23	0.09	–	–	–	–	–
		Post-vac		–	0.32	–	0.37	–	0.27	0.14	–	–	–	–	–
		PPV23	12
		Pre-vac		–	0.12	–	0.21	–	0.08	0.06	–	–	–	–	–
		Post-vac		–	0.14	–	0.21	–	0.07	0.11	–	–	–	–	–
		Control (PPV)	40
		Pre-vac		–	0.91	–	1.11	–	0.52	0.39	–	–	–	–	–
		Post-vac		–	1.66	–	4.7	–	1.79	1.57	–	–	–	–	–
Ataxia-telangiectasia Schubert et al. (2004) NC, RV (Germany) PCV7 (two doses; 0, 4 weeks)	ELISA GMC (µg/ml)	Patients	10														[79]
		Pre-vac		0.13	0.10	0.07	0.15	0.12	0.12	0.10	–	–	–	–	–
		Post-vac		1.50	0.37	0.13	0.61	0.32	0.92	0.46	–	–	–	–	–
		Controls	NR
		Pre-vac		0.24	0.63	0.32	0.68	0.46	0.93	0.67	–	–	–	–	–
		Post-vac		5.23	13.3	5.46	13.9	10.70	14.79	22.56	–	–	–	–	–
Down syndrome Kusters (2013) (The Netherlands) NC, PV PCV7/PCV7/PPV23 (0, 4, 12 weeks)	ELISA GMT (µg/ml)	Pre-vac Post-vac	18	0.1 3.7	0.13 3.1	0.11 2.1	0.89 14	0.15 4.0	0.12 2.8	0.28 7.9	– –	0.63 2.5	0.27 1.7	– –	1.5 4.3		[82]
Asplenic children
Asplenia Mikoluc et al. (2008) (Poland) NC, PV PCV7 (one dose; with or without prior PPV23)	ELISA GMC (µg/ml)	No prior PPV23	15													^ap < 0.001 for pre-PCV7 vs post-PCV7 Previous vaccination with PPV23 did not affect response to PCV7	[94]
		Pre-PCV7		0.20	0.19	0.51	1.55	0.70	1.83	0.65	–	–	–	–	–
		Post-PCV7		3.09^a	1.77	2.30	11.06	4.45	4.87	5.76	–	–	–	–	–
		Prior PPV23	15
		Pre-PCV7		0.52	0.23	0.77	1.21	0.76	1.15	0.61	–	–	–	–	–
		Post-PCV7		3.05^a	1.31	4.53	9.14	3.32	3.93	4.36	–	–	–	–	–
SCD Nowak-Wegrzyn et al. (2000) (USA) NC, PV 2-month age group: PCV7/PCV7/PCV7/PPV23 (age: 2, 4, 6, 24 months) 12-month age group: PCV7/PPV23 (age: 12, 24 months)	ELISA GMC (µg/ml)	2-month age group	28													GMC data not available for 12-month age group	[45]
		Pre-vac		–	0.11	–	0.18	–	–	–	–	–	–	–	–
		7 months		–	4.11	–	6.09	–	–	–	–	–	–	–	–
		25 months		–	25.49	–	19.71	–	–	–	–	–	–	–	–
SCD O’Brien et al. (2000) (USA) NC, PV Schedule A: PCV7/PCV7/PCV7/PPV23 (age: 2, 4, 6, 24 months) Schedule B: PCV7/PPV23 (age: 12, 24 months) Controls received Schedule A or B without PPV23	ELISA GMC (µg/ml)	Schedule A														^ap < 0.05, pre-vac SCD vs 1 month post-dose 3 SCD for all serotypes; ^bp < 0.05, pre-vac SCD vs before PPV23 SCD for all serotypes; ^cp < 0.05, 1-month post-dose 3 SCD vs before PPV23 SCD for all serotypes; ^Ap < 0.05, pre-vac SCD vs non-SCD; ^Bp < 0.05, 1-month post-dose 3 SCD vs non-SCD; ^Cp < 0.05, pre-vac SCD vs 1-month post-PCV7 for all serotypes; ^Dp < 0.05 before PPV23 vs 1-month post-PPV23 for all serotypes; ^Ep < 0.05, 1-month post-PCV7 vs before PPV23	[46]
		SCD
		Pre-vac^a,b	33	0.05^A	0.10^A	0.13^A	0.20	0.13	0.23^A	0.12^A	–	–	–	–	–
		Post-dose 3^a,c	31	2.67	4.03	2.26	5.93	3.10^B	6.08^B	5.2	–	–	–	–	–
		Before PPV^b,c	25	0.68	1.63	0.46	1.91	0.65	2.59	0.85	–	–	–	–	–
		Post PPV	23	15.04	24.64	9.29	18.02	16.33	44.19	13.77	–	–	–	–	–
		Controls (non-SCD)
		Pre-vac	11	0.15^A	0.38^A	0.44^A	0.51	0.24	0.79^A	0.31^A	–	–	–	–	–
		Post-dose 3	9	1.80	2.92	1.18	4.71	1.30^B	2.04^B	2.16	–	–	–	–	–
		Before PPV	5	0.75	0.64	0.39	1.00	0.57	1.14	0.33	–	–	–	–	–
		Post PPV	NR	–	–	–	–	–	–	–	–	–	–	–	–
		Schedule B
		SCD
		Pre-vac^C	13	0.02	0.05	0.08	0.11	0.03	0.08	0.04	–	–	–	–	–
		Post-PCV7^C	13	1.67	0.82	2.8^E	0.32^E	3.54^E	1.16	0.98	–	–	–	–	–
		Before PPV^D	11	0.64	0.44	0.64^E	2.31^E	0.41^E	2.17	0.58	–	–	–	–	–
		Post PPV^D	10	38.05	19.06	32.55	58.10	13.29	90.35	13.59	–	–	–	–	–
		Controls (non-SCD)
		Pre-vac Post-PCV7 Before PPV Post PPV	3 3 3 NR	0.03 2.20 0.83 –	0.13 0.45 1.00 –	0.18 1.59 2.32 –	0.04 2.08 2.88 –	0.03 2.62 0.90 –	0.21 2.27 3.33 –	0.9 0.55 2.00 –	– – – –	– – – –	– – – –	– – – –	– – – –
SCD Reinert 2007 (France) NC, PV PCV7/PCV7/PCV7/PPV23 (age: 2, 3, 4, 15–18 months)	ELISA GMC (µg/ml)	Pre-vac	48	0.08	0.23	0.25	0.49	0.16	0.35	0.13	–	–	–	–	–		[47]
		Post-PCV7 dose 3	45	7.81	5.93	5.23	14.76	4.59	8.15	4.55	–	–	–	–	–
		Pre-PPV23	45	0.71	1.60	0.74	3.76	0.47	1.20	0.75	–	0.02	0.14	0.26	–
		Post-PPV23	45	29.49	26.66	14.65	21.79	6.32	28.98	12.96	–	2.82	2.46	2.03	–
SCD Rivera-Olivero et al. (2014) (Venezuela) PV, NC Vaccine schedule as above	ELISA GMC (µg/ml)	Pre-vac Post-vac	22	0.53 4.63	1.8 5.28	0.73 4.68	3.14 17.16	0.71 4.54	2.59 6.81	1.03 5.93	– –	– –	– –	– –	– –		[89]
Asplenic adults
Asplenia Meerveld-Eggink et al. (2011) (The Netherlands) NC, PV PCV7/PCV7/PPV23 (0, 6 weeks, 6 months)	ELISA GMC (µg/ml)	Pre-vac	54	0.6	1.1	1.3	6.2	1.9	2.6	1.3	–	–	–	–	–	p values for comparisons with previous timepoints: ^ap<0.01; ^bp = 0.02; ^Ap = 0.03 for prior PPV23 vs no previous vaccination; ^Bp = 0.004 for prior PPV23 vs no previous vaccination; ^Cp = 0.02 for prior PPV23 vs no previous vaccination; *3 weeks post-full-vaccination (PCV/PCV/PPV)	[43]
		Post-dose 1	54	1.7^a	3.0^a	4.8^a	12.7^a	5.6^a	4.7^a	6.8^a	–	–	–	–	–
		Post-dose 2	54	2.0^a	4.5	4.7	12.2	5.6	5.4	9.1	–	–	–	–	–
		Post-PPV23	54	2.1	3.8	4.1^b	14.7	4.1	5.9	10.7	–	–	–	–	–
		No previous vac	13
		Pre-vac		0.36	0.67	0.78	3.89	0.89	1.77	0.71	–	0.39	0.10	–	0.58
		Post-vac*		2.36	4.5	5.21	9.74	2.26	4.55	6.89	–	0.68	0.19	–	0.74
		Prior PPV23
		Pre-vac	41	0.69	1.30	1.49	7.16	2.44^A	2.92	1.55	–	1.41	0.37^B	–	1.45
		Post-vac*		2.08	3.57	3.81	16.6	4.97	6.37	12.2	–	2.60	0.86^C	–	3.36
Asplenia Stanford et al. (2009) (UK) NC, RV PCV7 (one dose)/PPV23 (6 months), if not received within previous 5 years	ELISA GMC (µg/ml)	Pre-PCV7	109	1.10	1.67	1.48	8.18	3.75	3.11	1.78	–	1.27	–	2.03	–	Significant difference (p < 0.01) for all PCV7 serotypes for pre-vac vs post-vac. No significant differences for pre- and post-PCV7 for serotypes 1 and 5 In patients who had not previously received PPV23, differences in Ab concentrations were not significantly different following PPV23 compared with post-PCV7	[44]
		Post-PCV7	111	2.68	3.96	3.30	13.88	7.68	4.73	6.61	–	1.25	–	1.96	–
		Patients requiring PPV23 following PCV7
		Pre-PCV7	31	1.05	1.26	1.43	5.23	3.4	2.33	1.76	–	1.13	–	2.48	–
		Post-PCV7	33	2.63	2.74	3.26	11.28	6.64	3.67	5.58	–	1.10	–	1.99	–
		Pre-PPV23	31	1.65	2.08	2.16	7.55	4.70	2.96	4.23	–	0.98	–	2.19	–
		Post-PPV23	33	2.78	2.79	3.31	12.76	6.04	6.16	4.58	–	1.99	–	3.66	–
		Number of prior PPV23 doses
		One dose	71	2.60	3.23	3.25	15.25	6.88	4.06	5.71	–	1.32	–	2.21	–
		Two doses	25	0.71	4.67	2.22	6.85	8.62	5.58	7.71	–	0.96	–	1.60	–
		Three doses	12	3.45	9.07	5.84	24.45	9.03	8.61	9.79	–	2.12	–	2.26	–
		No doses	3	1.88	4.64	13.08	53.7	21.38	4.07	12.4	–	0.36	–	0.37	–
Asplenic children and adults
Asplenia Orthopoulos et al. (2009) (Greece) C, RV PCV7/PCV7/PPV23 (0, 1, 12 months) OR PCV7/PPV23/PPV23 (0, 1, 12 months)	ELISA GMC (µg/ml)	Group A: PCV/PPV/PPV	17													Significant difference between 2 months and 1 month for serotype 23F (group B) only Significant difference between 13 and 12 months for serotype 6B (group B) and 19F (group B)	[32]
		Baseline		–	6.3	5.7	12.8	–	9.4	4.5	–	–	–	–	–
		2 months		–	26.2	12.4	16.2	–	16.5	13.1	–	–	–	–	–
		13 months		–	17.2	9.2	16.7	–	7.4	6.7	–	–	–	–	–
		Group B: PCV/PCV/PPV	18
		Baseline		–	4.5	5.9	10.2	–	6.1	5.6	–	–	–	–	–
		2 months		–	18.8	12.6	22.2	–	10.2	23.7	–	–	–	–	–
		13 months		–	14.5	7.8	19.2	–	9.2	11.8	–	–	–	–	–
SCD Vernacchio et al. (2000) (USA) C, PV PCV7/PCV7/PPV23 (0, 8, 16 weeks) or PPV23 (one dose)	OPA GMT	PCV7/PCV7/PPV23	11													Significant differences between PCV7 and PPV23 groups in post-vac OPA GMT for serotypes 6B (p = 0.02), 14 (p = 0.05), 18C (p = 0.004), 19F (p = 0.009), and 23F (p = 0.0001) For ELISA GMC, significantly different post-vac GMCs for serotypes 14 (p = 0.04) and 19F (p = 0.02) only	[33]
		Post-vac		–	962	–	1810	512	290	659	–	–	–	–	–
		PPV23	12
		Post-vac		–	42.7	–	215	12.7	30.2	6	–	–	–	–	–
	ELISA GMC (µg/ml)	PCV7/PCV7/PPV23	11
		Post-vac		–	–	–	21.8	–	16.7	–	–	–	–	–	–
		PPV23	12
		Post-vac		–	–	–	5.16	–	4.10	–	–	–	–	–	–
Immunocompetent children
Asthma Rose et al. (2006) (Germany) C, PV PCV7 or PPV23 (one dose)	ELISA GMC (µg/ml)	PCV7	23													Serotypes 14 (p < 0.01) and 23F (p < 0.05) showed significantly stronger increases in GMC in the PCV7 group than in the PPV23 group	[57]
		Pre-vac		0.29	0.42	0.45	0.87	0.42	1.05	0.53	–	–	–	–	–
		Post-vac		1.39	0.98	1.34	2.75	1.48	2.71	1.23	–	–	–	–	–
		PPV23
		Pre-vac	38	0.35	0.29	0.41	0.66	0.29	0.75	0.25	–	–	–	–	–
		Post-vac		1.32	0.63	1.47	1.26	1.17	2.86	0.56	–	–	–	–	–
Asthma Rose et al. (2009) (Germany) NC, PV PCV7/PPV23 (0 + 2 or 10 months)	ELISA GMC (µg/ml)	Group A (2-month dosing interval)	36													Group A: Significant difference between visit 1 (pre-vac) and visit 2 (post-PCV7, 2 months) for serotypes 4 (p < 0.001), 6B (p < 0.01), 18C (p < 0.001), 19F (p < 0.001), and 23F (p < 0.01)	[39]
		Pre-PCV7		0.20	0.25	–	0.69	0.22	0.60	0.21	–	–	–	0.57	0.51
		Post-PCV7		3.04	1.01	–	2.3	2.87	2.72	1.37	–	–	–	0.66	0.64
		Group B 10-month dosing interval)	34													Group B: Significant difference between visit 1 (pre-vac) and visit 2 (post-PCV7, 2 months) for serotypes 4 (p < 0.001), 6B (p < 0.01), 18C (p < 0.001), 19F (p < 0.05), and 23F (p < 0.05)
		Pre-PCV7 Post-PCV7 Post-PPV23		0.19 3.09 14.9	0.27 1.44 4.43	– – –	0.65 2.67 16.5	0.19 3.75 10.1	0.58 2.58 10.4	0.25 2.57 4.84	– – –	– – –	– – –	0.50 0.53 2.54	0.43 0.51 1.95
Chronic lung disease Navarro et al. (2006) (Spain) NC, PV Aged <2 years: PCV7 (3 + booster doses; 2, 4, 6, 12–24 months) Aged >2 years: PCV7 (one dose)	ELISA GMC (µg/ml)	Vaccinated at study entry	14													Exact timings for timepoints not defined	[38]
		Time 0		0.70	1.90	1.00	2.40	1.60	6.57	0.80	–	–	–	–	–
		Time 1		12.3	16.6	11.5	39.9	10.6	16.8	11.4	–	–	–	–	–
		Time 2		2.30	12.5	3.70	8.40	3.60	4.50	5.10	–	–	–	–	–
Chronic lung disease Rivera-Olivero et al. (2014) (Venezuela) PV, NC Vaccine schedule as above	ELISA GMC (µg/ml)	Pre-vac Post-vac	9	3.30 3.26	0.77 3.66	0.52 3.25	1.87 10.47	1.08 2.25	2.62 5.64	1.45 4.90	– –	– –	– –	– –	– –		[89]
Chronic heart disease Rivera-Olivero et al. (2014) (Venezuela) PV, NC Vaccine schedule as above	ELISA GMC (µg/ml)	Pre-vac Post-vac	19	0.69 4.44	1.24 4.55	0.85 3.61	3.92 17.67	0.74 3.00	1.74 4.99	1.12 4.90	– –	– –	– –	– –	– –
Chronic kidney disease Rivera-Olivero et al. (2014) (Venezuela) PV, NC Vaccine schedule as above	ELISA GMC (µg/ml)	Pre-vac Post-vac	9	ND ND	0.80 3.55	0.38 3.42	1.15 7.90	0.24 3.13	1.36 4.31	0.18 2.96	– –	– –	– –	– –	– –
Cochlear implant Rose et al. (2004) (Germany) C, PV PCV7 or PPV23 (one dose)	ELISA GMC (µg/ml)	Group A1 (PCV7)	10													A1 = patients aged <2 years; A2 = aged 2–5 years; A3 = aged >5 years A1, significant differences between pre-vac and post-vac for all serotypes (p < 0.05); A2, significant differences between post-vac timepoints for PCV7 and PPV23 for all serotypes except 9V and 14 (p < 0.05); A3, significant differences between pre-vac and post-vac for all serotypes (p < 0.001)	[59]
		Pre-vac		0.2	0.2	0.2	0.4	0.1	0.3	0.2	–	–	–	–	–
		Post-vac		2.6	1.4	2	3.6	1.6	5.1	2.7	–	–	–	–	–
		Group A2
		PCV7	26
		Pre-vac		0.3	0.5	0.5	0.5	0.3	0.7	0.5	–	–	–	–	–
		Post-vac		2.8	2.1	2.9	3.6	3.2	7.7	3.2	–	–	–	–	–
		PPV23	12
		Pre-vac		0.2	0.3	0.3	0.5	0.2	0.5	0.2	–	–	–	–	–
		Post-vac		2.1	0.5	2.5	2.1	2.3	3.3	0.5	–	–	–	–	–
		Group A3 (PPV23)	120
		Pre-vac		0.6	1.0	0.7	1.2	0.8	2.8	0.7	–	–	–	–	–
		Post-vac		2.9	3.3	3.7	7.0	2.7	7.4	3.0	–	–	–	–	–
Immunocompetent adults
Chronic lung disease Dransfield et al. (2012) (USA) C, PV PCV7 or PPV23 (one dose)	ELISA GMC (µg/ml)	All patients														^aSignificant difference between PCV7 and PPV23 groups (p-values not provided)	[58]
		PCV7	91
		Pre-vac		0.28	0.90	0.78	2.53	1.07	3.01	0.74	–	–	–	–	–
		+1 month		1.95^a	3.19	4.87^a	15.73	9.65^a	7.54	7.76^a	–	–	–	–	–
		PPV23	88
		Pre-vac		0.30	0.89	0.83	2.59	1.16	3.20	0.58	–	–	–	–	–
		+1 month		0.74^a	2.26	2.72^a	10.8	4.25^a	6.79	1.88^a	–	–	–	–	–
		Vaccine-naive
		PCV7	45
		Pre-vac		0.23	0.92	0.74	1.67	0.71	3.23	0.55	–	–	–	–	–
		+1 month		1.88^a	3.96	6.32^a	20.18	13.73^a	8.13	10.86^a	–	–	–	–	–
		PPV23	41
		Pre-vac		0.26	0.95	0.67	2.57	1.02	3.22	0.47	–	–	–	–	–
		+1 month		0.73	2.38	2.48	12.76	4.92	6.50	1.62	–	–	–	–	–
		Prior PPV23 vaccine
		PCV7	46
		Pre-vac		0.34	0.88	0.83	3.80	1.60	2.81	0.98	–	–	–	–	–
		+1 month		2.01^a	2.58	3.77	12.34	6.84	6.99	5.58^a	–	–	–	–	–
		PPV23	47
		Pre-vac		0.33	0.85	1.00	2.60	1.31	3.18	0.70	–	–	–	–	–
		+1 month		0.75	2.16	2.93	9.40	3.77	7.05	2.12	–	–	–	–	–

Ab: Antibody; ART: Antiretroviral therapy; C: = Comparative; CLL: Chronic lymphocytic leukemia; conc: Concentration; FEV1: Forced expiratory volume in 1 second; FVC: Forced vital capacity; GMC: Geometric mean antibody concentration(s); GMT: Geometric mean titer(s); HC: Healthy controls; IPD: Invasive pneumococcal disease; LBW: Low birth weight; M+/I−: HIV-negative infants born to HIV+ mothers; M−/I−: HIV− infants born to HIV− mothers; MTX: Methotrexate; NBW: Normal birth weight; NC: Non-comparative; ND: Not determined; NR: Not reported; NS: Non-significant; NSAID: Non-steroidal anti-inflammatory drugs; OPA: opsonophagocytic assay; PLA: Placebo; PPV23: 23-valent pneumococcal polysaccharide vaccination; pre-vac: pre-vaccination; post-vac: Post-vaccination; PV: Primary vaccination; RA: Rheumatoid arthritis; RV: Revaccination; SCD: Sickle cell disease; SD: Standard deviation; SpA: Spondylarthropathy; URTI: Upper respiratory tract infection.

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