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

Abstract

The use of pneumococcal conjugate vaccine (PCV) in childhood pneumococcal immunization programs successfully reduced the incidence of pneumococcal disease in children. Nonetheless, there remains a high burden of pneumococcal disease in adults, especially the elderly, and children/adults with chronic medical conditions. Two pneumococcal vaccines are currently available for adults at risk of pneumococcal disease: the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the more recently licensed PCV13. As it is not possible to determine vaccine efficacy in all populations at risk of pneumococcal disease, immunogenicity studies, measuring pneumococcal-specific antibody concentrations and/or the opsonophagocytic activity of serum can provide valuable comparative data for PPV and PCV immunization. This article provides consolidated data on the immunogenicity of PCVs (largely PCV7, and a few studies with PCV9 or PCV13) based on a review of immunogenicity/safety studies in populations (mainly pediatric) at increased risk of pneumococcal disease.

Keywords:

• ELISA
• immunocompromised
• immunogenicity
• opsonophagocytic activity
• PCV
• risk group
• vaccination schedule

Streptococcus pneumoniae (pneumococcus) is a leading cause of serious illness and death worldwide, with invasive manifestations including sepsis, meningitis and bacteremic pneumonia [1–3]. The successful use of pneumococcal conjugate vaccine (PCV7) (comprising serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) in childhood pneumococcal immunization programs worldwide has led to a reduced frequency of vaccine-type invasive pneumococcal disease (IPD) in vaccine-eligible children (aged <2 or <5 years, depending on the study) [4,5]. Nevertheless, there remains a high burden of pneumococcal disease, primarily pneumococcal community-acquired pneumonia in adults, especially the elderly (aged >65 years) [2,6,7] and in individuals of all ages with certain medical conditions [8,9]. These conditions include chronic heart, hepatic or pulmonary disease, and diabetes mellitus, in immunocompetent individuals; immunosuppression due to acquired immunodeficiency syndrome or other conditions or to treatments that increase risk, including malignancies (solid tumor or hematologic) or transplantation (stem cell or organ); or asplenia, including sickle cell disease [8,10–13]. There are also data suggesting that children with asthma characterized as chronic and/or with recurrent exacerbations, despite optimal treatment, are at increased risk of IPD, although many health authorities consider asthma to be a risk factor only in children receiving oral corticosteroid therapy [14].

Until 2011, the 23-valent pneumococcal polysaccharide vaccine (PPV23) was the only vaccine licensed for active pneumococcal immunization in adults at risk of pneumococcal disease [15]. PCV13 (Prevenar 13^®, Pfizer; comprising serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) has been licensed in Europe since 2011 for adults aged ≥50 years, with the indication expanded in 2013 to include children and adults aged 6–49 years. PCV13 is indicated in Europe for the prevention of IPD, pneumonia and acute otitis media (AOM) caused by S. pneumoniae in infants and children from 6 weeks up to the age of 17 years, and for the prevention of IPD and pneumonia caused by S. pneumoniae in adults aged ≥18 years [16]. In the USA, PCV13 is indicated for the prevention of IPD and AOM in children aged 6 weeks to ≤5 years, for the prevention of IPD in those aged 6–17 years and for the prevention of IPD and pneumonia in those aged ≥50 years of age [17]. PCV13 is also available for use in adults in other countries worldwide, such as Argentina, Australia, Brazil, Indonesia, Malaysia, Philippines and Russia, with vaccination age for routine cohorts and at-risk group recommendations differing between countries. PCV10 (Synflorix^®, GlaxoSmithKline; comprising the additional serotypes: 1, 5, and 7F) is also available in many countries for active immunization against IPD, AOM and pneumonia in infants and children from 6 weeks up to 5 years of age [18].

Pneumococcal vaccination for children and adults at risk of pneumococcal disease is recommended in many countries, as exemplified by Europe [19,20]. Administration of PPV23 above the age of 2 years is recommended following PCV vaccination, to broaden serotype coverage [11,21]. PPV23 should be administered at least 2 months following PCV vaccination [22]. Evidence for the effectiveness of PPV23, including against IPD in adults with chronic illnesses or for the prevention of all-cause pneumonia in the general population, was reviewed in 2013 [23].

Given that the clinical trials to establish vaccine efficacy do not include all possible variations (e.g., by age group, by risk group, by schedule or by concomitant vaccine[s]), available safety and immunogenicity study data may be acceptable as comparative evidence. The WHO has provided a standardized ELISA protocol to ensure comparable results within and between laboratories with respect to the quantification of S. pneumoniae serotype-specific human IgG antibodies following PCV immunization [24]. The WHO ELISA protocol includes an absorption stage prior to the ELISA assay to inhibit the binding of non-specific antibodies in serum samples to serotype-specific pneumococcal polysaccharide. Originally, this involved a single pre-adsorption step with pneumococcal C-polysaccharide (C-PS), but the protocol now includes pre-adsorption with both C-PS and 22F polysaccharide. This protocol also specifies a standard human antipneumococcal reference serum (89-SF).

The responses by ELISA antibody concentration following a primary series vaccination in young children have been used to determine a correlate of protection against IPD, but are only applicable to pediatric populations. The IgG ELISA also does not take into account other isotypes such as IgM [25]. The WHO has recommended measuring opsonophagocytic activity of serum (OPA, also referred to as opsonophagocytic killing, OPK) to corroborate the functional activity of ELISA antibodies [26]. As OPA is posited to mimic natural host immune responses, it may act as a surrogate marker for vaccine efficacy [25]. Serum OPA can be assessed in vitro using a phagocytic cell line in the presence of a complement source and measuring the killing of a specific serotype of S. pneumoniae [27]. However, there is currently no standardized protocol for OPA, and no correlate of protection has been established for adults.

We performed a literature review of publications of immunogenicity and safety trials worldwide of PCVs in populations that are at higher risk of pneumococcal disease than the general population due to underlying chronic or immunocompromised conditions, to document immunogenicity as well as to provide a comprehensive summary of the methodologies used in these trials. The studies reviewed included both single-arm (non-comparative) and those that compared PCV with PPV23.

Search methodology & publication selection

This review was based on peer-reviewed articles rather than conference abstracts. A search of the PubMed database was conducted using the search term ‘PCV’. Search results were limited to papers published between 1 January 1999 and 1 July 2014. Papers were identified for inclusion in the review if they were published in a European Union language, and they reported immunogenicity data following immunization with a PCV in adults or children defined as being at elevated risk for pneumococcal infections. The following immunocompetent risk-group categories were included in the initial search and selection process: chronic or cyanotic heart disease; chronic liver or renal disease; chronic respiratory or lung disease (e.g., cystic fibrosis, bronchopulmonary dysplasia, recurrent pulmonary infections, chronic/severe asthma); pre-organ transplant recipients; central nervous system malformations, cerebrospinal leaks or liquor shunt; cochlear implant recipients; metabolic disease (e.g., diabetes); care home resident/permanent institutional care because of illness; smoking/exposure; alcoholism; and previous IPD. Children and adults with asplenia were also included. A range of individuals (of all ages) who were immunocompromised were represented: those with congenital or primary immunodeficiency (e.g., agammaglobulinemia, severe combined immunodeficiency, common variable immune deficiency, complement [C] deficiency [particularly early component deficiencies: C1, C2, C3, C4]); secondary immunodeficiency (e.g., HIV); nephrotic disease; bone marrow, hematopoietic stem cell and solid organ transplant recipients; neoplastic disease (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, lymphomas, leukemias, other diseases of the blood-forming organs); malignancies (immunosuppression due to malignancy or treatment); iatrogenic immunosuppression and chromosomal aberration (e.g., Down syndrome). Down syndrome and low birth weight were both classified as immunocompromising conditions. Down syndrome is associated with defects in the adaptive and innate immune system, and as a consequence these individuals may have a lower response to vaccines [28]. Children with low birth weight have a greater risk of pneumococcal disease in early life compared with full-term, age-matched children, possibly due to an immune system that has not completely matured and lack of maternal antibodies [29].

During the selection process, trials measuring vaccine immunogenicity outside a 4- to 8-week post-vaccination period were excluded, as were those not reporting geometric mean concentration or titer (GMC or GMT) values for ELISA or OPA and/or those only reporting the ratio of pre- to post-vaccination antibody concentrations and/or responder rates based on fold-rises in antibody concentrations. Publications were also excluded if they were interim analyses, sub-studies or follow-up studies, if there was only partial randomization, or the data were not split into separate vaccine groups. Only those publications reporting immunological data from PCV formulations that led to licensure were selected, and thus studies of investigational PCV formulations were excluded.

Immune response data (GMC for ELISA and GMT for OPA) from the selected publications have been tabulated within this review, where available. Reactogenicity and safety findings from these publications have also been summarized.

Results

In total, 3152 references were identified, of which 3057 were excluded on the basis of their title or abstract. Of the remaining references, 95 reported immunogenicity data for commercially available PCVs in children and/or adults at high risk of pneumococcal infection, while 61 of these articles (58 separate trials) met the inclusion/exclusion criteria (Figure 1) and are summarized within this review.

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

Overview of included clinical trials

Table 1 provides an overview of the trials included in this review. Only 13 of the 58 trials were comparative; the other 45 were non-comparative and, with the exception of one trial of PCV9 [30] and one trial of PCV13 [31], all evaluated PCV7. Twenty-eight studies were conducted in children, 21 in adults and 9 in both children and adults. The studies involved individuals with a variety of at-risk conditions, with the HIV risk factor accounting for 15 of the 58 trials.

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.

Comparative trials

PCV7 was compared with PPV23 in 13 trials; seven involved vaccine-naive children and/or adults, five involved children and/or adults who had previously received PPV23 and one involved both vaccine-naive and pre-vaccinated adults. Most (10/13) of these comparative trials involved asplenic or immunocompromised children and/or adults, and the majority (8/13) compared one dose of PCV7 with one dose of PPV23. In one study, the effect of sequential PCV7 and PPV23 vaccination schedules, PCV7/PCV7/PPV23 versus PCV7/PPV23/PPV23, on PCV-induced immunologic priming was assessed in asplenic children and adults with β-thalassemia (i.e., two doses of PCV7 at 0 and 1 month followed by a final PPV23 dose at 12 months [PCV7/PCV7/PPV23] vs one dose of PCV7 at 0 month followed by two doses of PPV23 at 1 and 12 months[PCV7/PPV23/PPV23]) [32]. Similarly, PCV7/PCV7/PPV23 (administered at 0, 8 and 16 weeks) was compared with a single dose of PPV23 in children and adults with sickle cell disease [33]. The immunogenicity of PCV7/PPV23 was evaluated in two trials that involved adults with HIV infection and in one trial involving adult renal transplant recipients: one trial (in HIV-infected adults) included the administration of placebo (PCV7/PPV23 vs PCV7/PCV7 or placebo/PPV23 or placebo/placebo), the other HIV trial compared PCV7/PPV23 with PPV23 alone, and the trial in renal transplant recipients compared PCV7/PPV23 with PPV23/PPV23 [34–36].

Non-comparative trials

Of the 45 non-comparative trials, 32 assessed primary vaccination and 9 assessed PPV23/PCV7, the PPV23 administered within the past 5 years in children and/or adults with immunocompromising conditions (e.g., chronic kidney disease or asplenia). Another four trials, all of which involved asplenic or otherwise immunocompromised children or adults, included previously vaccinated individuals as well as vaccine-naive individuals. A variety of vaccination schedules was used across the non-comparative studies. Within immunocompetent children, these schedules included PCV7/PCV7 administered 2 months apart in children with chronic kidney disease [37]; a 3 + 1 PCV7 schedule (at 2, 4, 6, 12–24 months of age) in children with chronic or recurrent lung disease <2 years of age, or one dose of PCV7 in those aged >2 years [38] and PCV7/PPV23 (2- or 10-month dosing interval) in children with asthma [39]. Within trials of individuals infected with HIV, vaccination schedules ranged from one dose of PCV7, either in previously vaccinated or unvaccinated adults and children [40,41], through to three PCV7 doses at 8-week intervals, followed by a booster PCV7 dose at 15 months and then PPV23 at 24 months in infants with HIV infection [42]. PCV7 (one to three doses) was administered prior to PPV23 in all but one of the trials involving children and/or adults with asplenia (including those with sickle cell disease) [32,43–47]. One dose of PCV13 was administered to adults with β-thalassemia who had previously received PCV7/PPV23 [31]. In most (4/5) of the trials of stem cell transplant recipients (children and/or adults), PCV7 was administered as three or four doses [48–51]; in 2/5 trials PCV7 administration was followed by a final PPV23 vaccination [49,52]. Solid organ recipients (children or adults) in three trials also received PCV7 (one to two doses) [53–55], followed by PPV23 [53–55].

Variability in immunologic assessments

An overview of the immunogenicity methodology used in the 58 trials included in this review is presented in Table 2. All 58 trials reported pneumococcal antibody concentrations as measured by ELISA, 33 of which used the WHO protocol (utilizing absorbent containing C-PS and/or 22F capsular polysaccharide and standard human antipneumococcal reference serum). The majority of the trials (n = 47) presented antibody concentrations as GMC values, including 41 trial publications that provided tabulated GMC data (summarized in Table 3). In addition, 52 trials reported serotype-specific and/or overall response rates based on thresholds and/or fold-rises; these response rates were based on antibody concentration thresholds in 29 trials, on fold-rises in eight trials and on combined thresholds and/or fold-rises in 15 trials. Nineteen of 58 studies used an antibody concentration threshold of ≥0.35 µg/ml, which the WHO recommends as a correlate of protection (applied 1 month after the final doses of the primary series) for the licensure of new PCVs for children. Thirteen of the trials reported OPA data, with five of these trials using a ≥1:8 responder criterion and seven reporting tabulated GMT OPA data (Table 2).

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.

In this review, we have focused on GMCs for ELISA and GMTs for OPA data rather than response rates because there are no established correlates of protection for adults and immunocompromised individuals. There was wide variability in the protective response criteria applied in the trials identified in this review (Table 2). One of the most frequently applied, the WHO-recommended threshold of 0.35 µg/ml, is a licensing criterion applied to a population of vaccinated individuals that was derived from pediatric data and thus is not applicable to other populations [52].

Immunogenicity of PCVs

Overview

PCV7 was immunogenic, as assessed by ELISA and/or OPA, for the risk groups included in this review, with the exception of one trial in children and adults with ataxia-telangiectasia (A-T) (Table 3) [56]. There was also evidence of improved immunogenicity from PCV7 compared with PPV23. Six of the 11 comparative trials with tabulated ELISA data demonstrated significantly greater increases in GMC values (or fold-rises) between pre-vaccination and post-vaccination assessments with PCV7 than with PPV23 for ≥2 serotypes [33–35,57–59], whereas in three trials, PPV23 was as immunogenic as PCV7 (two trials) or PCV7/PPV23 (one trial) [32,36,60]. For two of the four comparative trials reporting OPA data, PCV7 generated significantly greater OPA response than PPV23 [33,58].

HIV, transplantation and asplenia (including sickle cell disease) accounted for majority of the risk groups assessed in trials in this review, and thus are the focus of the following sections.

Human immunodeficiency virus

Trials in HIV-infected individuals varied in terms of design, vaccination schedules and population (i.e., children or adults; previously vaccinated or vaccine-naive); however, PCV7 was generally found to be immunogenic.

Two trials in adults with HIV compared PCV7 with PPV23 primary vaccination [34,35]. Felkin et al. compared the following two-dose vaccination sequences, PCV7/PCV7, PCV7/PPV23, placebo/PPV23 and placebo/placebo, all administered 8 weeks apart, in HIV-infected adults using ELISA and OPA measurements [34]. Eight weeks following the second vaccination, significantly greater antibody concentrations were observed in adults receiving PCV7/PCV7 (serotypes 4, 6B, and 9V) or PCV7/PPV23 (serotype 23F) than in those receiving placebo/PPV23 (p <0.05). OPA responses in these two study groups were also significantly greater than in those receiving placebo/PPV23 (PCV7/PCV7, serotypes 4, 6B, 9V; PCV7/PPV23, serotypes 9V and 23F) (p <0.05). PCV7/PCV7 or PCV7/PPV23 (administered 8 weeks after the first dose of PCV7) provided no additional increase in antibody concentration or OPA beyond that observed after the first dose of vaccine. In this PCV study in HIV-infected adults, vaccine-specific immunologic response did not appear to be affected by CD4 counts, degree of virologic control or use of highly active antiretroviral therapy (HAART). In a separate study, also in HIV-infected adults, PCV7/PPV23 (PCV7 followed 4 weeks later by PPV23 vaccination) resulted in significantly greater antibody concentrations for 6 of 7 serotypes (4, 9V, 14, 18C, 19F, and 23F) than with PPV23 alone [35].

In a study conducted before the introduction of antiretroviral therapy (ART), primary vaccination with a single dose of PCV7 also resulted in significant increases in IgG GMCs and OPK titers (for serotypes 4 and 14) 2 months post-vaccination in both HIV-infected and HIV-uninfected adults, with serotype 14 IgG levels and OPK titers being dependent on CD4⁺ cell counts in the HIV-infected adults [61]. In a trial demonstrating that zinc or vitamin A supplementation had no effect on immune response to PCV7, significant fold-rises in IgG GMCs for all PCV7 serotypes were observed in a HIV-infected adult population, most of whom were not receiving HAART [62]. Also, in both these trials, PCV7/PPV23, with the PPV23 administered 2 [61] or 6 months [62] following PCV7, did not increase IgG concentrations beyond those observed post-PCV7. A single dose of PCV7 was also shown to be immunogenic 1 month post-vaccination in HIV-infected (none receiving ART) and HIV-uninfected adults within a placebo-controlled trial [40]. A more recent trial in pneumococcal vaccine-naive HIV-infected adults, in which data were provided only as response rates, found that the immunogenicity of a single dose of PCV7 or PPV23 was improved by delaying vaccination until after reconstitution of the immune system (i.e., CD4 count >200 cells/mm³) (data not shown) [63]. Within this trial, no differences were observed between the immunogenicity of the two vaccines.

The effect of HAART on the immune response to PCV7/PCV7/PPV23 (two doses of PCV7 administered 3 months apart, followed by PPV23 administered 6 months later) in HIV-infected adults has also been evaluated in an observational cohort study (a pre-planned sub-study of Søgaard et al. [64]) [65]. There was some variability in antibody IgG GMC values between HAART-treated adults and those not receiving HAART (both following the second PCV7 and the PPV23 dose), although these differences were non-significant: GMC values for serotypes 9V, 14 and 18C tended to be higher in HAART-treated adults, while those for serotype 6B were lower. PPV23 vaccination did not increase IgG GMCs beyond those observed 1 month following the second PCV7 dose. OPA GMTs (1 month following the second PCV7 dose) were significantly greater among those who received HAART than in those who were HAART-naive (serotypes 14, 19F, and 23F), and these differences remained significant following adjustment for baseline CD4⁺ cell count. PPV23 vaccination increased OPA titers for serotypes 6B, 19F and 23F to above those found after the second PCV7 dose.

In a comparison of PCV7/PCV7 with PPV23/PCV7/PCV7, past administration (42–79 months previously) of PPV23 was not shown to affect the immune response of two doses of PCV7 (administered 4 weeks apart) in HIV-infected adults [66]. In both groups, significant increases in IgG GMCs were observed for all serotypes after the first PCV7 dose (p <0.01) and for all serotypes except 14 and 9V after the second dose, independent of whether individuals had a past history of PPV23 or no previous vaccination.

The immunogenicity of primary PCV vaccination has also been demonstrated in children with HIV infection [30,42,67,68]. In a placebo-controlled trial, Madhi et al. evaluated a primary vaccination with PCV9 (administered at 6, 10 and 14 weeks of age) in HIV-infected (mostly not receiving ART) and HIV-uninfected infants [30]. In both HIV-infected and HIV-uninfected groups, they found significantly greater IgG GMCs in PCV9-vaccinated children than in placebo recipients for all nine serotypes following the third PCV9 dose. However, HIV-uninfected infants had a superior functional response as demonstrated by the proportion of infants with a measurable OPA titer (≥1:8) for the three serotypes (6B, 19F and 23F) studied. In a follow-up trial [41], these children received a single PCV7 dose 5 years following the primary (PCV9 or placebo) vaccination series. After the PCV9 primary series, the immune response to PCV7 was lower in HIV-infected than in HIV-uninfected children. Following the PCV7 booster, HIV-infected children (both the PCV9 and placebo recipients) were less likely to have OPA responses than HIV-uninfected children, suggesting that HIV-infected vaccinees experienced a partial loss of anamnestic responses to PCV priming.

Madhi et al. [68] have also evaluated the effect of timing of ART in HIV-infected children on immune responses to a primary series of PCV7 (three doses administered at 6–12, 9–18, and 12–24 weeks of age), as well as the effect of perinatal HIV exposure in HIV-uninfected infants. Antibody concentrations were similar between HIV-infected infants receiving ART (HIV+/ART+) and HIV-infected infants not receiving ART (HIV+/ART−). Surprisingly, antibody concentrations were lower in HIV-uninfected infants born to HIV-seronegative mothers (M−/I−) than in HIV-uninfected infants born to HIV-infected mothers (M+/I−) (significant differences only observed for serotypes 6B and 23F). However, M−/I− infants had superior OPA responses compared with those in HIV+/ART− infants (p <0.01), and better OPA responses were observed in HIV+/ART+ than in HIV+/ART− infants (p <0.05). A more recent publication reporting the secondary end points from this trial has demonstrated similarity between the immune responses following the second and third doses of PCV7, although there were significantly higher proportions of children with antibody ≥0.35 µg/ml to serotypes 6B (all four groups) and 23F (M−/I− and HIV+/ART+ infants), and with OPA ≥8 to serotypes 23F (M−/I−, HIV+/ART− and HIV+/ART+ infants) following three doses than following two doses [69].

As with adults, PCV vaccination has been evaluated in HIV-infected children previously vaccinated with PPV23. Spoulou et al. reported greater (although non-significant) increases in GMCs in age-matched healthy controls than in children (aged 20–163 months) with symptomatic HIV infection 1 month following an initial PCV7 dose [70]. In the HIV-infected children who had previously received PPV23 (18–39 months earlier), PPV23/PCV7/PCV7, a second dose of PCV7 (administered 1 month after the first dose) failed to increase GMCs.

In contrast, Abzug et al. [71] observed incremental gains in GMCs with PCV7/PCV7/PPV23 after each vaccine dose (two doses of PCV7 followed by PPV23; all at 8-week intervals) in children aged 2 to <19 years, receiving stable HAART for ≥3–6 months, 75% of whom had received previous PPV23 vaccination. They also reported the following predictors of response: greater antibody concentration at entry, higher immune stratum (based on nadir CD4% before HAART and CD4% at screening), lower entry viral RNA, longer duration of the entry HAART regimen and age <7 years. Individuals from this study were subsequently randomized to receive one dose of PCV7 or PPV23 4–5 years after PCV7/PCV7/PPV23 vaccination (age range at revaccination: 8–22 years). This revaccination with PCV7 resulted in GMCs for serotypes 6B and 14 that were 1.5- to 3.0-fold higher than after the original PCV7/PCV7/PPV23 vaccination, whereas the GMC for serotype 1 following PPV23 was similar to that following PCV7/PCV7/PPV23 [72].

Transplantation

Findings from two trials of PCV7 vaccination in children and adults undergoing stem cell transplantation demonstrate the benefits of a PCV7 schedule administered prior to stem cell collection and then early after transplantation. PCV7 vaccination administered 6–17 days before stem cell collection improved subsequent immunological responses to a three-dose PCV7 schedule (at 3, 6, and 12 months) following transplantation compared with responses observed in those not receiving PCV7 prior to stem cell collection, with significantly greater IgG GMC values observed for three of the PCV7 serotypes (18C, 19F and 23F) following the third PCV7 dose [48].

In a separate trial, PCV7 vaccination only initiated 3 months after stem cell transplantation resulted in an immunological response similar to PCV7 vaccination initiated at 9 months following vaccination, which suggests that PCV7 can be administered early following stem cell transplantation to ensure protection against early life-threatening pneumococcal disease [49].

The immunogenicity of single doses of PCV7 or PPV23 has been compared in adult renal transplant recipients based on both ELISA and OPA. PCV7 vaccination resulted in a significantly greater fold-rise in antibody level at 8 weeks for serotype 23F [60]. However, no significant differences were observed between the two vaccines with respect to fold-rises in OPA titer. In a separate retrospective observational study, a sequential schedule of PCV7/PPV23 (administered 8 weeks apart) was evaluated in adults following heart or lung transplantation (median time lapse between transplantation and vaccination: 58.5 months) [54]. PCV7 was found to be immunogenic, as demonstrated by significant increases from baseline in GMCs for six of the PCV7 serotypes; however, IgG concentrations remained at similar levels as those post-PCV7 following subsequent PPV23 vaccination. Similarly, in a PCV7/PPV23 versus placebo trial involving adult liver transplant recipients, PCV7 resulted in significant increases in IgG GMTs compared with placebo; likewise, there were no differences between these two groups following subsequent PPV23 vaccination (administered 8 weeks later) [53].

The immunogenicity of PCV7 has been assessed in two additional trials involving pediatric solid organ transplant recipients [55,73]. Barton et al. [73] reported increases in GMCs with PCV7/PCV7/PCV7 (three doses, administered at 8-week intervals), which reached significance for serotypes 19F, 14, 6B, 23F and 9V. Following subsequent PPV23 vaccination (administered 8 weeks later), increases in GMCs were observed only for serotype 19F. Both heart or lung recipients derived additional benefit from the third dose of PCV7, whereas heart recipients demonstrated further responses to the subsequent PPV23 vaccination. In a separate case–controlled trial [55], the immunogenicity of sequential vaccination, PCV7/PCV7/PPV23 (pre-vaccination vs 6–8 weeks post-vaccination), was evaluated in children who had received solid organ (mostly heart or liver) transplants. Significant increases in IgG GMCs (except serotype 19F) were observed in the transplant group following the initial PCV7 dose, with similar GMCs observed between the transplant and control groups for serotypes 6B, 14, 18C and 19F. However, antibody concentrations in the transplant recipients did not significantly increase further following the second PCV7 dose or subsequent PPV23 dose. Heart transplant recipients were also reported to have lower antibody responses than liver transplant recipients.

Other immunocompromised risk groups

PCV7 has also been assessed in other immunocompromised risk groups, including those with arthritis, A-T, congenital or primary immunodeficiency, malignancies, Down syndrome, and low birth weight. These trials suggest that PCV7 is immunogenic in these immunocompromised children and adults, although the responses may be lower than in healthy individuals, and the immune response may be affected by immunomodulators. For example, within trials in children with juvenile idiopathic arthritis [74] and adults with chronic arthritis [75,76], a single dose of PCV7 resulted in a lower immune response in some of the children with juvenile idiopathic arthritis receiving TNF inhibitors, whereas in the adults, PCV7 immunogenicity was impaired by methotrexate, abatacept and rituximab, but not by TNF inhibitors or tocilizumab. In the adults with established rheumatoid arthritis, the immunogenicity was lower with rituximab than with abatacept and even lower when rituximab was combined with methotrexate [76]. Advanced disease activity and longer disease duration were also found to be predictors of an impaired antibody response (based on ≥twofold increase in antibody levels).

Two trials have also investigated the immunogenicity of PCV7/PCV7, with PCV7 administered as a primary dose [77] and then as a booster dose [78] (12–14 months apart), in children with idiopathic nephrotic syndrome. Each dose of PCV7 was found to be immunogenic 1 month after vaccination, with ≥94% individuals reaching the 0.35 µg/ml antibody cut-off for five or more serotypes. However, in both trials, those treated with mycophenolate mofetil and/or cyclosporine A in addition to prednisolone had a lower immune response to serotypes 4, 9V and 18C than those receiving no therapy or prednisolone-only therapy.

Conflicting findings were also observed in two trials involving children and adults with A-T. In a trial involving 14 individuals with A-T [56], significant increases in antibody GMCs (as measured by ELISA) were observed following a single dose of PCV7; however, the authors concluded that the individuals failed to produce an immune response based on their response criterion of a GMT >10 U/ml. In another trial of individuals with A-T, increases in antibody GMCs were reported for the PCV7 serotypes, although these increases were less than in healthy controls [79].

Similarly, a single dose of PCV7 produced a lower immune response in adults with chronic lymphocytic leukemia than in controls [80]. Nonetheless, the immunogenicity of PCV7 was improved by vaccinating individuals before the commencement of chemotherapy with development of hypogammaglobulinemia. The immunogenicity of PCV7/PCV7 (two doses administered 1 month apart) has also been demonstrated in children with hematological cancer or with solid tumors receiving maintenance chemotherapy, as well in those who had discontinued chemotherapy 3–12 months before vaccination [81].

A PCV7/PCV7/PPV23 schedule has also been shown to provide immunogenicity (demonstrated by ELISA and OPA) in children and adults with Down syndrome [82].

A few trials have evaluated the immunogenicity of PCV7 in infants with low birth weight [83–85]. Within a trial involving infants with low birth weight (split into two groups: birth weight <1000 or ≥1000 g), three doses of PCV7, administered at 2, 4 and 6 months of age, resulted in significant increases in PCV7 serotype antibody GMCs compared with pre-vaccination antibody concentrations, with no differences observed between the two groups [83]. Antibody concentrations increased again following a subsequent PCV7 dose at 16 months of age, with GMCs after the fourth dose being significantly greater than those following the third dose. Immunogenicity following the primary series was lowest for serotypes 6B and 23F in both groups. Similarly, infants in another trial with a birth weight ≤1000 g were found to have immune responses to all PCV7 serotypes (except 6B and 23F) following three doses of PCV7 that were similar to those in heavier premature infants, although lower birth weight as well as post-natal glucocorticoid exposure and lower current weight were found to be risk factors for poorer immunogenicity, especially to serotypes 6B and/or 23F [84]. A sub-analysis of a large PCV7 trial also found that immune response to the PCV7 serotypes did not differ significantly between infants with low birth weight and those with normal birth weight [85].

Asplenia/sickle cell disease

Prior PPV23 vaccination has been found to influence immune response to subsequent PCV7 vaccination in children and/or adults with asplenia. The immunogenicity of two vaccine strategies (PCV7/PCV7/PPV23 or PCV7/PPV23/PPV23 – first two doses administered 1 month apart followed by the third dose 12 months later) was compared in asplenic individuals (aged 12–41 years) who, historically, either had previously received PPV23 or who were PPV23-naive [32]. PCV7/PCV7/PPV23 and PCV7/PPV23/PPV23 both resulted in similar increases in antibody GMCs. However, individuals who had previously received two or more PPV23 doses had significantly lower fold-rises (baseline to 1 month) in antibody GMCs following the first dose of PCV7 for all serotypes except 6B as compared with vaccine-naive individuals (including age-matched PPV-naive, β-thalassemics), after adjusting for baseline values. Immune responses following the 12-month PPV23 dose were also inferior in those who had previously received two or more PPV23 doses historically, compared with vaccine-naive individuals. These findings are also supported by those from two other studies involving asplenic adults (the majority of whom had previously received PPV23); in these studies, increases in IgG GMCs were observed following an initial PCV dose but not following an initial PPV23 dose (Table 3) [43,44].

A separate study involving asplenic male adults with β-thalassemia who had received a PCV7 dose 7 years prior to the trial also demonstrated the ability of prior PPV23 vaccination to blunt subsequent PCV13 immunogenicity. Prior to PCV13 vaccination, antibody GMCs were >0.35 µg/ml in all individuals. Although there were significant increases in antibody concentrations for all serotypes 28 days after vaccination (data not shown), antibody concentrations (at day 28) correlated negatively with the number of previous PPV23 doses but correlated positively with the time since last PPV23 vaccination. Prior PPV23 was also found to have a negative effect on PCV13 immunological memory as measured by antigen-specific B-cell memory responses [31].

The immunogenicity of primary PCV7 vaccination (in a schedule of one to three doses followed by a final PPV23 vaccination) has also been evaluated in children with sickle cell disease [33,45–47]. In one study, Vernacchio et al. compared the sequence PCV7/PCV7/PPV23 (all administered 8 weeks apart) with PPV23-only vaccination (single dose) in children with sickle cell disease, measuring both OPA and ELISA [33]. A greater OPA response was observed with the PCV7/PCV7/PPV23 sequence than with PPV23 alone, as demonstrated by significantly greater OPA antibody GMTs for five of seven vaccine serotypes (6B, 14, 18C, 19F and 23F) after PPV23 vaccination. Antibody GMCs (as measured by ELISA) following PPV23 vaccination were significantly greater, however, for only two of seven serotypes (14 and 19F). Assessment of OPA titers showed increases following the second PCV7 dose and/or following the PPV23 dose for serotypes 4, 6B, 9V, 18C and 19F, which were not observed by ELISA.

Another trial evaluated PCV7/PCV7/PCV7/PPV23 (administered at 2, 3, 4 and 15–18 months of age) in infants with sickle cell disease [47]. Primary PCV7 immunization was found to be highly immunogenic as demonstrated by increases in GMCs throughout the PCV7 series, and the PCV7 series also primed for immune memory as indicated by increases in GMCs following the PPV23 final dose. Finally, O’Brien et al. [46] demonstrated that children with sickle cell disease achieved an immunological response that is comparable with individuals without sickle cell disease, following primary PCV7 vaccination administered according to age (infants aged <2 months: PCV7/PCV7/PCV7 at 2, 4 and 6 months; infants enrolled between 2 and 12 months of age: PCV7 at 12 months). Significant increases in antibody concentrations for the PCV7 serotypes were also observed following a final PPV23 vaccination (at 24 months), irrespective of the primary schedule. The immunological responses to pneumococcal vaccination observed in these two studies may have been due to the fact the children were not yet asplenic.

Immunocompetent risk groups

PCV7 has been evaluated in children and adults with chronic diseases (lung [including asthma] and kidney) as well as in cochlear implant recipients (Table 3). A single dose of PCV7 was compared with a single dose of PPV23 in three studies involving immunocompetent individuals (i.e., children with asthma [57] or a cochlear implant [59], and adults with chronic lung disease [58]). In each of these populations, significantly greater immune responses were observed (as demonstrated by pre- vs post-vaccination increases in antibody GMC values) in PCV7-vaccinated individuals than in those receiving PPV23 – for two serotypes (serotypes 14 and 23F [57]), for four serotypes (serotypes 4, 9V, 18C and 23F [58]), and for five serotypes (all PCV7 serotypes except serotypes 9V and 14 [59]). Within the trial of adults with chronic lung disease, PCV7 also demonstrated superior OPA response, with significantly greater OPK index values seen for five serotypes (4, 6B, 9V, 18C and 23F) 1 month post-vaccination in those receiving PCV7 compared with those receiving PPV23 [58]. Another trial compared two dosing schedules for PCV7/PPV23 vaccination in pre-school children with asthma [39]. A 10-month interval between the two vaccines was associated with significantly greater immunogenicity (GMCs for all serotypes except serotypes 5 and 7; p < 0.01) compared with a 2-month interval.

Safety of PCVs

Local and systemic reactogenicity data following PCV7 vaccination were reported in 31 of the 58 studies. Local reactions following PCV7 vaccination mostly comprised erythema, induration, pain and, in a few studies, movement impairment. Reactogenicity did not appear to increase with subsequent PCV7 doses [42,46,47], although frequencies of erythema and swelling were significantly lower after the first dose than after the third dose in a study of children undergoing stem cell transplantation [50]. Fever was the most commonly reported systemic reaction across the studies. Other systemic reactions included decreased appetite, headache, gastrointestinal reactions (nausea, vomiting and diarrhea), fatigue, myalgia/arthralgia and flu-like symptoms.

Adverse event data were reported in 30 of the 58 studies, although most focused on the likelihood of the exacerbation of the patient’s underlying chronic medical condition (e.g., organ rejection in transplant recipients). Serious adverse events after PCV7 were reported in three studies: gastroenteritis (7/49 individuals) and bronchiolitis (4/49 individuals), none of which were considered vaccine related, in infants with sickle cell disease during primary PCV7 vaccination (at 2, 3 and 4 months of age) [47]; foot infection and pneumonia (in one patient each and requiring hospitalization [relationship to vaccine not reported]) in adults with established arthritis vaccinated with a single PCV7 dose [75]; and mostly disease-related or transplant-related serious adverse events (not considered to be vaccine-related and including 24 fatal events) in stem-cell transplant recipients (children and adults) receiving three doses of PCV7 followed by PPV23 [49]. Deaths were reported in two HIV trials: four deaths (considered to be due to HIV-related complications) among 109 HIV-infected adults; in HIV-infected infants, there were two deaths and one death, respectively, in the PCV7 (n = 30) and placebo (n = 15) arms (relationship to vaccine not reported) [42,66]. Four deaths were also reported following a single dose of PCV7 (n = 91) in a study of adults with chronic lung disease (vs 7/90 deaths in those receiving PPV23; relationship to vaccine not reported) [58].

Expert commentary

Based on the 58 trials summarized in this review, PCV7 is immunogenic in children and adults at higher risk of pneumococcal disease than the general population, whether immunocompetent (n = 9), immunocompromised (n = 39) or asplenic (n = 12). Most of the trials were in individuals with HIV or asplenia (including sickle cell disease) or in transplantation recipients, while data are still lacking in many risk groups. Most (45/58) of the studies identified were non-comparative.

Cordonnier et al. recently reviewed pneumococcal immunization in immunocompromised individuals focusing on trials involving transplant recipients, or those with HIV infection, cancer or hematological malignancies [10]. They concluded that while there are data demonstrating the benefit of pneumococcal vaccination in individuals with HIV infection or those undergoing stem cell transplantation, more trials were required to define the optimal timing of vaccination in patients undergoing solid organ transplantation.

Our review also demonstrates the benefits of early PCV7 vaccination in individuals undergoing stem cell transplantation. However, the immunogenicity of PCV7 in solid organ transplant recipients was found to vary according to organ, with heart or lung recipients having the lowest responses. In adults with HIV, the functional immunogenicity of PCV7 appears to be significantly greater in those receiving HAART than in those not receiving HAART. Similarly, there is some evidence that the immune response in adults with HIV is improved by delaying vaccination until after reconstitution of the immune system. Furthermore, case–control studies suggest that certain immunocompromised individuals (e.g., children and adults with A-T, or adults with chronic lymphocytic leukemia) may have an immune response following PCV7 vaccination that is lower than healthy individuals. Additional trials in immunocompromised populations may be required to determine the optimal vaccination schedule.

Prior PPV23 vaccination also appears to blunt the immune response to subsequent PCV7 vaccination in asplenic children and adults, with the number of previous PPV23 doses inversely correlating with PCV immune response and length of time since the previous PPV23 correlating with superior response.

Comparative data from our review suggest that PCV7 may be more immunogenic than PPV23 in adults with HIV, children with asthma or a cochlear implant and in adults with chronic lung disease. Furthermore, immune response to a final dose of PPV23 after one or more initial doses of PCV7 varied across studies. PPV23 vaccination after PCV7 primary vaccination did not stimulate immune responses in adults with HIV and in children and adults with asplenia, although the timing between doses was only a few weeks to a few months, whereas increases in antibody concentrations were reported in young children (≤2 years of age) with sickle cell disease following a final PPV23 vaccination.

One potential reason for the differences observed between PCV and PPV immunogenity may be due to the ability of PCV to stimulate memory B-cell responses, whereas PPV has been shown to deplete peripheral B cells [86]. These distinct B-cell responses have been observed in adults, and may explain the hyporesponsiveness observed in some of the above populations following PPV23 vaccination. In adults aged 50–70 years vaccinated with PCV7/PCV7/PPV23, PPV23/PCV7/PCV7 or PCV7/PPV23/PCV7 (administered 6 months apart), PPV23 resulted in depletion of the peripheral B cell population, attenuating memory B-cell responses to subsequent PCV7 vaccination [86]. In contrast, PCV7 induced peripheral memory B-cell production following both initial and subsequent doses [86]. Similarly, a B-cell response was observed in adults aged 28–44 years following PCV7 vaccination 12–18 months following primary PCV7 vaccination [87]. The induction of a memory B-cell response following PCV7 vaccination suggests that it still could be used in individuals previously vaccinated with PPV23 in spite of hyporesponsiveness although timing and dosing need to be determined [86]. Data reviewed here suggest that a superior response is achieved by increasing the time between PPV23 and subsequent PCV7 vaccination.

It is important to select the correct immunological assessment for the population. Measurement of OPA titers is a useful complement to ELISA IgG concentrations to support the registration of new PCV formulations and, as it reflects functional immune responses in the host, it may be an ideal surrogate for protective responses in individuals [25,26]. With recent technical advances, OPA has become more frequently used in vaccine trials, and OPA data seem to correlate with disease protection, especially in immunocompromised patients [25]. However, there is a need to standardize the OPA protocol, so that results are comparable across different laboratories, and also to define a protective threshold. The 1:8 OPA threshold has so far been used at the population level in pediatric trials among healthy children but this threshold may not apply to other age groups or to high-risk groups [25].

Serotype-specific antibody concentrations as measured by ELISA can provide valuable information regarding the immunogenicity of PCV7 in populations at risk of pneumococcal disease. We found, however, that the ELISA methodology chosen for each study varied, with only around half of the trials adopting a protocol consistent with WHO recommendations [24]. The WHO has recommended a threshold antibody concentration of 0.35 µg/ml for protection against invasive disease in infants 1 month after a three-dose primary series. This threshold was derived from a pooled analysis of immunogenicity and efficacy data from completed PCV trials with invasive disease end points, but cannot be used with other clinical end points (e.g., pneumonia or otitis media). Also, this threshold may not be applicable to indications in other populations, such as adults and immunocompromised patients [52], or in substantiating protective immune responses in individuals vaccinated with PPV23 [57]. The response criteria chosen for anti-pneumococcal antibody concentrations varied across trials and included a variety of protective thresholds as well as fold-rises. Consequently, for the purposes of this review, we focused on antibody concentration (GMC) data.

Although the immunogenicity of PCV vaccination has been studied in parallel with its effectiveness in two trials involving individuals with HIV [30,88], further research is required to understand the appropriate thresholds for at-risk populations.

Five-year view

This review consolidates evidence on the immunogenicity of PCV7 in populations at high risk of pneumococcal disease and should help increase our understanding of the optimal approach to pneumococcal vaccination in these populations. Research is required to determine the best method for PCV vaccination, in terms of priming and induction of memory. The persistence of serum antibodies and the ability to revaccinate will provide insights into long-term protective immune responses. More studies will need to focus on higher-valent PCVs, such as PCV10 and PCV13.

Key issues

• The majority of safety and immunogenicity trials of PCV7 in children and adults at increased risk of pneumococcal disease were single arm (non-comparative)

• The methodology used to assess serotype-specific IgG and S. pneumoniae varied across trials, as did the immunogenic response criteria; there is currently no standardized protocol for OPA and no protective thresholds have been established.

• Immunogenicity of PCV7, as assessed by pneumococcal-specific antibody concentrations and/or OPA activity, has been demonstrated in immunocompetent, immunocompromised and asplenic children and adults at risk of pneumococcal disease.

• In HIV-infected adults, PCV7 primary vaccination resulted in significantly greater antibody concentrations and/or functional activity than PPV23, and subsequent PPV23 vaccination did not appear to enhance the PCV7 immune response.

• PCV7 or PCV9 vaccination was also immunogenic in children with HIV, although functional responses tended to be lower in HIV-infected children than in HIV-uninfected children.

• The benefits of early PCV7 vaccination were demonstrated in children and adults undergoing stem cell transplantation (either prior to or early after transplantation).

• PCV7 immunogenicity was demonstrated in adults and children undergoing solid organ transplants with some variability being reported according to the organ involved (e.g., heart or lung recipients appear to have the lowest responses).

• The immunogenicity of PPV23 following PCV7 primary vaccination varied within asplenic individuals; sequential PCV7 and PPV23 vaccination was immunogenic in infants with sickle cell disease, whereas PPV23 did not further enhance immune responses in adults with asplenia following primary PCV7 vaccination.

• There is also evidence from comparative trials that PCV7 may be more immunogenic than PPV23 in children with asthma or a cochlear implant and adults with chronic lung disease.

Acknowledgements

The authors take full responsibility for the content of this article and thank Neostar Communications Limited, Oxford, UK (funded by Pfizer, France) for their assistance in preparing the manuscript. The authors also wish to thank their Pfizer, USA colleagues, Rosalind Hollingsworth and Raul Isturiz, for their review of the manuscript.

Financial and competing interests disclosure

N Dartois and MA Fletcher are employees of Pfizer, France. E Bonnet was an employee of Pfizer, France. P Balmer is an employee of Pfizer, USA. The authors received writing assistance from Neostar Communications, and this was funded by Pfizer, France. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes