Globally, Streptococcus pneumoniae causes approximately 14.5 million cases of serious disease1 and approximately 1 million deaths annually in children younger than 5 years of age.2 S. pneumoniae is also the leading cause of bacterial pneumonia (30%–50%), especially in India, with the highest estimated annual number of new cases of clinical pneumonia (43 million per year) in the world.3 Between 123,000 and 164,000 children younger than 5 years of age are estimated to die annually from pneumococcal pneumonia in India.4
In infants and young children, the 7-valent pneumococcal conjugate vaccine (PCV7) is safe and effective in preventing invasive pneumococcal disease, otitis media, and pneumonia caused by the vaccine serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.5–8 Before the introduction of PCV7, approximately 52% of invasive pneumococcal disease cases in children younger than 5 years of age in India in 1993 to 1997 were caused by PCV7 serotypes/serogroups.9 To increase serotype coverage globally, a 13-valent pneumococcal conjugate vaccine (PCV13) that contains the PCV7 serotypes plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A) was developed. Serotype/serogroup coverage of PCV13 was estimated to be 55% to 75% in India during 1993 to 2000.9–11 Previous studies have demonstrated the immunogenicity and safety of PCV13 administered as an infant series plus toddler dose in children in North America,12,13 Europe,14–16 and Taiwan.17
This study in India assessed the immunogenicity and safety of PCV13 in comparison with PCV7 when administered at 6, 10, and 14 weeks of age according to the Expanded Program on Immunization schedule used in India, with a toddler dose at 12 months. In addition, the immune responses to antigens of concomitant vaccines, including pertussis antigens induced by diphtheria, tetanus, and whole-cell pertussis (DTwP), Haemophilus influenzae type b (Hib), and hepatitis B virus (HBV) combination vaccine (DTwP-Hib-HBV), and poliovirus antigens induced by oral poliovirus vaccine when administered with PCV13 were compared with the responses when administered with PCV7, measured 1 month after the infant series.
This was a phase 3, randomized, active-controlled, double-blind trial conducted at 12 sites in India from July 26, 2007 to December 7, 2009 (last serology completion date). Subjects were randomized to receive either PCV13 or PCV7 at 6, 10, and 14 weeks of age (infant series), and at 12 months of age (toddler dose) with concomitant vaccines, including DTwP-Hib-HBV vaccine and oral poliovirus vaccine at 6, 10, and 14 weeks of age. Measles vaccine was permissible at 9 months of age. Blood samples for immunogenicity assessment were collected 1 month after the infant series and 1 month after the toddler dose. This study was conducted in accordance with the ethical principles that have origins in the Declaration of Helsinki. The study was approved by the Drugs Controller General, India. Institutional Review Board approval was obtained at each site before the start of the study. Written informed consent was obtained from each subject’s parents or legal guardians before enrollment and before performance of any study-related procedures.
Eligible subjects were healthy infants 6 weeks of age (range, 42–72 days) at the time of enrollment who had not undergone previous vaccination with any pneumococcal, diphtheria, tetanus, pertussis, or Hib conjugate vaccines, who had no contraindication or anaphylactic reaction to any vaccine or vaccine-related component, and who had no history of culture-proven invasive disease caused by S. pneumoniae, significant neurological disorder or history of seizure, significant stable or other significant disorders, known or suspected immune deficiency or suppression, or receipt of blood products or gamma-globulin.
Clinical Hold Resulting in Changes to Protocol
From October 10, 2007 to December, 2007, this study was placed on clinical hold by the Drugs Controller General, India, to allow review of 4 serious adverse events from studies of PCV13 or PCV7 conducted outside of India. The protocol was amended to allow subjects who had visits outside of the study window in the infant series (because of the clinical hold) to continue in the study and to enroll additional subjects (cohort 2) who would receive the infant series vaccination on schedule. The immunogenicity and safety results presented here are for cohorts 1 and 2 combined.
Vaccines and Interventions
PCV13 contains serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. PCV13 was formulated in a manner similar to that of PCV7. As with PCV7, each of the polysaccharides is conjugated to CRM197, a nontoxic variant of diphtheria toxin. PCV13 contains 2.2 µg of each polysaccharide, except for 4.4 µg of serotype 6B, in 5.0 mM succinate buffer with 0.125 mg of aluminum as aluminum phosphate per 0.5-mL dose. The visual presentations of PCV13 and PCV7 were identical.
The DTwP-Hib-HBV vaccine contains diphtheria toxoid, tetanus toxoid, and whole-cell pertussis vaccine, hepatitis B surface antigen, and conjugated Hib (CRM197-Hib) vaccine adsorbed on aluminum phosphate. The trivalent, live, oral poliovirus vaccine contains types 1, 2, and 3 attenuated poliomyelitis viruses (Sabin strains) derived from primary monkey kidney cell culture.
PCV13 and PCV7 were administered by intramuscular injection into the anterolateral thigh muscle of the left leg. The DTwP-Hib-HBV vaccine was administered by intramuscular injection into the anterolateral thigh muscle of the right leg. The poliovirus vaccine was administered orally.
The evaluable infant or toddler immunogenicity populations included all subjects who received all assigned study vaccinations, adhered to the protocol requirements, had at least 1 valid and determinate assay result, and had no major protocol deviations.
Pneumococcal Vaccine Responses
Immune responses to PCV13 and PCV7 were assessed 1 month after infant dose 3 and 1 month after the toddler dose using a standardized enzyme-linked immunosorbent assay that measured serotype-specific anticapsular polysaccharide immunoglobulin G (IgG) levels.
Concomitant Vaccine Antigen Responses
Serum levels of IgG antibodies to pertussis antigens (pertussis toxoid, filamentous hemagglutinin, and pertactin) were measured using an anti-Bordetella pertussis enzyme-linked immunosorbent assay performed on blood samples collected 1 month after the infant series. Results were reported as enzyme-linked immunosorbent assay units per milliliter (EU/mL). Serum levels of antibody to poliovirus antigens (Sabin strains 1, 2, and 3) were measured using a polio in vitro plaque neutralization assay on blood samples collected 1 month after the infant series.
Local reactions (tenderness, swelling, and redness) at the site of the pneumococcal conjugate injection were monitored daily for 4 days after each vaccination. The parent or guardian measured the actual size of redness or swelling with a caliper and recorded the measurement in an electronic diary. Tenderness was recorded as absent, present, or interfering with limb movement. The measurements for redness and swelling were categorized as mild (0.5–2.0 cm), moderate (2.5–7.0 cm), or severe (>7.0 cm).
Systemic events (decreased appetite, irritability, increased sleep, decreased sleep, and fever) and the use of antipyretic medication to prevent or treat symptoms were monitored daily and recorded in the electronic diary for 4 days after each vaccination. Axillary temperature was collected daily at bedtime for 4 days after vaccination and if fever (axillary temperature ≥38°C) was suspected at any time during days 1 through 4. In the event of a fever, temperature was collected daily until the fever had resolved, with the highest temperature for the day recorded in the electronic diary. Fever was categorized as absent (<38°C), mild (≥38°C to ≤39°C), moderate (>39°C to ≤40°C), or severe (>40°C).
Adverse events were recorded from signing of the informed consent form to the postinfant series visit, and from the toddler dose until the posttoddler dose visit, based on clinical evaluation and questioning of the parent or guardian at each visit. With the toddler dose, all new diagnoses of chronic medical conditions since the postinfant series visit were recorded. Serious adverse events were collected throughout the study and recorded on case report forms at each visit.
For each of the pneumococcal serotypes, the primary endpoint was the proportion of subjects with serotype-specific IgG antibody concentrations ≥0.35 μg/mL (defined by the World Health Organization as a reference antibody concentration for assessment of vaccine efficacy against invasive pneumococcal disease in infants)18 at 1 month after the infant series (primary endpoint) and toddler dose (secondary endpoint). Antipneumococcal IgG geometric mean concentrations (GMCs) also were assessed after the infant series and after the toddler dose.
The primary endpoint for each of the whole-cell pertussis antigens was the proportion of subjects achieving a predetermined antibody level measured 1 month after the infant series, which was the concentration achieved by 95% of the subjects in the PCV7 group (pertussis toxoid ≥0.975 EU/mL, filamentous hemagglutinin IgG ≥3.91 EU/mL, and pertactin IgG ≥6 EU/mL). For the 3 poliovirus strains, the endpoints were the proportion of subjects achieving an antibody titer ≥1:8. GMCs (pertussis) or geometric mean titers (poliovirus) also were assessed after the infant series for each antigen of each vaccine group.
To assess differences between the 2 groups, the exact, unconditional, 2-sided, O’Brien-Fleming–adjusted 95% confidence intervals (CIs) of the difference in proportions (PCV13 minus PCV7) were calculated for the 13 pneumococcal serotypes and 6 concomitant antigens. Two-sided O’Brien-Fleming–adjusted 95% CIs for the ratios of GMCs or geometric mean titers (PCV13 to PCV7) also were used to compare the difference between the 2 vaccine groups. This was a descriptive study.
Incidence rates of local reactions, systemic events, adverse events, and serious adverse events were summarized for the PCV13 and PCV7 groups. The 2-sided Fisher exact test was used to determine statistical significance of differences between groups in percentages of subjects reporting events.
For regulatory reasons, an analysis was conducted for cohort 1 infant series data. The final statistical analysis of the infant series data was adjusted to account for this interim analysis, excluding polio data, which were not analyzed during the interim analyses.
Sample Size Estimation
The study was not powered for hypothesis testing. It was sized to allow estimation of the proportion of responders to within ±5.1% precision for the pneumococcal serotypes, and to allow estimation of the proportion of responders to within ±6.4% precision for the whole-cell pertussis antigens. A total of 354 subjects per cohort was to be enrolled to ensure that 300 subjects per cohort were evaluable.
Enrollment and Demographics
A total of 709 subjects in 2 different cohorts were randomized (PCV13, n = 354; PCV7, n = 355; Figure 1). The demographic characteristics of subjects were similar in both vaccine groups: 52% male; 100% Asian race; median age at enrollment 7 weeks; and median weight at enrollment 4.3 kg in both vaccine groups.
Immune Responses to PCV13 and PCV7 After the Infant Series
For each of the 7 common pneumococcal serotypes, the proportions of subjects achieving anticapsular polysaccharide IgG concentrations ≥0.35 µg/mL (ie, responders) (Table 1) and anticapsular polysaccharide IgG GMCs (Table 2) were similar for the PCV13 and PCV7 groups.
For each of the 6 additional pneumococcal serotypes, the proportions of responders (Table 1) and anticapsular polysaccharide IgG GMCs (Table 2) were higher in response to PCV13 compared with PCV7.
Immune Responses to PCV13 and PCV7 After the Toddler Dose
For each of the 7 common pneumococcal serotypes, anticapsular polysaccharide IgG GMCs increased substantially from the after the infant series to after the toddler dose (Table 2). Anticapsular polysaccharide IgG GMCs (Table 2) and proportions of responders (Table 1) were similar in both groups.
For 5 of the 6 additional serotypes, anticapsular polysaccharide IgG GMCs increased substantially from after then infant series to after the toddler dose; the exception was serotype 3 (Table 2). For all 6 of the additional serotypes, anticapsular polysaccharide IgG GMCs were higher in response to PCV13 compared with PCV7 after the toddler dose (Table 2). In addition, the proportions of responders were higher for 5 of the 6 additional serotypes in the PCV13 group compared with the PCV7 group; proportions were similar in both groups for serotype 19A (Table 1). In the PCV7 group, the proportions of responders were higher for serotypes 5, 6A, and 19A (74.3%–98.5%) than for serotypes 1, 3, and 7F (3.1%–12.9%)
Immune Responses to Concomitant Pertussis and Poliovirus Vaccines After the Infant Series
The proportions of responders to whole-cell pertussis and pertussis antigen GMCs and proportions of responders to poliovirus vaccine were similar in the PCV13 and PCV7 groups (Table 3).
Safety and Tolerability
Most local reactions were mild in severity, and rates of local reactions were similar in both groups (Table 4). No subject had severe swelling or severe redness during the infant series or after the toddler dose. Significant tenderness was reported in 15.8% to 42.2% and 17.1% to 40.5% of subjects in the PCV13 and PCV7 groups, respectively, with the highest rates occurring after dose 1 and the lowest rate occurring after the toddler dose.
Fever was mostly mild in severity in both vaccine groups (Table 5). The PCV13 group had a significantly lower rate of decreased sleep after dose 2 (37.9% vs 46.9%, respectively;P = 0.034) and a significantly lower rate of use of antipyretic medication to treat fever after dose 3 (54.5% vs 66.0%, respectively;P = 0.017) compared with the PCV7 group (Table 5).
Overall, adverse events were consistent with normal childhood illnesses. At least 1 adverse event was reported in 47.0% and 48.2% of subjects in the PCV13 and PCV7 groups, respectively, during the infant series, and in 15.2% and 12.5% of subjects, respectively, after the toddler dose. The most frequently reported category of adverse events in both vaccine groups was infections and infestations. There were no statistically significant differences between the PCV13 and PCV7 groups for adverse events considered related to study vaccines.
Serious Adverse Events
Serious adverse events were reported in 2.3% and 1.7% of subjects, respectively, in the PCV13 and PCV7 groups during the infant series, in 2.3% and 3.1% of subjects, respectively, after the infant series, and in 2.0% and 0.5% of subjects, respectively, after the toddler dose; none was considered related to study vaccine and rates of serious adverse events did not differ significantly between the PCV13 and PCV7 groups.
One subject in the PCV7 group died during the infant series 1 week after administration of the 14-week vaccination. This subject was hospitalized for respiratory syncytial virus–positive bronchiolitis on October 16, 2008, and subsequently died of cardiac arrest attributable to viral myocarditis on October 17, 2008. This event was judged to be not related to vaccination by the investigator. Because of this death, the Drugs Controller General, India, placed a second clinical hold on the study on November 7, 2008. The Drugs Controller General, India, agreed to the lifting of the hold at 11 investigational sites in April 2009, and at the last site in June 2009.
A total of 241 subjects (34.0%) discontinued during the infant series by withdrawing consent because of the clinical holds (Figure 1). Similar proportions of subjects in each group discontinued because of the study hold, whether by consent withdrawn or by request of parent or investigator. Other discontinuations are shown in Figure 1. Similar percentages of withdrawals were observed in both vaccine groups. In addition to the 1 child who died, 8 additional subjects were withdrawn or permanently discontinued participation because of adverse events (Figure 1). None of these adverse events was considered related to study vaccine.
Immune responses to the 7 common serotypes and the concomitant vaccines were similar for subjects receiving PCV13 and those receiving PCV7. Immune responses to the 6 additional serotypes were higher in the PCV13 group compared with the PCV7 group. Both PCV13 and PCV7 had similar safety profiles. These results are consistent with previous studies of PCV13.12–17,19
The higher-than-expected immune responses to serotypes 6A and 19A in PCV7 recipients were likely attributable to cross-reactivity to serotypes 6B and 19F, respectively. Previous studies have demonstrated cross-reactivity between serotypes 6A and 6B and between 19A and 19F in enzyme-linked immunosorbent assay IgG responses to pneumococcal conjugate vaccines, but functional responses, as measured by opsonophagocytic activity assays, were lower for serotypes 6A and 19A than for serotypes 6B and 19F.20,21 In studies comparing PCV7 and PCV13, functional responses for serotype 6A were lower in response to PCV7 compared with those elicited by PCV13.12,16 For serotypes 5 and 19A, IgG responses elicited by PCV7 do not possess functional opsonophagocytic activity, whereas responses to PCV13 do demonstrate functional opsonophagocytic activity.12,16 With respect to serotype 5, previous studies have demonstrated cross-reactivity with other bacteria, including Escherichia coli and Klebsiella,22,23 suggesting that the increased responses to serotype 5 in the present study might be attributable to environmental exposure to these bacteria.
Previous studies of PCV13 have shown similar safety profiles for PCV13 and PCV7.13–17,19 However, significant tenderness occurred in more subjects in our study for PCV13 and PCV7 groups (41%–42% for dose 1 and 16%–17% for the toddler dose) than in the previous studies (0%–15%).12–17,19 We do not have an explanation for this difference, but it was the same for PCV13 and PCV7 groups and was not associated with higher rates of redness or swelling. The rates of use of antipyretics to treat (28%–76%) or prevent (34%–89%) symptoms in this study were comparable with those reported in a study conducted in the United States (72%–91% for all doses).12 However, most other studies reported lower rates for the use of antipyretics.13–17
PCV13 serotype/serogroup coverage was estimated to be 55% to 75% in India in the 1990s.9–11 The large burden of disease caused by S. pneumoniae in Indian children younger than 5 years of age suggests that PCV13 could prevent a significant number of deaths annually. In 2007, Levine and Cherian advocated adding PCV7 to the national immunization program in India.4 However, contrary opinions have been expressed because of the relatively low serotype/serogroup coverage of PCV7 in India (approximately 52% in children younger than 5 years of age9).24,25 The higher serotype coverage of PCV13 vs PCV7 makes PCV13 a better option for inclusion in national immunization programs.
PCV13 induced immune responses that were comparable with those of PCV7 for the 7 common serotypes, and induced substantially greater responses for the 6 additional serotypes. This suggests that PCV13 will be as effective as PCV7 in preventing pneumococcal disease caused by the 7 common serotypes and will provide added protection against the 6 additional serotypes. PCV13 can be administered with whole-cell pertussis and oral poliovirus vaccines without impacting the immune responses to those concomitant vaccines. PCV13 has an acceptable safety profile in both infants and toddlers that is comparable with that of PCV7.
The authors thank the following for their assistance with this study: Amita Sapru, MD (KEM Hospital Research Centre, Pune, India); Keri Clarke (Clinical Scientist, Pfizer Inc, Maidenhead, Berkshire, UK); Georgina Keep (Clinical Project Manager, Pfizer Inc, Maidenhead, Berkshire, UK [former employee]); Ryan Newton (Clinical Scientist, Pfizer Inc, Maidenhead, Berkshire, UK); VimalThohan (Clinical Program Manager, Pfizer Inc, Maidenhead, Berkshire, UK [former employee]); Maria Lewin, MD (St. John’s Medical Center Hospital, Bangalore, India); Anand Prahalad, MD (St. John’s Medical Center Hospital, Bangalore, India); Sunitha Pinto (St. John’s Medical Center Hospital, Bangalore, India); Leni Grace Matthew, MD (Christian Medical College, Vellore, India); Anna Simon, MD (Christian Medical College, Vellore, India); Atul Goel, MD (Christian Medical College, Ludhiana); KanchiKamakoti (CHILDS Trust Hospital and the CHILDS Trust Medical Research Foundation, Chennai, India); and Dr. Sonali Palkar, DCH and Dr. Nandini Malahe, DNB (Bharati Vidyapeeth University Medical College, Pune, India).
This study was sponsored by Wyeth, which was acquired by Pfizer Inc in October 2009. Medical writing support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc. No honorarium, grant, or other form of payment was provided to authors, with the exception of funding needed for the conduct of the study. The funding source contributed to the study design; to the collection, analysis, and interpretation of data; and to medical writing support. YKA received grant funding paid to his institution for the conduct of this study from Pfizer Inc. SKL received grant funding paid to his institution for the conduct of this study and travel funding from Pfizer Inc to present research findings. AB received grant funding for the conduct of this study and travel funding from Pfizer Inc to present research findings. SB received grant funding from Pfizer Inc paid to his institution for the conduct of the study. JC received grant funding from Pfizer Inc paid to her institution for the conduct of this study. SRB received grant funding from Pfizer Inc for the conduct of this study paid to her institution. VPV received grant funding from Pfizer Inc paid to his institution for the conduct of this study and study vaccines. DG is an employee of Pfizer Inc Pharmaceutical India Pvt Ltd. QJ, MP, EAE, WCG and DAS are employees of Pfizer Inc. SPT was employed by Pfizer Inc while this study was conducted. The authors have no other funding or conflicts of interest to disclose.
1. O’Brien KL, Wolfson LJ, Watt JP, et al.Hib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374:893–902
2. World Health Organization.. Pneumococcal conjugate vaccine for childhood immunization–WHO position paper. Wkly Epidemiol Rec. 2007;82:93–104
3. Rudan I, Boschi-Pinto C, Biloglav Z, et al. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ. 2008;86:408–416
4. Levine OS, Cherian T. Pneumococcal vaccination for Indian children. Indian Pediatr. 2007;44:491–496
5. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187–195
6. Eskola J, Kilpi T, Palmu A, et al.Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409
7. Hansen J, Black S, Shinefield H, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs. Pediatr Infect Dis J. 2006;25:779–781
8. Grijalva CG, Nuorti JP, Arbogast PG, et al. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. 2007;369:1179–1186
9. Invasive Bacterial Infection Surveillance (IBIS) Group, International Clinical Epidemiology Network (INCLEN).. Prospective multicentre hospital surveillance of Streptococcus pneumoniae
disease in India. Lancet. 1999;353:1216–1221
10. Lee NY, Song JH, Kim S, et al. Carriage of antibiotic-resistant pneumococci among Asian children: a multinational surveillance by the Asian Network for Surveillance of Resistant Pathogens (ANSORP). Clin Infect Dis. 2001;32:1463–1469
11. Kanungo R, Rajalakshmi B. Serotype distribution & antimicrobial resistance in Streptococcus pneumoniae
causing invasive & other infections in south India. Indian J Med Res. 2001;114:127–132
12. Yeh SH, Gurtman A, Hurley DC, et al.004 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126:e493–e505
13. Vanderkooi OG, Scheifele DW, Girgenti D, et al.Canadian PCV13 Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine pediatric vaccinations in Canada. Pediatr Infect Dis J. 2012;31:72–77
14. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin Vaccine Immunol. 2010;17:1017–1026
15. Snape MD, Klinger CL, Daniels ED, et al. Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial. Pediatr Infect Dis J. 2010;29:e80–e90
16. Kieninger DM, Kueper K, Steul K, et al.006 study group. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 2010;28:4192–4203
17. Huang LM, Lin TY, Juergens C. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccines in Taiwan. Vaccine. 2012;30:2054–2059
18. World Health Organization Expert Committee on Biological Standardization.. 54th Report. Annex 2: Recommendations for the production and control of pneumococcal conjugate vaccines. 2005 Geneva, Switzerland World Health Organization
19. Bryant KA, Block SL, Baker SA, et al.PCV13 Infant Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125:866–875
20. Väkeväinen M, Eklund C, Eskola J, et al. Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae
, evoked by pneumococcal conjugate vaccines, in infants. J Infect Dis. 2001;184:789–793
21. Yu X, Gray B, Chang S, et al. Immunity to cross-reactive serotypes induced by pneumococcal conjugate vaccines in infants. J Infect Dis. 1999;180:1569–1576
22. Heidelberger M, Jann K, Jann B, et al. Relations between structures of three K polysaccharides of Escherichia coli and cross-reactivity in antipneumococcal sera. J Bacteriol. 1968;95:2415–2417
23. Heidelberger M, Nimmich W. Additional immunochemical relationships of capsular polysaccharides of Klebsiella and pneumococci. J Immunol. 1972;109:1137–1144
24. Mathew JL. Universal pneumococcal vaccination for India. Indian Pediatr. 2008;45:160–161
25. Mishra A, Mishra R. Universal pneumococcal vaccination in India: is it a priority? Indian Pediatr. 2008;45:161–162
immunogenicity; pneumococcal vaccine; pediatric; safety© 2013 Lippincott Williams & Wilkins, Inc.