After receipt of PCV13, the proportion of responders (definition is mentioned in Methods section) increased for all 13 serotypes in both groups (Table 1). IgG GMCs increased postvaccination by ≥2-fold for each of the 13 serotypes in both groups (Table 2). In both groups, the largest fold rises were observed for serotypes 1 and 7F, which increased by 108- to 124-fold in group 1 and by 28- to 35-fold in group 2.
Unsolicited AEs were considered generally consistent with illnesses common in these age groups. Two SAEs were reported in group 1 after dose 2 and 2 SAEs were reported in group 2, but none was considered related to the study vaccine. No deaths occurred during the study.
A subgroup analysis was conducted to compare safety outcomes among subjects who had received 3 or 4 doses of PCV7 prior to enrollment. In group 1, 29.4% of subjects had received 3 doses of PCV7 and 70.6% of subjects had received 4 doses prior to enrollment (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A988). In group 2, only 4.4% of subjects had received 3 prior doses of PCV7; therefore, the subgroup analysis was not conducted in group 2.
Rates of local reactions, systemic events, and AEs did not increase with number of prior doses of PCV7. Indeed, rates of local reactions tended to be higher in the 3-dose subgroup than the 4-dose subgroup, after both dose 1 (tenderness: 53.1% vs. 50.0%; swelling: 35.5% vs. 21.2%; redness: 46.9% vs. 36.6%) and dose 2 (tenderness: 76.0% vs. 50.0%; swelling: 29.2% vs. 20.4%; redness: 44.0% vs. 31.4%). Rates of systemic events tended to be higher in the 3-dose subgroup than the 4-dose subgroup, but no clear pattern could be discerned. A slightly higher proportion of AEs occurred in the 3-dose subgroup than the 4-dose subgroup after dose 1, and a lower proportion of AEs occurred in the 3-dose subgroup than the 4-dose subgroup after dose 2 (data not shown).
This study demonstrated that PCV13 was immunogenic, safe, and well tolerated in healthy children aged <5 years who had been previously vaccinated with 3 or 4 doses of PCV7. PCV13 boosted anticapsular IgG responses to the 7 serotypes of PCV7 and induced significant immune responses to the 6 additional serotypes in PCV13.
The primary end point of this study was the proportion of subjects with IgG concentration ≥0.35 μg/mL against each serotype in PCV13 after receipt of the vaccine. For both groups, ≥98% of subjects had IgG titers ≥0.35 μg/mL postvaccination with PCV13 for each of the serotypes in PCV13, with the exception of serotype 3, for which 94.5% and 92% of subjects in group 1 and group 2, respectively, had postvaccination titers ≥0.35 μg/mL. An additional indicator of immunogenicity was the at least 2-fold rise in geometric mean fold rises of post- versus prevaccination IgG titers, for each serotype contained in PCV7. Antibody responses to the 6 additional serotypes compared favorably to responses seen after 3-dose infant series in pivotal studies of PCV13, suggesting that they will be protective.15,16 A similar comparison to postinfant series antibody responses was used previously to determine the number of recommended doses of PCV7 for children 7 months to 5 years of age who were naive to PCV.17
Although all postvaccination titers in both groups for all 13 serotypes in PCV13 were well in excess of the serologic correlate of immunity of IgG ≥0.35 μg/mL, there was a marked variation in response between serotypes as well as to the response in group 1 as compared with group 2. For the serotypes in PCV7, postvaccination GMC were higher for each serotype in subjects in group 2 as compared with group 1. However, for the 6 additional serotypes in PCV13, the responses were more variable. For serotypes 1 and 5, postvaccination GMCs in group 1 were higher than group 2, GMCs for serotypes 6A and 19A were higher in group 2, and GMCs for serotypes 3 and 7F were similar. The reasons for these differences are not clear and are beyond the scope of this project.
Not unexpectedly, a high proportion of subjects in both groups had IgG titers ≥0.35 μg/mL against PCV7 serotypes prior to receipt of PCV13, likely because of the inclusion criterion requiring prior receipt of at least 3 doses of PCV7. Additionally, the proportion of subjects with antipneumococcal IgG ≥0.35 μg/mL was much higher for many of the PCV7 serotypes in group 1 than in group 2, probably due to the more recent receipt of PCV7 in among children in group 1. Prior to receipt of PCV13, IgG titers varied for the 6 additional serotypes, being much lower for serotypes 1, 3, and 7F than for 5, 6A, and 19A. The differences in IgG concentrations to serotypes 1, 3, and 7F between group 1 (0.04–0.06 μg/mL) and 2 (0.09–0.22 μg/mL) before receipt of PCV13 may represent a shorter duration of natural exposure to these serotypes in the younger age group. IgG titers to serotypes 5, 6A, and 19A before receipt of PCV13, in contrast, were higher than expected in a population that had not been directly immunized against these serotypes. This has been previously described for serotypes 6A and 19A, and is due to cross-reactive antipolysaccharide antibody responses to those serotypes.18,19 Although anti-6A antibodies elicited by PCV7 are somewhat associated with antipneumococcal opsonophagocytic assay activity, cross-reactive antibodies to types 5 and 19A are not, in contrast to the opsonophagocytic assay activity that is elicited subsequent to PCV13 immunization.15,16,20 Evidence suggests that certain Escherichia coli and Klebsiella antigens show some cross-reactivity with serotype 5 polysaccharide.21,22 Nonetheless, vaccination with PCV13 resulted in significant increases in proportions of responders and IgG concentrations to all 13 serotypes, including those serotypes with high titers before receipt of PCV13.
In this study, PCV13 was generally well tolerated. Local reactions and fever were generally mild or moderate, with no reports of severe redness or swelling, and only 1 report of severe fever. Rates of significant tenderness (8.8%–10.6%) were similar to rates following the toddler dose of PCV13 in a German study (dosing schedule: 3, 4, 5, and 12 months) and an US study (dosing schedule 2, 4, 6, and 12 months) (10.8% and 15.4%, respectively).15,16 There were no clinically significant differences in safety results between subjects receiving 3 prior doses of PCV7 and those receiving 4 prior doses. These results allay the theoretical concern of an Arthus reaction associated with an excessive number of inoculations with vaccines containing components of diphtheria (ie, the CRM component of PCV7 and PCV13). In fact, this study demonstrated, even after 5 doses of PCV, no increase in rates of local reactions or other adverse reactions with increasing number of doses.
A limitation of our study was the inability to determine antibody levels of subjects in group 1 after the first dose of PCV13, as blood was only collected after the final dose of vaccine. Thus, this study does not provide data on whether a single dose of PCV13 would be sufficient in the younger age group, which might be relevant in countries with reduced dosing schedules. Nonetheless, the robust response of group 2 subjects to 1 dose of PCV13 suggests there may be a similar response in the younger age group. In a study of PCV13 conducted in French children,23 infants were randomized to receive either 4 doses of PCV13 at 2, 3, 4, and 12 months of age; 4 doses of PCV7 at the same ages; or 3 doses of PCV7 at 2, 3, and 4 months of age; and 1 dose of PCV13 at 12 months of age. As compared with children who received PCV7, children who received PCV13, including those who received only a single dose of PCV13 at 12 months of age, had higher GMCs to the 6 additional serotypes in PCV13 when tested at 13 months of age.
The ACIP has recommended to the Centers for Disease Control and Prevention that PCV13 be included in the routine immunization schedule, replacing PCV7.10 The ACIP also recommends a single supplemental dose of PCV13 for all children 14 to 59 months of age who have received a complete PCV7 schedule.10 Similar recommendations have been made in other countries.
Evidence from several epidemiologic studies supports the use of a supplemental dose of PCV13 in children who have received 3 or 4 previous doses of PCV7. First, although the overall incidence of IPD is decreasing, the incidence of IPD due to nonvaccine serotypes is increasing, particularly serotype 19A.3–6,24–28 Besides increasing in frequency, serotype 19A is becoming less susceptible to commonly used first-line antimicrobial agents and many second-line agents.4,6 A manifestation of the disease burden associated with serotype 19A is the increase in hospitalizations due to complicated pneumococcal pneumonia.29–32 The older age of children with complicated pneumococcal pneumonia supports the perspective that a supplemental dose of PCV13 may be particularly beneficial in this age group.30,31,33 However, no clinical data are yet available that address this issue. Current guidelines recommend the use of a single dose of PCV13 in children aged 6 to 18 years with underlying conditions predisposing them to IPD, who have not received PCV13 previously.10 Ongoing studies are evaluating PCV13 as a catch-up vaccination in healthy children aged 6 to 18 years.
In conclusion, we have demonstrated that PCV13 is immunogenic and safe in children previously vaccinated with PCV7. By eliciting high antibacterial immune responses to the 6 additional serotypes, PCV13 may provide protection against these serotypes, which are important causes of pneumococcal disease globally.
The authors thank the members of the 3011 study group for their contributions to this study (mentioned in Appendix).
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APPENDIX 3011 Study Group: Contributing Physicians and Practices
Gerald Bader, MD (The Vancouver Clinic, Inc., Vancouver, WA); John Frey, MD (Monroe Medical Foundation, Monroe, WI); Kristina Bryant, MD (University of Louisville, Pediatric Clinical Trials Unit, Louisville, KY); Susan Keathley, MD (Little Rock Children's Clinic, P.A., Little Rock, AR); Richard Rupp, MD (University of Texas Medical Branch at Galveston, Department of Pediatrics, Galveston, TX); Anthony Johnson, MD (Arkansas Pediatric Clinic, Little Rock, AR); Kevin Rouse, MD (The Children's Clinic of Jonesboro, P.A., Jonesboro, AR); Shelly Senders, MD (Senders Pediatrics, Cleveland, OH); Michael Martin, MD (Advanced Pediatrics, Vienna, VA); Malcolm Sperling, MD (Edinger Medical Group, Fountain Valley, CA); Wilson Andrews, MD (Pediatrics and Adolescent Medicine, P.A., Woodstock, GA); Terry Payton, MD (Northwest Arkansas Pediatric Clinic, Fayetteville, AR); Michael Pichichero, MD (Research Institute, Rochester General Hospital, Rochester, NY); David Hurley, MD (Cottonwood Pediatrics, Murray, UT); Carina A. Rodriguez, MD (University of South Florida, Department of Pediatrics, Tampa, FL); William Kennedy, MD (Loma Linda University Health Care, Loma Linda, CA); Umesh Goswami, MD (Northern Illinois Research Associates, Dekalb, IL); Robbie Rhodes, MD (Central Arkansas Pediatric Clinic, Benton, AR); Matthew Cox, MD (Families First Pediatrics, South Jordan, UT); Laurie Harris-Ford, MD (Alpha Clinical Research, Clarksville, TN); Janet Tillisch, MD (Innovis Health/Odyssey Research, Fargo, ND); Todd Twogood, MD (Odyssey Research, Bismarck, ND); Stanley Grogg, MD (Oklahoma State University Center for Health Sciences Physicians, Pediatrics, Tulsa, OK); Henry Bernstein, MD (General Academic Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH); Carrie Byington, MD (University of Utah Hospitals and Clinics, Pediatric Clinic, Salt Lake City, UT); Christopher Chambers, MD (Thomas Jefferson University, Department of Family and Community Medicine, Philadelphia, PA); Mark Simpson, MD (Cary Pediatric Center, Cary, NC); Marshall Benbow, MD (Southwest Children's Research Associates, San Antonio, TX).
pneumococcal conjugate vaccine; immune response; safety; vaccines