Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine Given With Routine Pediatric Vaccination to Healthy Children in France

Hpital Armand Trousseau, Paris, France; 2Wyeth Vaccines Research, Paris, France; 3 Wyeth Vaccines Research, Pearl River, NY, USA; 4Multiple investigational sites, France.
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E Grimprel,1 F Laudat,2 SA Baker,3 MS Sidhu,3 C Sekaran,3 WC Gruber,3 EA Emini,3 DA Scott,3 on behalf of the 008 study group4

BACkGRounD
The incorporation of 7-valent pneumococcal conjugate vaccine (PCV7, Prevenar) into the routine childhood vaccination schedule in the US and other countries has been shown to be effective in preventing invasive pneumococcal disease (IPD), pneumonia, and otitis media in infants and young children. To increase serotype coverage globally, Wyeth is developing a 13-valent pneumococcal vaccine (PCV13) that contains the 7 polysaccharide serotypes included in PCV7 (4, 6B, 9V, 14, 18C, 19F, 23F) and an additional 6 serotypes (1, 3, 5, 6A, 7F, 19A). All are conjugated to the carrier protein CRM197. It is estimated that the addition of these 6 serotypes will increase coverage of vaccine- serotype IPD to 89% in Europe, 92% in the US and Canada, 86% in Oceania, 87% in Africa and Latin America, and 73% in Asia.1 These estimates are based on serotype distribution data prior to the introduction of PCV7 vaccination. The PCV13 clinical development plan includes studies of safety and tolerability, immunogenicity in different vaccination schedules, and concomitant vaccine antigen responses. As part of this plan, the present phase 3, randomized, active-controlled, double-blind, multicenter study assessed the safety and antipenumococcal immunogenicity of a toddler dose of PCV13 given at 12 months, following either a three-dose infant series of PCV13 or a three-dose infant series of PCV7. Immune responses to the common serotypes were also compared to recipients of a four-dose series of PCV 7.

RESuLtS
Private practice pediatricians located at 39 sites in France randomized 613 infants at the age of 2 months. All children who continued the study after the infant series and received the toddler doses were included in the safety analysis. The evaluable study population for pneumococcal immunogenicity is summarized in Table 1. table 1: Study Population at toddler Dose
GMC (g/mL)

Immunogenicity
Immune responses before and after the toddler dose are shown in Figure 3 and Figure 4.

Figure 3. Comparisons of Pneumococcal IgG GMCs (mg/mL) for the 7 Common Serotypes Before and After the Toddler Dose
12 10 8 6 4 2 0
4 6B 9V 14 18C 19F 23C 4 6B 9V 14 18C 19F 23C 4 6B 9V 14 18C 19F 23C

Figure 4. Comparisons of Pneumococcal IgG GMCs (mg/mL) for the 6 Additonal Serotypes Before and After the Toddler Dose
10 9 8 7 6 5 4 3 2 1 0

PCV13/PCV13

PCV7/PCV13

PCV7/PCV7

PCV13/PCV13

PCV7/PCV13

total 562 495 556

Vaccinated Median age (months) Included in the immunogenicity analysis* Completed**

273 12.1 241 268

137 12.1 121 137

152 12.0 133 151

GMC (g/mL)

PCV13/ PCV13 Group

PCV7/ PCV13 Group

PCV7/ PCV7 Group

6A

7F 19A

6A

7F

19A

Pre-toddler

Post-toddler

Pre-toddler

Post-toddler

*The evaluable for immunogenicity population was defined as follows: met all inclusion criteria; had at least 1 valid and determinate assay result for the proposed analysis; had no major protocol violations. **There were 6 withdrawals, 5 in Group PCV13/PCV13 (2 protocol violations; 1 failed to return; 1 parental request; 1 other) and 1 in Group PCV7/PCV7 (protocol violation).

For the 7 common serotypes, IgG GMCs were similar in all groups. For the 6 additional serotypes:
IgG GMCs were higher for 5 of the 6 serotypes in PCV13/PCV13 recipients vs. PCV7/PCV13; serotype 3 GMCs were comparable between the two groups. Importantly, GMCs for the 6 additional serotypes in PCV7/PCV13 recipients were similar to the GMCs obtained after a 3-dose infant series with PCV13.4,5

Safety and tolerability

Figure 1. Percent of infants experiencing local reactions after toddler dose
Mild Swelling Moderate Swelling Severe Swelling Mild Redness Moderate Redness Severe Redness Any Tenderness Significant Tenderness 0 20 40 60 80 PCV13/PCV13 PCV7/PCV13 PCV7/PCV7

For the common serotypes, the proportions of children with an IgG concentration 0.35 g/mL were >97% across all three groups (Table 2). table 2: Percent of Subjects Achieving Pneumococcal IgG Concentrations 0.35 g/mL to the 7 Common Serotypes 1 Month After the toddler Dose.
PCV7 Serotype 4 6B 9V 14 18C 19F 23F PCV13/PCV13 % 0.35 g/mL n=230-236 100.0 99.6 100.0 99.6 99.6 97.9 99.6 PCV7/PCV13 % 0.35 g/mL n=108-113 99.1 98.1 100.0 99.1 98.2 97.3 99.1 PCV7/PCV7 % 0.35 g/mL n=111-127 100.0 99.2 100.0 100.0 99.2 97.6 99.2

SuBJECtS AnD MEtHoDS

Healthy infants were randomly assigned at the age of 2 months (2:1:1) to receive one intramuscular injection of:
either 4 doses of PCV13 at 2, 3, 4, and 12 months of age or 4 doses of PCV7 at 2, 3, 4, and 12 months of age or 3 doses of PCV7 at 2, 3, 4 months, followed by 1 dose of PCV13 at 12 months of age DTaP-IPV/Hib was administered concomitantly at 2, 3, 4, and 12 months of age

Mild swelling or redness, 0.5 2.0 cm; moderate swelling or redness, 2.5 7.0 cm; severe swelling or severe redness >7cm. Significant tenderness = present and interfered with limb movement.

Figure 2. Percent of infants experiencing systemic events after toddler dose

Fever 38 but 39 Fever >39 but 40 Fever >40 Decreased appetite Decreased sleep Increased sleep Irritability Antipyretics preventive Antipyretics treatment PCV13/PCV13 PCV7/PCV13 PCV7/PCV7

For the additional serotypes, the proportions of responders with an IgG concentration 0.35g/mL were generally comparable between the subjects who received PCV13 following an infant series with PCV7 and the subjects who received PCV13 following a PCV13 infant series (Table 3). Importantly, the proportions of OPA responders and OPA GMTs were also comparable between the 2 study groups. There was no consistent pattern of a relatively greater response within either group. table 3: Serum IgG and Functional (oPA) Responses to the 6 Additional Serotypes 1 Month After the toddler Dose
PCV13/PCV13 oPA n=86-88 % titer 1:8 100.0 100.0 100.0 100.0 100.0 98.8 PCV7/PCV13 % 0.35 g/mL n=108-113 95.5 93.8 90.1 89.9 100.0 100.0 oPA n=89-90 % titer 1:8 98.9 97.8 97.8 98.9 100.0 97.8

Additional Serotype 1 3 5 6A 7F 19A

Local reactions (redness, swelling, and tenderness at the PCV injection site), systemic events (fever, decreased appetite, decreased sleep, increased sleep, and irritability), and use of antipyretics to treat or prevent symptoms were collected within 4 days of the 12-month vaccination using an electronic diary. Adverse events (AE) were collected through one month after the toddler dose. Blood samples for immunogenicity assessment were collected prior to the 12-month toddler dose and 1 month after. A standardized immunosorbant assay (ELISA) was used to measure the concentration of IgG anti-polysaccharide binding antibodies to the 13 pneumococcal serotypes in all PCV7 and PCV13 recipients. Geometric mean IgG antibody concentrations (GMC) and the proportion of subjects who achieved a serotype-specific IgG antibody concentration 0.35 g/mL were determined (based on World Health Organization [WHO] guideline for the determination of potentially effective anti-pneumococcal immune responses).2,3 Functional opsonophagocytic assay (OPA) antibody determinations were performed on a subset of 100 subjects/group for the 6 additional serotypes after the toddler dose for the 2 groups in which the subjects received PCV13 for this dose.

10

20

30

40

50

60

There were no differences in unsolicitied AEs, or serious AEs between the 3 groups.

% 0.35 g/mL n=230-236 100.0 94.8 100.0 100.0 100.0 100.0

GMt 126.0 345.3 244.2 1346.8 8126.2 804.1

GMt 61.6 428.9 131.0 891.4 17034.6 1072.4

GMC = geometric mean concentration; OPA = opsonophagocytic assay; GMT = geometric mean titer

SuMMARy
These data show that in children who received 3 doses of PCV7 followed by a dose of PCV13 in the second year of life, the immune responses to the 7 common serotypes were comparable with those seen in subjects boosted with PCV7. The PCV13 toddler dose after an infant series with PCV7 also elicited robust responses to the 6 additional serotypes that were comparable with the immune responses observed after a 3-dose infant series with PCV13, although somewhat less than the toddler response seen in children who had completed the infant series with PCV13. (The posttoddler responses to serotype 3 were comparable irrespective of whether the subjects had received PCV7 or PCV13 in the infant series.) The higher GMCs in the PCV13/PCV13 group suggest that memory was established for the additional serotypes during the infant series. A toddler dose of PCV13 is well tolerated and safe after an infant series with PCV7 or PCV13. These data indicate that only a single dose of PCV13 is necessary when given after an infant series with PCV7 to elicit appropriate levels of anti-polysaccharide antibodies against the 6 additional serotypes. Given that the 7 common serotype conjugates are identical between the 2 vaccines, and given that the immunogenicity profile of PCV13 has been shown to be similar for these serotypes, it can be recommended that switching to PCV13 can occur at any time in the schedule for infants who have not completed the Prevenar series (infant series and toddler dose).

REFEREnCES
1. GSP Summary Report (Stage1, Version1) for SAGE meeting November 6-8, 2007; October 18, 2007 version (public document). 2. World Health Organization. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Technical Report Series, No. 927, 2005. 3. Jodar L, Butler J, Carlone G, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine. July 4, 2003;21(23): 3265-3272. 4. Grimprel E, Scott D, Laudat F, Baker S, Gruber W. Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine Given with Routine Pediatric Vaccination to Healthy Infants in France. 2nd Vaccine Congress. Boston, MA, 2008. 5. Kieninger D, Kueper K, Steul K, Juergens C, Ahlers N, Baker S, et al. Safety and Immunologic Noninferiority of 13-valent Pneumococcal Conjugate Vaccine Compared to 7-valent Pneumococcal Conjugate Vaccine Given as a 4-Dose Series with Routine Vaccines in Healthy Infants and Toddlers. 46th Annual ICAAC IDSA Meeting. Washington, DC, 2008.

Acknowledgements:
Thanks to all the investigators who participated in the study: Pr. E Grimprel, Paris, and Doctors: R Alt, Strasbourg; O Arwani, Illkirch; P Attal, Garges ls Gonesses; S Barrois, Lyon; B Baszanger, Bourg Saint Maurice Cedex; S Benoit, Tours; B Blanc, Maromme; B Caurier, Jou Les Tours; F Ceccato, Tresses-Melac; F Chateil, Blanquefort; A Costi, Strasbourg; T David, Ecully; V Fournier, Lyon; J Lu Gasnier, Les Sables dOrlonne; M Guy, Nogent sur Marne; F Jeannerot-Meens, Villeneuve dAscq; K Kassmann, Draguignan; Z Klink, Thionville; F Laine, Le Havre; X Lanse, Le Havre; J C Leveque, Chlons en Champagne; J-F Lienhardt, Bondues; B Logre, Floirac; M Luppi, Le Pontet; S Menu Guillemin, Chlons en Champagne; M Navel, Ancenis; F Nourmamode, Talence; A Oudin, Nancy; H Pflieger, Strasbourg; H Porcheret, Challans; D Somerville, Brest; D Sror, Lingolsheim; B Szelechowski, Vitry sur Seine; F Thirion, Villers les Nancy; F Thollot, Essey-les-Nancy; P M Tran, Nice; J-L Vuillemin, Vandoeuvre-les-Nancy; R-R Wisnewsky, Creteil.

Presented at the 27th Annual Meeting of the European Society for Paediatric Infectious Disease (ESPID), June 9-13, 2009, Brussels, Belgium

This study was supported by Wyeth Vaccines Research.