Phase 1 trial of a 13-valent pneumococcal conjugate vaccine in healthy adults

Vaccine 25 (2007) 6164–6166

Short communication

Phase 1 trial of a 13-valent pneumococcal conjugate vaccine in healthy adults夽,夽夽 Daniel A. Scott a , Steven F. Komjathy b , Branda T. Hu a , Sherryl Baker a , Lois A. Supan a , Carol A. Monahan a , William Gruber a , George R. Siber a , Stephen P. Lockhart c,∗ a

c

Wyeth Vaccines Research, 401 N. Middletown Road, Pearl River, NY 10965, USA b PRA International, Clinical Pharmacology Center, Lenexa, KS 66219, USA Wyeth Vaccines Research, Huntercombe Lane South, Taplow, Maidenhead SL6 0PH, United Kingdom Received 4 April 2007; received in revised form 25 May 2007; accepted 4 June 2007 Available online 26 June 2007

Abstract In a Phase 1 study, 15 healthy subjects were randomized to receive a 13-valent pneumococcal conjugate vaccine (PCV13) and 15 to receive a 23-valent pneumococcal polysaccharide vaccine (23vPS). Antibody responses were measured immediately before and approximately one month after vaccination. Serotype-specific antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) and an opsonophagocytic assay (OPA) for functional antibodies. PCV13 was as immunogenic or more immunogenic than 23vPS and was well tolerated. © 2007 Elsevier Ltd. All rights reserved. Keywords: 13-valent; Pneumococcal; Conjugate; Vaccine; Adult; Immunogenicity; IgG; Opsonophagocytic; Reactogenicity; Safety

The introduction in the USA of a 7-valent pneumococcal conjugate vaccine (PCV7, Prevnar® ) covering serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F has had a substantial impact on invasive pneumococcal disease (IPD) in infants and, by an indirect effect, in adults [1]. A 13-valent pneumococcal conjugate vaccine (PCV13) has been developed, which uses the same protein carrier (nontoxic diphtheria toxin crossreactive material 197; CRM197 ) as PCV7, and covers the same serotypes as PCV7, but also includes conjugates to serotypes 1, 3, 5, 6A, 7F, and 19A. Although there are some variations between regions, serogroups 1, 3, 5, and 7 are common causes of IPD around the world [2,3]. Serotype 6B in 夽 This study was presented in part at the Fifth International Conference on Pneumococci and Pneumococcal Diseases, Alice Springs, Australia in April 2006 (Abstract PO10.21). 夽夽 Daniel Scott, Branda Hu, Sherryl Baker, Lois Supan, Carol Monahan, William Gruber, and Stephen Lockhart are employees of Wyeth. George Siber was an employee at the time the study was conducted and is now retired. This study was funded by Wyeth. ∗ Corresponding author. Tel.: +44 1628 413 889; fax: +44 1628 413 891. E-mail address: [email protected] (S.P. Lockhart).

0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.06.004

PCV7 produces only partial protection against serotype 6A [1]. Serotype 19F in PCV7 appears to produce poor protection against serotype 19A; although small compared to the overall reduction in IPD, there has been an increase in serotype 19A IPD since the introduction of PCV7 [4]. This report describes a Phase 1 clinical trial of PCV13 in healthy adults. A total of 30 healthy adults (mean age 30.4 years, range 18–49 years), who had not received prior pneumococcal immunization, were enrolled at a single center in Lenexa, Kansas, USA, and randomized to receive a single intramuscular dose of either PCV13 (n = 15) or a 23-valent pneumococcal polysaccharide vaccine (23vPS; n = 15). All subjects were evaluable for immunogenicity and safety. Demographic characteristics of the two groups were comparable for gender, ethnicity, and age distribution. PCV13 contains 2 ␮g of each pneumococcal serotype except for 4 ␮g of serotype 6B, 29 ␮g of CRM197 , succinate buffer, and aluminum phosphate. 23vPS includes 25 ␮g of each polysaccharide and includes all serotypes covered by PCV13 except serotype 6A. Subjects recorded local reactogenicity in a diary on the day of vaccination and for the

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Table 1 Antibody measurements approximately one month after vaccination OPA (titer−1 )

IgG (␮g/mL) PCV13

23vPS

PCV13

23vPS

Serotype

GMC

(95% CI)

GMC

(95% CI)

GMT

(95% CI)

GMT

(95% CI)

1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F

3.11 2.21 2.17 7.07 17.42 24.47 6.01 5.13 12.89 17.80 17.25 14.43 17.45

(1.48, 6.54) (1.49, 3.28) (0.88, 5.40) (2.67, 18.72) (9.83, 30.86) (13.43, 44.57) (2.82, 12.84) (3.10, 8.48) (5.39, 30.83) (9.91, 31.97) (11.41, 26.07) (7.00, 29.76) (9.39, 32.44)

3.01 1.31 2.34 3.36 4.48 7.28 5.36 3.56 11.40 2.95 8.30 4.34 2.47

(1.73, 5.25) (0.73, 2.35) (1.23, 4.43) (1.33, 8.46) (2.87, 6.99) (4.23, 12.53) (2.66, 10.80) (2.55, 4.95) (4.41, 29.42) (1.25, 6.93) (5.31, 12.96) (2.00, 9.40) (0.90, 6.82)

467 35 2580 489 2702 5161 2964 10809 9855 2464 741 1351 3566

(193, 1126) (19, 64) (1727, 3856) (161, 1483) (1148, 6360) (254, 10453) (1553, 5659) (5762, 20277) (5570, 17437) (1051, 5775) (416, 1321) (629, 2904) (1330, 9559)

244 13 2353 323 140 1867 3251 4705 8579 741 562 708 588

(123, 486) (9, 19) (1553, 3564) (117, 887) (43, 464) (677, 5148) (1767, 5982) (2066, 10718) (5772, 12754) (198, 2776) (198, 1597) (383, 1306) (328, 1055)

Geometric mean concentration (GMC) for serotype specific IgG is in ␮g/mL. Geometric mean titer (GMT) for opsonophagocytic assay is in inverse titer.

subsequent 14 days. They also recorded oral temperature daily at bedtime, and whenever they felt feverish, for seven days. Adverse events were recorded up to the one-month visit. Blood samples were obtained from all subjects just prior to vaccination and approximately one month after vaccination. Pneumococcal serotype-specific anticapsular polysaccharide IgG for each of the serotypes in PCV13 was measured by ELISA using both C-polysaccharide and 22F serotype capsular polysaccharide absorption, as previously described [5]. Functional opsonophagocytic antibodies were measured by an in vitro OPA method using differentiated HL60 cells as effector cells. The OPA titer was expressed as the reciprocal of the serum dilution that caused a 50% reduction of the colony-forming units compared to a control that contained no human serum, as previously described [6]. Confidence limits on geometric mean concentrations (GMCs) and geometric mean titers (GMTs) were back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers. This trial was performed under an Investigational New Drug Application (IND) and was approved by the Mid*Lands Institutional Review Board (Leawood, Kansas, USA). All subjects gave written informed consent for their study participation. No subjects experienced fever of 38 ◦ C or higher on the day of vaccination or during the subsequent seven days. One subject in the PCV13 group and two subjects in the 23vPS group reported induration at the injection site. One subject in the PCV13 group and three subjects in the 23vPS group reported redness at the injection site. In no instance did the induration or redness exceed 4 cm. All 15 subjects in the PCV13 group reported injection site tenderness, as did 13 of the 15 subjects in the 23vPS group. This was reported as interfering with limb movement by 10 subjects in the PCV13 group and four subjects in the 23vPS group. Two subjects in the PCV13 group reported three adverse events (abdominal pain, nail avulsion, and myalgia) and three subjects in the 23vPS group reported three adverse events (thirst, conjunc-

tivitis, and headache). No adverse events were considered to be related to study vaccine. No serious adverse events were reported during this trial. Antibody responses are summarized in Table 1. Point estimate GMCs of pneumococcal serotype-specific antibodies were higher for 11 of 12 matching serotypes (except serotype 4) in the PCV13 group compared to the 23vPS group. Similarly, point estimate OPA GMTs in the PCV13 group exceeded those in the 23vPS group for 11 of 12 matching serotypes (except serotype 7F). Matching serotypes for which the PCV13 group had greater responses than the 23vPS group with nonoverlapping 95% confidence intervals were serotypes 6B, 18C, and 23F for IgGs, and serotype 3 for OPAs. The IgG GMC for serotype 4 and OPA GMT for serotype 7F were lower in the PCV 13 group than in the 23vPS group, but 95% confidence intervals overlapped. For serotype 6A, which is not included in 23vPS, the PCV13 group IgG GMC and OPA GMT were greater than for the 23vPS group, with nonoverlapping 95% confidence intervals. Our findings are consistent with two other studies that assessed ELISA IgG responses to an investigational 5-valent pneumococcal oligosaccharide CRM197 conjugate vaccine in previously unimmunized healthy adults <65 years of age [7,8], which showed higher responses to some serotypes after a conjugate vaccine compared to responses after 23vPS. Studies with an investigational 11-valent diphtheria toxin and tetanus toxin mixed-carrier vaccine [9] and PCV7 [10] also showed generally higher IgG GMCs after a conjugate vaccine compared to a 23vPS vaccine. However, these studies were too small to achieve significance. In contrast, studies with an investigational 4-valent [11] or 7-valent vaccine using a meningococcal outer membrane protein as the conjugate protein [12,13] generally have shown lower IgG GMCs after a conjugate vaccine than after 23vPS, although the differences were not significant in these small studies. In general, both vaccines were well tolerated. There was more tenderness at the injection site, including tenderness

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interfering with limb movement, in the PCV13 group than 23vPS group. This will require further study in larger trials in target populations. In conclusion, PCV13 was more immunogenic than 23vPS for most of the shared serotypes in the two vaccines. PCV13 was generally well tolerated. Results from this Phase 1 study with 15 subjects receiving PCV13 justify further clinical development of PCV13 in infants and adults.

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