Vaccine Information: PREVNAR 13 (Page 6 of 8)

14.3 Prevnar 13 Immunogenicity Clinical Trials in Adults

Six Phase 3 or Phase 4 clinical trials^{6–8,10,11,13} were conducted in the US and Europe evaluating the immunogenicity of Prevnar 13 in different adult age groups, in individuals who were either not previously vaccinated with PPSV23 (PPSV23 unvaccinated) or who had received one dose of PPSV23 (PPSV23 previously vaccinated).

Each study included healthy adults and immunocompetent adults with stable underlying conditions including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviors (e.g., alcoholism and smoking) that are known to increase the risk of serious pneumococcal pneumonia and invasive pneumococcal disease. A stable medical condition was defined as a medical condition not requiring significant change in therapy (i.e., change to new therapy category due to worsening disease) or hospitalization for worsening disease 6–12 weeks prior to receipt of the study vaccine.

Immune responses elicited by Prevnar 13 and PPSV23 were measured by a mcOPA antibody assay for the 13 pneumococcal serotypes contained in Prevnar 13. Serotype-specific mcOPA antibody GMTs measured 1 month after each vaccination were calculated. For the 12 serotypes in common to both vaccines, noninferiority between vaccines was met if the lower limit of the 2-sided 95% confidence interval (CI) of the GMT ratio (Prevnar 13/PPSV23) was greater than 0.5.

The response to the additional serotype 6A, which is contained in Prevnar 13 but not in PPSV23, was assessed by demonstration of a ≥4-fold increase in the anti-6A mcOPA antibody titer above preimmunization levels. A statistically significantly greater response for Prevnar 13 was defined, for the difference in percentages (Prevnar 13 minus PPSV23) of adults achieving a ≥4-fold increase in anti-6A mcOPA antibody titer, as the lower limit of the 2-sided 95% CI greater than zero. For comparison of mcOPA antibody GMTs, a statistically greater response for serotype 6A was defined as the lower limit of the 2-sided 95% CI of the GMT ratio (Prevnar 13/PPSV23) greater than 2.

Of the 6 Phase 3 or Phase 4 clinical trials, 2 noninferiority trials^6,7 were conducted in which the immune responses to Prevnar 13 were compared with the immune responses to PPSV23; one in PPSV23 unvaccinated adults aged 18 through 64 years⁶ (Study 6), and one in PPSV23 previously vaccinated adults aged ≥70 years⁷ (Study 7). A third study compared immune responses to a single dose of Prevnar 13 to the response to Prevnar 13 administered one year after a dose of PPSV23 in adults aged 60 through 64 years who were PPSV23 unvaccinated at enrollment⁸ (Study 8). The study also compared immune responses of PPSV23 as a single dose to the responses to PPSV23 administered one year after a dose of Prevnar 13. Two studies assessed the concomitant administration of Prevnar 13 with seasonal inactivated Fluarix (IIV3) in the US¹⁰ (Study 10) and Europe¹¹ (Study 11). One study (Study 13) assessed the concomitant administration of Prevnar 13 with seasonal inactivated Fluzone Quadrivalent (IIV4) in PPSV23 previously vaccinated adults ≥50 years of age in the US.

Overall across the clinical studies evaluating the immunogenicity of Prevnar 13 in adults, persons 18 through 64 years of age responded at least as well as persons 65 years and older, the age group evaluated in a clinical endpoint efficacy trial.

Clinical Trials Conducted in PPSV23 Unvaccinated Adults

In an active-controlled modified 1 double-blind clinical trial⁶ (Study 6) of Prevnar 13 in the US, PPSV23 unvaccinated adults aged 60 through 64 years were randomly assigned (1:1) to receive Prevnar 13 or PPSV23. In addition, adults aged 18 through 49 years and 50 through 59 years were enrolled and received one dose of Prevnar 13 (open-label).

In adults aged 60 through 64 years, the mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by PPSV23 for the 12 serotypes in common to both vaccines (see Table 24). In addition, the lower limit of the 95% confidence interval for the mcOPA antibody GMT ratio (Prevnar 13/PPSV23) was greater than 1 for 8 of the serotypes in common.

For serotype 6A, which is unique to Prevnar 13, the proportion of subjects with a ≥4-fold increase after Prevnar 13 (88.5%) was statistically significantly greater than after PPSV23 (49.3%) in PPSV23-unvaccinated adults aged 60 through 64 years. OPA antibody GMTs for serotype 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23 (see Table 25).

The mcOPA antibody GMTs elicited by Prevnar 13 in adults aged 50 through 59 years were noninferior to the corresponding mcOPA antibody GMTs elicited by Prevnar 13 in adults aged 60 through 64 years for all 13 serotypes (see Table 25).

In adults aged 18 through 49 years, the mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by Prevnar 13 in adults aged 60 through 64 years for all 13 serotypes (see Table 25).

Table 25: mcOPA Antibody GMTs in PPSV23-Unvaccinated Adults Aged 18 Through 49 Years or Aged 50 Through 59 Years Given Prevnar 13 and in Adults Aged 60 Through 64 Years Given Prevnar 13 or PPSV23 (Study 6)*^, †^, ‡^, §^, ¶

	Prevnar 13	Prevnar 13	Prevnar 13	PPSV23	Prevnar 13 18–49 Relative to 60–64 Years	Prevnar 13 50–59 Relative to 60–64 Years	Prevnar 13 Relative to PPSV23, 60–64 Years #
Serotype	18–49 Years Þ N=836–866	50–59 Years Þ N=350–384	60–64 Years N=359–404	60–64 Years N=367–402
	GMT	GMT	GMT	GMT	GMT Ratio (95% CI)	GMT Ratio (95% CI)	GMT Ratio (95% CI)
GMT, Geometric Mean Titer.
* Study conducted in US NCT00427895 (Study 6). † Noninferiority was defined for the 13 serotypes in adults aged 18 to 49 years, for the 12 common serotypes in adults aged 60 to 64 years and for the 13 serotypes in adults aged 50 to 59 years as the lower limit of the 2-sided 95% CI for GMT ratio greater than 0.5. ‡ mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured. § Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. ¶ Evaluable Immunogenicity Population. # For serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined for analysis in cohort 1 as the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2. Þ Open label administration of Prevnar 13. ß 6A is a serotype unique to Prevnar 13 but not contained in PPSV23.
1	353	211	158	119	2.4(2.03, 2.87)	1.3(1.07, 1.65)	1.3(1.07, 1.65)
3	91	94	96	90	1.0(0.84, 1.13)	1.0(0.82, 1.18)	1.1(0.89, 1.29)
4	4747	2904	2164	1405	2.3(1.92, 2.76)	1.3(1.06, 1.70)	1.5(1.18, 2.00)
5	386	322	236	198	1.9(1.55, 2.42)	1.4(1.08, 1.74)	1.2(0.95, 1.50)
6A ß	5746	4469	2766	343	2.2(1.84, 2.67)	1.6(1.28, 2.03)	8.1(6.11, 10.67)
6B	9813	3350	2212	998	4.9(4.13, 5.93)	1.5(1.20, 1.91)	2.2(1.70, 2.89)
7F	3249	1807	1535	829	2.9(2.41, 3.49)	1.2(0.98, 1.41)	1.9(1.52, 2.26)
9V	3339	2190	1701	1012	2.9(2.34, 3.52)	1.3(1.08, 1.53)	1.7(1.40, 2.02)
14	2983	1078	733	819	4.9(4.01, 5.93)	1.5(1.14, 1.89)	0.9(0.69, 1.16)
18C	3989	2077	1834	1074	2.3(1.91, 2.79)	1.1(0.89, 1.44)	1.7(1.32, 2.21)
19A	1580	968	691	368	2.3(2.02, 2.66)	1.4(1.17, 1.68)	1.9(1.53, 2.30)
19F	1533	697	622	636	3.0(2.44, 3.60)	1.1(0.89, 1.41)	1.0(0.78, 1.23)
23F	1570	531	404	87	4.2(3.31, 5.31)	1.3(0.96, 1.80)	4.6(3.37, 6.38)