# Presentation: 670977

## Basis for Developing a Pneumococcal Conjugate Vaccine for Adults

**George R. Siber, MD**
**Executive Vice President and **
**Chief Scientific Officer**
**Wyeth Vaccines Research**
**VRBPAC, November 17, 2005**

## Summary

**Need for another pneumococcal vaccine for adults**
**Advantages of the conjugate pneumococcal vaccine**
**Potential public health impact of adult pneumococcal conjugate**
**Proposed regulatory basis for licensing pneumococcal conjugate vaccine for adults**
**Feasibility of efficacy trials for community acquired pneumonia or invasive pneumococcal disease (IPD)**

**Question # 1**
**Why do we need another Pneumococcal Vaccine for Adults?**

## Because there are limitations of 23vPs vaccine

**Antibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991)**
**Effectiveness is very low in immunocompromised patients**
**23vPs induces hyporesponsiveness to either another dose of 23vPs (Torling, et al Vaccine, 2003)  or to a dose of conjugate (deRoux, et al IDSA, 2005)**
**Re-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine, 2005)**
**Therefore, 23vPs is generally given only once, which provides only a narrow window of protection during a prolonged period of risk (ACIP recommendation:  MMWR, 1997)**

## And because there remains a substantial invasive pneumococcal disease burden in the US (2004 rates with 60% uptake of 23vPs Vaccine)

**Cases**

**Cases per 100,000**

**Deaths**

**Age Group Years**

**Estimated # of deaths**

**Age Group Years**

**And because there remains a substantial invasive pneumococcal disease burden in the US (2004 rates with 60% uptake of 23vPs Vaccine)**

**CDC, ABC Surveillance 2004 (provisional)**

**Question #2**
**What are the advantages of a pneumococcal conjugate vaccine for adults?**

## Pneumococcal Conjugate Offers Additional Benefits over Ps Vaccine

**Conjugate antibody responses are significantly better or non-inferior to 23vPs**
- By both ELISA and OPA
**Conjugate does not induce hyporesponsiveness to subsequent 23vPs or a 2****nd**** dose of conjugate**
**Conjugate can therefore be used to extend the age range of protection against pneumococcal disease (i.e.,50-64yo) and to provide long-term protection by repeat dosing, if needed**

## Randomized Trial in Naïve Elderly 70+ years of age (Germany)

**Randomized Trial in Naïve Elderly ****70+ years of age (Germany)**

**PnC**

**PnC**

**Ps**

**Ps**

**PnC**

**(****PnC****/****PnC****)**

**(****PnC****/****Ps****)**

**(****Ps****/****PnC****)**

**Year 1**

**Year 2**

**N = 110**

**N = 109**

- Bleeds for IgG, OPA pre and 1 month post year 1 and year 2 dose

**N=43**

**N=38**

**N=78**

## Immunogenicity of Prevnar vs 23vPs after Dose 1 – ELISA Antibody

*** statistically significant**

*****

*****

*****

*****

** *******

**Immunogenicity of Prevnar vs 23vPs ****after Dose 1 – ELISA Antibody**

*****

**GMC (****μg/ml)**

## Immunogenicity of Prevnar vs 23vPs after Dose 1 – OPA

*****

*****

*****

**OPA GMT**

**7vPnC  N = 110; 23vPs N = 104-107**
*** statistically significant**

*****

## Randomized Trial in Naïve Elderly Does Prior Ps affect the response to PnC?

**Randomized Trial in Naïve Elderly ****Does Prior Ps affect the response to PnC?**

**PnC**

**PnC**

**Ps**

**PnC**

**(****Ps****/****PnC****)**

**Year 1**

**Year 2**

**N = 61**

**Ps**

**N = 62**

## Prior 23vPs Blunts the Response to Subsequent Prevnar (Hyporesponsiveness)

**7vPnC (N=61); 23vPs/7vPnC (N=62)**
***  Statistically significant**

**ELISA GMC (********g/mL)**

*****

*****

*****

*****

*****

*****

## Prior Prevnar Does Not Blunt the Response to a 2nd Dose of Prevnar

**7vPnC (N=61); 7vPnC/7vPnC (N=31)**

**ELISA GMC (********g/mL)**

## Randomized Trial in Naïve Elderly Does prior PnC affect the response to Ps?

**PnC**

**Ps**

**Ps**

**PnC**

**Randomized Trial in Naïve Elderly ****Does prior PnC affect the response to Ps?**

**Year 1**

**Year 2**

**N=62**

**PnC**

**(****PnC/****Ps****)**

**N = 30**

## Prior Prevnar Does Not Blunt the Response to Subsequent 23vPs – ELISA Antibody

**23vPS (N=62); 7vPnC/23vPs (N=30)**

**ELISA GMC (********g/mL)**

## Would Ps induced hyporesponsiveness improve with longer interval?

**ELISA GMC ****μg/ml**

**Seattle Study:  **_**>**_** 5 year interval**
**Wyeth Study:  1 year interval**

**Lisa Jackson, unpublished, by permission**

**Ps/PnC 1 yr (Wyeth) (n=62)**
**Ps/PnC >5yr (Seattle) (n=44)**
**Ps/Ps 5yr (Seattle) (n=44)**

## 23vPS reduces the response to subsequent doses of 23vPS (Torling, Vaccine 2003)

**Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, for serotypes 1, 4, 7F, 14, 18C, and 19F. Note that the *****Y*****-axis scale for serotype 14 differs from the other serotypes. A: before vaccination; B: 4 weeks after vaccination; C: 1 year after vaccination; ****D: revaccination after 4–7 years****; E: 4 weeks after revaccination. . (Torling, Vaccine 2003)**

## Prevnar Immunogenicity in the Elderly support the following

**Prevnar conjugate can be used repeatedly without inducing hyporesponsiveness**
**23vPS can be given after pneumococcal conjugate vaccine without hyporesponsiveness**
**If both vaccine are used to maximize coverage conjugate should be used first **

**Question # 3**
**What is the potential public health impact of pneumococcal conjugate vaccine for adults?**

## Estimated Impact on Invasive Pneumococcal Disease-Simplifying Assumptions:

|  | 23vPs | 13v Conjugate | Reference |
| --- | --- | --- | --- |
| Serotype coverage | 75% | 56% | ABC surv. 2003 |
| IPD rates | See briefing package. Rates adjusted upward for effect of 23vPs (per Fry et al) |  | ABC, 2004 US census |
| Efficacy
(immuno-competent) | 88% for 5 years, declining to 0% by 15 years | 88%
Maintained over at-risk period | Shapiro, NEJM 1991 (PS) |
| Efficacy
(immuno- compromised) | 0% | 0% | Shapiro, NEJM 1991 (PS) |
| Vaccine uptake | 60% in >65 y/o
43% in high risk <65 y/o
0% in healthy <65 y/o | 60% in > 50 y/o       
 | NHIS, 2004/MMWR, 2004 |

## Impact of Extending The Age Range of Protection

**50 yr**

**65 yr**

**70 yr**

**IPD Cases (Deaths) Preventable/yr**

**2979 (489)**

**23vPs alone**

## Impact of Extending The Age Range of Protection

**50 yr**

**65 yr**

**70 yr**

**IPD Cases (Deaths) Preventable/yr**

**2979 (489)**

**23vPs alone**

**13vPnC alone**

**5544 (895)**

**86% more than 23vPs**

## Impact of Extending The Age Range of Protection

**566 (93)**
_**5544 (895)**_

**6110 (988)**

**Impact of Extending The Age Range of Protection**

**50 yr**

**65 yr**

**70 yr**

**IPD Cases (Deaths) Preventable/yr**

**2979 (489)**

**23vPs alone**

**Conjugate with re-vaccination**

**13vPnC alone**

**5544 (895)**

**86% more than 23vPs**

## This is Conservative Estimate of Public Health Impact of PnC	

**1.  Does not assume higher IPD efficacy, despite higher ELISA and OPA antibody responses**
**2.  Does not assume protection of immunocompromised, although HIV (+) patients and other high risk groups respond better to PnC than Ps**
**3.  Assumes no efficacy against pneumonia, although OPA antibody after PnC in elderly is similar to OPA post 3 doses of PnC in infants.**

**Question #4**
**Are serologic studies adequate to demonstrate efficacy of adult pneumococcal conjugate?**

## Historically 2 Approaches Used for Licensure of Polysaccharide-based Vaccines

**1.  When there is no vaccine to prevent the disease in a particular age group, an efficacy trial is required, if feasible**
- 14vPneumococcal Ps
- Group A and C Meningococcal Ps
- Hib Ps in toddlers
- Hib conjugate in infants
- Pneumococcal conjugate in infants
**2.  When there is already a licensed vaccine to prevent the disease in a particular age group, immunogenicity comparison has been acceptable to extend coverage or to improve immunogenicity. **
- 23vPneumococcal Ps after 14vPs in adults
- 4vMeningococcal Ps after 2vPs in adults
- Hib conjugate after Hib Ps in toddlers
- 4vMening conjugate after 4vPs in adolescents

## Proposal Licensing Criteria for Adult Pneumococcal Conjugate

**# 1.****  ****Based on regulatory precedents the efficacy of Pneumococcal conjugate vaccine for adults can be proven by showing serologic non-inferiority to the shared serotypes in the licensed 23vPs vaccine based on OPA**
**# 2. Lack of hyporesponsiveness to 2****nd**** dose of conjugate (which enables using repeated doses, if needed, to maintain protection)**
**# 3. Lack of hyporesponsiveness to 23vPs given subsequently, (which enables extending serotype coverage in high risk groups, if desired)**

## Scientific Basis for Proving Efficacy Based on Serologic Studies

**1.  ****The efficacy/effectiveness of 23vPs is established.  The capsular Ps is the protective antigen**
**2.  Antibody is the protective mechanism against IPD (passive immunization)**
**3.  Opsonophagocytosis is the functional mechanism whereby antibody protects**
**4.  Induction of opsonophagocytic activity (OPA) is believed to correlate with clinical efficacy and is proposed as the primary basis for comparing adult vaccines**
**5.  Antibody binding assays (e.g., ELISA) can be used as a surrogate when they correlate highly with OPA (e.g., in infants after conjugate vaccine.)**

## Efficacy of 23v Ps Vaccine for IPD has been established

| Study | Population | Vaccine | Efficacy vs IPD |
| --- | --- | --- | --- |
| Austrian, 1976 | S. African Miners | 6, 13 valent | 82% * |
| Riley, 1977 | Papua New Guinea | 14 valent | 86%** |

| Study | Population | Vaccine | Efficacy vs IPD |
| --- | --- | --- | --- |
| Shapiro, 1991 | Elderly/high risk | 14, 23  |  |
|  |   Overall | 	 | 56% (42, 67) |
|  |   Immunocompetent |  | 61% (47, 72) |
|  |   Immunocompromised |  | 21% (-55,60) |
| Butler, 1993 | Elderly/high risk
  Overall
  Immunocompetent | 14, 23 valent | 
57% (45, 66)
75% (57, 85) |

**Effectiveness**

**Efficacy**

*** By blood culture ** By blood culture or lung tap**

## Rationale for OPA as a Surrogate for Clinical Efficacy in Adults

**OPA in infants is high and so is efficacy, i.e., high OPA correlates with high efficacy**
**Type 19F has lower OPA in infants than the other 6 types in Prevnar**
**Although efficacy of Prevnar is high for 19F IPD, it is low for otitis media and inhibition of colonization**

## ELISA and OPA of Infants (140-1) after 3 Doses of Prevnar (7 mos)

| Serotype | ELISAGMC (μg/ml) | OPAGMT |
| --- | --- | --- |
| 6B | 5.18 | 1887.6  |
| 9V | 1.88  | 3551.3  |
| 18C | 2.88  | 1558.6  |
| 19F | 4.17  | 203.2  |
| 23F | 2.16  | 4845.5  |

**N=33-34**

## Efficacy of Prevnar in Infants by Serotype

| Serotype | IPD    EfficacyKaiser 1 | IPD Effectiveness(ABC) 2 | Otitis (Finland) 3 | Colonization(Israel) 4 |
| --- | --- | --- | --- | --- |
| 4 | - | 87 (39, 97) | 49 (-176, 91) | - |
| 6B | 86 (-11,100) | 88 (65, 96) | 84 (62, 93) | 88 (46, 91) |
| 9V | 100 (-42, 100) | 100 (79, 100) | 54 (-48, 86) | 61 (17, 82) |
| 14 | 100 (60, 100) | 94 (80, 98) | 69 (20, 88) | 49 (4, 73) |
| 18C | 100 (49, 100) | 96 (82, 99) | 58 (-4, 83) | - |
| 19F | 85 (32, 98) | 81 (52, 93) | 25 (-14, 51) | 21 (-17, 46) |
| 23F | 100 (15, 100) | 96 (70, 99)  | 59 (35, 75) | 47 (12, 67) |
| All VT | 97 (83, 100) | 92 (86, 95) | 57 (44, 78) | 50 (34, 62) |

**Black S., et al PIDJ 2000**
**Whitney C., personal communication**
**Eskola J., NEJM 2001**
**Dagan R., JID 2002**

## Low OPA explains why elderly are at risk of IPD Despite Good ELISA Antibody

**The conundrum:  Elderly adults have similar ELISA antibody levels, even prior to immunization, as infants after Prevnar.  Yet they are at high risk of IPD.**
**The explanation:  Pneumococcal Ab in the elderly have lower opsonic function relative to infant Ab**

## Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar

|  | Infants – Post 3 doses 7vPnC |  | Elderly - Unimmunized |  |
| --- | --- | --- | --- | --- |
|  | ELISA |  | ELISA |  |
| 6B | 5.18 |  | 1.04 |  |
| 9V | 1.88  |  | 0.87 |  |
| 18C | 2.88  |  | 1.15 |  |
| 19F | 4.17  |  | 1.17 |  |
| 23F | 2.16  |  | 0.95 |  |

**Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)**

## Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar

|  | Infants – Post 3 doses 7vPnC |  | Elderly - Unimmunized |  |
| --- | --- | --- | --- | --- |
|  | ELISA | OPA | ELISA | OPA |
| 6B | 5.18 | 1890 | 1.04 | 58.1 |
| 9V | 1.88  | 3550  | 0.87 | 129 |
| 18C | 2.88  | 1560  | 1.15 | 46.9 |
| 19F | 4.17  | 203  | 1.17 | 13.6 |
| 23F | 2.16  | 4850  | 0.95 | 42.4 |

**Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar**

**Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)**

**After a single dose of Prevnar, the elderly increase OPA antibody titers to levels similar to infants after 3 doses**

## OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants

|  | Infants (140-1)(post 3 doses PnC) |  | Elderly (166-508)(post 1 dose PnC) |  |
| --- | --- | --- | --- | --- |
| Type | ELISA | OPA | ELISA | OPA |
| 6B | 5.18 |  | 8.02 |  |
| 9V | 1.88  |  | 9.82 |  |
| 18C | 2.88  |  | 12.97 |  |
| 19F | 4.17  |  | 5.5 |  |
| 23F | 2.16  |  | 12.4 |  |

**Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)**

## OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants

|  | Infants (140-1)(post 3 doses PnC) |  | Elderly (166-508)(post 1 dose PnC) |  |
| --- | --- | --- | --- | --- |
| Type | ELISA | OPA | ELISA | OPA |
| 6B | 5.18 | 1888  | 8.02 | 1351.2 |
| 9V | 1.88  | 3551  | 9.82 | 2914.6 |
| 18C | 2.88  | 1559  | 12.97 | 1317.5 |
| 19F | 4.17  | 203  | 5.5 | 182.2 |
| 23F | 2.16  | 4845  | 12.4 | 1309.3 |

**Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)**

## Proposed Licensing Criteria for Adult Pneumococcal Conjugate

**Demonstrate non-inferiority of the immune response of the shared serotypes in the 13 valent conjugate and 23vPs vaccines**
-    Primary comparison is based on OPA
**Demonstrate no hyporesponsiveness to 2****nd**** dose of 13vPnC**
- To support repeat dosing with 13vPnC for long term protection, if needed
**Demonstrate no hyporesponsiveness to subsequent dose of 23vPs**
- To support extending serotype coverage with 23vPnC in high-risk groups, if desired

**Question #5**
**Is an Efficacy Trial Feasible for Invasive Pneumococcal Disease or Community Acquired Pneumonia?**

## Constraints on Performing Pneumococcal Conjugate Vaccine Efficacy Trials in Adults for CAP or IPD

**Placebo-controlled trial is necessary to assess efficacy of 13vPnC**
**Placebo is not possible in high risk adults who are currently recommended to receive 23vPs**
- > 65 year olds
- < 65 year olds with high risk conditions
**Therefore, only healthy <65 y/o can be studied**
- In this age-group 72% of all invasive disease occurs in high-risk groups (2004 ABC Surveillance).
- Therefore, IPD rates in healthy <65 y/o are much lower than the published rates for this age group overall

## Pneumococcal Conjugate Vaccine Efficacy Trials

**Studies of IPD or CAP in healthy <65y/o would require enormous sample sizes (>100,000/limb) for adequate power**
**Alternative designs (e.g., sequential 13vPnC/23vPs vs 23vPs alone in high risk groups) cannot demonstrate the efficacy of 13vPnC alone and would be even larger than placebo controlled trials**
**Post-marketing effectiveness studies are the only feasible way to assess impact of 13vPnC on IPD and CAP**

## What is the Sample Size to Show IPD  Efficacy Trial in 50-64 y/o Healthy Adults?

**Assumptions:**
**Incidence rate of 25 per 100,000 (high), 15 per 100,000 (intermediate) or 7.5 per 100,000 (low)**
**	**Note:  CDC estimates pre Prevnar (’99-’00) are 9.9/100,000 in healthy 50-64 y/o. (Kyaw et al. JID 2005)
**56% of IPD covered by 13vPnC**
**True V****E**** of 70%, 80% or 90% for vaccine type IPD**
**90% power **
**Lower 95% confidence interval of **_**>**_** 30% **
**Trial length of 3 yrs: 1 yr enrollment, 2 yrs follow-up**

## Invasive Disease Efficacy Trial in 50-64 y/oSample Size Calculations

## Demonstration of Efficacy against CAP is Risky and/or Impractical

**Can ethically study only < 65 y/o without underlying conditions ******** ******** low CAP risk ******** very large sample sizes**
**Proportion of all CAP due to pneumococcus is not known, making required trial size uncertain ******** ******** risk**
**Etiologic diagnosis of pneumonia would enable smaller trial size, but no validated techniques exist (sensitivity and specificity unknown) ******** ******** risk:**
**	****Lack of validated outcome is “show-stopper” for VT-specific CAP efficacy trial**
**Ability to enroll large numbers of healthy, low risk adults and to ascertain outcomes by non-routine methods is uncertain ******** ******** risk**

## Conclusions

**The 13v pneumococcal conjugate vaccine has the potential for a significant public health impact because it can extend the duration of protection throughout the high risk period**
**The 23vPs vaccine may be given after the 13vPnC to expand serotype protection in high-risk patients**
**Efficacy of a conjugate vaccine in adults can be proven by showing non-inferiority of the immune response to the licensed polysaccharide vaccine for the serotypes in the conjugate vaccine **
**Placebo controlled efficacy studies in the adult population are not feasible due to ethical considerations and size**
**Effectiveness against IPD can be confirmed by post marketing studies**

## BACK-UPS

## HIV+ Study: PS can be given after PnC if desired

**Conducted under the auspices of the Agence National de Recherches sur le SIDA (ANRS)**

** ****PnC/23vPS at least as good as or better than 23vPS alone**

**P<0.05 for all serotypes except 6B**

**GMCs after PS**

**1 month interval between vaccines**

## OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants

|  | Infants (140-1)(post 3 doses PnC) |  |  | Elderly (166-508)(post 1 dose PnC) |  |  | Elderly (166-508)(post 1 dose 23vPs) |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Type | ELISA | OPA | OPA/ ELISA | ELISA | OPA | OPA/ ELISA | ELISA | OPA | OPA/ ELISA |
| 6B | 5.18 | 1888  | 364.6  | 8.02 | 1351.2 | 168.5 | 4.56 | 809.2 | 177.3 |
| 9V | 1.88  | 3551  | 1884.4  | 9.82 | 2914.6 | 296.7 | 3.63 | 984.6 | 271.6 |
| 18C | 2.88  | 1559  | 540.9  | 12.97 | 1317.5 | 101.6 | 6.82 | 464.6 | 68.1 |
| 19F | 4.17  | 203  | 48.7  | 5.5 | 182.2 | 33.1 | 4.43 | 202.7 | 45.8 |
| 23F | 2.16  | 4845  | 2243.1  | 12.4 | 1309.3 | 105.7 | 3.97 | 302.4 | 76.3 |

**Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)**

## Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar

|  | Infants – Post 3 doses |  |  | Elderly - Pre |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | ELISA | OPA | OPA/ELISA | ELISA | OPA | OPA/ELISA |
| 6B | 5.18 | 1890 | 365  | 1.04 | 58.1 | 55.7 |
| 9V | 1.88  | 3550  | 1880  | 0.87 | 129 | 147 |
| 18C | 2.88  | 1560  | 541  | 1.15 | 46.9 | 40.7 |
| 19F | 4.17  | 203  | 48.7  | 1.17 | 13.6 | 11.7 |
| 23F | 2.16  | 4850  | 2240 | 0.95 | 42.4 | 44.4 |

**Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)**

**What is the sample size estimate for a CAP efficacy trial?**

## Community Acquired Pneumonia Efficacy Trial in 50-64 y/o Healthy Adults

**Assumptions for sample size calculations:**
- Event rate for CAP of 350 per 100,000 person-years
- 30% of CAP is pneumococcal
- 56% of pneumococcal CAP is vaccine-type (13vPnC)
- Vaccine efficacy of 70% for CAP due to vaccine serotypes
- 90% power
- Lower 95% confidence limit _>_ 0% (and _>_  30% for VTCAP)
- Trial length of 3 yrs: 1yr enrollment, 2yrs mean follow-up

## Community Acquired Pneumonia Efficacy Trial: Sample Size Calculation (50-64 y/o)

**With these assumptions**
- Event rate for CAP due to vaccine types is 58.8 / 100,000                       (350 x 0.3 x 0.56)
- Effectiveness against all CAP is 11.8% (.70 x .30 x .56)
**Sample size per group for average 2 years of follow-up**

|  | No. of cases in placebo gp. | No. of subjects per gp. |
| --- | --- | --- |
| All CAP (LCI95 > 0) | 2,676 | 199,123 |
| VT CAP (LCI95 > 0)
                      (LCI95 > 30)
 | 35
69                                 | 20,420
41,691 |
| (assuming 100% specificity and 100% sensitive assay) |  |  |

**REACTOGENICITY OF Prevnar vs 23vPs in elderly adults**

## Local Reactions* within 7 Days of Prevnar or 23vPs

**Swelling at injection site**

**Pain at injection site**

**Redness at injection site**

*** ****More severe reactions in red **

## Systemic Reactions* within 7 Days of Prevnar or 23vPs

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**7vPnC **

**23vPs **

**7vPnC****-23vPs**

**23vPs****-7vPnC**

**7vPnC****-7vPnC**

**% Subjects**

**Dose 1**

**Dose 2**

*** **

- NS

- NS

*** Fever **_**>**_** 38****°C, fatigue, headache, chills, rash, vomiting, decreased appetite, muscle and/or joint pain. **
** ****Marks significant differences compared to group following hyphen (-).**

## Seattle Study: PnC and Ps as a second dose after Ps > 5 years previous 

**Redness**

**Arm Mvt Limited**

**Pain**

**Swelling**

***Jackson, L., Neuzil, K., Whitney, C. et al Vaccine 2005***

**Local Reactions within 7 Days**

## 23vPS reduces the response to subsequent doses of 23vPS

**Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, and 1 year after primary vaccination, in 61 middle age and elderly persons  (Torling, Vaccine 2003)**

## 23vPS reduces the response to subsequent doses of 23vPS

**Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, and 1 and 3 years after primary vaccination, in 20 middle age and elderly persons.  (Torling, Vaccine 2003)**

## 23vPS reduces the response to subsequent doses of 23vPS

**Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, in relation to age at primary vaccination. Circles: 50–68 years; squares: ≥69 years. (Torling, Vaccine 2003)**

**O = 50 – 68 years**
****** ****= **_**>**_** 69 years**

## 23vPS reduces the response to subsequent doses of 23vPS

**Geometric mean antibody fold increase to six pneumococcal capsular polysaccharide antigen, and all types combined, after primary vaccination and revaccination with 23-valent pneumococcal vaccine in 61 patients. (Torling, Vaccine 2003)**

## 23vPS reduces the response to subsequent doses of 23vPS

**Geometric mean antibody fold increase after primary vaccination and revaccination, respectively. (Torling, Vaccine 2003)**