+-------------+--------------------------------------------------------+
| **          | The Alaska Department of Health and Social Services    |
| Abstract:** | recommends vaccination with PPV-23 for all adults aged |
|             | 55 years and older and revaccination with PPV-23 every |
|             | 6 years thereafter. The duration of protection         |
|             | conferred by PPV-23 is not known; however, ACIP does   |
|             | not routinely recommend more than one revaccination    |
|             | because of the lack of safety data. Data are needed to |
|             | determine the safety and immunogenicity of vaccination |
|             | practice in Alaska.                                    |
+-------------+--------------------------------------------------------+
| **Specific  | The objective of the study is to evaluate the safety   |
| aims:**     | and immunogenicity of the State of Alaska's policy of  |
|             | revaccination with 23-valent pneumococcal              |
|             | polysaccharide vaccine (PPV-23) every 6 years for      |
|             | adults aged 55 years and older. The specific aims are: |
|             |                                                        |
|             | (1) to compare incidence and severity of vaccine       |
|             |     reactions in persons aged 55 to 74 years receiving |
|             |     primary vaccination with PPV-23 with those         |
|             |     receiving revaccination at the Alaska Native       |
|             |     Medical Center clinic                              |
|             |                                                        |
|             | (2) to compare antibody response in Alaskan elders     |
|             |     receiving primary PPV-23 with those receiving      |
|             |     revaccination.                                     |
+-------------+--------------------------------------------------------+
| **Ba        | Despite the availability of vaccines, pneumococcal     |
| ckground:** | disease remains a significant cause of morbidity and   |
|             | mortality throughout the world. A 23-valent            |
|             | pneumococcal polysaccharide vaccine (PPV-23) has been  |
|             | licensed in the United States since 1983. The Advisory |
|             | Committee on Immunization Practices (ACIP) recommends  |
|             | a one-time vaccination with PPV-23 for all persons 65  |
|             | years of age or older on the basis of its              |
|             | effectiveness against pneumococcal bacteremia.^1^ One  |
|             | revaccination after 5 or more years is recommended for |
|             | persons aged ≥ 65 years if the first vaccine was given |
|             | before age 65.                                         |
|             |                                                        |
|             | Alaska Natives have a significantly higher rate of     |
|             | invasive pneumococcal disease compared to non-Native   |
|             | Alaskans.^2-4^ Additionally, age-related increases in  |
|             | rates of invasive pneumococcal disease occur at a      |
|             | younger age among Alaska Natives compared to           |
|             | non-Natives living in Alaska. Because of these         |
|             | findings, the state of Alaska has recommended          |
|             | vaccination with PPV-23 beginning at age 55 followed   |
|             | by revaccination every 6 years for all Alaskans.^5^    |
|             |                                                        |
|             | The ACIP does not recommend routine revaccination more |
|             | than once because there are insufficient data on the   |
|             | safety and effectiveness of additional doses. Existing |
|             | data suggest that revaccination with PPV-23 is         |
|             | associated with few systemic adverse events, although  |
|             | local side effects are more common with revaccination  |
|             | than with initial vaccination. A retrospective review  |
|             | found similar rates of local and systemic reactions    |
|             | among 179 Alaska Native elders who received a third    |
|             | dose of PPV-23 compared to 180 receiving a first or    |
|             | second dose.^6^ However, this study was based on a     |
|             | retrospective medical record review and would have     |
|             | only detected the most severe reactions---i.e., those  |
|             | requiring medical care.                                |
|             |                                                        |
|             | Several studies of pneumococcal polysaccharide vaccine |
|             | immunogenicity have documented waning antibody levels  |
|             | 3 to 5 years following vaccination and a variable      |
|             | response to revaccination.^7-10^ In Alaska Natives, an |
|             | earlier study utilizing radioimmunoassay found that    |
|             | anti-capsular antibody levels fall to baseline within  |
|             | 5 years after vaccination, but will rise again after   |
|             | revaccination.^11^ In addition to measurements of      |
|             | antibody levels, assessment of antibody function is    |
|             | perhaps more important in predicting protection        |
|             | against pneumococcal infection. Several assays have    |
|             | been developed to evaluate antibody function including |
|             | avidity and opsonophagocytosis. Studies analyzing      |
|             | antibody function after pneumococcal vaccination in    |
|             | older adults are limited in number and have yielded    |
|             | varying results.^12-14^ No data are available on       |
|             | antibody concentration or function in older patients   |
|             | receiving third or fourth doses of PPV-23.             |
+-------------+--------------------------------------------------------+
| **Study     | This is a 2-year prospective observational study. We   |
| des         | will enroll Alaskans ages 55-74 years of age who       |
| ign/Plan:** | present to their medical provider at the family        |
|             | practice clinic of the Alaska Native Medical Center    |
|             | for primary and repeat doses of PPV-23. Patients will  |
|             | be excluded if 1) fewer than 6 years have passed since |
|             | receipt of PPV-23, 2) there is a history of invasive   |
|             | pneumococcal infection, 3) there is a history of       |
|             | hypersensitivity to any component of the vaccine, 4)   |
|             | there is a history of previous pneumococcal            |
|             | vaccination with the 14-valent vaccine, or 5) the      |
|             | patient has an immunocompromising medical condition or |
|             | is receiving immunosuppressive therapy.                |
|             |                                                        |
|             | We will recruit patients from three groups. Group 1:   |
|             | Persons aged 55-74 years who present for primary       |
|             | PPV-23 vaccination. Group 2: Persons aged 55-74 years  |
|             | who present for their 2^nd^ PPV-23. Group 3: Persons   |
|             | aged 55-74 years who present for their 3^rd^ or 4^th^  |
|             | PPV-23. Many persons will have received the first dose |
|             | of PPV-23 before age 55 years because of               |
|             | non-immunocompromising medical conditions, such as     |
|             | diabetes mellitus or chronic cardiopulmonary diseases. |
|             | All participants will provide informed consent. All    |
|             | participants will have a baseline blood draw and then  |
|             | receive the vaccination. A vaccine diary will be       |
|             | completed by each participant to assess for reactions  |
|             | during the 3 days after vaccination. Parameters of     |
|             | interest include injection site erythema and swelling, |
|             | fever, use of analgesics, or utilization of medical    |
|             | facilities. A repeat blood draw to determine antibody  |
|             | response to vaccination will be obtained one month     |
|             | after vaccination. Patient recruitment and follow-up   |
|             | will be conducting using methods and tools developed   |
|             | as part of a recently completed study comparing        |
|             | immunogenicity and reactogenicity of PPV-23 to that of |
|             | pneumococcal conjugate vaccine in Alaska Native        |
|             | elders.                                                |
|             |                                                        |
|             | Baseline and follow-up sera will be analyzed for 1)    |
|             | levels of pneumococcal capsule-specific IgG, as        |
|             | measured by modified ELISA, 2) opsonophagocytosis, and |
|             | 3) antibody avidity.                                   |
|             |                                                        |
|             | Data from this study will be analyzed by the study     |
|             | personnel at the CDC/AIP. Analysis will address the    |
|             | following questions: 1) Do a higher proportion of      |
|             | persons experience side effects following 3^rd^ or     |
|             | 4^th^ doses of vaccine compared to those receiving     |
|             | 1^st^ or 2^nd^ doses 2) What is the immune response to |
|             | primary vaccination with PPV-23 in Alaskan elders and  |
|             | how does it compare to the response following 2^nd^,   |
|             | 3^rd^, and 4^th^ doses? Chi-square and/or Fisher's     |
|             | exact test will be used to assess and compare the      |
|             | proportion of participants developing reactions in the |
|             | three study groups. Geometric mean concentration will  |
|             | be calculated after log transformation. The proportion |
|             | of participants with greater immune responses than a   |
|             | particular value will be compared using chi square     |
|             | tests and logistic regression analysis.                |
|             |                                                        |
|             | With a sample size of 375 (125 recruited into each     |
|             | Group) we would be able to detect a difference in the  |
|             | proportion of significant local reactions of 5% vs.    |
|             | 15% in primary vaccines vs. repeat vaccinees (2^nd^    |
|             | dose and 3^rd^/4^th^ dose) with α=.05 and β=.20.       |
|             | Because the correlation between antibody function and  |
|             | vaccine effectiveness is unknown, results of           |
|             | immunogenicity analyses will be presented in a         |
|             | descriptive format.                                    |
+-------------+--------------------------------------------------------+

**References**

1\. Centers for Disease Control and Prevention. Prevention of
pneumococcal disease: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep1997;46:1-24.

2\. Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA, Peters HV, Parks
DJ. The epidemiology of invasive pneumococcal disease in Alaska,
1986-1990\--ethnic differences and opportunities for prevention. J
Infect Dis 1994;170:368-76.

3\. Davidson M, Schraer CD, Parkinson AJ, et al. Invasive pneumococcal
disease in an Alaska Native population, 1980 through 1986. JAMA
1989;261:715-8.

4\. Rudolph KM, Parkinson AJ, Reasonover AL, Bulkow LR, Parks DJ, Butler
JC. Serotype distribution and antimicrobial resistance patterns of
invasive isolates of *Streptococcus pneumoniae*: Alaska, 1991-1998. J
Infect Dis 2000;182:490-6.

5\. State of Alaska Section of Epidemiology. Pneumococcal vaccine
program expanded\--routine booster added in Alaska. State of Alaska
Epidemiology Bulletin 1994;10.

6\. Walker F, Singleton R, Bulkow LR, Hurlburt D, Strikas R, Butler JC.
Safety of pneumococcal revaccination among Alaska Native adults.
Abstracts of the 40th Interscience Conference on Antimicrobial Agents
and Chemotherapy.

7\. Mufson MA, Hughey DF, Turner CE, Schiffman G. Revaccination with
pneumococcal vaccine of elderly persons 6 years after primary
vaccination. Vaccine 1991;9:403-7.

8\. Musher DM, Groover JE, Rowland JM, et al. Antibody to capsular
polysaccharides of *Streptococcus pneumoniae*: prevalence, persistence,
and response to revaccination. Clin Infect Dis 1993;17:66-73.

9\. Jackson LA, Benson P, Sneller V-P, et al. Safety of revaccination
with pneumococcal polysaccharide vaccine. JAMA 1999;281:243-248.

10\. Lackner TE, Hamilton RG, Hill JJ, Davey C, Guay DR. Pneumococcal
polysaccharide revaccination: immunoglobulin g seroconversion,
persistence, and safety in frail, chronically ill older subjects. J Am
Geriatr Soc 2003;51:240-5.

11\. Davidson M, Bulkow LR, Grabman J, et al. Immunogenicity of
pneumococcal revaccination in patients with chronic disease. Arch Intern
Med 1994;154:2209-2214.

12\. Artz AS, Ershler WB, Longo DL. Pneumococcal vaccination and
revaccination of older adults. Clin Microbiol Rev 2003;16:308-318.

13\. Romero-Steiner S, Musher DM, Cetron MS, et al. Reduction in
functional antibody activity against *Streptococcus pneumoniae* in
vaccinated elderly individuals highly correlates with decreased IgG
antibody avidity. Clin Infect Dis 1999;29:281-8.

14\. Rubins JB, Puri AK, Loch J, et al. Magnitude, duration, quality,
and function of pneumococcal vaccine responses in elderly adults. J
Infect Dis 1998;178:431-40.