Pneumococcal Conjugate Vaccine for Immunocompromised Patients

1
Pneumococcal Conjugate Vaccine for
Immunocompromised Patients

• Donna M. Ambrosino, M.D.
• Professor and Director
• Massachusetts Biologic Laboratories
• University of Massachusetts Medical School

2
Risk and Immune Response to Polysaccharides

• Age (i.e., elderly)
• Other immunocompromised groups

3
Protective Response Documented toDecline with Age

• Production of high affinity antibodies a
• Long-lasting memory response to immunization b
• DTH to antigens seen in earlier life c
• a Goidl, et al. J. Exp. Med. 144, 1037 (1976)
• b McElhaney, et al. J. Gerentol. Med. Sci. 47,
  MS (1992)
• c Roberts-Thomson, et al., Lancet ii, 368 (1974)

4
Controversial Observation(i.e., conflicting data
exists)

• CD4 / CD8 ratio change during adulthood
• IL4 production changes during adulthood
• IFN-gamma production changes during adulthood
• NK activity changes during adulthood

5
Rates of Invasive Pneumococcal Disease by Age
GroupUnited States, 1998
5
3
CDC. MMWR 2000 49 (no. RR-9)
6
Immunocompromised Patient Groups To Be Discussed

• Asplenics
• Hodgkins Disease Patients
• Sickle Cell Patients
• HIV Patients
• BMT Patients

7
Rate of Invasive Pneumococcal Disease By
Underlying Disease Category
Infants 2 Yrs.
Adults
8
Special Considerations for Vaccine Strategies for
Immunocompromised Patients

• Who to immunize?
• Cost implications
• Immunogenicity
• When to immunize?
• Timing relative to transplant
• Timing relative to disease progression
• Timing relative to splenectomy
• Which vaccine to use?
• 23-valent
• Conjugate
• Both

9
Old Myths Die Hard

• Asplenics actually respond relatively well to
  Polysaccharides

10
IgM and IgG Antibody Responses to Capsular
Polysaccharides of Hib and Pneumococcal Serotypes
IgM HIB
IgG HIB

•  
• Controls
• ? Splenectomized 2 trauma

Molrine DC, et al. J Infect Dis 1999
11
Recommendations for Asplenics

• Use 23-valent vaccine
• For children lt 5 years (at least 2 doses of
  conjugate followed by 23-valent)
• Caveat For ITP patients on steroids, would
  immunize after splenectomy when off steroids
• Red Book 2003 (p. 498)

12
Total anti-HIB Antibody Concentrations in
Patients with Hodgkins Disease Displayed by Time
Since Diagnosis
Before Immunization
? Received additional dose of vaccine before
treatment
After Immunization
Molrine DC, et al. Ann Intern Med 1995
13
Priming with 7-OMPC Conjugate Vaccine Followed By
23-valent in Patients treated for Hodgkins
Disease
plt 0.05


Primed (7OMPC-23PS) Unprimed (23PS)







Chan CY, et al. J Infect Dis 1996
14
Sickle Cell Pneumococcal IgG ELISA Data
PCV7-PCV7-PV23
PV23
PCV7-PCV7-PV23
PV23
Geometric Mean IgG Concentration µg/mL
PV23
PCV7-PCV7-PV23
PV23
PCV7-PCV7-PV23
PV23
PCV7-PCV7-PV23
PCV7-PCV7-PV23
PV23
PV23
PCV7-PCV7-PV23
Vernacchio L et al. J Pediatr 1998133275-8. 
15
Functional Antibody Responses to Pneumococcal
Vaccines in Children and Young Adults with
Sickle Cell Disease
Serotype 6B
Serotype 14
PCV7-PCV7-P23
PCV7-PCV7-PV23
PV23
PV23
Serotype 18C
Serotype 19F
Geometric Mean Opsonophagocytic Titer (Dilution
1)
PCV7-PCV7-PV23
PCV7-PCV7-PV23
PV23
PV23
Serotype 23F
PCV7-PCV7-PV23
PV23
Vernacchio L, et al. J Infect Dis 2000
16
Antibody Responses to Pneumococcal Vaccines among
HIV-infected Adults


plt0.05

Feikin DR, et al. Vaccine 2002
17
Recommendations for Older SCD / HIV Patients

• Conjugate followed by 23-valent may increase
  responses
• No official recommendation to use conjugate for
  these groups for those gt 5 years

18
Ps Vaccines and Hematopoietic Cell Transplants
(i.e., bone marrow, stem cell, etc.)

• Series of studies for HIB and Pneumo Conjugate
  Vaccines

19
Rationale for Immunizations after HCT

• Infections are common after HCT
• Delayed recovery of immune function
• Defects in humoral and cell mediated immunity
• Decline in protective immunity to
  vaccine-preventable diseases

20
Antibody Concentrations to Vaccine-Preventable
Diseases Before and After BMT
Diphtheria
HIB
Polio
Parkkali T, et al. APMIS 1996 104 385-6
21
Effect of Donor Immunization on Antibody
Responses in Allogeneic BMT
Immunized Donor Group
Immunized Donor Group
Unimmunized Donor Group
Unimmunized Donor Group
Molrine, et al. Blood 1996 873014
22
Effect of Pre-harvest Immunization with
HIB-conjugate Vaccine in Autologous BMT


Immunized before harvest
Unimmunized before harvest
Molrine, et al. Bone Marrow Transplant 1996 17
1151
23
Pneumococcal Infections after HCT

• Estimates of pneumococcal disease after HCT range
  from 2 - 36
• Median time of occurrence is 9 - 15 months
• Allogeneic HCT and chronic GVHD are associated
  with higher risk for sepsis

24
Occurrence of Pneumococcal Infection After Blood
or Marrow SCT
Kulkarni S, et al. Blood 2000 95 3684
25
Molrine et al (Blood, 2003)Randomized Study of
Allogeneic Patients

• To examine whether immunization with a
• 7-valent pneumococcal conjugate vaccine (PCV7)
  is immunogenic in BMT patients
• To examine the effect of donor immunization with
  PCV7 on antibody responses of patients immunized
  after BMT

26
Comparison of Antibody Responses to Vaccine
Serotypes of HCT Patients with Immunized Donors
to those with Unimmunized Donors
IgG Antibody µg/ml
Months After Transplant
27
Comparison of Antibody Responses to Vaccine
Serotypes of HCT Patients with Immunized Donors
to those with Unimmunized Donors
IgG Antibody µg/ml
Months After Transplant
28
Antibody Responses of HCT Patients to Non-Vaccine
Serotypes
29
Comparison of Percent Protected to All Seven
Vaccine Serotypes After HCT

• Serotype-specific IgG Pn Ab gt 0.5 ?g/ml
• Donor Group 3 mos 6 mos 12 mos 13 mos
• Immunized 57 67 60 75
• Unimmunized 54 36 35 64
• p value NS 0.05 NS NS
• Serotype-specific IgG Pn Ab gt 1.00 ?g/ml
• Donor Group 3 mos 6 mos 12 mos 13 mos.
• Immunized 43 42 50 65
• Unimmunized 23 7 15 56
• p value NS 0.007 0.02 NS
• 
  
  

30
Antibody Responses to PCV7 Compared to PPV23 at
13 Months Post HCT

• Geometric Mean IgG (?g/ml)
• Serotype P value
• 4 0.0001
• 6B 0.0001
• 9V 0.0001
• 14 0.0001
• 18C 0.0001
• 19F 0.022
• 23F 0.0001

PCV7 Group (3, 6, 12 mos) 2.83 7.38 4.60 8.57 4.14
5.25 6.95
PPV23 Group (12 mos) 0.60 1.11 0.90 1.52 0.74 2
.27 0.54
31
Study Conclusions

• Donor immunization with pneumococcal conjugate
  vaccine enhances antibody responses early after
  HCT
• Three doses of pneumococcal conjugate vaccine are
  immunogenic in HCT patients regardless of donor
  immunization

32
Current CDC Recommendations for Polysaccharide
Immunization after HCT

• Three doses of HIB-conjugate vaccine at 12, 14
  and 24 months after HCT
• Two doses of 23-valent pneumococcal
  polysaccharide vaccine (PPV23) at 12 and 24
  months after HCT.
• MMWR 2000 49(No. RR-10) 84-85

33
Our Recommendations

• Immunization with 7-valent pneumococcal conjugate
  vaccine should be considered for allogeneic HCT
  patients and replace use of 23-valent
  pneumococcal polysaccharide vaccine
• Donor immunization should be used when possible
  to maximize early benefit for HCT patients
• Red Book 2003, Some experts recommend
  multiple-dose schedule of pneumococcal conjugate
  and/or polysaccharide vaccine at 12 and 24
  months.

34
(No Transcript)
35
Comparison of Immunization Schedules after SCT
4 Doses
3 Doses
1 Dose
2 Doses
4 Doses
3 Doses
2 Doses
1 Dose
3
3
Vance E, et al. Bone Marrow Transplant 1998
22737
36
Materials and Methods

• Vaccine
• 7-valent Pneumococcal Conjugate
• (PCV7, Wyeth Lederle Vaccines)
• includes serotypes 4, 6B, 9V, 14, 18C, 19F, 23F
• conjugated to protein carrier CRM197
• Antibody Assay
• IgG ELISA standardized with controls and reagents
  qualified by WLVP