# Presentation: 575315

## Pneumococcal Conjugate Vaccine for Immunocompromised Patients

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

## Risk and Immune Response to Polysaccharides

- Age (*i.e.*, elderly)
- Other immunocompromised groups

## Protective Response Documented toDecline 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)

## 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

## Rates of Invasive Pneumococcal Disease by Age GroupUnited States, 1998

**5**

**3**

**CDC. MMWR 2000; 49 (no. RR-9)**

## Immunocompromised Patient Groups To Be Discussed

- Asplenics
- Hodgkin’s Disease Patients
- Sickle Cell Patients
- HIV Patients
- BMT Patients

## Rate of Invasive Pneumococcal Disease By Underlying Disease Category

**Infants ≤ 2 Yrs.**

**Adults**

## 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

## Old Myths Die Hard

**Asplenics actually respond relatively well to Polysaccharides**

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

- **Controls**
- ○** ****Splenectomized 2° trauma**

**Molrine DC, et al. J Infect Dis 1999**

**IgM HIB**

**IgG HIB**

## Recommendations for Asplenics

- Use 23-valent vaccine
- For children _<_ 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)

## Total anti-HIB Antibody Concentrations in Patients with Hodgkin’s Disease Displayed by Time Since Diagnosis

**● ****Received additional dose of  vaccine before treatment  **

**Molrine DC, et al.  Ann Intern Med 1995**

**Before Immunization**

**After Immunization**

## Priming with 7-OMPC Conjugate Vaccine Followed By 23-valent in Patients treated for Hodgkin’s Disease

** ****p< 0.05**

- *

- *

- *

- *

- *

- *

- *

- *

- *

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

**Chan CY, et al. J Infect Dis 1996**

## Sickle Cell Pneumococcal IgG ELISA Data

**PCV7-PCV7-PV23**

**PV23**

**PCV7-PCV7-PV23**

**PV23**

**PV23**

**PCV7-PCV7-PV23**

**PCV7-PCV7-PV23**

**PV23**

**PCV7-PCV7-PV23**

**PV23**

**PCV7-PCV7-PV23**

**PV23**

**PV23**

**PCV7-PCV7-PV23**

**Vernacchio L et al. J Pediatr 1998;133:275-8. **

**Geometric Mean IgG Concentration ****μg/mL**

## Functional Antibody Responses to Pneumococcal Vaccines in Children and Young Adults with Sickle Cell Disease

**Functional Antibody Responses to Pneumococcal Vaccines in Children and Young Adults ****with Sickle Cell Disease**

**Serotype 6B**

**Serotype 14**

**PCV7-PCV7-P23**

**Geometric Mean Opsonophagocytic Titer (Dilution –1)**

**Serotype 18C**

**PCV7-PCV7-PV23**

**Serotype 19F**

**PCV7-PCV7-PV23**

**PV23**

**Serotype 23F**

**PCV7-PCV7-PV23**

**PCV7-PCV7-PV23**

**PV23**

**PV23**

**PV23**

**PV23**

**Vernacchio L, et al. J Infect Dis 2000**

## Antibody Responses to Pneumococcal Vaccines among HIV-infected Adults

**Feikin DR, et al.  Vaccine 2002**

- *

- *

- *

**p<0.05**

## 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 _>_ 5 years

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

**Series of studies for HIB and Pneumo Conjugate Vaccines**

## 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

## Antibody Concentrations to Vaccine-Preventable Diseases Before and After BMT

**HIB**

**Diphtheria**

**Polio**

- Parkkali T, *et al*. APMIS 1996; 104: 385-6

## Effect of Donor Immunization on Antibody Responses in Allogeneic BMT

- Molrine, *et al*. Blood 1996; 87:3014

- Immunized Donor Group

- Immunized Donor Group

- Unimmunized Donor Group

- Unimmunized Donor Group

## 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

- *

- *

## 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

## Occurrence of Pneumococcal Infection After Blood or Marrow SCT

**Kulkarni S, *****et al*****. Blood 2000; 95: 3684**

## 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

## 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**** **

**Comparison of Antibody Responses to Vaccine Serotypes of HCT Patients with Immunized Donors to those with Unimmunized Donors**

## Comparison of Antibody Responses to Vaccine Serotypes of HCT Patients with Immunized Donors to those with Unimmunized Donors

**Months After Transplant**

**IgG Antibody μg/ml**

**Comparison of Antibody Responses to Vaccine Serotypes of HCT Patients with Immunized Donors to those with Unimmunized Donors**

## Antibody Responses of HCT Patients to

**Non-Vaccine Serotypes**

## Comparison of Percent Protected to All Seven Vaccine Serotypes After HCT

**Serotype-specific IgG Pn Ab **_**>**_** 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 **_**>**_** 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

## 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

## 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

## 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**

## 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.”

## Comparison of Immunization Schedules after SCT

- Vance E, *et al*. Bone Marrow Transplant 1998; 22:737

-  1 Dose

- 2 Doses

- 3 Doses

- 4 Doses

- 4 Doses

- 3 Doses

- 2 Doses

- 1 Dose

**3**

**3**

## 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