Is early revaccination after ALL therapy feasible ?
Evaluation of loss of antibodies and responsiveness to (re-)vaccination in children after treatment for acute lymphocytic leukemia.

Tailored and intensified therapy for children with ALL (acute lymphatic
leukaemia) has led to an improved 5 years survival, instead of the earlier 80%,
it approaches now the 90%. (1-5) Attending this low mortality rate after the
end of treatment means preventing invasive vaccin preventable infections. There
are only a few studies with respect to the incedence of such diseases. (11-14)
Chemotherapy is immunosuppressive, it causes a decrease of the number of B and
T cells. The immunity against infections is diminished, there is a loss of
protective antibody level provided by previous immunizations and reduced
efficacy of (re-) immunization. (16,17)
It is still not clear if and when children require revaccination after
completion of chemotherapy for ALL. The numbers of B and T-cells increase from
3 months after the end of treatment but a complete recovery may take up to 1
year. (11-13) The number of B cells is recovering faster than the CD4 T helper
cells. (13,14) The number of memory T cells remain mostly intact. Quick (re-)
vaccination, keeps the vulnerable period for potentially very threatening
diseases as short as possible. A recent survey showed a good response on (re)
vaccination (H. influenzae B, Tetanus, Meningokokken C, Polio and Measles) 6
months after the end of chemotherapy. (25) This response may differ for
conjugated (T cell dependent) and polysaccharides (T cell independent)
vaccines, this hasn't been investigated in this population. We've included both
types of pneumococcal vaccine in the (re) vaccination program. The use of both
vaccins will result in the expansion of serotype coverage in the high risk
children and older age groups. Besides we know children with ALL carry a more
than 10-fold higher risk of invasive pneumococcal disease than the general
pediatric population. (11,12)

To determine effect of early (re) vaccinations after the current intensive
chemotherapy for ALL. We will determine if there is a difference in respons to
conjugated (T cell dependent) and polysaccharide (T cell independent) vaccines.
This may result in a guideline for the revaccination of children treated with
standard antileukemia chemotherapy in the Netherlands.

Prospective multicenter study.
Patients will be revaccinated with the DKTP-Hib, BMR, MenC and 7 valent
conjugate pneumococcal vaccines from the Dutch National Infant Vaccination
Programme and will be vaccinated with 23- valent polysaccharide pneumococcal
vaccine, after they finished DCOG ALL10 protocol treatment. Responses will be
measured in serum 4 weeks after each vaccination. Simultaneously,
immunophenotypic reconstitution will be measured by flowcytometry.

Prospective multicenter trial. The study will take place in 4 university
medical centers in the Netherlands. (UMC Utrecht, VU MC, AMC and UMCG) .The
duration will be 7 months. In the flow chart below an overview of the
procedures that subjects will undergo in the course of research.

T= -1 month
- To fill in a questionnaire (part of the CRF); questions about their pre- ALL
vaccination status, if they had immunoglobulins during treatment etc.

T=0 months (after completion chemotherapy = END ALL10 chemotherapy, ± 2 weeks)
- Venapunction (VP) 1 (during anesthesia for regular ALL 10 treatment bone
marrow
puncture)
- Immunophenotyping (UMC Utrecht only)
- Serostatus DKTP-Hib, BMR, MenC, Pneu
• If the patient has a protective serostatus* against each vaccine preventable
disease he/she will be excluded from the rest of the study.
• If the patient has a protective serostatus* against >= 1 of each vaccine
preventable he/she will not be vaccinated against these diseases, but will get
the vaccines against the diseases he/she is not protected to..



T=3 months (± 2 weeks)
- VP 2
- Serostatus DKTP-Hib, BMR, MenC, Pneu
- Immunophenotyping (UMC Utrecht only)
- Vaccination in separate limbs:
- DKTP-HiB vaccine (Pediacell+Hib®): 0,5 ml i.m.
- 7-Valent Pneumococcen conjugaat vaccine (Prevenar®): 0,5 ml i.m.

T=4 months (± 2 weeks)
- VP 3
- Serostatus DKTP-Hib, BMR, MenC, Pneu
- Vaccination
- 7-Valent Pneumococcen conjugaat vaccine (Prevenar®): 0,5ml i.m.
- Meningococcus type C conjugaat vaccin (NeisVac-C®): 0,5 ml i.m.

T=5 months (± 2 weeks)
- VP 4
- Serostatus DKTP-Hib, BMR, MenC, Pneu

T= 6 months (± 2 weeks)
- VP 5
- Serostatus DKTP-Hib, BMR, MenC, Pneu
- Immunophenotyping (UMC Utrecht only)
- Vaccination in separate limbs:
- Pneumococcal vaccine 23-valent polysaccharide (Pneumo 23®): 0,5 ml i.m
- BMR-Vaccine RIVM: 0,5 ml s.c. (upper arm)

T= 7 months (± 2 weeks)
- VP 6
- Serostatus DKTP-Hib, BMR, MenC, Pneu

* Protected when:
- DKTP-HiB vaccine: Hib, anti-PRP antibody concentrations >=1, 0 µg/mL
- 7-Valent Pneumococcen conjugaat vaccine: a geometric mean concentration of >=
0, 35
µg/ml.
- Pneumococcal vaccine 23-valent polysaccharide: a geometric mean concentration
of
>= 0, 35 µg/ml.
- Meningococcus type C conjugaat vaccine SBA titer >=1:128.
- BMR-Vaccine: Any detectable titer of neutralizing antibody against
poliovirus. For measles,
a concentration>= 120 mIU/mL.

Burden:
6 venapunctures
a maximum of 5 i.m. injections
a maximum of 1 s.c. injection

Risk:
Vaccination reaction

Benefit:
Protection against vaccine preventable diseases