Tuesday, May 27, 2008

Immunodeficiency 6


Patients commonly ask whether they should receive vaccinations. Their enquiries have two purposes; they want to know if vaccination is safe and if it is effective. Although vaccination may sometimes transiently raise the peripheral lymphocyte count, there is no evidence that it triggers an exacerbation of the CLL. On the other hand, patients with CLL should be regarded as immunodeficient as far as vaccination with live attenuated organisms is concerned and these should be avoided. A list of such vaccines is given in Table 1.

Table 1

Vaccines that should be avoided in CLL

Poliomyelitis (oral)
Typhoid (oral)
Yellow fever

Vaccines that are permissible

Cholera (oral)
Haemophilus influenzae type b
Hepatitis A
Hepatitis B
Poliomyelitis (injection)
Tick-borne encephalitis
Typhoid (injection)

Patients with CLL respond very poorly to vaccination. Even newly diagnosed Rai stage 0 patients with normal serum immunoglobulins fail to mount a primary response against a previously unseen antigen though on repeated injection about half the patients are able to mount a secondary response at a level substantially less than in normal individuals [33]. Vaccination studies in CLL have been comprehensively reviewed by Sinisalo [34]. Over the past fifty years there have been numerous investigations of vaccination against Streptococus pneumoniae, Haemophilus influenzae type b, influenza, tetanus, diphtheria, mumps, and Salmonella typhi. In general antibody responses to vaccines have been weak. Protein vaccines have produced weak to moderate responses in up to 50% of patients, chiefly in early stage patients with normal serum immunoglobulin levels, but responses to polysaccharide vaccines have been virtually zero [34]. There have been several attempts to enhance responses.

Histamine exerts a complex influence on the immune response via receptors on dendritic cells, macrophages and T and B lymphocytes. It is involved in the regulation or helper T cell polarity and through the type 2 histamine receptor interferes with regulatory T cell function [35]. Attempts have been made to enhance antibody responses to vaccines using the H-2 antagonist, ranitidine. One such study used ranitidine 300mg twice daily for 90 days in an attempt to enhance antibody production to Haemophilus influenzae type B (Hib) conjugated to tetanus toxoid and influenza virus with vaccines given on day 0 and boosted on day 45. The study showed a significantly increased response rate of 90% compared with 43% for controls in patients receiving the ranitidine with the Hib vaccine though no significant difference could be seen for the influenza vaccine [36]. Improved responses to the tetanus toxoid conjugated Hib vaccine against both Hib and tetanus were also reported following ranitidine treatment by an independent group, but ranitidine failed to induce any responses to an unconjugated pneumococcal polysaccharide vaccine. Patients receiving ranitidine had higher levels of interleukin-18, a proinfllammatory cytokine that induces T cells to produce -interferon [37].

The problem of poor response to polysaccharide vaccines can be partially overcome by conjugation to protein antigens. In the case of Hib, conjugation to tetanus toxoid is effective [36, 37]. For pneumococcal vaccines, conjugation to diphtheria CRM197 carrier protein produces an more effective vaccine capable of elliciting antibody responses in 40% of patients with CLL, most effectively in Binet stage A patients [38]. Studies using this vaccine with ranitidine are awaited.

Patients with CLL undergoing splenectomy will almost certainly not benefit from vaccination with pneumococcal polysaccharide vaccines. Vaccination with the conjugated vaccine maight be tried, but prophylaxis with appropriate antibiotics should be considered mandatory.


33. Hamblin-TJ, Verrier jones J, Peacock DB. The immune response to phiX174 in man IV Primary and secondary antibody production in patients with chronic lymphocytic leukaemia. Clin Exp Immunol 1975; 21:101-8.
34. Sinisalo M. Responses to vaccine antigens in chronic lymphocytic leukaemia. Academic Dissertation. University of Tampere Medical School, Finland. 2008. Available at http://acta.uta.fi/pdf/978-951-44-7271-8.pdf
35. Jutel M, Blaser K, Akdis CA. The role of histamine in regulation of the immune response. Chem Immunol Allergy 2006; 91:174-87.
36. Jurlander J, deNully Brown P, Skov PS et al. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukaemia. Leukemia 1995; 9:1902-9.
37. Van der Velden AM, Van Velzen-Blad H, Claessen AM et al. The effect of ranitidine on antibody responses to polysaccharide vaccines in patients with B-cell chronic lymphocytic leukaemia. Eur J Haematol 2007; 79:47-52.
38. Sinisalo M, Vilpo J, Itala M, Vakevainen M, Taurio J, Aittoniemi J. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia. Vaccine 2007; 26:82-7.


Anonymous said...

Should pneumovax 23 be on the permissable list?

Richard said...

After your post on the Prevenar vaccine I persuaded my GP to get my immunoglobulins measured as I thought they might give an indication as to whether there was any point in my having a vaccination. I expected all the levels to be depressed and I see you suggest that IgA is usually the first to drop.

IgG was mid normal range, IgM was within normal range but one SD below normal but IgA was ABOVE normal at 4.69 (0.8-4).

Is this another problem rearing its head or is it something one might expect in the early stages when one has a few too many B cells.

Terry Hamblin said...

Thanks for the comments. I suppose pneumovax 23 should be even though it doesn't work. IgA going down first was jus an old report. Any and every patern has been seen.

Richard said...

There is anecdotal evidence, from CLL websites, that some CLL patients have fewer infections than their peers when first diagnosed.

Have the figures you quote on reduced immunoglobulins typically been measured in patients with advanced disease and have any studies been made of levels when people first present with disease in its early stages.

Anonymous said...

I am wondering if any results are available on the Imiquimod enhancement study?

Also, there are some indications that exercise can boost the immune system but I am not aware of studies showing this to be true for CLL patients. Do you have any information on this?

Terry Hamblin said...

Everybody with CLL has some degree of impairmant of immunity. Even newly diagnosed patients tend to have some reduction of serum Ig, though as time passes it gets worse. I have seen normal Igs fall to very low in 3 years without treatment.

Terry Hamblin said...

The imiquamod study ios not yet complete. There is no evidence that exercise can boost the immune system. You have to realise that the suppression of the immune system in CLL is a result of specific damage done by teh presence of the CLL cells It cannot be remedied by non-specific 'boosts'. The only thing I know that makes a difference is treatment with high dose rituximab.

Anonymous said...

There is no scientific reason for it, but I am a good example of a CLL patient who was suddenly very healthy. The flu, colds and other diseases would sweep through the office, and I would never, ever get any of it.

Now, almost 10 years into CLL, I am no longer 'protected'.

There is no reason why this should be, but I can attest that, at least in my case, I was remarkably healthy.

Anonymous said...

I've read all of your sections about innunodeficiency and although I'm sure this comment would be better placed in one of the other ones, I'm placeing it here. The Journal of Experimental Medicine posted an article "Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo."
Volume 202, No. 6, 2005. This may be a link: www.jem.org/cgi/content/full/202/6/817
There is a summary article in the same edition titled "Blocking acid, boosting T cells". Do you believe this antimalarial drug could help CLLers respond better to some vaccines?

Terry Hamblin said...

Thanks for the link. It is clearly a mechanism worth exploring.

Sierra said...

My husband, diagnosed with stage 0 CLL 11/04 is traveling to India in July. It was suggested that he get vaccinated for HEP a, b and c. What is the general concensus regarding that?

Terry Hamblin said...

Have all the vaccines that are permissable.

Sierra said...

He should NOT get HEP c?

Terry Hamblin said...

There is no vaccine for hepatitis C.