Monday, November 19, 2007

Vaccination against pneumonia

People keep asking about vaccination against pneumonia and although I have been able to give some advice, it hasn't been very encouraging advice. In general people with CLL don't respond well to vaccination and vaccination against polysaccharide antigens such as are present on the pneumococcus bacterium is particularly hopeless, especially in patients who have advanced, treated or longstanding disease. I have been advocating the use of the conjugated vaccine, Prevenar®, but only on theoretical grounds that it ought to be better, and with no documented evidence that proves that it is better. Now at last there is a paper that gives some facts and figures. Marjatta Sinisalo and colleagues from Finland have vaccinated 52 patients with CLL and 25 age- and sex-matched controls with Prevenar® pneumococcal conjugate vaccine (published today on-line in the journal, Vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination.

In the case of pneumococcal polysaccharide vaccine, in previous studies no antibody response has been detected (Hartkamp et al, Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia, Vaccine 2001; 19:1671–1677; Sinisalo et al, Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia, Br J Haematol 2001; 114:107–110.)

Here is a quote from an editorial in Clinical and Experimental Immunology about conjugate vaccines by David Goldblatt of the Institute of Child Health in London:

Polysaccharide antigens are large molecules consisting of repeating epitopes which are not processed by antigen-presenting cells (APC) but interact directly with B cells, inducing antibody synthesis in the absence of T cells (thus designated T-independent antigens). T cells can influence the antibody response to certain polysaccharides, such as the capsular polysaccharide of S. pneumoniae type 3, (S. pneumoniae is the microbiologists’ name for pneumococus) but an absolute requirement for T cells has not been demonstrated. T-independent responses are restricted in a number of ways. Most importantly, they fail to induce significant and sustained amounts of antibody in young children below the age of 18 months. While polysaccharides are immunogenic in older children and adults, the characteristics of the antibody responses are rather restricted. They are dominated by IgM and IgG2, are relatively short lived and a booster response cannot be elicited on repeated exposure. This failure to induce immunological memory is also reflected in the absence of demonstrable affinity maturation. In contrast to polysaccharides, antibody responses to protein antigens have an absolute requirement for T cells. The consequence of this T cell help are that antibody responses to protein antigens can be elicited in the very young and immunity is long lived due the generation of immunological memory. Antibody responses to protein antigens are dominated by the IgG1 and IgG3 subclasses and affinity maturation can be demonstrated over time.

As a result conjugate vaccines have been introduced for vacinating infants against both haemophilus influenzae and pneumococus. Studies have already shown that CLL patients do respond better to conjugate Hib vaccines but hitherto there are no data for Prevenar. Readers should note that haemophilus influenzae is nothing to do with influenza, and that it is not a significant pathogen in CLL. Pneumococcus is by far the most important pathogen in CLL pneumonia and one for which a decent vaccine is urgently needed.

So what did they find? As expected the immune response to Prevenar in CLL patients was significantly worse than for normal controls. However, if the vaccine had been administered at an early stage in the disease, before commencement of chemotherapy and the development of hypogammaglobulinemia, almost 40% of the patients developed a significant response to at least six antigens.

There is one further caveat, the serotype coverage of the 7-valent conjugate vaccine against invasive pneumococcal infections in patients ≥65 years was only 56% compared to that of 86% in 23-valent polysaccharide vaccine. So even in patients with early stage disease who have never had treatment and have not developed hypogammaglobulinemia, only about a quarter of patients will be protected against pneumonia by this vaccine, which is, I suppose better than nothing, but there is a lot more yet to do.


Debbie Light said...

Thank you Dr. Terry!Thank you for caring so much for us CLLers that you go to great lengths to see we know what is best for us and when!

You are an amazing human being as well as one of the Best CLL Drs. in the world!Can we clone you?Work on that,would you?

Wishing you and your family the most Blessed Christmas and Happy New Year!

God Bless,
Debbie Light

Richard said...

Are there any risks in having vaccination against pneumonia or influenza for patients with indolent CLL. Can vaccination trigger a change to a more virulent form of CLL or perhaps trigger AIHA, or do such things, if they occur at all, only occur with live viruses?

Terry Hamblin said...

There is a theoretical risk that CLL cells may be induced to multiply by vaccination. Relase of B-cell growth factors is part of any immune response and these might trigger an increase in CLL cells. Indeed patients often report an increased white count afyter vaccination. However, this is usually transitory and there is no evidence that vaccination per se is harmful. Vaccination with live viruses risks the possiblity that the virus might not be repelled and that even in its attenuated form it might damage the patient.

M.Sinisalo said...

I am very pleased that our study on vaccinations in CLL (Vaccine,2007,26:82-7) was noticed in Your blog.I have thought this theoretical risk of stimulation of B-cells after vaccinations lately quite often.(I had my academic dissertation on vaccine responses in CLL on 11 April, 2008, available: Antigen stimulation theory in the progression of CLL, as well as role of infections as potential triggers for CLL development have raised this concern. In our small studies with CLL vaccinations, no progression in CLL was observed. Infections are still the main concern in CLL, and all the efforts to prevent them are important. Conjugate pneumococcal vaccines may be the one way, but to prove their clinical efficiency needs large clinical trials. So large that they are almost impossible to run in the small country like ours.

With kind regards,
Marjatta Sinisalo, Tampere University Hospital,Finland