Immunization of immunosuppressed patients: Knowledge, practices and serological response

Background
Given the high incidences of influenza and invasive pneumococcal disease (IPD) in kidney transplant recipients (KTRs), immunization against influenza and pneumococci is recommended in KTRs and kidney transplant waiting list patients (WLPs). However, prior studies have displayed low vaccine uptake and lack of immunization guidance in these patient populations. Currently, there are two commercially available pneumococcal vaccines on the market. A purified polysaccharide vaccine and a conjugate vaccine. The first vaccine induces a restricted immunoglobulin G response without recruiting T lymphocytes or generating memory B lymphocytes. The conjugate vaccine induces a T lymphocyte response, thereby promoting B lymphocyte differentiation into both memory B lymphocytes and antibody-secreting plasma cells. Pneumococcal vaccination for KTRs is recommended as prime-boost vaccination consisting of the conjugate vaccine followed by the purified polysaccharide vaccine after minimum 8 weeks. An approach adapted from other patient populations, where it has been viewed superior to the purified polysaccharide vaccine alone. Furthermore, previous studies have demonstrated a possible dose dependent vaccine response for both vaccines in healthy adults. Increased dosage of pneumococcal vaccines have never been assessed in KTRs or WLPs, and the prime-boost approach is not thoroughly tested either.  

Aim of thesis
The aim of the thesis is, in KTRs and WLPs, to 1) asses the degree of vaccination with influenza and pneumococcal vaccines which are recommended according to national and international guidelines 2) assess eventual predictors influencing vaccine acceptance and uptake 3) evaluate whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination.

Methods and studies
This thesis is based on a cross-sectional study and a randomized clinical trial. Study 1. Uptake and predictors for influenza and pneumococcal vaccines in Danish KTRs and WLPs. For this cross-sectional study, a questionnaire was designed and distributed to eligible WLPs and KTRs, during their scheduled visits to the different hospitals involved. Self-reported data on demographics, vaccine uptake and received vaccine guidance were analysed. Predictors for vaccine uptake and proportion of participants who were vaccinated were described. Study 2. A multi-centre, phase 3, parallel-group, randomized, non-blinded clinical trial conducted to investigate whether pneumococcal prime-boost vaccination with double dosage (DD) of PCV13 and PPV23 resulted in increased immunogenicity in WLPs and KTRs, compared to normal dosage (ND). Participants were assigned in parallel groups to receive either ND or DD of both vaccines 12 weeks apart. Follow-up was 96 weeks. KTRs had to have received their transplant within the last 1½ year. Primary endpoint was difference in proportion of participants in the two dosage arms achieving a ‘protective response’ defined as an average antibody geometric mean concentration (GMC) ≥1 mg/L calculated as a mean across the twelve pneumococcal serotype-specific IgG antibodies measured five weeks after PPV23. Furthermore, the average pneumococcal antibody GMC level and serotype-specific IgG antibodies with ≥2-fold increases were assessed.

Results
Study 1. Totally, 220 patients participated in the survey (KTRs 54.1% and WLPs 45.9%). During the latest flu season, 92 (41.8%) participants had been vaccinated against influenza with no significant difference between the WLPs and KTRs. Significantly more WLPs had been influenza vaccinated prior to the latest season (p = 0.007). The 120 participants who were not vaccinated against influenza in the latest season stated the following three main reasons for not being vaccinated 1) I perceive my health as good, with no need for immunization (38.3%) 2) I was not informed that the vaccine was recommended (27.5%) and 3) I am afraid of side effects (17.5%). Pneumococcal vaccine uptake ever was 9 participants (4.1%) evenly divided between KTRs and WLPs. Only 10 participants had ever been offered a pneumococcal vaccine. In multivariable analysis, any prior influenza vaccination was a positive predictor for influenza vaccination during the latest season (OR 5.79, CI95 2.44-13.76); (p<0.001), and recommendation provided by a nonphysician was a negative predictor (OR 0.34, CI95 0.13-0.92); (p=0.03). Study 2. In total, 236 patients were screened for eligibility and 139 enrolled (WLP-ND = 32, WLPDD = 33 and KTR-ND = 39, KTR-DD = 35). Five weeks after PPV23, WLP-DD had a significantly higher proportion of participants with a ‘protective response’, compared to WLP-ND (20 (66.7%) vs 11 (35.5%); p=0.015). At week 12, 48 and 96, the groups were comparable. There were no significant differences between KTR-ND and KTR-DD, at any visit. Number of antibodies with ≥2- fold increases were significantly higher after PPV23 in all groups, and so were average pneumococcal antibody concentrations in 3 out of 4 groups. The average pneumococcal antibody concentration declined over time in WLPs and KTRs. However, at week 96, in all four treatment groups, the average pneumococcal antibody concentration was still significantly above baseline level, and stable, compared to week 48.

Conclusion
Both influenza and pneumococcal vaccine uptake are sub-optimal in Danish WLPs and KTRs, and lack of immunization guidance seem to be the main cause. Counselling should be made mandatory as it appears that, if the patients first have been influenza vaccinated, they will continue to do so prospectively. Furthermore, a doctor should provide the information. Based on the randomized trial, we found that DD of both pneumococcal vaccines used according to the prime-boost vaccine strategy may be recommendable in WLPs. Moreover, PPV23 increases immunogenicity in both KTRs and WLPs, compared to that obtained by PCV13 alone.