TY - GEN
T1 - Immunization of immunosuppressed patients
T2 - Knowledge, practices and serological response
AU - Larsen, Lykke
PY - 2022/9/2
Y1 - 2022/9/2
N2 - 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.
AB - 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.
U2 - 10.21996/d8cg-hf97
DO - 10.21996/d8cg-hf97
M3 - Ph.D. thesis
PB - Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
ER -