The development of more tolerable and effective cytoreductive regimens and better supportive care has increased not only the number of surviving transplant patients returning to school and the workplace, but the age of surviving population (21
), individuals particularly vulnerable to severe invasive pneumococcal infections even in the absence of HCT (14
). Although the current CDC and EBMT vaccination guidelines recommend the Hib conjugate vaccine following HCT (7
), both recommend the use of PPV23 either as a single dose of PPV23 at 12 months (EBMT) or sequential doses at 12 months and 24 months (CDC). Nevertheless, several studies have shown a dichotomy between the responses of allogeneic transplant recipients to pure polysaccharide vaccines compared with protein-conjugated vaccines. Barra et al. demonstrated that only 4 of 20 (25%) adult allogeneic transplant recipients given the pure polysaccharide H flu vaccine developed a specific IgG response compared with 11 of 20 (55%) patients given the H flu conjugate vaccine (p<0.05) (31
). Guinan et al. studied the responses of 21 allogeneic and 14 autologous HCT recipients immunized with H flu conjugate vaccine and the polysaccharide pneumococcal vaccine, Pnu-immune, (Lederle laboratory Division, American Cyanamid Co., Pearl River, NY) (9
). Following the 24 month immunization, only 19% of patients developed protective titers against the 6 measured pneumococcal serotypes (1, 3, 6A, 7F, 8, 9N), while 80% responded the HIB-conjugate vaccine. Our study similarly demonstrates that the majority of patients who fail the pneumococcal polysaccharide vaccine are capable of responding to HIB. In addition, we show that 77% of patients unable to respond to PNCRM7 responded to the conjugated HIB vaccine. The greater response to the HIB conjugate versus the pneumococcal conjugate vaccine may reflect the fact that the former vaccine contains a single protein-saccharide conjugate, is inherently more immunogenic, and/or expands memory T and B cell populations persisting from prior childhood immunization or natural infection with Haemophilus influenza.
To date, this is the largest study evaluating PNCRM7 responses following allogeneic HCT and the first to evaluate PNCRM7 responses in adult recipients of an unmodified or T cell depleted unrelated HCT or adults following a T cell depleted HCT from any donor type. Although retrospective, it includes 80% of all patients transplanted during a defined period (2002–2005) who survived disease-free >1 year. Molrine et al. evaluated PNCRM7 response in 65 unmodified HLA-matched related HCT recipients (median age: 40 years) immunized with PNCRM7 at 3, 6, and 12 months, 30 of whom received grafts from donors immunized before bone marrow harvest (32
). After the first immunization, antibody responses in the immunized donor group were significantly higher for 5 of the 7 vaccine serotypes. Although response after the 3rd
PNCRM7 immunization was not evaluable in approximately 30% of the starting population due to relapse (n=8), death from other causes (n=5), thrombocytopenia (n=3), missed vaccines (n=2), or DLI (n=1), 60% of the remaining patients in both groups demonstrated significant pneumococcal titers to all 7 serotypes. In a prospective, randomized double blind trial in adult recipients of an HLA-matched related HCT, Kumar and colleagues compared the effect of vaccinating donor-recipient pairs with a single PPV23 or PNCRM7 (33
). Donors were vaccinated at least two weeks prior to stem cell harvest; patients at 6 months post HCT. At 12 months post HCT, the mean number of serotypes for which a response was observed was 1.8 in the PPV23 group and 3.1 in the PNCRM7 group. Similar to the study of Storek et al., no advantage to pre-HCT immunization of the donor and/ or host with PPV23 was observed (34
). Meisel et al. studied the response of 43 patients < 17 years of age after a related (45%) or unrelated (55%) HCT. demonstrating that 74% of 43 patients responded to all 7 vaccine serotypes following the third immunization (35
). In a study of 30 children vaccinated according to the Royal College of Paediatrics and Child Health guidelines, Patel and colleagues demonstrated that 80% responded to each of the serotypes contained in PNCRM7 when given two monthly doses initiated at 15 months or 21 months following an HLA-matched sibling (n=10) or unrelated HCT (n=20), respectively (36
). Considering the poor response of transplant recipients to PPV23 (9
) and its failure to reduce the incidence of pneumococcal pneumonia even in healthy middle-aged and elderly adults (38
), this and the above studies (33
) support further trials of PNCRM7 in adults and children following HCT.
The EBMT (4
) and CDC guidelines (2
) advocate revaccination at fixed intervals following transplant, irrespective of patient age, donor or hematopoietic cell type, intensity of conditioning, presence of chronic graft versus host disease, or use of post transplant rituximab. Nevertheless, many of these variables affect the kinetics of T and B cell reconstitution following HCT (19
), and likely the ability of patients to respond and maintain protective titers following vaccination (40
). Only the Royal College of Paediatrics and Child Health guidelines stratify the timing of vaccination on the basis of donor type (autologous and HLA matched sibling HCT versus all other donors) due to the delayed recovery of immune competence often associated with receipt of an unrelated or HLA mis-matched donor transplant (19
). Our study demonstrates that in older patients response to PNCRM7 is significantly better in those vaccinated after acquisition of minimal milestones of immune reconstitution, milestones reached at different time points post HCT, depending on age and presence of chronic GVHD (19
). It also shows that even within a population of patients who have achieved minimal milestones of immune reconstitution, not all patients respond suggesting that qualitative and/or quantitative differences in effector and memory helper T and B cells are likely to differentiate responders and non-responders. It is possible that certain vaccines such as tetanus and polio may elicit responses in the majority of patients early post HCT due to expansion of memory T and B cells transferred with the graft. In contrast, vaccines such as recombinant Hepatitis B (41
) and pneumococcus may constitute neoantigens requiring generation of T and B cells from donor lymphoid progenitors developing within the host thymus and other tissues of the lymphoid system. Our study demonstrated a relationship between higher numbers of circulating CD4+CD45RA+ T cell numbers and improved PNCRM7 response suggesting that responders had achieved a significant level of reconstitution from precursor populations developing within the host. The correlation; however, was not absolute. Thus, impaired reconstitution of B cell precursors or antigen presenting cells may persist in some patients despite de novo T cell reconstitution.
Although invasive pneumococcal infections occur more frequently in patients with chronic GVHD, deaths from these infections occur in patients with and without chronic GVHD (1
) as well as in autologous transplant recipients (5
). This study, as well as the majority of studies evaluating PNCRM7 response to date, have not included large numbers of patients with chronic GHVD, either by design or early death from chronic GVHD in enrolled patients (32
). Clearly, there is a need to design multi-center prospective trials which do include patients with limited and potentially extensive chronic GVHD in order to identify the most effective vaccination strategy to elicit protection against pneumococcal disease in the highest proportion of patients at the earliest time possible. Inclusion in such trials of correlative studies analyzing in vitro immune reconstitution should identify immune characteristics most predictive of early and durable immune responses.
Prior to the introduction of the conjugated pneumococcal vaccine, 3,000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7 million cases of otitis media due to pneumococcus occurred annually in this country, causing 40,000 deaths per year (reviewed in 7
). Following widespread vaccination of infants with PNCRM7, rates of invasive pneumococcal disease due to penicillin resistant strains decreased from 6.3 cases in 1999 to 2.7 cases/100,000 in 2004 (42
). The reduction in pneumococcal infections in children vaccinated with PNCRM7 (13
) and the seroconversion rates noted in this and other studies, suggest that the impact of PNCRM7 should be prospectively studied in a large multi-center trial. To improve responses in older patients, strategies such as a primary series of 4 doses of PNCRM7, the use of B and T cell immunomodulatory agents, such as interleukin-7 (43
) and/or the addition of an adjuvant as incorporated in the recombinant Hepatitis B vaccine, Fendrix, should be explored (44
). To provide even more comprehensive coverage in this at-risk population, future studies assessing the PCV13 vaccine, currently being tested in healthy adults and children (45
) should be undertaken.