Pneumococcal immunization in immunocompromised hosts: where do we stand? Expert Review of Vaccines Downloaded from by Nyu Medical Center on 10/09/14 For personal use only.

Expert Rev. Vaccines 13(1), 59–74 (2014)

Catherine Cordonnier*1, Diana Averbuch2, Se´bastien Maury1 and Dan Engelhard2 1 Hematology Department, Henri Mondor Hospital, Assistance PubliqueHoˆpitaux de Paris (AP-HP) and Universite´ Paris-Est-Cre´teil, Cre´teil 94000, France 2 Pediatric Department, Pediatric Infectious Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel *Author for correspondence: Tel.: +33 149 812 057 Fax: +33 149 812 067 [email protected]; [email protected]

Immunocompromised patients are all at risk of invasive pneumococcal disease, of different degrees and timings. However, considerable progress in pneumococcal immunization over the last 30 years should benefit these patients. The 23-valent polysaccharide vaccine has been widely evaluated in these populations, but due to its low immunogenicity, its efficacy is suboptimal, or even low. The principle of the conjugate vaccine is that, through the protein conjugation with the polysaccharide, the vaccine becomes more immunogenic, T-cell dependent, and thus providing a better early response and a boost effect. The 7-valent conjugate vaccine has been the first one to be evaluated in different immunocompromised populations. We review here the efficacy and safety of the different antipneumococcal vaccines in cancer, transplant and HIV-positive patients and propose a critical appraisal of the current guidelines. KEYWORDS: antipneumococcal vaccine • conjugate vaccine • immunesuppression • invasive pneumococcal infection • polysaccharide vaccine

Streptococcus pneumoniae (pneumococcus) naturally colonizes the nasopharynx and can be found in about 10% of healthy adults and 40% of healthy children. S. pneumoniae commonly causes otitis media, sinusitis and lower respiratory tract infection. S. pneumoniae is the predominant pathogen in community-acquired pneumonia, accounting for about 20–50% of bacterial cases. In developing countries, more children are killed by pneumonia than any other disease. Invasive pneumococcal disease (IPD), defined as isolation of S. pneumoniae from a normal sterile site such as blood, cerebrospinal fluid or pleural fluid, is relatively common in infants, elderly and immunocompromised hosts of all ages. Clearance mechanisms, mainly ciliary action, normally lead to removal of the pneumococci from eustachian tubes, sinuses and bronchi. Anticapsular antibodies are needed for phagocytosis of pneumococci by neutrophils and macrophages. Therefore, immunologically naive or impaired individuals are prone to severe pneumococcal infections. Also, as the spleen plays a major role in clearance of unopsonized pneumococci from the blood stream, overwhelming pneumococcal infection


may occur after splenectomy or in those whose spleen does not function normally, as found in sickle cell disease. The main predisposing conditions to IPD include either primary (such as Bruton’s congenital agammaglobulinemia) or secondary (such as multiple myeloma, chronic lymphocytic leukemia, lymphoma, HIV infection, post hematopoietic stem cell [HSCT] and solid organ transplantation [SOT]) defective antibody formation, defective complement, primary (such as cyclic neutropenia) or secondary (such aplastic anemia) neutropenia, poor functioning neutrophils (such as in alcoholism or immunosuppressive therapy) and asplenia. Due to the increased incidence of IPD in various immunocompromising conditions, active immunization has been explored for decades, both with the polysaccharide and conjugate vaccines, in immunocompromised hosts. Here, we review the currently available data on the risk of IPD, and on the efficacy and safety of antipneumococcal vaccines in different settings of immunedepression, including oncology and hematology patients, transplant recipients and HIV-positive individuals. We neither address the immunization of patients

 2014 Informa UK Ltd

ISSN 1476-0584



Cordonnier, Averbuch, Maury & Engelhard

with sickle cell disease, who are not classically considered as immunodepressed, as oncology or transplant patients, nor children with inherited immune deficiencies, considering this as a very restricted and specialized area. Specific issues of pneumococcal infection in immunocompromised patients

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Increased susceptibility to S. pneumoniae infection in immunocompromised patients

When compared with healthy controls of the same age range, they mostly have a lower response to the pneumococcal vaccines and have a faster decline of specific antibodies after vaccination. Over 30 years ago, it was reported that 7/26 (27%) long-term survivors after allogeneic HSCT developed IPD [1]. Numerous reports later confirmed the predisposition of HSCT recipients to IPD, both in retrospective and prospective studies [2,3]. Cancer, hematologic malignancies, SOT and HIVinfection are also identified as various causes of increased IPD risk. A retrospective Canadian survey ran from 2000 to 2004 showed an overall attack rate of IPD of 11 cases/ 100,000 per year in the adult population, but a rate of 143 cases/100,000 per year in lung cancer and of 673 cases/ 100,000 per year in multiple myeloma [4]. A similar US survey done among adults over 1999-2000 showed an overall incidence rate of IPD of 8.8 cases/100,000 persons in healthy adults, 100.4 in adults with abused alcohol, 300.4 in patients with solid tumor, 422.9 in patient with HIV/AIDS and 503.1 in patients with hematologic malignancies [5]. Consistently, over recent years, immunocompromised patients have been represent a significant proportion (30.7%) of IPD cases in the whole population [6]. Due to the increasing use of antipneumococcal vaccination worldwide, we may hypothesize that herd immunity could reduce the incidence of IPD in immunocompromised patients. Data supporting this hypothesis are, however, available only in HIV-infected patients [7]. All of these immunodepressed conditions have common predisposing factors for IPD. Not only hypogammaglobulinemia (primary or secondary to lymphoproliferative disorders or to HSCT), but also specific anti-pneumococcal antibody defect [8–11] and IgG2 deficiency [9], hyposplenism (either due to splenectomy, or due to splenic irradiation [12] and memory cell defects (including those observed in HIV-infected or HSCT patients with chronic graft-versus-host disease [GVHD]) are all predisposing factors to IPD, and may also impact on the response to vaccines. Are serotypes & resistance to beta-lactams different in immunocompromised patients when compared to others?

Few data are available to know whether S. pneumoniae strains involved in IPD episodes in immunocompromised patients are different from the ones encountered in the overall population, regarding anti-bacterial resistance and serotypes, or not. This is an important issue, both from a therapeutic point of view, and for the expected coverage of the vaccines in these populations. Several studies show that the serotypes observed in 60

immunocompromised patients are covered by the currently available vaccines in the range of 60–100% according to the population, country and time period [2,13–16]. In the USA, 50% of IPD cases among immunocompromised adults occurring in 2011 were due to serotypes covered by the 13-valent conjugate vaccine (PCV13), and an additional 21% were covered by the 23-valent polysaccharide vaccine (PPV23) [17]. Serotype 6A that is covered by PCV13 but not by the PPV23, was found to be more prevalent in patients with hematological malignancies [4], but this was not found in other series [14]. While immunocompromised patients are prone to receive many courses of antibacterials, thus, making them at risk of developing IPD due to antibacterial-resistant strains, there is no evidence that the strains isolated in these populations have different susceptibility profiles when compared to those which are isolated in the general populations with similar age and at the same time [14,18], except may be for the drug trimethoprim/ sulfamethoxazole that these patients often receive at low, suboptimal, antibacterial dose for pneumocystis prophylaxis [16]. Immunization program in a given area may probably impact both on the incidence and serotype prevalence of IPD as it has been shown for HIV-infected adults, but marginally on the antibacterial susceptibility of the strains when compared to non-HIV-infected patients [7]. Anti-pneumococcal vaccines & specific concerns on antipneumococcal immunization in immunocompromised patients The 23-valent polysaccharide vaccine

PPV23 (Pneumovax) has been available worldwide since 1983 replacing the 1976 14-valent polysaccharide vaccine (PPV14). PPV23 still covers approximately 95% of the S. pneumoniae strains responsible for IPD in North America and Europe. Its main limitation is due to its polysaccharidic formulation which is poorly immunogenic with no boost effect, especially in patients under the age of 5 years or older than 65 years old, patients with IgG2 deficiency and in the immunocompromised populations. An additional concern is that repeated doses of PPV23 can induce immune tolerance and hyporesponsiveness when any subsequent pneumococcal vaccines are given [19,20], but this effect usually varies according to the serotypes [21,22]. The conjugate vaccines

The benefit of the conjugate vaccines is supported by the covalent conjugation of each pneumococcal polysaccharide to a protein carrier which converts most of the immune response from T-cell independent to T-cell dependent, leading to high efficacy in infants and a better and longer lasting antibody response. Although the antigens of the conjugate vaccines were chosen among the most frequent pathogenic strains in humans, they cover only 80% of pneumococcal disease in the general population, which is lower than the coverage offered by the polysaccharide vaccine. The conjugate vaccines include the 7-valent (PCV7) Prevnar (Wyeth Pharmaceuticals), licensed in 2000, Expert Rev. Vaccines 13(1), (2014)

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Pneumococcal immunization in immunocompromised hosts

the 10-valent (PCV10) Synflorix (GSK), licensed in 2009, and the more recent PCV13 Prevnar (Pfizer) vaccine, which replaced the PCV7 from 2010. An additional 9-valent (PCV9) conjugate was developed by Wyeth, but has never been licensed. All the serotypes of PCV7 were included in the PCV13, and all the serotypes of the PCV13 are included in the PPV23, with the exception of 6A, included in the PCV13 and not in the PPV23. Conflicting results exist about the compared avidity or opsonic functional activities of the antibodies induced either by PPV23 or by PCV [19]. However, there is strong data to support that in healthy infants and children, PCV induces a better production of IgG antibodies and increases the IgG/IgM ratio on repeated vaccination; however, after a PCV priming, PPV23 as a booster dose induces higher concentrations of antibodies than a PCV boost [19,20]. It is to be noticed that the amount of pneumococcal antigen contained in one dose of PPV23 is six to 10-fold more than in the PCV. This difference may explain a better effect of PPV23 here, despite the protein conjugation of the PCV. Specific concerns on immunization in immunocompromised patients

Three main concerns are seen when choosing any approach for anti-pneumococcal vaccination in immunocompromised patients: • The lack of consensus on the protective levels of specific antibodies in such populations; • The optimal timing of immunization in specific situations; • The durability of the response, and consequently of the protection with a given schedule. These issues should be discussed, considering that in such populations, we may offer protection with alternative methods poorly considered in the normal population, in other words, antibiotic prophylaxis, or immunoglobulin (Ig) administration. However, even in allogeneic HSCT recipients where prophylactic administration of penicillin or amoxicillin is common at least during the first year after transplant, the efficacy of such alternative preventive strategy has never been evaluated properly. Additionally, the increasing resistance rate of pneumococci makes this approach not satisfying for the transplant community. Criteria to define protection to IPD in immunocompromised patients

Until now, there is no data to define biological criteria of protection to IPD in immunocompromised patients. This is mainly due to the low number of patients in the studies: for example, the largest prospective study on antipneumococcal vaccine published so far in HSCT recipients included only 158 patients [23]. The only immunocompromised population where clinical effectiveness of the pneumococcal vaccination was demonstrated is in the HIV-infected children who were


given PCV during infancy: in a randomized, double-blind study in South Africa, PCV9 reduced the incidence of IPD due to serotypes included in the vaccine, in following 2.3 years by 65% (as compared with 83% among children without HIV infection) [24]. Furthermore, the complexity of factors leading to high risk of IPD in such populations probably makes it difficult to define a clear cutoff of antibody levels which could be indicative of protection, and which, additionally, may vary among the different serotypes and specific populations. Therefore, although the clinical pertinence of protective antibody cutoffs and other biological parameters used for assessing the vaccine response in the healthy population is not clearly established in immunocompromised populations, it is usual to use the ones recommended in the healthy population. These parameters are: • Geometric mean antibody concentrations (GMCs); • Fold increase (usually ‡4) in antibody concentration from baseline (before vaccine); • Functionality of induced antibody measured by an opsonophagocytic activity assay (OPA) of ‡8; • Mainly: serotype-specific antibody concentration, with protective cutoffs varying in the literature from >0.15–1 mg/ml until 2003, then, on the proposal of the WHO recommendations: >0.35 mg/ml which is, nowadays, considered as a consensual protective level in the healthy population [25], using ELISA. Investigators have used these cutoffs, either on one [26], or on all serotypes [23] included in the assessed vaccine. For assessing the response to PPV23, some antigens are usually chosen, rather than all the 23. Correlation between specific antibody titres and functional activity of the antibodies showed conflicting results in transplant patients [26–28] and whether functional tests should be systematically performed for assessing the response is debated. Due to the low number of patients in most studies evaluating immunocompromised populations, it is practically impossible to demonstrate the clinical effectiveness of pneumococcal vaccines, for example, a decreased incidence of IPD in patients immunized versus in those who are not immunized. Therefore, the laboratory criteria, although debated, are often the only ones we may use. Conversely, in HIV-infected patients where the size of the cohorts may be larger, a clinical benefit of vaccination could be demonstrated [29,30]. Finally, as there is no data published with the PCV13 in the immunocompromised populations so far, but as PCV7 is no more available, all the recent guidelines recommend the conjugate vaccine in immunocompromised patients, although based on more restricted valent-conjugate vaccines and especially PCV7, mention PCV13. Timing of immunization according to the risk

Most of the immunocompromised patients have an immunity evolving over time. One example is allogeneic HSCT where transplant is followed by a long immune deficiency, lasting at 61


Cordonnier, Averbuch, Maury & Engelhard

Table 1. Main guidelines available for antipneumococcal immunization in immunocompromised hosts. Risk group


Special consideration on time for giving vaccines

Concerns and pending issues


Non-transplant oncology and hematology patients

Pneumococcal vaccine-naı¨ve adults: one dose of PCV13 followed by one dose of PPV23 at least 8 weeks later A second dose of PPV23, 5 years later†


Optimal timing (before? during? after treatment?) Indications of alternative methods (e.g., passive immunization strategies)


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Previous vaccination with PPV23: one dose of PCV13 >1 year after the last PPV23 Eventually an additional PPV23 (>8 weeks after PCV13 and >5 years after the last PPV23) HSCT recipients

Three doses of PCV13 to be started between 3 and 6 months after transplant, followed by either a dose of PPV23, or a dose of PCV13 (the later in case of chronic GVHD)

Start between 3–6 months after transplant

Indications and feasibility of donor immunization Need for boosts in long term survivors (>2 years after transplant)


SOT adult recipients

One dose of PPV23 before transplant, and then one dose every 3–5 years

Before transplant, then 3–5 years later

No conjugate vaccine proposed in the program If pre-transplant vaccination is close to transplant, no boost is planned before 3–5 years later


Same guidelines as for non-transplant oncology and hematology patients

No precise timing after transplantation

Optimal timing for immunization Decrease of antibody levels during the first months after transplant. Efficacy of pretransplant vaccination for the risk of IPD during the first months/years after transplant: Need for boosts? Risk of graft-rejection?


SOT pediatric recipients

PCV and PPV23 before and after transplant Children below 2 years: PCV Children above 5 years: PPV23 Children 2–5 years: specific program according to the previous anti-pneumococcal vaccination

No precise timing after transplantation

HIV-infected adults

For pneumococcal vaccine-naı¨ve a dose of PCV13, followed by a dose of PPV23 at least 8 weeks later. Additional PPV23 dose 5 years later

For those who previously have received ‡1 dose(s) of PPV23: PCV13 dose ‡1 year after the last PPV23 dose. For those who previously have received only one dose of PPV23, a second dose of PPV23 should be given at least 5 years after the first one

Specific IgG levels are significantly lower than among HIV seronegative subjects [103]


HIV-infected children

At the first year of life: 4 doses of PCV13. For those not vaccinated during infancy - two dose catch-up PCV13. HIV-positive children 2 years or older, should get also PPV23

In some African countries, national programs of all infants’ vaccination with 3 doses of PCV10 have been started, as PCV13 is not available

The immune response may be reduced among symptomatic children and in those with low CD4+ counts [91,94,96]



These guidelines are proposed to hematologic malignancies (leukemia, lymphoma, Hodgkin disease and multiple myeloma) and generalized malignancy. AMMI: Association of Medical Microbiology and Infectious Diseases; ASBMT: American Society for Blood and Marrow Transplantation; CBMTG: Canadian Blood and Marrow Transplantation Group; CDC: Centers for Disease Control; CIBMTR: Center for International Blood and Marrow Transplant Research; EBMT: European Group for Blood and Marrow Transplantation; IDSA: Infectious Diseases Society of America; NMDP: National Marrow Donor Program; SHEA: Society for Healthcare Epidemiology of America. ACIP: Advisory Committee Immunization Practices; AST: American Society for Transplantation; GVHD: Graft-versus-host disease; HSCT: Hematopoietic stem cell transplant; IPD: Invasive pneumococcal disease PCV13:13-valent conjugate vaccine; PPV23:23-valent polysaccharide vaccine; SOT: Solid organ transplant. ‡

least 1 year, and with a gradual recovery which is mainly influenced by chronic GVHD [31–33]. For a long time, IPD has been considered as a late infection after HSCT, for example, occurring after 6 months from transplant, and even years later [1]. However, more recent data have shown that early cases may be observed before 3 months of transplant and be associated with a significant mortality [2]. HSCT patients might thus 62

benefit from an early immunization if their immunity has recovered the capacity to respond to vaccination. Similarly in HIV-infection, the vaccine response will be low at a time when the CD4+ lymphocyte counts are low, and better if one waits for CD4+ recovery following antiretroviral treatment (ART) [34,35]. Consequently, there are such settings that create a dilemma between vaccinate early after the risk is identified, Expert Rev. Vaccines 13(1), (2014)

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(with may be a non-optimal vaccine response, but already a risk of getting the disease) or wait for a better immune recovery thus, making the patient a better responder. Some investigators did prefer to wait and get a better response in populations known to have an evolving immunity [36,37]. Such strategies might select the ‘good’ patients and not represent the issues of immunization in the whole population [38]. In the example of HSCT, as the risk of IPD starts from transplant, we may consider that more at-risk patients, in other words, those with GVHD in the first months of transplant, are not optimally protected with such strategy. Durability of the response to vaccine in immunocompromised patients

Few data are available regarding the durability of the response to vaccine in these populations. An old study suggests that an anti-pneumococcal IgG antibody level >1.0 mg/ml, one month after the initial dose(s), is predictive of long-term protection [39]. However, due to the low specificity of early generation pneumococcal antibody detection tests, such results should be considered with caution nowadays [40]. In allogeneic HSCT, vaccinating early (3 months after transplant) versus late (9 months) after transplant with three doses of PCV7 followed by one dose of PPV23, although initially non-inferior, raises a risk of lower antibody levels at 24 months [23]. After renal transplant, the durability of the response at 3 years appears to be more dependent on the initial (8 weeks) post-vaccination response and on the serotype, than on the type (PCV7 or PPV23) of vaccine initially given [41]. However, long-term studies are too few to clearly establish whether later boosting is needed in many situations or not. Non-transplanted, oncology & hematology patients Prevalence

Cancer and hematological malignancies represent around 30% of all cases of IPD in patients aged over 65 years [6]. In a large, retrospective study run at the M.D. Anderson Cancer Center between 1998–2002 on 122 pneumococcal bacteremic patients, solid and hematologic malignancies were equally represented [18]. The more frequent malignancies were acute leukemia (18%), plasmocytic disorders (11%) and lung cancer (14%). Ten percent of the patients had received autologous or allogeneic HSCT. Of course, these percentages are very depending on the accrual of the underlying disease in the center, and do not give any indication on the prevalence of S. pneumoniae bacteremia in each disease. Noteworthy, 29% of the patients had concomitant noncancerous comorbidities, and only 17% were neutropenic. The predisposition to IPD of patients with Hodgkin‘s disease has been identified at a time when splenectomy was part of staging [12,42]. In a large series of 325 patients with Hodgkin’s disease, and not vaccinated before splenectomy, the prevalence of IPD was estimated to be 20.5-fold higher than the one observed in the general Norwegian population [43]. In


children with acute lymphoblastic leukemia (ALL), a German survey showed a 10-fold higher risk than in healthy children [44]. This predisposition was related to the lower levels of specific antibodies when compared to age-matched unvaccinated healthy controls [9]. Noteworthy, although acute myeloid leukemia (AML) patients have been poorly investigated concerning to IPD, antibody concentrations were not different in children with AML, matched for age, when compared to children with ALL [10]. IPD is also a serious complication in hematologic malignancies characterized by a B-cell defect, such as multiple myeloma and chronic lymphocytic leukemia (CLL) [45]. Efficacy & safety of PPV23 & PCV7 in cancer & non-transplanted, hematology patients

The efficacy of PPV23 has been evaluated in different studies, often mixing cancer and lymphoma patients [46], and sometimes with controls [46,47]. The immune response of the cancer patients was always lower than that of healthy controls, even in patients receiving mild or moderately immunosuppressive regimens [46,47]. However, the immune response in patients with non-Hodgkin’s lymphoma and splenectomized was in the range of 45%, not different of patients splenectomized for other reasons [48]. The PPV23 response has been also considered to be poor [49–51], or even absent in CLL [47] and not enhanced with ranitidine [52] or GM-CSF stimulation [51]. This clearly questions the benefit of PPV23 vaccination in lymphoproliferative disorders, a situation where regular intravenous Ig can quickly and durably offer protective antipneumococcal antibodies [53] and decrease infectious complications, with a maximal benefit for the patients who failed to respond to PPV23 [54]. Two studies suggest that the response to PPV23 in patients with BCLL [49] or myeloma [55] is better in patients with less advanced stages of the disease corresponding to higher g-globulin levels, total IgG-levels and IgG-subclasses 2 and 4 levels. In one Swedish study, only 55% of splenectomized patients with hematologic malignancies responded to PPV23 and the poor responders did not benefit from revaccination [56]. Although not comparative, better responses seem to have been obtained with PCV7 than with PPV23, either with one dose priming a subsequent dose of PPV23 in Hodgkin’s disease [57], or with two doses given at 4 weeks apart to children with solid tumors or ALL, with a response rate of 86–100% on the seven vaccine antigens [58]. No serious adverse event following any of the vaccines was reported in either group. Current guidelines

The more recent guidelines of the US Advisory Committee Immunization Practices (ACIP) recommend that adults aged >19 years with immunocompromising conditions, including leukemia, lymphoma, Hodgkin’s disease, generalized malignancy and multiple myeloma, should be vaccinated with a first dose of PCV13, then a dose of PPV23 at least 8 weeks later and are benefited from PPV23 revaccination 5 years later [17]. This is a minimal practice to protect high-risk patients. However, these guidelines do not address the difficult question of 63


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the timing of this vaccination: from the time the diagnosis of the underlying disease is known, or as soon as a therapy is proposed, or stopped. Taking the example of CLL or myeloma where studies suggest that the vaccine response is better in the early stages of the diseases, and especially before treatment, one may consider that the earlier we vaccine, the better will be the response. In fact, few data exist on the durability of the response in such setting. Only one study in splenectomized patients immunized with PPV23, suggest that the antibody levels decrease to nonprotective levels in approximately 1–2 years after vaccination [56]. Prospective studies evaluating the need for boosts in patients on and off therapy are needed (TABLE 1). Hematopoietic stem cell transplant recipients Prevalence of IPD in HSCT recipients

The more recent available data suggest an overall incidence of IPD after HSCT from 5.97 in Europe [2] to 7 in the USA [3] for 1000 transplants. This incidence was significantly higher in bone marrow versus peripheral blood stem cell transplant, in allogeneic versus autologous transplant (12.2 vs 4.60/1000), with an incidence up to 18.85 cases for 1000 transplants in case of GVHD [2]. The Toronto Invasive Bacterial Diseases Network concluded an incidence rate of 347 infections/ 100,000 persons per year in the HSCT population, far more than that observed in the general population (11.5/100 000/ year) [15]. Death attributable to IPD varies between 13% [3] and 20% per episode [2]. Efficacy & safety of PPV23 in HSCT recipients

The low specific antipneumococcal antibody levels after HSCT, the relationship between these low levels and the occurrence of IPD and the low capacity to respond to pneumococcal polysaccharide antigens within the first 6 months following HSCT were identified in the early 1980’s [33,59]. Twenty one allogeneic and 14 autologous HSCT recipients received PPV23 at 12 and 24 months, or at 24 months [60]. After 24 month administration, only 19% of the patients developed protective antibody levels to the 6 serotypes assessed. Another study failed to show any benefit of PPV23 administered to 85 allogeneic HSCT recipients on day-1, day 50 and day 365 of transplant, when compared to a single dose at day 365 [61]. Only two patients developed a local reaction, both after a day-1 dose, in other words, at the beginning of the neutropenic phase. One of these two patients needed surgical excision of a local thigh fasciitis. No other severe side effect was reported. From 2005, all studies integrated the conjugate vaccine in their vaccination schedule, first a prime boost by PCV and then PPV23. When given after two or three doses of PCV7, it has been shown that one dose of PPV23, not only increases the response to the PCV7 antigens, but also extends the serotype coverage to the additional pneumococcal antigens, with a final response rate on the two assessed antigens (PN1 and PN5) between 68 and 87% [62]. 64

Efficacy & safety of PCV7 after HSCT

So far, no data are available in the HSCT population with PCV13; studies are ongoing. The only available data are those with PCV7, with different doses and timings. The improved immunogenicity of the conjugate vaccine over the PPV23 has been demonstrated in a randomized trial including 64 pairs of donors and recipients of allogeneic HSCT [63]. Both the PCV7 vaccination of the donor before harvest, and the vaccination of the recipient by one dose of either PCV7 or PPV23 at 6 months, showed the superiority of the immune response with the conjugate. This benefit, however, was low since even in the PCV7 group, the response to >one serotype at 12 months after transplant was only 38%, and no patient responded to all the seven serotypes [Kumar D, Pers. Comm.]. This low response rate may be explained by only one dose of conjugate given, and the antibody level assessment 6 months after vaccination. The very first study with repeated PCV7 doses after allogeneic HCST included three doses at 3, 6 and 12 months after transplant [64]. The response, assessed at 13 months, varied from 64-75%, according to the fact that the donor was immunized before harvest, or not. Another study in 53 allogeneic HSCT children assessed a schedule of three doses of PCV7 at 1 month interval, from 6-9 months after transplant [65]. The response measured 1 month later was in similar range, with 55.8% after the second dose, and with 74.4% after the third dose. Another schedule with two doses of PCV7 from 12 months post-transplant, followed by one dose of PPV23, was evaluated in 26 adults who had received a reduced-intensity conditioning regimen [38]. More than 73% of the patients developed antibody levels (>0.35 mg/ml) to pneumococcal serotypes, except for serotype 6B. However, these patients, all off-immunesuppression, were vaccinated at a median of 15 months after transplant. This response rate, compared to previous studies where patients were immunized during the first 6 or 12 months, indirectly confirms that the more we wait, the better the response. Finally, the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation compared an early vaccination (starting from 3 months after transplant) versus a late vaccination (starting from 9 months) in allogeneic HSCT recipients, with 3 doses of PCV7 at 1 month interval, followed by one dose of PPV23, administered 6 months later, in other words, at 12 or 18 months after a myeloablative transplant [23]. This study showed that an early vaccination was not inferior to a late vaccination (79 vs 82% of response, respectively), and could therefore offer protection during the very first months of transplant. Furthermore, there was a significant correlation between IgG titers and functional titers measured by opsonophagocytic assay [27]. However, the early schedule was more often associated with a decrease of the specific antibodies at 24 months of transplant. This study supports the more recent international guidelines which recommend initiating the conjugate antipneumococcal vaccination from 3– 6 months after HSCT [66]. The efficacy and safety of PCV7 was also assessed in autologous HSCT recipients [67]. Sixty one patients, eligible for Expert Rev. Vaccines 13(1), (2014)

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Pneumococcal immunization in immunocompromised hosts

autologous HSCT, were randomized to receive one dose of PCV7 before marrow harvest. All patients then received three doses of PCV7 at 3, 6 and 12 months after transplant, and 45 were finally evaluated (25 who were vaccinated before harvest, and 20 who were not), most of them with non-Hodgkin lymphoma. A protective concentration for all the serotypes was obtained for 60–87% of the patients. The GMCs of pneumococcal antibodies were higher in patients immunized before transplant compared with those immunized after transplant with, however, some differences of the benefit of the pretransplant dose according to the serotype. It should be noticed that the benefit of the pre-transplant dose was mainly observed during the early months of transplant. Overall, in three studies using different primary endpoints, different cut offs of antibody levels and different timings of vaccination and assessment, the response rate to at least two doses of PCV7 given during the first year after allogeneic HSCT was between 35% and 86% [23,64,65]. This response was improved in patients transplanted with a younger donor [23,64] and impaired by chronic GVHD [64]. None of these studies showed severe side effects of the vaccine. Comparable results were obtained after autologous HSCT with some benefit of pretransplant dose observed during the early months of transplant in patients immunized also before marrow harvest [67]. Benefit of donor immunization before allogeneic HSCT

No benefit of pretransplant vaccination of the donor with PPV23 was shown for the recipient in a randomized trial [61], results of which were confirmed later on [63]. As for the conjugate vaccine, vaccinating the donor with one dose of PCV7 before harvest enhanced the antibody response of the recipient to a PCV7 dose given 3 months after transplant, but this benefit did not persist after the third dose at 12 months [64]. In routine practice vaccinating the donor, when there is no recommendation of doing so in the healthy population of the same age range, may be difficult. Additionally, such practice should be impossible to adopt with unrelated donors and is not applicable after cord blood transplants. Current guidelines for HSCT recipients

The current guidelines recommend to initiate the antipneumococcal vaccination from 3–6 months after transplant with three to four doses of PCV13 at 1 month interval, followed by one dose of PPV23 [66], without any specific consideration for children who may have already received PCVs. In patients with chronic GVHD where the response to PPV23 may be suboptimal, it is suggested to replace the PPV23 by an additional dose of PCV13. Although patients with GVHD may have a lower immune response than patients without GVHD, postponing vaccinations in case of GVHD is not recommended since patients with GVHD are the most at-risk of IPD. We should, however, consider that even in the best HSCT populations for vaccine response (no GVHD, no immunesuppression), the response rate is never 100%. Measuring the specific antipneumococcal antibodies after vaccination may


be difficult in routine, but should be especially useful in patients with severe chronic GVHD. Moreover, in case of IPD in a patient who has been vaccinated, it is of utmost importance to serotype the responsible strain, in order to evaluate the benefit of additional doses, or eventually prefer Ig in case of hypogammaglobulinemia (TABLE 1). Due to the lack of large data, autologous HSCT recipients usually benefit from the same recommendations than the allogeneic HSCT recipients. Although their risk of developing IPD is lower than allogeneic HSCT recipients, though this risk remains higher than in healthy people. SOT recipients Prevalence of IPD in SOT recipients

In a large, Canadian prospective population-based surveillance, the incidence of IPD in SOT between 1995 and 2004 was estimated to be, by decreasing order: 354/100,000 persons per year after liver transplant, 239/100,000 person per year after lung transplant and 104/100,000 person per year after kidney transplant [14]. The overall incidence in SOT recipients was of 146 cases/100,000 transplanted persons per year as compared with 11.5/100,000 cases in the general population, in other words, a 12.7-fold higher risk after SOT was observed. These results were consistent with previous studies in lung [16] and kidney [68] transplants. No case was reported after heart and pancreas transplant in this series. In heart transplant, a study published in 1990 estimated the incidence of IPD at 36 cases/ 1000 patients per year and reported a decrease in the antipneumococcal antibodies in six patients in the first 6 months after transplant [69]. In the literature, the median time elapsed between SOT and IPD is very variable: especially short after heart transplant (mean: 58 days, range: 35–132), while no case was reported before 4 months after lung transplant [16], which was longer in other SOTs, with a mean of 6.35 years [14]. These different timings of IPD after SOT, although influenced by the length of follow-up and competitive risks in the different cohorts, should be considered regarding the optimal immunization schedule. Efficacy & safety of PPV23 in SOT recipients After heart or lung transplantation

Two studies, including 16 heart transplant recipients in one [70] and 35 in the other [71], showed that the immune response to PPV23, assessed by an ELISA test between 75 and 100%, was close to that of healthy controls of the same age range, but not equal between all serotypes, for example, only 50% for serotype 3 versus 75–94% in the other tested serotypes (4, 5, 8, 14, 18,19 and 23) [70]. However, it should be noticed that these studies obviously selected long-term survivors, since the patients were vaccinated 14.5–80.8 months [70] and 55– 122 months [71] after transplant. In children heart-transplanted before 4 years of age, and between the age of 2–20 years at time of vaccination, only 25% of them responded to PPV23 [72]. A more recent study which assessed the durability of antipneumococcal antibodies in the first 18 months after 65


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heart transplant showed a significant decrease from 3 to 6 months after transplant, even in the 27 patients vaccinated before transplant [11]. Consequently, the pre-transplant immunization was not very protective since eight of the 27 patients vaccinated before transplant, and two of the five non-vaccinated patients did develop at least one episode of pneumococcal infection, challenging the benefit of the pre-transplant vaccination with PPV23 alone. We are not aware of prospective studies with PPV23 alone in lung transplant. This lack of data may explain a low (62%) rate of pretransplant vaccination in lung transplant candidates [73]. After liver transplantation

A first study assessed the efficacy and safety of PPV23 given a mean of 3 years after liver transplantation [74]. The immune response of the 15 transplant patients was comparable to that of 23 healthy controls. A larger study evaluated the immune response to one dose of PPV23 in 45 patients with liver disease and on a waiting list for transplant [75]. Although most patients responded to the PPV23, their immune response was significantly lower than that of 13 healthy controls, especially in terms of specific IgG. In the 25 patients who were effectively transplanted, the specific antibody levels assessed 3 months after transplant were at or below prevaccination levels, with IgM significantly lower, challenging the benefit of a pretransplant vaccination to cover the risk of the first months after transplant [75]. After renal transplantation: In children, one dose of PPV23 induced an immune response, evaluated on serotypes 3 and 14, in 61–76% of the patients, with no difference both in the initial efficacy and in the antibody decline 1 year later between renal transplant recipients and children with chronic renal failure [39]. However, no indication was given in that study neither about the time elapsed between transplant and vaccination in the transplant group, nor about the possible difference in response according to age. In adult transplant recipients, the rate of protection (>0.5 mg/ml) after one dose of PPV23 given after 2.6 and 8.2 years of transplantation was 95%, without any impact of time after transplant, age or number of immunosuppressive drugs. However, in another study where PPV23 was given earlier (mean time of 1.2 years after transplant), the response to each PCV7 serotypes after one dose of PPV23 was poor, between 13 and 40% [28]. Three years later, antibody titers against 6 of the 7 serotypes (except serotype 14 not tested) had declined below the protective level, supporting the revaccination practice 3–5 years after the initial dose in SOT patients [76]. In all these studies, no serious adverse event related to the vaccine as well as no increased risk of graft rejection was reported. Efficacy & safety of conjugate vaccine in SOT recipients

One hundred and thirteen liver transplant recipients were randomized to receive either PCV7 or placebo, followed 8 weeks later by one dose of PPV23 [26]. Eight weeks later, the response was not different in both the groups, whatever the 66

parameter of assessment (GMC, percentage of response by serotype, percentage of response to >1 serotype or OPA) were. Rejection rate was not different in the two groups (1.8 vs 5.3%, n.s.). It should be noticed that this study was run in patients transplanted 2.5–3.3 years ago, and that the primary objective was based on a cutoff of 0.35 mg/ml and a >twofold increase of antibody titers from baseline, was assessed for only one serotype. This may have masked a possible difference of response between transplant patients and controls. In renal transplant, the same group has compared one dose of PCV7 versus one dose of PPV23 given in 60 patients naı¨ve for any pneumococcal vaccine, a mean of 1.2 year after transplant [28]. No difference was observed between the vaccines, both in terms of early immune response and in terms of minor adverse events. A response to at least one serotype of the PCV7 was seen in 53.3% of the PPV23 group, and in 73.3% of the PCV7 group. Although there was a trend for a better efficacy of PCV7 over PPV23 on several parameters (i.e., median number of serotypes responding, number of patients responding to serotypes 4, 9V, 18C and 19F), none of those differences was statistically significant except for a better response of serotype 23F and marginally for serotype 6B, an antigen which is known to be poorly immunogenic. No graft rejection was observed within the 8 weeks following vaccination. Two other studies give important data in pediatric SOT recipients [77,78]. The first study aimed to evaluate the pertinence of the guidelines of the American Academy of Pediatrics which recommended two doses of PCV 7 at 8 week intervals, followed by one dose of PPV23 in SOT children [78]. Twenty five children (liver transplant: 13; heart transplant: 11; multivisceral:1) between the age of 2 and 18 year, were vaccinated from 6 months after transplant, and were compared to 23 healthy children. Significant rises in antibody GMCs were observed in both groups, but lower in the SOT groups for certain serotypes, with surprisingly no clear benefit of neither the second PCV7 dose nor of the PPV23 dose. The heart transplant recipients seemed to be lower responders than the liver transplant recipients. The second study [77] included 81 children aged 7.8 (0.6–17.5) years with heart (n = 31), liver (n = 18), lung (n = 5) and kidney (n = 27) transplants, received three doses of PCV7 followed by one dose of PPV23 at 8 weeks apart (from 4 months after transplant), the schedule was very close to the one recommended in HSCT patients [23,66]. No serious vaccine related adverse effects were noticed. After two doses of PCV7, a two-fold increase in GMCs was observed in all SOT groups. Heart and lung recipients demonstrated additional benefit from a third dose of PCV7. The heart transplant recipients, who were among the lower responders showed most benefit from boosting with PPV23. A retrospective study of 26 adults including 12 lung and 14 heart transplant recipients, vaccinated by one dose of PCV7 between 14 and 197 months after transplant, showed a twofold increase of GMCs in 26– 61% of the patients, varying according to the serotype. No benefit appears after a subsequent dose of PPV23 on the Expert Rev. Vaccines 13(1), (2014)

Pneumococcal immunization in immunocompromised hosts

PCV7 serotype antibody levels, and the response to the serotypes included in PPV23 and not in PCV7 was in comparable ranges [79].

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Current guidelines for SOT patients

The more recent guidelines of the American Society for Transplantation (AST) for SOT recipients [76] recommend to first vaccinate the adult candidates to SOT prior to transplantation with one dose of PPV23, on the basis of the absence of clear benefit of PCV7 [26], then with a dose of PPV23 3–5 years later. However, as the time on the waiting list for transplant is variable, this second PPV23 dose 3–5 years after the first one may be given at various times after transplant. The 2012 ACIP guidelines propose that SOT recipients who were not previously exposed to pneumococcal vaccine may start with one dose of PCV13 followed by one dose of PPV23 (no sooner than 8 weeks later) and revaccination with one dose of PPV23 (5 years later) but this does not address the issue of the optimal timing in the close period before and after transplant (TABLE 1) [17]. Due to the low response to polysaccharide antigen in children below the age of 5 years, independent of any immunesuppression, specific considerations are needed in immunocompromised children. Additionally, a substantial number of children candidates to SOT have been nowadays previously vaccinated with a conjugate vaccine. This issue has been addressed by the AST Infectious Diseases Community of Practice [76] which recommends that children >5 years should receive PPV23 while children 1, and even 5–8 years after transplant [70,71,74]. These long-term survivors, however, are selected good-risk patients and good vaccine responders. A pretransplant vaccination, although convenient when the patient is on a waiting list, does not optimally cover the risk of IPD early after transplant, due to the rapid decline of antibodies [11,75]. Therefore, any schedule combining a pretransplant vaccination with PPV23 and a boost 3–5 years later, without any boost dose in the interval, likely offers a suboptimal protection to IPD during the first months or years after transplant. Although the benefit of PCV is debated in SOT [26,28], the immune response to PCV has never been lower than the response to PPV23 on the antigens included in the conjugate vaccine. The superiority of the conjugate vaccine has been established in other populations, like HSCT [63] or HIVpositive patients [80]. Considering these data, the need for an early protection, the safety of such vaccines and the risk of hyporesponsiveness when PPV23 is given before the conjugate vaccine, starting with one or two doses of PCV13 should be considered, though waiting for more data.


The transplant community seems to be reluctant for an early vaccination after SOT, due to a theoretical risk of immune reaction triggered by the vaccine leading to a risk of graft rejection or HLA-immunization, as reported after viral infections. Renal transplant recipients developed low levels of anti-HLA antibodies following the administration of the 2009 AS03-adjuvanted H1N1 vaccines. In two of the 20 patients who were followed at 6 months, clinical events possibly related to de novo anti-HLA antibodies were observed [81]. We were, however, unable to find any data supporting that antipneumococcal vaccine, conjugate or not, could increase the risk of graft rejection in SOT, or of anti-HLA immunization. HIV-infected patients Prevalence

S. pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. In the absence of ART, the risk of IPD is 40-fold greater in HIV-infected children [82,83] and 10– 300-fold greater in adults [84,85], 25% of whom having an additional episode within the next 12 months [86,87]. Although ART reduces the risk of IPD, it still remains 20–40-fold higher than in age-matched general population [83,84,88]. In the USA, for adults with HIV, the rate of IPD is 173/100,000 [17]. Even after indirect effects of the infant generalized immunization with PCV, the incidence of IPD caused by the seven serotypes included in PCV7 remained high, estimated at 64 cases/ 100,000 AIDS persons aged 18–64 years [89]. This is probably because of the deficiencies in humoral response due to the depleted or persistent defects in memory cell function, which persist during ART administration [90]. Moreover, the finding that HIV-infected children had lower GMCs and required higher concentration of antibody for 50% killing activity on OPA suggests functional impairment of antibody in HIVinfected children. Thus, HIV-infected children may need higher than ‡0.35 mg/ml serotype-specific antibody concentration for preventing IPD [24]. Hence, effective preventive approaches are needed to lower the incidence of IPD in HIV adults. Efficacy & effectiveness of PCV in HIV-infected children

Comparison of immune responses to PCV vaccination between HIV- infected and-uninfected children were reported in several studies [91–98]. In the absence of ART in African children, 1 month after a primary three-dose series of PCV9 given at 6, 10 and 14 weeks of age, the proportion of HIV-infected children with antibody concentrations ‡0.35 mg/ml to vaccine serotypes ranged between 63 and 93% compared with 79– 100% in HIV-uninfected infants. The GMCs were also lower. Similarly, the proportion of HIV-infected infants with OPA ‡8 for the studied serotypes was lower for serotypes 6B (78 vs 96%), 19F (46 vs 91%) and 23F (57 vs 93%) [94,96]. There are studies reporting a better immune response when PCV was administered while the children were on ART, or if vaccination was done when the CD4+ cell percentage was ‡25% or the nadir CD4+ was >15% [94,99]. 67

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Cordonnier, Averbuch, Maury & Engelhard

GMCs and OPA are expected to decrease over time among symptomatic HIV-1 infected children [94,97]. A booster dose of PCV given 12 months after primary series may lead to anamnestic responses. A multicenter study with HIV-infected children aged between 2–19 years receiving ART, who received two doses of PCV7 followed by one PPV23 dose 8 weeks apart demonstrated that higher antibody concentration at baseline, higher CD4+ cell percentage at vaccination, higher nadir CD4+ percentage along HIV history, lower HIV-viral loads, longer duration of current ART regimen and younger age were predictors of better immune response [100]. The nine serotypes included in PCV9 vaccine covered 83– 91% of IPD-causing serotypes among HIV-infected children prior to the evaluation of its effectiveness [101,102]. In the randomized, double-blind study in South Africa, 19,922 children received PCV9 and 19,914 received placebo at 6, 10 and 14 weeks of age. The vaccine reduced the incidence of a first episode of IPD due to serotypes included in the vaccine, following 2.3 years by 83% in un-infected children and by 65% in HIV-infected children [24]. Five years after vaccination, the risk of IPD was further reduced to 39% in the absence of a booster dose of PCV or ART access while in healthy children, it remained unchanged [94]. Safety of PCV in HIV-infected children

In all the studies of HIV-infected children, PCV is generally well tolerated [24,92,93,99,100]. However more frequent severe signs and symptoms among PCV recipients than placebo, including diarrhea, rash, fever and anemia, were reported [99]. In the South African study, a higher rate of asthma was reported among PCV9 recipients versus non-vaccinated children and a lower CD4+ cell percentage at the 5 year follow-up [95]. Efficacy & effectiveness of PPV23 & PCV in HIV-infected adults

There are several studies on PPV23 in HIV-infected adults. In Uganda, 1 month after PPV23 vaccination, HIV-infected patients demonstrated a significant rise in capsular-specific IgG for three of four serotypes tested, but levels were significantly lower than among HIV seronegative subjects [103]. However, a European study had demonstrated earlier that 1 month after PPV23 vaccination, normal antibody formation was observed in HIV-infected individuals, including those with low (200 cells/ml, were conducted in the USA and Europe. In the first study, PCV7 resulted in higher antibody concentration and OPA for certain serotypes than PPV23 in a fourarm randomized trial with two doses of vaccines and/or placebo administered to HIV-infected subjects 8 weeks apart (PCV7-PCV7, PCV7-PPV23, placebo-PPV23 and placeboplacebo groups). A second PCV7 dose 8 weeks after the first PCV7 dose did not produce any further increase in antibody response [80]. In a randomized Phase II controlled trial in HIV adults with CD4+ cell counts of 200–500 cells/ml and HIV RNA

Pneumococcal immunization in immunocompromised hosts: where do we stand?

Immunocompromised patients are all at risk of invasive pneumococcal disease, of different degrees and timings. However, considerable progress in pneum...
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