Recommendations for immunizations in stem cell transplantation

Investigations over the past decade have documented that there is a decline in immunity to vaccine preventable diseases in many SCT recipients. The majority of immunization studies conducted in SCT recipients to date support the use of multi-dose regimens for most protein and polysaccharide-conjugate vaccine antigens. The consensus immunization schedule recommended by ACIP/IDSA/ASBMT provides guidance for centers to utilize available vaccines in their SCT populations. With the exception of pneumococcal disease, a schedule beginning at 12 months after SCT is reasonable given the low incidence of disease in HSCT recipients for most of the recommended vaccines and improved immune reconstitution in most recipients by one year post transplant. SCT recipients respond poorly to unconjugated pneumococcal polysaccharide vaccine and the development of polysaccharide-protein conjugate vaccines against S. pneumoniae holds promise to impact potentially on clinical disease in this population. In addition, the strategy of donor immunization may also be effective in eliciting early protective immune responses to vaccine antigens. Future challenges will be the development of safe and effective vaccines against the viral pathogens responsible for considerable morbidity and mortality after SCT.     

Primary respiratory syncytial virus infection: pathology, immune response, and evaluation of vaccine challenge strains in a new mouse model

Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract illness in young children. Vaccine development has been hampered by the experience of the formalin-inactivated vaccine tested in the 1960's. Currently, several vaccine candidates are under development and immune response to these candidate vaccines must be evaluated closely. We introduce a novel low-dose murine model of RSV infection and a new pathologic scoring system for the resultant pulmonary disease. We have also developed new sensitive methods for measuring cytokine expression. We then used this new model to test vaccine challenge strains of RSV in order to determine their pathogenicity.     

Effects of alum adjuvant or a booster dose on immunogenicity during clinical trials of group B streptococcal type III conjugate vaccines

Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-microg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 microg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-microg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 microg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.     

Protective antibody responses to pneumococcal conjugate vaccine after autologous hematopoietic stem cell transplantation.

Patients undergoing autologous hematopoietic stem cell transplantation (autoHCT) are at increased risk for infection with Streptococcus pneumoniae and have impaired antibody responses to pneumococcal polysaccharide vaccines. We performed this study to examine the ability of autoHCT patients to respond to a heptavalent pneumococcal conjugate vaccine (PCV7) given after transplantation and to determine whether there was a potential benefit of immunizing these patients before stem cell collection. Sixty-one patients scheduled for autoHCT were randomized to receive either PCV7 or no vaccine before stem cell collection. After stem cell reinfusion, all study patients were immunized with PCV7 at 3, 6, and 12 months. Pneumococcal immunoglobulin G antibody concentrations were measured at the time of each immunization and 1 month after the 12-month dose. Serotype-specific pneumococcal antibody concentrations were significantly higher in patients immunized with PCV7 before stem cell collection compared with patients not immunized before their stem cells were collected for 6 of 7 serotypes at 3 months, 6 of 7 serotypes at 6 months, 4 of 7 serotypes at 12 months, and 3 of 7 serotypes at 13 months. After the 3-dose series of PCV7 after autoHCT, >60% of study patients had protective concentrations of antibody to all 7 vaccine serotypes regardless of immunization before stem cell collection. Pneumococcal conjugate vaccine is immunogenic in autoHCT patients and may be an effective strategy to prevent invasive disease after transplantation.     

Vaccines for transplant recipients

Immune dysregulation and immunosuppression regimens impact on the ability of transplant recipients to respond to immunizations. The distinct challenges of immunizations to benefit stem cell transplant recipients and solid organ transplant recipients are discussed separately. Recommended vaccines for stem cell transplant recipients and solid organ transplant candidates are suggested. New approaches to consider to enhance immune responses of transplant recipients are discussed.     

Comparison of an opsonophagocytic assay and IgG ELISA to assess responses to pneumococcal polysaccharide and pneumococcal conjugate vaccines in children and young adults with sickle cell disease

Children with sickle cell disease were immunized with either 2 doses of 7-valent pneumococcal conjugate vaccine followed by 1 dose of 23-valent pneumococcal polysaccharide vaccine or a single dose of 23-valent vaccine. Functional antibodies to 7 vaccine serotypes were measured by a flow cytometric opsonophagocytic assay (OPA) and compared with IgG anticapsular polysaccharide antibody concentrations measured by ELISA. Moderate correlations were found between OPA and ELISA antibody titers for all 7 serotypes (r values, 0.41-0.70; P<.001 for all serotypes). After immunization with 23-valent vaccine, geometric mean antibody titers by OPA were significantly higher in the combined schedule group for 5 of 7 vaccine serotypes but were significantly higher for only 2 of 7 serotypes as measured by ELISA. The ability of OPA to show a greater differential response to the 2 immunization schedules used in this study suggests that it may be useful in the evaluation of immunization regimens involving pneumococcal conjugate vaccines.     

Prevention of allograft HCV recurrence with peri‐transplant human monoclonal antibody MBL‐HCV1 combined with a single oral direct‐acting antiviral: A proof‐of‐concept study

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL‐HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct‐acting antiviral (DAA) to prevent HCV recurrence post‐transplant in an open‐label exploratory efficacy trial. Eight subjects received MBL‐HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post‐transplantation. Following FDA approval of sofosbuvir, two subjects received MBL‐HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8‐12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post‐treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2‐12 weeks post‐treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof‐of‐concept study demonstrates that peri‐transplant immunoprophylaxis combined with a single oral direct‐acting antiviral in the immediate post‐transplant period can prevent HCV recurrence.     

Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters

Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P<0.0001) in the primary disease hamster model and from 78% to 32% (P<0.0001) in the less stringent relapse model.     

Effect of monophosphoryl lipid A (MPL) on T-helper cells when administered as an adjuvant with pneumocococcal-CRM197 conjugate vaccine in healthy toddlers

As new vaccines are developed, novel adjuvants may play an important role in eliciting an effective immune response. We evaluated the safety and adjuvant properties of monophosphoryl lipid A (MPL in 129 healthy toddlers immunized with two doses of nine-valent pneumococcal-CRM(197) protein conjugate vaccine (PCV9) combined with 10, 25, or 50 micro g of MPL with or without alum (AlPO(4)). Vaccine-specific humoral and cell-mediated responses were examined following the second dose of study vaccine. All doses of MPL were well-tolerated and a dose-dependent effect of MPL on specific cellular responses was observed. The 10 micro g MPL dose significantly enhanced CRM(197)-specific T-cell proliferation (P=0.02) and interferon-gamma (INF-gamma) production (P=0.009) compared to responses of controls who received PCV9 with AlPO(4). In contrast, CRM(197)-specific T-cell proliferation and interferon-gamma production of the 50 micro g MPL/AlPO(4) group were decreased when compared to controls although these differences did not reach statistical significance. IL-5 and IL-13 responses after immunization showed a similar pattern with increased production in the 10 micro g MPL group and decreased production in the 50 micro g MPL/AlPO(4) group compared to controls. There were no differences in serum IgG antibody concentrations to the nine vaccine pneumococcal capsular polysaccharides and carrier protein between the MPL-containing and control vaccine groups. These findings demonstrate a dose-dependent effect of MPL on T-helper cell type 1 (TH-1) responses to the carrier protein and also suggest an effect on T-helper cell type 2 (TH-2) responses.     

Human Monoclonal Antibody MBL‐HCV1 Delays HCV Viral Rebound Following Liver Transplantation: A Randomized Controlled Study

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon‐α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL‐HCV1) on viral clearance was examined in a randomized, double‐blind, placebo‐controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL‐HCV1 (n = 6) or placebo (n = 5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL‐HCV1 was well‐tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log₁₀ IU/mL) from baseline was significantly greater (p = 0.02) for the antibody‐treated group (range ?3.07 to ?3.34) compared to placebo group (range ?0.331 to ?1.01) on days 3 through 6 posttransplant. MBL‐HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p < 0.001). As with other HCV monotherapies, antibody‐treated subjects had resistance‐associated variants at the time of viral rebound. A combination study of MBL‐HCV1 with a direct‐acting antiviral is underway.