Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation

Patients undergoing hematopoietic cell transplantation (HCT) are at increased risk for infections with Streptococcus pneumoniae and have long-lasting, impaired antibody responses to pneumococcal polysaccharide vaccines. We examined whether donor immunization with a heptavalent pneumococcal conjugate vaccine (PCV7) would elicit protective antibody responses to additional doses of vaccine administered early after transplantation. Ninety-six patients scheduled to receive an allogeneic hematopoietic cell transplant were randomized with their donors to receive either a dose of PCV7 vaccine or no vaccine before transplantation. All patients received PCV7 at 3 months, 6 months, and 12 months following transplantation, and serotype-specific antibody concentrations were determined after each dose. Following HCT, geometric mean antibody concentrations of patients in the immunized donor group were significantly higher for 5 of the 7 vaccine serotypes after one dose (P <.05) and for 4 of the 7 serotypes after 2 doses of vaccine (P <.03). Sixty-seven percent of patients in the immunized donor group had presumed protective IgG concentrations more than or equal to 0.50 microg/mL to all 7 serotypes following the first dose of vaccine compared to 36% in the unimmunized donor group (P =.05). After the third dose of vaccine, both groups had more than 60% of patients with concentrations at least 0.50 microg/mL to all vaccine serotypes. Donor immunization enhances early antibody responses of patients undergoing HCT to pneumococcal conjugate vaccine. A 3-dose schedule of PCV7 vaccine at 3, 6, and 12 months is immunogenic in these patients regardless of donor immunization.     

Human T lymphotropic virus type II infection and humoral responses to pneumococcal polysaccharide and tetanus toxoid vaccines

Infection with human T lymphotropic virus type II (HTLV-II) has been linked to an increased incidence of bacterial pneumonia. To determine whether HTLV-II infection is associated with impaired humoral immune responses, we immunized a cohort of HTLV-II-infected subjects and matched uninfected control subjects with 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines. The pneumococcal polysaccharide vaccine elicited comparable and significant increases in concentrations of IgG against all 5 serotypes tested at 1 and 6 months after immunization in both groups. The avidity and opsonophagocytic functions of the anticapsular IgG were similar. The concentrations of tetanus toxoid-specific IgG also increased comparably and significantly over time in both groups. Thus, HTLV-II-infected persons develop robust humoral responses to potentially protective polysaccharide and protein vaccines.     

Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients.

As a consequence of the significantly larger inoculum of lymphoid cells present in peripheral blood stem cell (PBSC) harvests compared to bone marrow (BM), it is possible that autoPBSCT recipients may have an earlier and*or enhanced response to vaccines. Until data to confirm this become available, the European Blood and Marrow Transplantation Association (EBMT) recommend that all transplant recipients be immunized in the same way regardless of stem cell source. We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Antibody responses in sibling HLA-matched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. Fifty patients were enrolled. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Serological responses were poor and no significant difference in response to any of the vaccines used was seen between the three transplant cohorts. We provide no evidence that current EBMT guidelines be modified. Large prospective vaccine studies are needed to address the issue more fully.     

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.     

Rapidly fatal pneumococcal septicemia in systemic lupus erythematosus

Streptococcal pneumoniae septicemia was responsible for the deaths of 3 patients with chronic systemic lupus erythematosus. The absence of a spleen likely contributed to sepsis in 2 patients. One patient had been immunized with 14-valent pneumococcal vaccine with a doubling of serum antibody concentrations at one month to all vaccine capsular polysaccharide types except for Types 1 and 12. The patient died 74 months after immunization of pneumococcal Type 1 sepsis.     

Functional antibodies elicited by an 11-valent diphtheria-tetanus toxoid-conjugated pneumococcal vaccine

The aluminium-adjuvanted 11-valent pneumococcal conjugate vaccine containing polysaccharides 1, 4, 5, 7F, 9V, 19F, and 23F (coupled to tetanus protein) and polysaccharides 3, 6B, 14, and 18C (coupled to diphtheria toxoid) elicits high antibody concentrations in Filipino infants when given at ages 6, 10, and 14 weeks and 9 months simultaneously with the national vaccination program. We evaluated functional activity of these antibodies by using a viable cell opsonophagocytic assay (OPA). The OPA titers correlated (r=0.53-0.74) with the respective antibody concentrations. The geometric mean OPA titers after 3 vaccine doses were 276.9 (serotype 4), 12.3 (serotype 6B), 46.0 (serotype 14), 119.3 (serotype 19F), and 206.3 (serotype 23F). The functionality of antibodies increased after the fourth dose of vaccine (i.e., the concentration required for in vitro killing of pneumococci decreased). Both the quantity and quality of antibodies are important in the evaluation of immunogenicity of pneumococcal vaccines.     

Pneumococcal conjugate vaccine provides early protective antibody responses in children after related and unrelated allogeneic hematopoietic stem cell transplantation

Following allogeneic hematopoietic stem cell transplantation (alloHSCT), children are at risk of life-threatening pneumococcal infections. Whereas vaccination with polysaccharide vaccines fails to elicit protective immunity in most alloHSC transplant recipients, pneumococcal conjugate vaccines may effectively prevent invasive disease by eliciting T-cell-dependent antibody responses. Here, we report safety and immunogenicity in 53 children immunized with a regimen of 3 consecutive doses of a heptavalent pneumococcal conjugate vaccine (7vPCV) in monthly intervals starting 6 to 9 months after alloHSCT. Immunization was well tolerated with no vaccine-related serious adverse events. Serologic response rates evaluable in 43 patients ranged from 41.9% to 86.0% and 58.1% to 93.0% after 2 and 3 vaccinations, respectively, with 55.8% and 74.4% of patients achieving protective antibody levels to all 7 vaccine serotypes. Our study provides the first evidence that vaccination with 7vPCV is safe and elicits protective antipneumococcal antibody responses in pediatric recipients of related or unrelated donor alloHSC transplants within the first year following transplantation. This trial was registered at www.clinicaltrials.gov as NCT00169728.     

Titers of antibody to pneumococci in allogeneic bone marrow transplant recipients before and after vaccination with pneumococcal vaccine

To understand the susceptibility of allogeneic bone marrow transplant recipients to pneumococcal infection, we measured the level of type-specific antibodies to pneumococcal capsular polysaccharide in serum from ten marrow recipients. Seven recipients received marrow from matched sibling donors who had recently been vaccinated with polyvalent pneumococcal vaccine. Titers of IgG antibodies to two pneumococcal serotypes (7F and 14) declined significantly during the first year after transplantation. IgM antibodies remained low or declined after transplantation, but IgM antibodies to type 7F increased during the latter half of the first year. Pneumococcal vaccine was administered to seven marrow recipients approximately two years after transplantation. Vaccinated recipients had lower postvaccination titers of type-specific IgG antibody than did vaccinated normal adults and vaccinated sibling donors, and the recipients had normal levels of type-specific IgM antibodies. Thus, the susceptibility of marrow graft recipients to pneumococcal disease may be related to lowered concentrations of antibody to pneumococci after engraftment.     

The effect of ranitidine on antibody responses to polysaccharide vaccines in patients with B-cell chronic lymphocytic leukaemia

OBJECTIVES: To analyse the effects of ranitidine treatment on vaccination induced antibody responses in patients with chronic lymphocytic leukaemia (CLL). METHODS: Fifty CLL patients were vaccinated with tetanus conjugated Hib vaccine and a 23-valent pneumococcal polysaccharide vaccine with (n = 25) or without (n = 25) ranitidine treatment in a matched case--control setting. Anti tetanus toxoid (TT), anti-Hib and anti-pneumococcal antibody levels were determined before and after vaccination. Additionally, cytokine levels were assessed in patients treated with ranitidine. RESULTS: Vaccination-induced increases in anti-Hib and anti-TT antibody levels were higher in the ranitidine group compared with the control group. Anti-pneumococcal antibody responses were not improved by administration of ranitidine. Higher levels of IL-18 were found in patients treated with ranitidine compared with healthy controls. Levels of IL-6, IL-8, IL-18, RANTES, IP-10, sVCAM-1 and sICAM-1 were within normal ranges and did not change during ranitidine treatment. CONCLUSION: Ranitidine treatment improves vaccination-induced T-cell dependent antibody responses in patients with CLL but has no beneficial effect on the response to vaccination with unconjugated polysaccharide antigens.     

Pneumococcal vaccination: the response of patients with alcoholic liver cirrhosis

Patients with cirrhosis have an increased risk of dying from pneumococcal pneumonia. Their immunological response to pneumococcal vaccination is not known. We compared the antibody response to challenge with a 14-valent purified pneumococcal polysaccharide vaccine in 15 patients with biopsy-proven alcoholic liver cirrhosis, 10 healthy volunteers and 10 patients with chronic obstructive pulmonary disease. Preimmunization levels for Danish type 1 pneumococcal polysaccharide were lower among cirrhotics than patients with chronic obstructive pulmonary disease. Four and 12 weeks after immunization, no significant differences were found in antibody concentrations between the three groups. We conclude that patients with alcoholic cirrhosis can produce an adequate antibody response to pneumococcal polysaccharide antigen.     

Antibody Response to Pneumococcal Vaccination in Patients with Myelomatosis

17 patients with myelomatosis were vaccinated with a 14-valent pneumococcal capsular polysaccharide vaccine. In comparison to 12 healthy controls, they had statistically significant lower combined geometric mean antibody concentrations (the geometric means of all 14 antigens), both before and 4 weeks after the immunization. Mean antibody increases, however, were remarkably similar in the 2 groups. After 18 months the geometric mean antibody concentrations of the patient group had returned to preimmunization levels or lower for 7 out of 14 antigens. 1 case of pneumococcal bacteraemia occurred in the patient group 8 1/2 months after vaccination in spite of a significant initial antibody response against the infecting serotype 23 F. Pneumococcal vaccination in patients with myelomatosis appears to yield subnormal antibody responses and therefore probably insufficient protection against pneumococcal infection.     

Similar antibody concentrations in Filipino infants at age 9 months, after 1 or 3 doses of an adjuvanted, 11-valent pneumococcal diphtheria/tetanus-conjugated vaccine: a randomized controlled trial

In Filipino infants, 1 dose of an adjuvanted, 11-valent pneumococcal conjugate vaccine (serotypes 1, 4, 5, 7F, 9V, 19F, and 23F conjugated to tetanus protein; and serotypes 3, 6B, 14, and 18C conjugated to diphtheria toxoid) administered alone at age 18 weeks (11PncTD1) elicited similar antibody concentrations at age 9 months as those elicited by 3 doses (11PncTD3) administered concomitantly with national program vaccines, at ages 6, 10, and 14 weeks. Geometric mean antibody concentrations ranged from 0.36 microg/mL (for serotype 18C) to 5.81 microg/mL (for serotype 4), for the 11PncTD1 vaccine, and from 0.32 microg/mL (for serotype 18C) to 5.01 microg/mL (for serotype 19F), for the 11PncTD3 vaccine. The proportion of infants with threshold antibody concentrations > or =0.35 microg/mL was also similar (ranges, 55.6%-100% for the 11PncTD1 vaccine and 42.9%-100% for the 11PncTD3 vaccine). The functional activity of antibodies expressed as opsonophagocytic activity titers was similar in the 11PncTD1 and 11PncTD3 groups. This finding is an important one for countries with financial constraints and high pneumococcal disease burden.     

Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers

To test for immunologic memory after a single dose of meningococcal C conjugate (MCC) vaccine in toddlers, 226 children 12-18 months old were randomized to receive 1 of 3 MCC vaccines, with a C polysaccharide booster 6 months later. The protein conjugate was diphtheria mutant toxoid in 2 vaccines (MCC-CRM(197)) and was tetanus toxoid in the third (MCC-TT). One month after the MCC vaccines, 91%-100% of children had serum bactericidal antibody (SBA) titers > or =8, and 89%-100% had a > or =4-fold increase. Geometric mean titer (GMT) increased from <4 to 215 (95% confidence interval [CI], 166-279). MCC-TT induced higher SBA GMTs (P<.001) and higher proportions with SBA > or =8 (P=.02) than did the MCC-CRM(197) vaccines. By 6 months, GMTs had decreased to 55.1 (95% CI, 40-76), but IgG antibody avidity increased (P<.001). Induction of immunologic memory was confirmed by a GMT of 1977 (range, 1535-2547) after the polysaccharide booster and a further increase in avidity. This evidence justified the use of a single dose in a catch-up immunization program for children 1-18 years old.     

Kinetics of antibody concentration and avidity for the assessment of immune response to pneumococcal vaccine among children with bone marrow transplants

The kinetics of the immune response to the 23-valent pneumococcal polysaccharide vaccine (PPV) were studied in 38 children who received bone marrow transplants (BMTs). Anti-pneumococcal antibody concentrations increased 1 and 3 months after vaccination for all 5 serotypes tested, but, in 21 children, the vaccine was not adequately immunogenic. Children vaccinated <18 months after receiving a BMT had a 4.2-fold increased odds of poor response (P=. 06). Antibody concentrations returned close to baseline levels 9 months after vaccination. Avidity declined significantly as early as 1 month after vaccination and remained low thereafter. Antibody concentration responses to PPV were superior among 9 healthy control children (P=.001); 37 of 38 children with a BMT elicited adequate, persistent immune responses to Haemophilus influenzae conjugate vaccine. Immune responses to PPV in children with a BMT are suboptimal, short lived, and associated with declining avidity. The different kinetics of antibody concentration and avidity indicate that both markers should be used for evaluating pneumococcal vaccines in this high-risk population.     

A randomized, double-blind trial of pneumococcal vaccination in adult allogeneic stem cell transplant donors and recipients.

BACKGROUND: Adult allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk of invasive pneumococcal disease but have suboptimal responses to the recommended pneumococcal polysaccharide vaccine (PPV23). Pneumococcal conjugate vaccine (PCV7) may improve immunogenicity in this population, and a donor vaccination strategy may benefit patients undergoing HSCT. METHODS: Sixty-four pairs of donors and recipients scheduled to undergo HSCT were randomized to receive either PPV23 or PCV7. Vaccinations were administered to donors before transplantation and to recipients at 6 months after transplantation. Serotype-specific antipneumococcal titers were measured in donors at the time of harvest and in recipients before transplantation and 6 and 12 months after transplantation. RESULTS: Overall, immunogenicity was poor with both strategies. However, at 6 months, response to at least 1 serotype was seen in 0 (0%) of 19 and 8 (38.6%) of 21 evaluable recipients whose donors had received PPV23 and PCV7, respectively (P=.003). At 12 months, response was seen in 10 (55.6%) of 18 and 20 (90.9%) of 22 HSCT recipients who had received PPV23 and PCV7, respectively (P=.02). Multivariate logistic regression revealed that, at 12 months after transplantation, the type of vaccine given was the only significant factor affecting response, with an odds ratio of 8.85 (95% confidence interval, 1.62-47.6; P=.012) favoring PCV7. CONCLUSION: A donor and recipient paired vaccination strategy with PCV7 demonstrated safety and greater immunogenicity than did a similar strategy with PPV23.     

Magnitude of interference after diphtheria-tetanus toxoids-acellular pertussis/Haemophilus influenzae type b capsular polysaccharide-tetanus vaccination is related to the number of doses administered.

We compared the antibody response to Haemophilus influenzae type b capsular polysaccharide (PRP) after 1, 2, or 3 doses of a diphtheria-tetanus toxoids-acellular pertussis (DTaP) vaccine combined with a PRP-tetanus conjugate (PRP-T) vaccine, followed by separate injections of DTaP and PRP-T vaccines for the last 1 or 2 doses. Healthy infants were recruited from pediatric practices and were immunized according to recommended schedules. A significant decrease in the mean anti-PRP (from 5.25 to 2.68 microg/mL) and anti-tetanus toxoid antibody responses (from 0.13 to 0.09 Eq/mL) was observed as the number of doses of the DTaP/PRP-T combination vaccine increased (P<.02 and P=.01, respectively). In contrast, the mean anti-diphtheria toxoid antibody response increased with increasing numbers of DTaP/PRP-T doses (P=.0001). The effects of interference were not eliminated by the completion of the primary series with 1 or 2 doses of the DTaP and PRP-T vaccines given separately.     

The emergency department as part of a successful strategy for increasing adult immunization

To evaluate acceptance of the emergency department as a setting for vaccine delivery, we interviewed and offered pneumococcal vaccine to 338 high-risk ED patients presenting with unrelated complaints. Only 27 (8%) had previously been immunized with pneumococcal vaccine. Of the unimmunized, 187 (60%) initially indicated that they would accept vaccine during their current ED visit, and 51 (37%) of those without immediate medical contraindications were immunized. Willingness to take pneumococcal vaccine in the ED was independent of whether the patient had a primary medical provider (P = .77). Our immunization strategy complements other vaccination schemes that target those at high risk for pneumococcal disease and may in particular serve those patients who use the ED as their primary source of health care.     

Immunologic response to a single dose of tetanus toxoid in older people

OBJECTIVES: Several studies have demonstrated that a large percentage of older people are inadequately immunized against tetanus. The aim of this study was to assess the immunity against tetanus in a group of individuals aged 69 and older and to examine the immune response to a single dose of tetanus toxoid. DESIGN: A convenience sample of 115 residents of a large retirement home, aged 69 and older, was studied. After a blood sample for anti-tetanus antibody titer, a single dose of tetanus toxoid vaccine was administered. Repeat titers were obtained 6 weeks after the vaccination and analyzed by ELISA assay. Antibody levels equal to or greater than 0.1 IU/mL were considered protective. RESULTS: Sixty-seven of 115 (58.3%) individuals had adequate antibody titers. Those individuals who reported having been vaccinated with tetanus toxoid in the past were more likely to be immunized adequately compared with those who reported having never been vaccinated (66.7% vs 39.3%, P = .02). After vaccination, 34 of 46 (73.9%) individuals with inadequate antibody titers became seropositive. Those who remained seronegative had mean prevaccination antibody titers significantly lower than those who seroconverted. Sixteen of 17 (94.1%) persons who reported having been vaccinated in the past and were found to be seronegative developed adequate antibody titers following vaccination, compared with only nine of 16 (56.2%) who reported never having been vaccinated (P = .04). There was no association between seroconversion rate and age, sex, underlying diseases, and army service. CONCLUSIONS: Most individuals will develop an adequate anti-tetanus antibody titer following administration of a single dose of tetanus vaccine. A history of past immunization is a good predictor of becoming adequately immunized. It is important that physicians follow the current recommendations for adult immunization and initiate campaigns to ensure that the older population is protected against tetanus.     

Effect of total lymphoid irradiation on levels of serum autoantibodies in systemic lupus erythematosus and in rheumatoid arthritis

The effects of total lymphoid irradiation (TLI) on serum levels of autoantibodies, and of antibodies to diphtheria toxoid, tetanus toxoid, and pneumococcal polysaccharide in patients with lupus nephritis were compared with those previously observed in rheumatoid arthritis (RA) patients. Baseline levels of antibodies to diphtheria toxoid and tetanus toxoid decreased significantly after TLI in patients with lupus and RA, but antibody levels to pneumococcal polysaccharide remained unchanged. After TLI, the levels of antinuclear and anti-DNA antibodies were reduced significantly in lupus, but levels of rheumatoid factor, antinuclear, and antigranulocyte antibodies all tended to increase in RA.     

Antibody response to a Haemophilus influenzae type b polysaccharide tetanus toxoid conjugate vaccine in splenectomized children and adolescents.

20 children and adolescents 4-18 years old and splenectomized for various reasons (spherocytosis (n = 6), idiopathic thrombocytopenia (n = 8), other (n = 6)) were immunized once with a Haemophilus influenzae type b (Hib) polysaccharide tetanus toxoid conjugate vaccine. Prior to vaccination 10/20 patients had anticapsular antibodies below what could be considered the minimum protective level in splenectomized (0.6 micrograms/ml), whereas all obtained high antibody levels after vaccination. In addition 1 infant with congenital asplenia was vaccinated at 2,4 and 6 months of age, and was shown to respond well after the second and third injection with serum antibody concentrations of 0.84 and 10.7 micrograms/ml respectively. Because asplenic individuals have an increased risk of invasive Hib infection, these data suggest that vaccination of such individuals against Hib may be justified.