Poor Long-Term Efficacy of Prevnar-13 in Sickle Cell Disease Mice Is Associated with an Inability to Sustain Pneumococcal-Specific Antibody Titers

Background

One of the most common causes of morbidity and mortality in children with sickle cell disease (SCD) is infection with the pneumococcal bacterium (Streptococcus pneumoniae). Unfortunately, the polysaccharide-conjugate vaccine appears to be less effective in individuals with SCD when compared to the general population. We sought to better understand the relative efficacy of pneumococcal vaccination in a SCD mouse challenge model.

Methods

Transgenic control and SCD mice were monitored for mortality after intranasal pneumococcal infection or pneumococcal vaccination with Prevnar-13 and type-matched challenge. Anti-pneumococcal antibody titers were measured by ELISA and opsonophagocytosis was measured in vitro.

Results

Mortality after pneumococcal infection was similar between control and SCD mice. However, after three intramuscular polysaccharide-conjugate vaccinations, all control mice were protected following high-dose intranasal infection, whereas 60% of SCD mice died. Anti-pneumococcal antibody titers showed initial IgG and IgM responses in both groups, but waning titers were observed in the SCD group, even after boosting. When functionally assayed in vitro, serum from SCD mice 13 weeks after a second booster shot maintained little to no ability to opsonize pneumococci, while serum from control mice sustained a significantly higher capacity opsonization. Thus, it appears that SCD mice do not maintain antibody responses to pneumococcal polysaccharides after Prevnar-13 vaccination, thereby leaving them susceptible to mortality after type-matched infection.

Conclusion

Our results emphasize the need to better understand the correlates of immune protection in SCD so that pneumococcal vaccines can be improved and mortality reduced in this susceptible population.     

Randomized,Single Blind,Controlled Trial to Evaluate the Prime-Boost Strategy for Pneumococcal Vaccination in Renal Transplant Recipients

Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values ≥1 µg/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (P = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5–4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9–6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime–boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants.

Trial Registration

EudraCT 2007-004590-25.     

Pneumococcal antibody concentrations and carriage of pneumococci more than 3 years after infant immunization with a pneumococcal conjugate vaccine

Background

A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3–4 years after primary vaccination.

Methodology/Principal Findings

We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38–52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6–8 weeks and 16–18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6–8 weeks after PCV-7, but only the 6B difference was sustained at 16–18 months. There was no significant difference in nasopharyngeal carriage between the two groups.

Conclusions/Significance

Pneumococcal antibody concentrations in Gambian children were high 34–48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months.     

Role of whole-cell pertussis vaccine in severe local reactions to the preschool (fifth) dose of diphtheria-pertussis-tetanus vaccine.

OBJECTIVE: To estimate the contribution of whole-cell pertussis vaccine to severe local reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine. DESIGN: Double-blind randomized controlled trial. SETTING: Urban community. PARTICIPANTS: Volunteer sample of 200 healthy children 4 to 6 years old who were eligible for the fifth dose of DPT vaccine. INTERVENTIONS: Children received, in both arms, either diphtheria toxoid-tetanus toxoid (DT) and monovalent pertussis vaccines (group A, 99 children) or DPT and meningococcal vaccines (group B, 101 children). All were licensed products from single lots. The children were assessed 24 hours later by a trained observer. Serum samples obtained before vaccination were tested for antibodies to tetanus and diphtheria toxins and five pertussis antigens by means of enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of severe local reactions (an area of redness or swelling or both of 50 mm or greater) 24 hours after vaccination. Relation between serum antibody levels before vaccination and rates of severe local reactions to corresponding vaccines. RESULTS: All of the subjects were followed up 24 hours after vaccination. Severe redness was present in 38% given DPT vaccine, 29% given intramuscular pertussis vaccine and 9% given DT vaccine (p < or = 0.002, three-way comparison). Severe swelling was common after vaccination with all three products. After intramuscular pertussis vaccination a relation was evident between the prevaccination levels of antibody to whole-cell pertussis bacteria and the rates of redness (p < 0.02) but not between the prevaccination subcellular antibody levels and the rates of redness. CONCLUSION: That pertussis vaccine resembled the DPT vaccine in causing severe redness suggests that it is the principal cause of such reactions after DPT vaccination. The DT vaccine was also reactogenic; thus, cumulative sensitization to one or more of its constituents may be a factor.     

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction

The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA).

Methods

Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2.

Results

In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%.

Conclusion

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.

Trial registration

NCT00828997 and EudraCT EU 2007-006539-29.     

Fecal IgA antibody responses after oral poliovirus vaccination in infants and elder children

We investigated fecal IgA antibody responses after oral polyvalent poliovirus vaccination. Infants were given vaccines twice with an interval of 6 weeks. Specific IgA antibodies in the feces were determined by enzyme-linked immunosorbent assay, and viruses were isolated in tissue cultures. We found that, after the first vaccination, antibody responses seemed to be elicited only against the serotypes of isolated viruses. After the second vaccination, however, antibodies were detected to all three serotypes with higher titers, suggesting that the first vaccination induced the immunologic memory. The IgA antibodies had virus-neutralizing activity, and existed in the feces as both intact 11S and fragmented 4S molecules. Next, children were given the third vaccination 3 or 9 years later. Fecal IgA antibody responses were found to be poorer in elder children, while they responded with high serum neutralization titers. The secretory IgA memory seemed to last much shorter the serum IgG memory.     

Effects of delivery method on serological responses of bighorn sheep to a multivalent Pasteurella haemolytica supernatant vaccine

The safety and efficacy of a remotely delivered multivalent Pasteurella haemolytica supernatant vaccine (serotypes A2 and T10) were examined in captive Rocky, Mountain bighorn sheep (Ovis canadensis canadensis). Twenty bighorn sheep were grouped according to baseline leukotoxin neutralizing antibody titers (< or =2 or >2 log2(-1)) and vaccination history (previously vaccinated or unvaccinated). Within these groups, animals were randomly assigned to one of two delivery treatments: hand injection (control) or biobullet implantation. All bighorns received a single dose from the same lot of vaccine (n = 10/treatment); four additional animals were injected intramuscularly with 0.9% saline as unvaccinated sentinels. Mild, transient lameness one day after hand injection or biobullet implantation was the only adverse effect. Serum neutralizing antibody titers to P. haemolytica leukotoxin differed between delivery treatments (P = 0.009) and among baseline titer/vaccination history groups (P = 0.013). Neutralizing titers were higher among hand-injected bighorns. Although neutralizing titers were lower among implanted bighorns than hand-injected controls at 1 wk (P = 0.002) and 2 wk (P = 0.021) after vaccination, seroconversion rates in response to implantation (6/10) and hand injection (9/10) did not differ (P = 0.303). Agglutinating antibody titers to T10 were high and did not vary over time or between delivery treatments. Agglutinating antibody titers to A2 in the hand-injected controls were not different (P > or = 0.07) than those in bighorns vaccinated with biobullet implantation. These data demonstrate that although hand injection elicits higher absolute titers, biobullet implantation may also stimulate effective antibody responses to P. haemolytica supernatant vaccine. Further evaluation of biobullet vaccination against pneumonic pasteurellosis in free-ranging populations of wild bighorn sheep is warranted.     

Antibody and Plasmablast Response to 13-Valent Pneumococcal Conjugate Vaccine in Chronic Lymphocytic Leukemia Patients – Preliminary Report

Background

Chronic lymphocytic leukemia (CLL) leads to significant immune system dysfunction. The predominant clinical presentation in 50% of patients involves recurrent, often severe, infections. Infections are also the most common (60–80%) cause of deaths in CLL patients. The scope of infections varies with the clinical stage of the disease. Treatment-naive patients typically present with respiratory tract infections caused by encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. Since 2012, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended in the United States and some EU countries for pneumococcal infection prevention in patients with CLL (besides the long-standing standard, 23-valent pneumococcal polysaccharide vaccine, PPV23). The aim of this study was to compare the immune response to PCV13 in 24 previously untreated CLL patients and healthy subjects.

Methods

Both groups were evaluated for: the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses and selected peripheral blood lymphocyte subpopulations including the frequency of plasmablasts before and after immunization.

Results

Adequate response to vaccination, defined as an at least two-fold increase in specific pneumococcal antibody titers versus pre-vaccination baseline titers, was found in 58.3% of CLL patients and 100% of healthy subjects. Both the CLL group and the control group demonstrated a statistically significant increase in the IgG2 subclass levels following vaccination (P = 0.0301). After vaccination, the frequency of plasmablasts was significantly lower (P<0.0001) in CLL patients in comparison to that in controls. Patients who responded to vaccination had lower clinical stage of CLL as well as higher total IgG, and IgG2 subclass levels. No significant vaccine-related side effects were observed.

Conclusions

PCV13 vaccination in CLL patients is safe and induces an effective immune response in a considerable proportion of patients. To achieve an optimal vaccination response, the administration of PCV13 is recommended as soon as possible following CLL diagnosis.     

Pneumococcal polysaccharide vaccination in allogeneic hematopoietic stem cell transplantation recipients: a prospective single-center study

Few studies have evaluated the response of allogeneic hematopoietic stem cell transplantation [allo-HSCT] recipients to pneumococcal polysaccharide vaccine-23 [PPSV23] in the modern transplant era when more elderly patients undergo allo-HSCT. We administered a single dose of PPSV23 to 30 allo-HSCT recipients and evaluated serotype-specific antibody responses using IgG measured by enzyme-linked immunosorbent assay and opsonophagocytic assay [OPA] titers in a multiplexed opsonophagocytic killing assay. The median patient age was 54 years [range, 23–68], and the interval from allo-HSCT to vaccination was 756 days [range, 389–1903]. No severe adverse effects were observed. The median positive response rates at 1 month and 1 year post-vaccination for the 7 serotypes measured by IgG were the same at 43% [range, 33–57], while those for 8 serotypes measured by OPA were 72% [range, 55–86] and 55% [range, 52–62], respectively. Peripheral blood stem cell transplantation improved vaccine response based on OPA titers at 1 month post-vaccination. During the median follow-up period of 1135 days post-vaccination, one patient developed pneumococcal bacteremia at 998 days. Our study suggests that PPSV23 vaccination in allo-HSCT recipients is safe and may result in a serological response.     

Pneumococcal antibody concentrations of subjects in communities fully or partially vaccinated with a seven-valent pneumococcal conjugate vaccine

Background

A recent trial with PCV-7 in a rural Gambian community showed reduced vaccine-type pneumococcal carriage in fully vaccinated compared with control communities. We measured pneumococcal polysaccharide antibody concentrations in this trial to understand further the mechanisms underlying the observed changes.

Methods

A single-blind, cluster-randomized (by village) trial was conducted in 21 Gambian villages. In 11 villages, all residents received PCV-7 (Vaccine group); in 10 control villages only children <30 months old or those born during the study received PCV-7. Subjects over the age of 30 months resident in vaccine villages received a single dose of PCV-7 whilst those in control villages received a single dose of a serogroup C meningococcal conjugate vaccine. Serum antibody concentrations against specific pneumococcal polysaccharides were measured in approximately 200 age-stratified subjects before, 4–6, 12 and 24 months following vaccination.

Results

Baseline pneumococcal antibody concentrations were generally high and increased with age up to 10 years. One dose of PCV-7 increased geometric mean antibody concentrations (GMC) in vaccinated versus control villages for vaccine serotypes 6B and 18C, and 4 and 18C, in the young (under 5 years) and older age groups (5+ years) respectively. There were significantly higher proportions of subjects in the vaccinated than in the control communities with an antibody concentration believed to protect against carriage (>5.0 µg/mL) for all but serotype 9V of the PCV-7 serotypes in the older group, but not in the younger age group.

Conclusion

Higher antibodies in vaccinated communities provide an explanation for the lower pneumococcal carriage rates in fully vaccinated compared to control communities.

Trial Registration

Controlled-Trials.com ISRCTN51695599 51695599.     

Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases – a longitudinal study

IntroductionPatients undergoing immunosuppressive therapy are at increased risk of infection. Community-acquired pneumonia and invasive pneumococcal disease account for substantial morbidity and mortality in this population and may be prevented by vaccination. Ideally, immunization to pneumococcal antigens should take place before the start of immunosuppressive treatment. Often, however, the treatment cannot be delayed. Little is known about the efficacy of pneumococcal vaccines during immunosuppressive treatment. The objectives of this study were to determine the percentage of vaccine-naïve, immunosuppressed adults with inflammatory diseases seroprotected against Streptococcus pneumoniae and to assess factors associated with the immunogenicity, clinical impact and safety of 23-valent pneumococcal polysaccharide vaccine (PPV) in seronegative subjects.MethodsThis observational study included patients 18 years of age and older who were receiving prednisone ≥20 mg/day or other immunosuppressive drugs. Exclusion criteria were PPV administration in the previous 5 years, intravenous immunoglobulins and pregnancy. Serum immunoglobulin G (IgG) antibody levels against six pneumococcal serotypes were measured. Seropositivity was defined as IgG of 0.5 μg/ml or greater for at least four of six serotypes. Seronegative patients received PPV, and seropositive patients were included as a comparison group. Vaccine response and tolerance were assessed after 4–8 weeks. Disease activity was evaluated on the basis of the Physician Global Assessment scores. Serology was repeated after 1 year, and information on any kind of infection needing medical attention was collected. Outcomes were the proportion of seropositivity and infections between vaccinated and unvaccinated patients.ResultsOf 201 included patients, 35 received high-dose corticosteroids and 181 were given immunosuppressive drugs. Baseline seronegativity in 60 (30 %) patients was associated with corticotherapy and lower total IgG. After PPV, disease activity remained unchanged or decreased in 81 % of patients, and 87 % became seropositive. After 1 year, 67 % of vaccinated compared with 90 % of observed patients were seropositive (p < 0.001), whereas the rate of infections did not differ between groups. Those still taking prednisone ≥10 mg/day tended to have poorer serological responses and had significantly more infections.ConclusionsPPV was safe and moderately effective based on serological response. Seropositivity to pneumococcal antigens significantly reduced the risk of infections. Sustained high-dose corticosteroids were associated with poor vaccine response and more infections.     

The effect of infectious bovine rhinotracheitis vaccine on reproductive efficiency in cattle vaccinated during estrus

Nineteen nulliparous, sexually mature heifers free of antibody to infectious bovine rhinotracheitis (IBR) virus were given two 35 mg intramuscular injections of Lutalyse 10 days apart to synchronize estrus and randomly divided into control and vaccinated groups. On the day of the last Lutalyse injection, modified live IBR virus vaccine was administered intramuscularly to each animal in the vaccinated group and each group was placed with a proven sire for 35 days. After the vaccination, samples were taken for isolation of virus and for determination of serum neutralizing antibody titers. No virus shedding occurred after intramuscular vaccination. However, the conception rate was markedly lower in the vaccinated group than in the control group. These results suggest that the intramuscular inoculation of modified live IBR virus vaccines into cattle during estrus is contraindicated.     

Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers

Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-microg doses of hemagglutinin from each virus strain with either 3, 10, or 30 microg of heat-labile Escherichia coli enterotoxin (LTK63) and 990 microg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-microg doses of hemagglutinin with 30 microg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 microg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 microg LTK63 with the biovector, occurring in 7/15 (47%; P=0.0103), 8/15 (53%; P=0.0362), and 14/15 (93%; P=0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 microg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P=0.0491) and B/Guandong (P=0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.     

A novel bivalent Pasteurellosis-RHD vaccine candidate adjuvanted with Montanide ISA70 protects rabbits from lethal challenge

In the present study, a bivalent vaccine against Pasteurella multocida and rabbit hemorrhagic disease virus (RHDV) was formulated with Montanide™ ISA70 oil adjuvant (Seppic, Paris, France). Its efficacy was evaluated and compared to similar monovalent preparations and commercially available monovalent vaccines. White new Zeeland rabbit groups (n = 10) received 2 successive doses of the tested vaccines and were challenged 2 weeks after 2nd dose with Pasteurella multocida and RHDV or either pathogens according to their vaccination schedule. Challenged not-vaccinated group of rabbits (n = 10) was included as a control. The bivalent and monovalent ISA70 preparations were found stable, safe, sterile, pure and of low viscosity. Group 3 (GP3) which received bivalent vaccine showed the highest antibody geometric mean titers against Pasteurella multocida and RHDV evaluated by ELISA and hemagglutination inhibition (HI) respectively. Following virulent challenge; Gp3 rabbits were 90% protected from challenge over other groups that showed 80% protection. Detection of either pathogen in the livers of dead and euthanized rabbits had failed except for non-vaccinated controls. The bivalent vaccine candidate was fully protective. Immunization against both pathogens can be achieved by single vaccination.     

Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease.

Although pneumococcal vaccine has been recommended for patients with chronic obstructive pulmonary disease (COPD), its efficacy in this population has not been shown. A double-blind randomized controlled trial of 14-valent pneumococcal vaccine was carried out in 189 men and women aged 40 to 89 years with a clinical diagnosis of COPD and a forced expiratory volume in 1 second of less than 1.5 L. Of the 189, 92 received the vaccine and 97 received saline placebo. In a randomly chosen subsample of those who received the vaccine the mean titres of specific IgG antibody to selected pneumococcal polysaccharide serotypes increased two- to threefold by 4 weeks after vaccination. Over a 2-year period the rates of death, hospital admissions and emergency visits and the mean length of hospital stay were not significantly different in the two groups. Although a protective effect of 14-valent pneumococcal vaccine could not be shown, the small size of the sample and the relatively low follow-up rates preclude firm conclusions about efficacy from these data alone. The elevated antibody levels before vaccination in some of the patients, suggesting prior infection with Diplococcus pneumoniae, may partly explain the findings.     

Maternal antibodies against tetanus toxoid do not inhibit potency of antibody responses to autologous antigen in newborn rhesus monkeys

Background

Our previous study suggested newborns have competent immune systems with the potential to respond to foreign antigens and vaccines. In this study, we examined infant immune responses to tetanus toxoid (TT) vaccination in the presence of maternal antibody to TT.

Methods

We examined changes in plasma levels of tetanus toxoid‐specific IgG1 (anti‐TT IgG1) in a total of eight infant rhesus macaques from birth through 6 months of age using a commercial Monkey Anti‐TT IgG1 ELISA kit.

Results

A significant correlation between anti‐TT IgG1 levels in vaccinated dams and their paired newborn infants was detected in control (non‐vaccinated) infants as previously reported. Maternal anti‐TT IgG1 levels declined rapidly within 1 month of birth in non‐vaccinated infants (n=4). In four infants vaccinated with TT at birth, we found two had rapid and robust antibody responses to vaccination. Interestingly, the other two first showed declining TT antibody levels for 2 weeks followed by increasing levels without additional vaccine boosts, indicating all four had good antibody responses to primary TT vaccination at birth, despite the presence of high levels of maternal antibodies to TT in all four infants.

Conclusions

Our data indicate that newborn macaques have competent immune systems that are capable of generating their own primary antibody responses to vaccination, at least to tetanus antigens. Maternal antibodies thus do not significantly impair antibody response to the vaccination, even when received on the day of birth in infant rhesus macaques.     

Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis

Introduction

An adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix®) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA).

Methods

Patients with arthritis (n = 291; mean age 57 years, 64% women) participated. Hemagglutination inhibition (HI) assay was performed on blood samples drawn before and after a mean (SD) of 8.3 (4) months following vaccination. A positive immune response i.e. seroconversion was defined as negative prevaccination serum and postvaccination HI titer ≥40 or a ≥4-fold increase in HI titer. All patients were divided into predefined groups based on diagnosis (RA or SpA) and ongoing treatment: methotrexate (MTX), anti-tumor necrosis factor (anti-TNF) as monotherapy, MTX combined with anti-TNF, other biologics (abatacept, rituximab, tocilizumab) and non-steroidal anti-inflammatory drugs (NSAIDs)/analgesics. Predictors of positive immune response were studied using logistic regression analysis.

Results

The percentage of patients with positive immune response in the different treatment groups was: 1. RA on MTX 42%; 2. RA on anti-TNF monotherapy 53%; 3. RA on anti-TNF + MTX 43%; 4. RA on other biologics (abatacept 20%, rituximab 10% and tocilizumab 50%); 5. SpA on anti-TNF monotherapy 76%; 6. SpA on anti-TNF + MTX 47%; and 7. SpA on NSAIDs/analgesics 59%. RA patients on rituximab had significantly lower (P < 0.001) and SpA on anti-TNF monotherapy significantly better response rates compared to other treatment groups (P 0.001 to 0.033). Higher age (P < 0.001) predicted impaired immune response. Antibody titers 3 to 6 months after vaccination was generally lower compared to those within the first 3 months but no further decrease in titers were observed 6 to 22 months after vaccination.

Conclusions

Rituximab treatment severely reduced antibody response to pH1N1 influenza vaccine. The other treatment groups showed acceptable antibody responses. Protective antibody titers could be detected up to 22 months after vaccination in the current patient population, with the exception of rituximab treated patients.     

Effect of vaccination against pneumococcal infection in children with type 1 diabetes mellitus

Vaccination with polysaccharide pneumococcal vaccine "Pneumo 23" (Sanofi Pasteur, France) was performed in 31 children with type 1 diabetes mellitus (DM1) as well as in 19 children with respiratory tract diseases (asthma, chronic pneumonia), which formed comparison group. Fourty-three unvaccinated children with DM1 were included in the control group. Dynamics of IgG levels to mixture of pneumococcal polysaccharides (PS) included in the vaccine as well as to PS of serotypes 3, 6B, 9N, 23F, and to cell wall polysaccharides of Streptococcus pneumoniae were assessed. Using ELISA method, significant increase of IgG levels to mixture of PS and to PS of pneumococcal serotype 3 was detected. Although intensity of immune response to vaccination in children with respiratory diseases was significantly higher compared to children with DM1 (mean geometric titer of antibodies, proportion of patients with high antibody titers, and with 4-fold seroconversion). Development of methods to strengthen immune response in children with DM1 vaccinated against pneumococcal infection is required.     

Pneumococcal vaccine immunization of patients with renal impairment

The immunogenicity of the polyvalent pneumococcal vaccine was studied in renal allograft recipients and dialysis patients. There was no significant overall difference in the antibody response of the allograft recipients compared to control subjects at 1 month following immunization. Chronic hemodialysis patients had significantly lower postvaccination antibody levels for 6 of 12 serotypes. Better graft function in the allograft recipients correlated positively with higher antibody levels. Azathioprine and prednisone in dosages employed had no consistent effect on antibody response. No deterioration of renal function ascribable to the vaccine was observed. Patients were sampled at 1, 2, and 3 1/2 years following immunization. Geometric mean titers (GMT) were calculated for all the serotypes per group for each time of sampling. There was a significant decrease with time in antibody GMTs for all the groups (P less than 0.01). Chronic hemodialysis patients had significantly lower GMTs than control subjects and allograft recipients at 1, 2, and 3 1/2 years postimmunization (P less than 0.05). The 3 1/2 years postimmunization antibody levels were very low in dialysis patients, suggesting that reimmunization of these patients may be required.     

Colony blot assay: a useful method to detect multiple pneumococcal serotypes within clinical specimens

The efficacy of pneumococal conjugate vaccines in young children may be complicated by serotype replacement. We developed a colony blot assay which enables the identification of re-colonization with novel serotypes (replacement), overgrowth by minor co-colonizing serotypes or suppression of previously predominant vaccine serotype strains as a result of vaccination. This method allows the identification of multiple serotypes in a single specimen in a ratio of 1:1000. In order to demonstrate the potential of our method, we investigated the consecutive nasopharyngeal samples of 26 children who had shown a shift in pneumococcal colonization after conjugate vaccination. Mixed colonization was found once in 15 pre-vaccination samples and four times in 26 post-vaccination samples. In the remaining children 'true replacement' had presumably occurred. Hence, we conclude that the colony blot assay is an easy to apply method, which allows the identification of different pneumococcal serotypes within single clinical specimens.