Pertussis Antibody Concentrations Research Articles

Impact of maternal diphtheria-tetanus-acellular pertussis vaccination on pertussis booster immune responses in toddlers: Follow-up of a randomized trial

BackgroundTransplacentally transferred antibodies induced by maternal pertussis vaccination interfere with infant immune responses to pertussis primary vaccination. We evaluated whether this interference remains in toddlers after booster vaccination. MethodsIn a prior phase IV, observer-blind, placebo-controlled, randomized study (NCT02377349), pregnant women in Australia, Canada and Europe received intramuscular tetanus-reduced-antigen-content diphtheria-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) at 270/7–366/7 weeks’ gestation, with crossover immunization postpartum. Their infants were primed (study NCT02422264) and boosted (at 11–18 months; current study NCT02853929) with diphtheria-tetanus-three-component acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTaP-HepB-IPV/Hib) and 13-valent pneumococcal conjugate vaccine. Immunogenicity before and after booster vaccination, and reactogenicity and safety of the booster were evaluated descriptively. Results263 (Tdap group) and 277 (control group) toddlers received a DTaP-HepB-IPV/Hib booster. Pre-booster vaccination, observed geometric mean concentrations (GMCs) for the three pertussis antigens and diphtheria were 1.4–1.5-fold higher in controls than in the Tdap group. No differences were observed for the other DTaP-HepB-IPV/Hib antigens. One month post-booster vaccination, booster response rates for pertussis antigens were ≥ 92.1% and seroprotection rates for the other DTaP-HepB-IPV/Hib antigens were ≥ 99.2% in both groups (primary objective). Higher post-booster GMCs were observed in controls versus the Tdap group for anti-filamentous hemagglutinin (1.2-fold), anti-pertussis toxoid (1.5-fold) and anti-diphtheria (1.4-fold). GMCs for the other DTaP-HepB-IPV/Hib antigens were similar between groups. Serious adverse events were reported for three toddlers (controls, not vaccination-related). One death occurred pre-booster (Tdap group, not vaccination-related). ConclusionsAs a consequence of interference of maternal pertussis antibodies with infant immune responses to pertussis primary vaccination, pertussis antibody concentrations were still lower in toddlers from Tdap-vaccinated mothers before DTaP-HepB-IPV/Hib booster vaccination. After the booster, antibody concentrations were lower for filamentous hemagglutinin and pertussis toxoid but not for pertactin. The clinical significance of this interference requires further evaluation.Clinical Trial Registration.ClinicalTrials.gov: NCT02853929.

Impact of tetanus-diphtheria-acellular pertussis immunization during pregnancy on subsequent infant immunization seroresponses: follow-up from a large randomized placebo-controlled trial

BackgroundPertussis immunization during pregnancy results in high pertussis antibody concentrations in young infants but may interfere with infant immune responses to post-natal immunization. MethodsThis phase IV, multi-country, open-label study assessed the immunogenicity and safety of infant primary vaccination with DTaP-HepB-IPV/Hib and 13-valent pneumococcal conjugate vaccine (PCV13). Enrolled infants (6–14 weeks old) were born to mothers who were randomized to receive reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) during pregnancy (270/7–366/7 weeks’ gestation) with crossover immunization postpartum. All infants received 2 or 3 DTaP-HepB-IPV/Hib and PCV13 doses according to national schedules. Immunogenicity was assessed in infants pre- and 1 month post-primary vaccination. The primary objective was to assess seroprotection/vaccine response rates for DTaP-HepB-IPV/Hib antigens 1 month post-primary vaccination. Results601 infants (Tdap group: 296; control group: 305) were vaccinated. One month post-priming, seroprotection rates were 100% (diphtheria; tetanus), ≥98.5% (hepatitis B), ≥95.9% (polio) and ≥94.5% (Hib) in both groups. Vaccine response rates for pertussis antigens were significantly lower in infants whose mothers received pregnancy Tdap (37.5–77.1%) versus placebo (90.0–99.2%). Solicited and unsolicited adverse event rates were similar between groups. Serious adverse events occurred in 2.4% (Tdap group) and 5.6% (control group) of infants, none were vaccination-related. ConclusionsPertussis antibodies transferred during pregnancy may decrease the risk of pertussis infection in the first months of life but interfere with the infant’s ability to produce pertussis antibodies, the clinical significance of which remains unknown. Safety and reactogenicity results were consistent with previous experience.Clinical Trial Registration: ClinicalTrials.gov: NCT02422264.

Lower Sustained Diphtheria and Pertussis Antibody Concentrations in Inflammatory Bowel Disease Patients.

Patients with inflammatory bowel disease (IBD) are often immunosuppressed, and those patients receiving anti-tumor necrosis factor α (TNF) therapy can have lower antibody responses to vaccines. Pertussis cases are at their highest levels in the post-vaccine era. There is little data regarding responses to the Tdap (tetanus, diphtheria, and acellular pertussis) vaccine in IBD patients. The aim of this study was to compare sustained vaccine-induced Tdap antibody concentrations in a cohort of IBD patients stratified by medication regimens with healthy controls (HC) who had received an adult Tdap booster. We performed a cross-sectional study evaluating antibody responses to Tdap vaccine among IBD patients compared to HC. Our study consisted of three patient groups: adults with IBD stratified by maintenance medication regimen: (1) thiopurine monotherapy; (2) anti-TNF monotherapy; and (3) combination therapy (anti-TNF and immunomodulator (thiopurine or methotrexate)). Ninety IBD patients and 20 HC participated. Pertussis pertactin antibody concentrations were significantly lower in IBD patients (p = 0.021) compared to HC, and those on anti-TNF agents (monotherapy or combination) had lower antibody concentrations compared to those on thiopurine monotherapy (p = 0.028). Diphtheria antibody concentrations were also lower in IBD patients (p < 0.001), and those on anti-TNF agents (monotherapy or combination) had lower antibody concentrations compared to the thiopurine monotherapy group (p < 0.001). IBD patients on anti-TNF agents had lower antibody concentrations to diphtheria and pertussis. These findings suggest a need for different Tdap booster schedules for IBD patients on anti-TNF therapy. Clinical Trials Registry NCT02434133.

Summary of the NACI Update on Immunization in Pregnancy with Tetanus Toxoid, Reduced Diphtheria Toxoid and Reduced Acellular Pertussis (Tdap) Vaccine.

In Canada, pertussis is an endemic and cyclical disease, with peaks occurring at two- to five-year intervals. Although pertussis incidence varies by age group, unvaccinated or undervaccinated infants are at greatest risk of infection and associated complications. Since the last National Advisory Committee on Immunization (NACI) recommendations published in 2014, new evidence on the safety and effectiveness of tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis (Tdap) vaccine administration in pregnancy has become available. To provide guidance on maternal immunization in pregnancy as a strategy to reduce disease incidence and severe outcomes (defined as hospitalization or death) from pertussis infection in infants less than 12 months of age. The NACI reviewed evidence on the burden of disease in Canada, vaccine safety and immunogenicity and vaccine effectiveness in jurisdictions that have implemented maternal immunization programs. A total of 59 articles were identified, retrieved and included in the literature review to inform this statement. In the majority of reviewed studies, post immunization increases in antibody levels resulted in more than 90% of women achieving anti-PT levels greater than or equal to 10 IU/ml one month following immunization. In infants, maternal immunization was found to result in increased pertussis antibody concentrations. In the majority of studies, following the receipt of the fourth diphtheria, tetanus and pertussis (DTaP) dose after 15 months of age, no statistically significant differences in antibody levels and avidity were observed between infants whose mothers received Tdap in pregnancy and those whose mothers did not receive Tdap in pregnancy. No major maternal or infant safety issues, including pregnancy outcomes, were reported in the reviewed literature. Effectiveness of maternal Tdap immunization in pregnancy was estimated to be over 90% against pertussis in infants younger than two months of age, with no deaths observed among infants whose mothers received Tdap prior to 36 weeks of pregnancy. Maternal immunization with Tdap in pregnancy also resulted in a reduction in infant disease severity and hospitalization. Vaccine effectiveness was also reported to persist after the receipt of the first three DTaP doses, with immunization in pregnancy resulting in additional protection of up to 70% in children whose mothers received Tdap in pregnancy. There is now strong evidence to support the NACI recommendation that immunization with Tdap vaccine should be offered in every pregnancy. This is ideally administered between 27 and 32 weeks of gestation but evidence also supports providing maternal Tdap over a wider range of gestational ages, from 13 weeks up to the time of delivery, in view of programmatic and unique patient considerations.

Third-Trimester Maternal Vaccination Against Pertussis and Pertussis Antibody Concentrations.

To compare pertussis antibody concentrations in maternal venous serum (at the time of delivery) and umbilical cord arterial serum among women vaccinated with the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine from either 27-30 6/7 weeks of gestation or from 31-35 6/7 weeks of gestation. We conducted a prospective cohort study of pregnant women divided into two groups based on when Tdap was administered: 27-30 6/7 weeks of gestation and 31-35 6/7 weeks of gestation. Paired maternal and umbilical cord samples were obtained at the time of delivery to determine immunoglobulin G (IgG) concentrations to pertussis toxin and pertactin. Eighty-eight pregnant women were enrolled. Cord serum pertussis toxin IgG concentrations were approximately twice maternal serum pertussis toxin IgG concentrations (91.6 vs 48.6 enzyme-linked immunoassay [ELISA] units/mL, P<.01) and were significantly correlated (Pearson correlation coefficient=0.85, P<.01). There was no significant difference in maternal serum pertussis toxin IgG concentrations (48.6 vs 48.6 ELISA units/mL, P=.99), cord serum pertussis toxin IgG concentrations (92.1 vs 90.7 ELISA units/mL, P=.95), and cord serum pertactin IgG concentrations (798 vs 730 international units/mL, P=.73) between the two groups. Furthermore, there was no correlation between time from vaccination to delivery and these three parameters. Cord serum pertussis toxin IgG concentrations were greater than 10 ELISA units/mL (ie, in the protective range) in 87% and 97% of those vaccinated from 27-30 6/7 weeks of gestation and from 31-35 6/7 weeks of gestation, respectively (P=.13). Maternal vaccination against pertussis between 27 and 36 weeks of gestation was associated with a high percentage of newborns with antibody concentrations conferring protection and did not vary by gestational age at vaccination.

Low pertussis antibody levels in maternal and umbilical cord blood samples in Turkey.

Pertussis continues to cause significant mortality and morbidity in many countries despite high vaccine coverage, especially among young infants. The aim of the study was to determine pertussis antibody levels in paired maternal and cord blood samples, to evaluate the placental transfer of these antibodies, and to assess whether newborn infants have adequate antibody levels against pertussis. Antibody titers to pertussis toxin (anti-PT) and filamentous hemagglutinin (anti-FHA) were measured by in-house enzyme linked immunosorbent assay (ELISA) in 251 paired maternal delivery and cord blood samples. Geometric mean concentrations (GMCs) of pertussis antibodies and cord:maternal GMC ratios were calculated. GMCs of maternal anti-PT and anti-FHA antibodies at delivery were 4.12 and 9.89 EU/ml, respectively. Cord GMCs were 133% and 131% of maternal delivery values for PT and FHA, respectively; demonstrating effective placental transfer. However, cord pertussis antibodies were at a low concentration; 5.49 EU/ml for PT and 12.73 EU/ml for FHA. Only 34.6% of infants had protective anti-PT levels (≥10 EU/ml) at birth. Anti-pertussis antibody concentrations were extremely low in pregnant women in Turkey where childhood pertussis vaccination coverage has been high for a long time. Despite effective placental antibody transfer, umbilical cord pertussis antibody concentrations are similarly low. A majority of young infants are vulnerable to pertussis infection until the onset of primary vaccinations. These data support the need for pertussis vaccination during pregnancy to prevent infant infection in Turkey.

Antibody responses after primary immunization in infants born to women receiving a pertussis-containing vaccine during pregnancy: single arm observational study with a historical comparator.

In England, antenatal pertussis immunization using a tetanus/low-dose diphtheria/5-component acellular-pertussis/inactivated-polio (TdaP5/IPV) vaccine was introduced in October 2012. We assessed infant responses to antigens in the maternal vaccine and to those conjugated to tetanus (TT) or the diphtheria toxin variant, CRM. Infants of 141 TdaP5/IPV-vaccinated mothers in Southern England immunized with DTaP5/IPV/Haemophilus influenzae b (Hib-TT) vaccine at 2-3-4 months, 13-valent pneumococcal vaccine (PCV13, CRM-conjugated) at 2-4 months and 1 or 2 meningococcal C vaccine (MCC-CRM- or MCC-TT) doses at 3-4 months had blood samples taken at 2 and/or 5 months of age. Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae 2 + 3 (FIMs), diphtheria, tetanus, Hib, MCC and PCV13 serotypes were compared to responses in a historical cohort of 246 infants born to mothers not vaccinated in pregnancy. Infants had high pertussis antibody concentrations pre-immunization but only PT antibodies increased post-immunization (fold-change, 2.64; 95% confidence interval [CI], 2.12-3.30; P < .001), whereas FHA antibodies fell (fold-change, 0.56; 95% CI, .48-.65; P < .001). Compared with infants of unvaccinated mothers, PT, FHA, and FIMs antibodies were lower post-vaccination, with fold-differences of 0.67 (0.58-0.77; P < .001), 0.62 (0.54-0.71; P < .001) and 0.51 (0.42-0.62; P < .001), respectively. Antibodies to diphtheria and some CRM-conjugated antigens were also lower, although most infants achieved protective thresholds; antibodies to tetanus and Hib were higher. Antenatal pertussis immunization results in high infant pre-immunization antibody concentrations, but blunts subsequent responses to pertussis vaccine and some CRM-conjugated antigens. In countries with no pertussis booster until school age, continued monitoring of protection against pertussis is essential.

The effect of body mass index on post-vaccination maternal and neonatal pertussis antibody levels

The objective was to determine if there is an association between maternal body mass index (BMI) and maternal and neonatal pertussis antibody concentrations following vaccination. This is a nested cohort study of 123 women who received the Tdap vaccine during pregnancy. Women were stratified by BMI into three groups – normal, overweight, and obese, based on first trimester or pre-pregnancy BMI. Maternal and umbilical cord serum samples were tested for post-vaccination pertussis IgG antibody. The mean maternal pertussis antibody concentration was 167.5U/mL for normal BMI (n=29), 169.8U/mL for overweight BMI (n=54), and 175.5U/mL for the obese BMI groups (n=40). The mean fetal pertussis antibody concentrations were 182.3U/mL, 191.4U/mL, and 197.7U/mL for these groups respectively. Seroprotection was achieved in 89.7% of neonates (26/29) in the normal BMI group, 87.0% (47/54) in the overweight BMI group, and 97.5% (39/40) in the obese BMI group. None of these differences reached statistical significance. Maternal BMI does not affect the maternal or neonatal pertussis antibody response to the Tdap vaccine in women who receive the vaccine in pregnancy. Maternal BMI is unlikely to affect the neonatal protective effects of a standard dose of Tdap vaccine in pregnancy. PrécisMaternal and umbilical cord antibody response to the pertussis vaccine is not affected by maternal body mass index.

Immunogenicity and reactogenicity of Infanrix™ when co-administered with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrix™ and Pediarix™

BackgroundCo-administration of an investigational quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) with the fourth dose of diphtheria–tetanus–acellular pertussis vaccine (DTaP) at age 15–18 months was investigated in 3-dose Haemophilus influenzae type b-meningococcal serogroups C/Y conjugate vaccine (HibMenCY-TT)-primed toddlers. MethodsInfants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine, or Hib-TT and DTaP-HBV-IPV (Control). HibMenCY-TT+ DTaP-HBV-IPV vaccinees were re-randomized (2:2:1) to receive MenACWY-TT at 12–15 months and DTaP at 15–18 months (MenACWY-TT group); MenACWY-TT co-administered with DTaP at 15–18 months (Coad group); or HibMenCY-TT at 12–15 months and DTaP at 15–18 months (HibMenCY-TT group). Controls received DTaP at 15–18 months. Only children in the HibMenCY-TT group received a fourth dose of Hib conjugate vaccine due to Hib conjugate vaccine shortage at the time of the study. DTaP immunogenicity and reactogenicity were assessed one month post-vaccination. ResultsPre-defined statistical non-inferiority criteria between Coad and Control groups were met for diphtheria, tetanus and filamentous haemagglutinin but not pertussis toxoid and pertactin. Following vaccination ≥99% of children had anti-diphtheria/anti-tetanus concentrations ≥1.0IU/ml. Pertussis GMCs were lower in all investigational groups versus Control. In post hoc analyses, pertussis antibody concentrations were above those in infants following 3-dose DTaP primary vaccination in whom efficacy against pertussis was demonstrated (Schmitt, von König, et al., 1996; Schmitt, Schuind, et al., 1996). The reactogenicity profile of the Coad group was similar to DTaP administered alone. ConclusionRoutine booster DTaP was immunogenic with an acceptable safety profile when co-administered with MenACWY-TT vaccine in HibMenCY-TT-primed toddlers. These data support the administration of a fourth DTaP dose following a 4-dose HibMenCY-TT vaccination series, or co-administered with MenACWY-TT in HibMenCY-TT-primed children.

The relationship between concentration of specific antibody at birth and subsequent response to primary immunization

Background and aimsTrans-placentally acquired antibodies can protect infants from infection in the first months of life. However, high concentrations of antibody at birth may impact the infant's own immune response to primary immunization. We examine the relationship between concentration of specific antibody to Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid and pneumococcal antigens at birth and following primary immunization. MethodsHealthy mother–infant pairs were recruited from a UK maternity unit. Peripheral blood samples were obtained at birth and 4 weeks after primary immunization. Specific antibody concentrations were determined using enzyme-linked immunosorbent assays. Pertussis antibody concentrations >50IU/ml, Tetanus antibody levels >0.1IU/ml and Hib antibody levels >0.15mg/l were regarded as protective. ResultsFollowing primary immunization, 35/36 (97%) infants had specific antibody concentrations associated with protection against Hib, 32/36 (89%) against pertussis and 36/36 (100%) against tetanus. Concentrations of all specific antibodies were significantly higher than at birth (p<0.0001), except anti-tetanus toxoid, p=0.41. However, there was an inverse correlation between infant antibody concentration at birth and fold-increase in antibody concentration post-immunization for tetanus: rs −0.86 (95%CI −0.93 to −0.74), p<0.0001; pneumococcus: rs −0.82 (95% CI −0.91 to −0.67), p<0.0001; pertussis: rs −0.77 (95% CI −0.89 to −0.58), p<0.0001 and Hib: rs −0.66 (95%CI −0.82 to −0.42), p<0.0001. The highest concentrations of specific IgG at birth were associated with lower concentrations post-immunization for tetanus (p=0.009) and pneumococcus (p=0.03). This association was not observed for Hib (p=0.88) or pertussis (p=0.14). ConclusionHigher antibody concentration at birth appeared to inhibit the response to infant immunization for tetanus and pneumococcus; the effect was less marked for Hib and pertussis. However, the majority of infants achieved high antibody levels post-immunization. This supports maternal immunization, as high levels of maternally derived antibody at birth may not inhibit infants’ immunization responses in a clinically relevant manner.

Immune Responses in Infants Whose Mothers Received Tdap Vaccine During Pregnancy

The effect of maternal Tdap vaccination on infant immunologic responses to routine pediatric vaccines is unknown. This was a cohort study of infants whose mothers received or did not receive Tdap vaccine during pregnancy. Maternal and cord blood samples were collected at delivery; infant blood samples were collected before and after primary series and booster dose of diphtheria, tetanus, and acellular pertussis (DTaP) and other vaccines. Geometric mean antibody concentrations or titers to pertussis, hepatitis B, tetanus, diphtheria, Haemophilus influenzae type b and polio antigens were measured. Mean maternal-to-cord blood antibody ratios were calculated. At delivery, maternal and cord antibody concentrations to pertussis antigens were higher in the Tdap group (n=16) than control group (n=54; maternal: 1.9- to 20.4-fold greater; cord: 2.7- to 35.5-fold greater). Increased antibody concentrations persisted for infants at first DTaP (3.2- to 22.8-fold greater). After primary series, antibody concentrations to pertussis antigens were lower in Tdap group (0.7- to 0.8-fold lower), except for fimbriae types 2 and 3 (FIM) (1.5-fold greater). Antibody concentrations to pertussis antigens before and after booster dose were comparable (prebooster: Tdap group 1.0- to 1.2-fold higher than controls; postbooster: 0.9- to 1.0-fold lower). Differences in FIM values at these time points are difficult to interpret, due to varying FIM content among DTaP vaccines administered to infants in both groups. Maternal Tdap immunization resulted in higher pertussis antibody concentrations during the period between birth and the first vaccine dose. Although slightly decreased immune responses following the primary series were seen compared with controls, differences did not persist following the booster.