A phase IV, multi-centre, randomized clinical trial comparing two pertussis-containing vaccines in pregnant women in England and vaccine responses in their infants

Background Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens). Methods This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP5-IPV (n = 77) or TdaP3-IPV (n = 77) at 28–32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum. Results Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n = 67) or TdaP3-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV- and TdaP3-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56–0.90] and 0.78 [0.61–0.98], respectively); by 13 months of age, this difference was no longer observed. Conclusion Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy. Trial registration ClinicalTrials.gov, NCT02145624, registered 23 May 2014

Expression of Bordetella pertussis Antigens Fused to Different Vectors and Their Effectiveness as Vaccines

Pertussis is an acute respiratory tract infection caused by Bordetella pertussis. Even though its current vaccine coverage is relatively broad, they still have some shortcomings such as short protection time and might be incapable of blocking the spread of the disease. In this study, we developed new pertussis vaccine candidates by separately fusing three pertussis antigens (B. pertussis fimbriae 2 “Fim2”, pertussis toxin S1 subunit “PtxS1”, and filamentous hemagglutinin “FHA1877–2250”) to each of two immune-boosting carrier proteins (B subunits of AB5 toxin family: cholera toxin B subunit “CTB” and shiga toxin B subunit “StxB”). We then immunized mice with these fusion antigens and found that they significantly increased the serum antibody titers and elicited high bactericidal activity against B. pertussis. After CTB-or StxB-fused antigen-immunized mice were challenged with a non-lethal dose of B. pertussis, the bacterial loads in different tissues of these mice were significantly reduced, and their lung damage was nearly invisible. Furthermore, we also demonstrated that these candidate vaccines could provide strong prophylactic effects against a lethal challenge with B. pertussis. Overall, our candidate vaccines conferred better immune protection to mice compared with pertussis antigen alone. This B5 subunit-based vaccine strategy provides a promising option for vaccine design.

A phase IV, multi-centre, randomized clinical trial comparing two pertussis-containing vaccines in pregnant women in England and vaccine responses in their infants

BackgroundPertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens).MethodsThis multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England from 2014-2016. Women were randomized to receive TdaP5-IPV (n=77) or TdaP3-IPV (n=77) at 28-32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled postpartum.ResultsFollowing infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n=67) or TdaP3-IPV (n=63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV and TdaP3-IPV vaccinated mothers compared to infants born to unvaccinated mothers (n=45) (geometric mean ratio: 0.71 [0.56-0.90] and 0.78 [0.61-0.98], respectively); by 13 months of age, this difference was no longer observed.ConclusionBlunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy.Clinical Trials identifierClinicalTrials.gov: NCT02145624

1385. Concomitant Administration of Liquid Porcine Circovirus-free Human Rotavirus Vaccine with Routine Pediatric Vaccines Does Not Impact Immune Responses in Infants: Results from a Phase 3, Randomized Trial in the United States

Background Porcine circovirus type 1 (PCV-1) material was detected in the human rotavirus vaccine (HRV) in 2010. Although no safety risk was identified for infants vaccinated with HRV, a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the limit of the tests used) was developed, which showed comparable immunogenicity and safety profile to the initial HRV. We assessed the non-inferiority of immune responses elicited by routine vaccines (co-)administered with either liquid (Liq) PCV-free HRV or lyophilized (Lyo) HRV, and the immunogenicity and safety of HRVs in infants. Methods In this phase 3, randomized, single-blind study (NCT03207750) in the United States, healthy infants aged 6–12 weeks received 2 doses of Liq PCV-free HRV or Lyo HRV at study month (M)0, M2 and routine vaccines at M0, M2, M4 (Figure 1). Co-primary objectives were to hierarchically demonstrate non-inferiority of immune responses to routine vaccine antigens when (co-)administered with Liq PCV-free HRV compared to Lyo HRV, 1 month post-dose 3 of the routine vaccines and to rule out a 10% decrease in seroresponse to pertussis antigens. Immunogenicity and safety of HRVs were also evaluated (Figure 1). Figure 1. Study design Results 1272 infants were vaccinated and 990 (Liq PCV-free HRV: 489; Lyo HRV: 501) were included in the per-protocol set. All statistical criteria were met for the 2 co-primary objectives (Table 1). Seroprotection/seropositivity rates were ≥ 99.3% for all DTaP-HBV-IPV antigens, ≥ 97.4% for Hib and ≥ 90.8% for most PCV13 serotypes. Geometric mean concentrations/titers for the routine vaccine antigens were comparable between groups (Table 2). 76.3% of infants in Liq PCV-free HRV and 78.9% in Lyo HRV had anti-RV antibody concentration ≥ 20 U/mL. The incidence of solicited (Figure 2) and unsolicited adverse events (AEs) were similar in both groups. Of 75 serious AEs (SAEs), 2 (Lyo HRV: abdominal distension; intussusception) were considered vaccine-related by investigator; 1 fatal SAE (Liq PCV-free HRV: sudden infant death syndrome) was considered non-vaccine related by investigator. Table 1. Non-inferiority of the immune responses to routine vaccine antigens when (co-)administered with HRV (Liq PCV-free HRV vs Lyo HRV) and exclusion of 10% decrease in seroresponse to pertussis antigens, 1 month post-dose 3 (per-protocol set) Table 2. Seroprotection/seropositivity rates and geometric mean concentrations/titers for the routine vaccines antigens 1 month post-dose 3 (per-protocol set) Figure 2. The incidence of solicited adverse events occurring within 7 days post-vaccination (overall/infant, exposed set) Conclusion Routine vaccines (co-)administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles compared to (co-)administration with Lyo HRV. Funding GlaxoSmithKline Biologicals SA Disclosures Remon Abu-Elyazeed, MD, PhD, GSK group of companies (Employee) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support) Leentje Moerman, PhD, GSK group of companies (Employee) Michael Povey, MSc, GSK group of companies (Employee) Shelly Senders, MD, Pfizer (Grant/Research Support) Dan Bi, MD, MPH, GSK group of companies (Employee)

Antibodies to Bordetella pertussis antigens in maternal and cord blood pairs: a Thai cohort study

Background Pertussis is a vaccine-preventable disease, yet an increasing incidence of pertussis occurs in many countries. Thailand has a long-standing pertussis vaccination policy, therefore most expectant mothers today had received vaccines as children. The resurgence of pertussis among Thai infants in recent years led us to examine the pre-existing antibodies to Bordetella pertussis antigens in a cohort of 90 pregnant women. Methods We evaluated the IgG to the Pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) in maternal and cord blood sera using commercial enzyme-linked immunosorbent assays (ELISA). Results When values of >10 IU/ml were accepted as potential protective concentrations, we found that the percentages of unprotected infants were 73.3%, 43.3% and 75.5% for anti-PT, anti-FHA and anti-PRN IgG, respectively. Discussion These results may explain the susceptibility for pertussis among newborn infants in Thailand and support the requirement for a pertussis booster vaccine during pregnancy, which may contribute to the passive seroprotection among newborns during the first months of life.