Jeanne-Marie Jacquet

Persistence of antibodies and immune memory to hepatitis B vaccine 20 years after infant vaccination in Thailand

Booster vaccination against hepatitis B (HBV) is not currently recommended, although debate continues on the duration of protection after priming. We assessed antibody persistence and immune memory to hepatitis B 20 years after priming with a recombinant HBV-vaccine during infancy. Infants were vaccinated at birth, 1, 2 and 12 months of age. A subset received a booster dose at Year 5. Antibody persistence was measured approximately yearly until Year 20. Immune memory was assessed by administration of HBV booster dose. At Year 20, anti-HBs seroprotection rates and GMCs tended to be higher in Year 5 boosted than unboosted recipients (83.9% versus 60.5%). After the Year 20 booster dose, anti-HBs anamnestic responses were within the same range 95.8% of subjects in both groups. Primary and booster vaccination with HBV-vaccine in infants induces sustained seroprotection and immune memory against hepatitis B for up to 20 years. Higher persisting seroprotection rates in subjects boosted at Year 5 did not translate into apparent differences in immune memory in a high endemic country.

Decennial Administration of a Reduced Antigen Content Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine in Young Adults

BACKGROUND Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a-lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS Eighty-two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00610168 .

Immunogenicity and reactogenicity of four doses of diphtheria-tetanus-three-component acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccine coadministered with 7-valent pneumococcal conjugate Vaccine.

Background: The 7-valent pneumococcal (7vPn) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit. Methods: An open, randomized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine and a 7vPn conjugate vaccine when coadministered at 2, 3 and 4 months and 12–23 months of age, compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone. Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose. Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose. Results: A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine (170 without and 175 with the 7vPn vaccine coadministered) and 266 returned for booster vaccination (122 without and 144 with coadministration of the 7vPn vaccine). After primary vaccination, antibody responses against the common antigens were similar in both groups, with seroprotection rates of 93.6–100% and with similar antibody decay before booster vaccination. The fourth dose induced a vigorous booster response, with seroprotection/vaccine response rates of 96.8–100%. Response to the 7vPn primary and booster vaccination was within previously reported ranges. Differences in reactogenicity resulted from higher incidences of symptoms after concomitant vaccination. Rectal temperature >39.5°C was observed after 1.2% of the coadministered vaccine doses during primary vaccination and after 2.8% of the booster vaccine doses. Conclusion: Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe.

Evidence of protection against clinical and chronic hepatitis B infection 20 years after infant vaccination in a high endemicity region

Summary.  Vaccination against hepatitis B virus (HBV) immediately after birth prevents neonatal infection by vertical transmission from HBV carrier mothers. There is an ongoing debate whether infant vaccination is sufficient to protect against infection when exposed to HBV later in life. We studied 222 Thai infants born to HBsAg −/+ and HBeAg −/+ mothers who were vaccinated with recombinant hepatitis B vaccine at 0‐1‐2‐12 months of age. A subset of 100 subjects received a booster dose at age 5 years. Blood samples collected yearly for 20 years were examined for anti‐HBs antibodies and serological markers of hepatitis B infection (anti‐HBc, HBsAg, and in selected cases HBeAg, anti‐HBe, HBV DNA). During the 20‐year follow‐up, no subject acquired new chronic HBV infection or clinical hepatitis B disease. During the first decade, possible subclinical breakthrough HBV infection (anti‐HBc seroconversion) was only observed in subjects born to HBsAg +/HBeAg + mothers (6/49 [12.2%]). During the second decade, breakthrough HBV infections were detected in all groups (18/140 [12.8%]). Increases in anti‐HBs concentrations that were unrelated to additional HBV vaccination or infection were detected in approximately 10% of subjects in each decade. Primary infant vaccination with a recombinant hepatitis B vaccine confers long‐term protection against clinical disease and new chronic hepatitis B infection despite confirmed hepatitis B exposure. (http://www.clinicaltrials.gov NCT00240500 and NCT00456625)

A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (Boostrix™) is immunogenic and well tolerated in adults

Reduced-antigen-content diphtheria-tetanus-acellular-pertussis (dTpa) vaccines are predominantly recommended for once-in-a-lifetime use. A second dTpa (Boostrix™, GlaxoSmithKline Biologicals) administration in 164 adults previously vaccinated with dTpa 10 years previously was evaluated. Before the decennial booster, 89.4% and 94.8% subjects were seroprotected (antibodies ≥0.1 IU/mL) for diphtheria and tetanus, respectively. One-month post-booster, all subjects were seroprotected/seropositive against all vaccine antigens. Robust GMC increases indicated a booster response similar to the first booster. The decennial booster was well tolerated without serious adverse events, consistent with product experience. This study supports replacing traditional Td boosters with dTpa, and use of Boostrix™ as a decennial booster. This study is registered at www.clinicaltrials.com NCT00548171.

Review of 8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)

Combination vaccines that include multiple antigens within one formulation are now widely accepted as an effective means of eliciting protection against several diseases at the same time. Owing to improvements in quality and convenient modes of administration, they have become part of routine pediatric practice. Hexavalent vaccines, including diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b antigens represent the latest advance in the development of combination vaccines. Over 8 years since its first licensure, this review looks at the immunogenicity, efficacy and safety profile of the only hexavalent pediatric vaccine currently in use – Infanrix hexa™ (diphtheria, tetanus, acellular pertusis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline Biologicals, Rixensart, Belgium) – through published clinical trials and postmarketing surveillance data. These data show DTPa–HBV–IPV/Hib to be highly immunogenic and well tolerated across a range of different primary and booster vaccination schedules, as well as when administered concomitantly with other licensed vaccines (e.g., pneumococcal conjugate vaccine). Additional issues surrounding the use of hexavalent vaccines are also reviewed.

Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine.

Background: This study evaluated the concurrent use of meningococcal C tetanus conjugate (MenC-TT) vaccine (NeisVac-C) with DTaP-based combinations, according to 2 vaccination schedules, one of which included hepatitis B vaccination at birth (Trial DTaP-HBV-IPV/Hib-097). Methods: Healthy infants were randomized to receive either DTaP-HBV-IPV/Hib (Infanrix hexa) at 2, 4, and 6 months (N = 115) or HBV at birth followed by DTaP-HBV-IPV/Hib at 2 and 6 months and DTaP-IPV/Hib (Infanrix-IPV Hib) at 4 months (N = 115). In both groups 2 doses of MenC-TT conjugate were coadministered at 2 and 4 months, and compared with 3 doses of MenC-CRM197 conjugate (Meningitec) coadministered at 2, 4, and 6 months with DTaP-HBV-IPV/Hib (N = 120). Antibody concentrations were measured at 2, 6 and 7 months. Solicited local and general symptoms, unsolicited symptoms, and serious adverse events (SAEs) were recorded. Results: All MenC-TT recipients had seroprotective concentrations of anti-PRP antibodies (≥0.15 μg/mL) 1 month after the third vaccine dose and all had SBA-MenC titers ≥1:8 after the second dose of MenC-TT. These responses were noninferior to those seen after 3 doses of DTaP-HBV-IPV/Hib and MenC-CRM. Anti-PRP antibody GMCs were significantly higher in MenC-TT than MenC-CRM vaccinees (7.9, 7.3, 3.8 μg/mL, respectively). Immune responses to all other coadministered antigens were unimpaired, with seroprotection/seropositivity rates ≥98.1% in MenC-TT vaccinees. All schedules studied were well tolerated, with no differences in reactogenicity between the study groups. Conclusions: Coadministration of DTaP-HBV-IPV/Hib or DTaP-IPV/Hib with 2 doses of MenC-TT conjugate vaccine is safe, well tolerated, and immunogenic, with no impairment of the response to the coadministered antigens.

Booster Vaccination After Neonatal Priming with Acellular Pertussis Vaccine

After a birth dose of acellular pertussis (aP) and diphtheria (DT)aP-hepatitis B virus (HBV)-inactivated polio vaccine (IPV)/Haemophilus influenza type b (Hib) at 2, 4, and 6 months, a booster dose of DTaP-HBV-IPV/Hib at 12 to 23 months induced strong anti-pertussis booster responses. Thus, neonatal aP priming did not lead to immune tolerance to pertussis antigens. However, it elicited bystander interference on HBV, Hib, and diphtheria responses.

A fourth dose of DTPa-IPV vaccine given to 4-6 year old children in Italy and Sweden following primary vaccination at 3, 5 and 11-12 months of age

Healthy 4–6 y old children from Italy and Sweden immunized with DTPa and inactivated or oral polio vaccines at 3, 5 and 11–12 months of age, received 1 dose of combined DTPa-IPV (n=211) or DTPa+IPV as separate doses (n=205) in a randomized trial. The pre-booster seroprotection rates were similar in each group and were above 60% against all antigens except diphtheria (31.3% and 37.0%) and PT (21.5% and 25.9%) in the DTPa-IPV and DTPa+IPV groups, respectively. At least 99.5% of subjects had seroprotective antibody levels against diphtheria, tetanus and polioviruses and ≥96% showed a vaccine response to each pertussis antigen after vaccination. Post-booster antibody levels increased at least 51-fold for anti-diphtheria and anti-tetanus, at least 18-fold for anti-pertussis antibodies and at least 32-fold for antibodies against all 3 poliovirus types, compared to prior levels. DTPa-IPV was comparable to DTPa+IPV in terms of seroprotection rates and mean antibody levels against each vaccine antigen. Similar reactogenicity profiles were observed between groups including swelling >50 mm [13% (9.1, 18.7) vs 17% (12.4, 23.4)] or involving an adjacent joint [0% (-,-) vs 1.5% (0.3, 4.3)] and were consistent with previous reports. The combined DTPa-IPV vaccine could be used to add DTP valences to the IPV vaccine currently given to children in Scandinavia and Italy at 4–6 y of age and reinforce protection against 4 diseases.

Lasting immune memory against hepatitis B in children after primary immunization with 4 doses of DTPa-HBV-IPV/Hib in the first and 2nd year of life.

BackgroundFew studies have assessed long term persisting immunity against hepatitis B virus (HBV) in children vaccinated during infancy with combined vaccines containing recombinant HBV surface antigen (HBs). We assessed antibody persistence and immune memory in children 4-5 years of age, previously vaccinated with four doses of combined hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix hexa™).MethodsImmune memory was assessed in 301 children through administration of a challenge dose of monovalent HBV vaccine.ResultsAt 4-5 years of age, 85.3% of subjects had persisting anti-HBs antibody concentrations ≥ 10 mIU/mL, rising to 98.6% after the HBV challenge dose. All but 12 subjects (95.8%) achieved post-challenge anti-HBs concentrations ≥ 100 mIU/mL. The post-challenge anti-HBs GMC rose by 100-fold compared to pre-challenge concentrations. An anamnestic response to the HBV vaccine challenge was observed in 96.8% of subjects, including 17/21 (81.0%) of children with initially undetectable antibodies (<3.3 mIU/mL). All but 4 of 42 subjects (90.5%) with anti-HBs antibodies <10 mIU/mL prior to the challenge dose, achieved seroprotective levels afterwards. A 4-fold rise in antibody concentration after the challenge dose was observed in 259/264 (98.1%) of initially seropositive subjects. The magnitude of the post-challenge responses was proportional to pre-challenge anti-HBs levels. No serious adverse events were reported during the study.ConclusionThe combined DTPa-HBV-IPV/Hib vaccine induced lasting immune memory against hepatitis B. Long term protection afforded by DTPa-HBV-IPV/Hib is likely to be similar to that observed following priming with monovalent HBV vaccines.Trial registrationhttp://www.clinicaltrials.gov 106789 NCT00411697