Ilse Dieussaert

Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine

Background: The immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed and compared with the 7-valent pneumococcal conjugate vaccine (7vCRM). Methods: Healthy subjects (1650) were randomized to be vaccinated with 3 doses of PHiD-CV or 7vCRM (Prevenar™/Prevnar™) at 2-3-4 months of age and a fourth booster dose at 12–18 months. Serotype-specific pneumococcal responses (GlaxoSmithKlines ELISA with 22F-inhibition) and opsonophagocytic activity (OPA) were measured 1 month after primary and booster vaccinations. Results: The primary objective to demonstrate noninferiority of PHiD-CV versus 7vCRM (in terms of percentage of subjects with antibody concentration ≥0.2 &mgr;g/mL) for at least 7 of the 10 vaccine serotypes was reached as noninferiority was demonstrated for 8 serotypes. Although, noninferiority could not be demonstrated for ELISA responses against serotypes 6B and 23F, a post-hoc analysis of the percentage of subjects with OPA titers ≥8 suggested noninferiority for the 7 serotypes common to both vaccines including 6B and 23F. Priming of the immune system against all vaccine serotypes was confirmed by robust increases in ELISA antibody levels (∼6.0–17 fold) and OPA titers (∼8–93 fold) after a fourth consecutive dose of PHiD-CV. Conclusions: PHiD-CV induces ELISA and functional OPA antibodies for all vaccine serotypes after primary vaccination and is noninferior to 7vCRM in terms of ELISA and/or OPA threshold responses. Effective priming is further indicated by robust booster responses.

Immunogenicity and safety of AS03-adjuvanted 2009 influenza A H1N1 vaccine in children 6-35 months.

We report on the evaluation of the immunogenicity and reactogenicity/safety of AS03-adjuvanted vaccine against pandemic influenza A/H1N1/2009 in young children. In this open-label, randomized study, 157 healthy children aged 6-35 months received two doses (21 days apart) of split-virion inactivated A/California/7/2009 H1N1 vaccine containing either (i) 1.9microg hemagglutinin (HA) and AS03(B) (5.93mg tocopherol) (N=104) or (ii) 3.75mug HA and AS03(A) (11.86mg tocopherol) (N=53). At 21 days following the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the percentage of children with hemagglutination-inhibition titers of >or=40 against the vaccine strain rose from 3.0% before vaccination to 100%. The seroconversion rate was 99% and the geometric mean titer (GMT) increased from 6 to 313. After the second dose the GMT increased further to 2008. The higher dose AS03(A)-adjuvanted 3.75microg HA vaccine did not further increase the immune response. Solicited symptoms reported within 7 days following vaccination were mainly mild to moderate. After the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the most common solicited symptoms were pain at the injection site (35.6%) and irritability (31.7%). Fever (axillary >or=37.5 degrees C) was reported with an incidence of 20.2%. After the second dose reactogenicity tended to increase (injection site pain: 41.3%; irritability: 46.2%; fever >or=37.5 degrees C: 67.3%). Spontaneously reported adverse events with an intensity that prevented normal activities were documented for 2.9-6.7% of doses with only one event (vomiting) considered related to vaccination. There was one serious adverse event reported in the AS03(A)-adjuvanted 3.75microg HA vaccine group (traumatic brain injury) which was not considered as related to vaccination. In conclusion, these data suggest that a first dose of AS03(B)-adjuvanted A/H1N1/2009 vaccine containing 1.9microg HA in children 6-35 months old is highly immunogenic and that the overall reactogenicity profile is acceptable although reactions including fever tend to increase after a second dose.

Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with different Neisseria meningitidis serogroup C conjugate vaccines.

Background: Immunogenicity of the candidate 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed when coadministered with other routine pediatric vaccines including different Neisseria meningitidis serogroup C conjugate vaccines. Methods: One thousand five hundred forty-eight healthy infants received, according to a balanced (1:1:1:1) randomization, either PHiD-CV coadministered with (1) DTPa-HBV-IPV/Hib (Infanrix hexa™) and MenC-CRM (Meningitec™), (2) DTPa-HBV-IPV/Hib and MenC-TT (NeisVac-C™), or (3) DTPa-HBV-IPV (Infanrix penta™/Pediarix™) and Hib-MenC-TT (Menitorix™); or 7vCRM (Prevenar™/Prevnar™) coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2-4-6 months of age with a booster dose at 11–18 months. Serotype-specific pneumococcal responses were measured by 22F-inhibition ELISA and opsonophagocytic (OPA) assay. Results: In all 3 coadministration groups, PHiD-CV was immunogenic for each of the 10 pneumococcal vaccine serotypes as assessed by post-primary and post-booster antibody ELISA and OPA responses. When coadministered with DTPa-HBV-IPV, Hib, and MenC antigens, PHiD-CV responses after the third primary dose were within the same range as 7vCRM responses in terms of the percentage of subjects achieving an ELISA antibody concentration ≥0.2 &mgr;g/mL for all common vaccine serotypes (over 92% of subjects) except for serotype 6B (at least 87% of subjects). ELISA and OPA immune responses were also evident after the second primary doses of PHiD-CV or 7vCRM vaccine, although antibody levels were below that achieved after 3 primary doses, particularly for serotypes 6B and 23F. The kinetics of the immune responses from after the second dose to after the booster dose were similar for most of the serotypes in both PHiD-CV and 7vCRM groups. Conclusions: PHiD-CV was immunogenic when coadministered with other routine pediatric vaccines including MenC conjugate vaccines.

Immunogenicity of routinely used childhood vaccines when coadministered with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV).

Background: The choice of non-typeable Haemophilus influenzae Protein D as main carrier protein in the candidate 10-valent pneumococcal conjugate vaccine (PHiD-CV, GlaxoSmithKline Biologicals), was driven in part to avoid carrier-mediated suppression and possible bystander interference with coadministered vaccines. Immunogenicity data from 3 primary and 2 booster vaccination studies were assessed for possible impacts of PHiD-CV coadministration on immune responses to routinely administered childhood vaccines, in comparison to 7-valent pneumococcal conjugate vaccine (7vCRM) coadministration. Methods: Randomized, controlled studies in which PHiD-CV or 7vCRM vaccines were coadministered with DTPa-[HBV]-IPV/Hib, DTPa-[HBV]-IPV, DTPw-HBV/Hib, IPV, and OPV, combined Hib-Neisseria meningitidis serogroup C vaccine (Hib-MenC-TT), standalone MenC-TT or MenC-CRM vaccines. Results: One month after primary vaccination, >96% of PHiD-CV recipients had seroprotective antibody concentrations against diphtheria, tetanus, poliovirus types 1 and 3, Hib (≥0.15 &mgr;g/mL), SBA-MenC (≥1:8), and >94% were seropositive for antibodies against pertussis antigens. Somewhat lower responses against poliovirus type 2 in study A (compared with poliovirus type 1 and 2 responses) and hepatitis B in the 6-, 10-, and 14-week schedule in the Philippines (compared with hepatitis B responses in the other studies) were observed after coadministration of both PHiD-CV and 7vCRM vaccines. Antitetanus and anti-PRP antibody geometric mean concentrations (GMCs) tended to be higher after PHiD-CV coadministration, probably because of the TT carrier protein for serotype 18C in PHiD-CV. Booster vaccination induced substantial increases in antibody GMCs for all coadministered antigens. These responses were generally within the same range in PHiD-CV and 7vCRM groups. Observed anti-PRP responses remained higher in PHiD-CV recipients after the booster dose. Conclusions: Coadministration of PHiD-CV with commonly used childhood vaccines induced high levels of seroprotection/seropositivity against all targeted diseases. No evidence of negative interference on the immune response to any of the coadministered vaccine antigens was observed when compared with the current routine practice of 7vCRM coadministration.

The 10-Valent Pneumococcal Non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) Coadministered With DTPw-HBV/Hib and Poliovirus Vaccines : Assessment of Immunogenicity

Background: Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was evaluated when coadministered with DTPw-HBV/Hib and OPV at 6, 10, and 14 weeks of age in the Philippines, or with DTPw-HBV/Hib and IPV at 2, 4, and 6 months of age in Poland. Methods: In this double-blind, controlled study (107007/NCT00344318), 400 Filipino and 406 Polish infants 6 to 12 weeks of age were randomized (3:1) to receive either PHiD-CV or the 7-valent pneumococcal conjugate vaccine (7vCRM). Immune responses were assessed 1 month post-dose III. Results: Percentages of infants with anti-pneumococcal antibody concentrations ≥0.2 &mgr;g/mL (GSKs 22F-inhibition ELISA) were within the same range for both pneumococcal conjugate vaccine groups, with the exception of serotypes 6B and 23F for which lower percentages were observed in the PHiD-CV group in Poland. At least 98.2% of PHiD-CV vaccinees had antibody concentrations ≥0.2 &mgr;g/mL against pneumococcal serotypes 1, 5, and 7F. In both countries, anti-pneumococcal antibody geometric mean concentrations against serotypes 18C and 19F were higher in the PHiD-CV group than in the 7vCRM group. Antibody geometric mean concentrations for most of the other common serotypes were within the same range for both groups in the Philippines and were lower in the PHiD-CV group in Poland. Functional responses (opsonophagocytic activity [OPA]) were observed for all vaccine serotypes in both countries. Conclusions: PHiD-CV was immunogenic against each of the 10 pneumococcal vaccine serotypes when coadministered with DTPw-HBV/Hib and poliovirus vaccines.

A single dose, combined vaccine against typhoid fever and hepatitis A: Consistency, immunogenicity and reactogenicity

BACKGROUND Vaccines against hepatitis A and typhoid fever are well established and have an excellent safety and immunogenicity profile. Yet these diseases, which share the same geographic distribution, remain an important cause of morbidity in travelers to endemic countries. Combined vaccination provides dual protection and improves compliance and coverage for travelers. METHODS This multicenter study evaluated the consistency of three lots of combined hepatitis A and typhoid fever vaccine. A total of 462 healthy subjects, aged 15-50 years, were enrolled and randomly allocated to 3 groups. The single dose of vaccine contains 25 microg typhoid Vi polysaccharide and at least 1,440 ELISA units of inactivated hepatitis A in a 1 mL dose. RESULTS Bioequivalence of all production lots was shown in terms of safety and immunogenicity. Pain at injection site was the most frequent reported local symptom, and headache was the most frequent reported general symptom. As early as 14 days after immunization >95% of the subjects were positive for anti-Vi antibodies and >86% were positive for anti-HAV antibodies. The GMTs and seropositivity rates were maintained during the 6 month follow-up. CONCLUSION The first combined vaccine against typhoid fever and hepatitis A was safe and elicited a very good immune response, with the majority of subjects seropositive at 1 month for both antigens. This combined vaccine offered more convenience and rapid seroconversion to travelers.

Immunogenicity of Twinrix in older adults: a critical analysis.

Twinrix™(GlaxoSmithKline Biologicals, Rixensart, Belgium) is the first combined vaccine to provide protection against both hepatitis A and B. This review presents a critical analysis of antibody responses stratified by age following vaccination with Twinrix in 264 adults aged above 40 years. A month after completion of a 0-, 1-, 6-month vaccination schedule with Twinrix, a good response was observed for both anti-HAV and anti-HBs serum antibodies, suggesting that is an effective vaccine in older adults.

Immunogenicity and safety of AS03-adjuvanted H1N1 pandemic vaccines in children and adolescents

Vaccines with acceptable efficacy profile against the H1N1 A/California/7/2009 virus are needed for use in children. The two studies presented here evaluated the immunogenicity and the reactogenicity/safety of A/H1N1/2009 vaccines containing either 3.75 μg haemagglutinin antigen (HA) and AS03(A)-adjuvant (3.75 μg HA/AS03(A) study) (N=210 [53, 57 and 100 in the 3-5, 6-9 and 10-17 years age strata, respectively]) or 1.9 μg HA and AS03(B)-adjuvant (1.9 μg HA/AS03(B) study) (N=244 [61, 65 and 118 in the 3-5, 6-9 and 10-17 years age strata, respectively]), given as two-dose series. Although the haemagglutination inhibition antibody titres were higher in the 3.75 μg HA/AS03(A) study, both vaccine dosages were highly immunogenic and exceeded regulatory acceptance criteria after the first and the second doses. Seroprotection rates reached 100% and seroconversion rates ranged from 98.2% to 99.1% after each dose of both vaccine dosages. Geometric mean titres increased from 456.5 to 1538.5 and from 297.9 to 1106.7 between the first and the second doses in the 3.75 μg HA/AS03(A) study and the 1.9 μg HA/AS03(B) study, respectively. Despite an observed slight increase of the reactogenicity following the second dose in the 3.75 μg HA/AS03(A) study, the vaccines safety profiles were considered clinically acceptable. In conclusion, both dosages of the AS03-adjuvanted A/H1N1/2009 pandemic influenza vaccines were highly immunogenic and well-tolerated in children and adolescents.

Safety and immunogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine coadministered with measles-mumps-rubella-varicella vaccine in children aged 12 to 16 months.

Background: A booster dose of pneumococcal conjugate vaccine may be administered at the same age as measles-mumps-rubella-varicella (MMRV) vaccination. This study examined the safety, reactogenicity, and immunogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with MMRV vaccine. Methods: In this open, controlled study, 325 healthy children aged 12 to 14 months were randomized to 1 of 3 groups: the first group (N = 110) received PHiD-CV and MMRV vaccine followed 6 to 8 weeks later by MMRV and DTPa-HBV-IPV/Hib vaccines; the second group (N = 101) received DTPa-HBV-IPV/Hib and MMRV vaccines followed 6 to 8 weeks later by PHiD-CV and MMRV vaccine; the third group (N = 114) received PHiD-CV and DTPa-HBV-IPV/Hib vaccine during 1 vaccination visit. Immune responses were assessed with GlaxoSmithKlines 22F-inhibition enzyme-linked immunosorbent assay (for PHiD-CV), commercial enzyme-linked immunosorbent assay (for MMR), or indirect immunofluorescence assay (for varicella). Adverse events were recorded by the parents/guardians. Results: After the first vaccination, 2 peaks in fever (rectal temperature ≥38°C) were observed; at days 0 to 2, related to PHiD-CV and DTPa-HBV-IPV/Hib vaccination, and at days 4 to 12, related to MMRV vaccination. Booster responses to pneumococcal antigens and protein D and seroconversion rates for all MMRV vaccine components were high. Conclusions: PHiD-CV and MMRV vaccine can be coadministered without compromising the safety and immunogenicity profiles of either vaccine.

Accelerated vaccination schedules provide protection against hepatitis A and B in last-minute travelers.

Hans D. Nothdurft, MD, PhD: Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany; Jane Zuckerman, MD: Academic Centre for Travel Medicine & Vaccines, WHO Collaborating Centre for Travel Medicine, Royal Free and University College Medical School, University College London, London, UK; M. Stoffel, MD, and I. Dieussaert, Ir: GlaxoSmithKline Biologicals (GSK Bio), Rixensart, Belgium; Pierre Van Damme, MD, PhD: Centre for the Evaluation of Vaccination, WHO Collaborating Centre for Prevention and Control of Viral Hepatitis, University of Antwerp, Belgium.