Emmanuel Vidor

Immunogenicity and safety of a new liquid hexavalent combined vaccine compared with separate administration of reference licensed vaccines in infants.

Objective. The immunogenicity and safety of a new liquid hexavalent vaccine (diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-hepatitis B-polyribosyl ribitol phosphate conjugated to tetanus protein; Hexavac; Aventis Pasteur MSD, Lyon, France) are compared with those of reference vaccines [diphtheria-tetanus-acellular pertussis-inactivated polio vaccine reconstituting lyophilized purified Haemophilus influenzae polysaccharide conjugated to tetanus protein vaccine (Pentavac; Aventis Pasteur MSD) and hepatitis B vaccine (H-B-Vax II; Aventis Pasteur MSD)] injected separately at the same visit in a prospective multicenter, comparative, open label trial. Methods. Infants were randomized to receive Hexavac (n = 423) or Pentavac and H-B-Vax II (n = 425) as a primary immunization series at 2, 4 and 6 months of age. Seroprotection and seroconversion rates against all antigens at 1 month after the primary series were compared between the two vaccine groups with 95% confidence intervals (CI0.95) and were considered clinically equivalent (not inferior) when the upper limit of the 95% confidence interval on the difference (reference, hexavalent) was below predefined differences. Results. Hexavac met and surpassed the predefined criteria for clinical equivalence to Pentavac and H-B-Vax II given concomitantly. It elicited similar seroprotection and seroconversion rates against all antigens. Seroprotection and seroconversion rates obtained 1 month after the third dose of Hexavac were >90% for all antigens. The postimmunization antibody geometric mean titers (GMT) for hepatitis B and purified Haemophilus influenzae polysaccharide were about 2-fold higher in infants who received the reference vaccines than in infants who had received Hexavac. GMTs for poliovirus antibodies tended to be enhanced in infants vaccinated with Hexavac. GMTs for all other antigens were very similar among both groups. Hexavac was generally well-tolerated. At least one local reaction was reported in 20.3% of Hexavac injections compared with 15.8% at the Pentavac injections site and 3.8% at the H-B-Vax II injections site. These reactions were generally mild and transient. At least one systemic adverse event was reported in 45.7% of Hexavac injections compared with 42.2% of Pentavac and H-B-Vax II injections (mild fever, irritability and drowsiness were most frequently reported). The frequency of adverse events was not significantly different between groups. No vaccine-related serious adverse event occurred during the study. Conclusion. This liquid hexavalent vaccine was generally well-tolerated and provided immune responses adequate to be protective against six infectious diseases with a single injection, given at 2, 4 and 6 months of age.

Clinical immunogenicity and tolerance studies of liquid vaccines delivered by jet-injector and a new single-use cartridge (Imule®): comparison with standard syringe injection

A new needleless jet-injector, Mini-Imojet, was developed that administers liquid vaccines from a single-use, pre-filled cartridge named Imule, which avoids the risk of cross-contamination. We conducted clinical trials in several settings in France and West Africa to compare the immunogenicity and tolerance of five vaccines (influenza vaccine, Vi capsular polysaccharide typhoid vaccine, tetanus toxoid vaccine, diphtheria-tetanus-whole cell pertussis vaccine, and inactivated hepatitis A vaccine) administered with the Imule system vs standard syringe technique. In each vaccine study, all subjects of either group were tested for serum antibody titres to calculate the geometrical mean titres and seroconversion rates after complete vaccination. Immediate local-reactions were noted after each injection, and local and general reactions were evaluated during a predetermined period of follow-up. When delivered by the Imule technique, all the administered vaccines were of equivalent or superior immunogenicity, compared to the syringe technique. The tolerance to vaccines injected by the Imule system was acceptable in all studies. The most frequently observed reactions were mild (e.g. minor bleeding, superficial papules, erythema and induration) and could be considered to be inherent to the injection technique. The technical and safety advantages of the Mini-Imojet/Imule system, compared to sterilizable, standard disposable or autodestruct syringes and to classical multi-dose vial jet-injectors, reinforces the interest of this new injection technique for collective immunizations.

Randomized controlled study of fractional doses of inactivated poliovirus vaccine administered intradermally with a needle in the Philippines

OBJECTIVE Comparison of a fractional inactivated poliovirus vaccine (IPV) dose administered intradermally (ID) to a full dose administered intramuscularly (IM). METHODS Healthy Filipino infants were randomized to receive IPV as either a fractional (1/5(th)) dose ID by needle injection or a full dose IM at 6, 10, and 14 weeks and a booster at 15-18 months of age. Pre- and post-vaccination anti-polio 1, 2, and 3 titers were estimated. Adverse events were monitored throughout the study. RESULTS Following primary series vaccination, anti-polio 1, 2, and 3 titers were ≥8 (1/dil) in 99-100% of participants, and the ID route was non-inferior to the IM route. Depending on the study group, antibody persistence was detected in 83-100% of participants, and the booster dose resulted in a strong anamnestic response in all groups. The incidence of adverse events in each group was similar, except for injection-site erythema (higher in the ID group). CONCLUSIONS Primary series and booster vaccination of a fractional IPV dose administered by the ID route was highly immunogenic and well tolerated. These data confirm the medical validity of using fractional ID doses of IPV. The programmatic feasibility of implementing affordable mass vaccination programs based on this delivery mode has yet to be established.

Haemophilus influenzae type b vaccine: reconstitution of lyophilised PRP-T vaccine with a pertussis-containing paediatric combination vaccine, or a change in the primary series immunisation schedule, may modify the serum anti-PRP antibody responses.

Summary Immunogenicity data obtained after primary series immunisations against Haemophilus influenzae type b (Hib), using a vaccine prepared by conjugating the capsular polysaccharide of Hib to tetanus toxoid (ActHIB™), were compiled from 146 study groups comprising 85 clinical trials or vaccination programs conducted between 1987 and 1999. ActHIB™ was administered as a monovalent lyophilised vaccine, injected either in association with another paediatric vaccine (at separate administration sites) or in combination (where the different vaccines are mixed together in the same syringe before injection). Review of these data reveals two trends. First, PRP-T vaccine, given either alone or in combination with DTwcP, resulted in a stronger anti-PRP serum antibody response than when PRP-T was combined with DTacP vaccine. Second, an accelerated (i.e. one-month interval) immunisation schedule tended to induce a poorer anti-PRP antibody response than did the more widely spaced, standard inoculation schedules. Although an in-depth analysis of these over 11 000 study subjects on an individual basis with multivariate analysis or multifactorial statistical methods might eventually provide working hypotheses to fully understand these phenomenon, the various licensed, PRP-T-containing paediatric combination vaccines have proved to be clinically effective.

Immunogenicity of a two-component (PT&FHA) acellular pertussis vaccine in various combinations

Immunogenicity data for the pertussis components of the French diphtheria-tetanus-two component acellular pertussis vaccine (DTaP2Fr) obtained after primary series of immunizations were compiled from 75 study groups comprising 36 clinical trials or vaccination programs conducted between 1987 and 2006. DTaP2Fr vaccine was administered either as a standalone vaccine or as the backbone of several combination vaccines that included IPV, HepB, and/or PRP-T antigens. Most of the variability in responses was associated with differences in the schedules, and to a lesser extent the geographical region where the study was performed, suggesting the importance of ethno-ecological factors. However the addition of other vaccine antigens did not affect the immunogenicity of the aP2Fr antigens. The immune responses to the PT and FHA antigens of the DTaP2Fr vaccine used in the Senegal efficacy trial, which established its good efficacy relative to a highly effective DTwP vaccine, was in the middle of the range of titers observed during other studies using the 2-4-6 months schedule conducted with the same vaccine. The consistent immunogenicity of the DTaP2Fr vaccine is accompanied by effectiveness in controlling pertussis disease in the areas where it is used on a large scale with good vaccination coverage.

Immunogenicity and safety of a new inactivated hepatitis A vaccine : a clinical trial with comparison of administration route

A bicentre, controlled, randomized, open trial was carried out in order to compare the immunogenicity and the reactogenicity of PASTEUR MERIEUX Sérums et Vaccins inactivated Hepatitis A Vaccine on adults, when used with different routes of administration [intramuscular (i.m.), subcutaneous (s.c.) and needless injection using a Jet injector device]. Vaccines were given at two doses 6 months apart to 147 seronegative subjects. Anti-Hepatitis A virus (HAV) titres were performed at each visit by modified radioimmunoassay assay. After the first dose, 138 subjects except one seroconverted (s.c.). After booster dose, all subjects exhibited high levels of HAV antibodies. The higher titres were observed with Jet injector (GMT: 305 mIU ml-1 after the first dose and 3727 mIU ml-1 after the booster dose), followed by the i.m. route (210 mIU ml-1, 3152 mIU ml-1) and the s.c. route (165 mIU ml-1, 2082 mIU ml-1). No statistically significant differences were observed in the three paired comparisons (i.m. vs jet injector; jet vs s.c., im vs s. c.). This inactivated hepatitis A vaccine appeared to be highly immunogenic after one single dose and one booster 6 months later.

Immunological priming of one dose of inactivated hepatitis A vaccine given during the first year of life in presence of maternal antibodies

BACKGROUND In hepatitis A virus (HAV)-seronegative infants, inactivated hepatitis A vaccines are highly immunogenic. On the contrary, in infants who are HAV-seropositive before vaccination, the interfering effect of passively-transferred maternal anti-HAV antibodies leads to lower post-primary immunization anti-HAV levels, as compared to those achieved by seronegative infants. One possible way to overcome this drawback is to delay hepatitis A vaccination later during the first year of life. The objective of the study was to document the immunogenicity of an inactivated hepatitis A vaccine in 6 months old HAV-seropositive infants, given as two dose regimen consisting of a single primary immunization at 6 months of age, followed by a booster dose 6 months later. METHODS The immunogenicity of one hepatitis A vaccine (Avaxim pediatric, Aventis Pasteur) was documented in 108 6 months old, HAV-seropositive infants randomly assigned to receive one priming dose of hepatitis A vaccine either concomitantly with (Group 2) or 2 weeks after the third dose of routine diphteria-tetanus-whole cell pertussis reconstituting lyophilized tetanus conjugated Haemophilus influenzae type b (DTwcP//PRP approximately T) vaccine and oral poliomyelitis vaccine (OPV) (Group 1). A booster dose was given 6 months later, concomitantly with MMR vaccine. RESULTS The 91 infants who were HAV-seropositive (ELISA titer >20 mIU/ml) at the moment of primo vaccination remained seropositive 1 month later. Geometric mean titers (GMT) decreased from 292 and 278 mIU/ml 1 month after the first dose, to 77.6 and 76.0 mIU/ml 6 months after, in Groups 1 and 2, respectively. Post-booster titers increased markedly in both groups, with GMTs of 1731 and 1866 mIU/ml and geometric mean post/pre-immunization titer ratios of 22.3 and 24.6, respectively. CONCLUSIONS These results suggest that immunological priming induced by a single dose of Avaxim pediatric administered to 6 or 6.5 months old, HAV-seropositive infants is present and should not preclude the use of this vaccine in such populations.

Safety and immunogenicity of a new formulation of an inactivated hepatitis A vaccine.

The safety and immunogenicity of a new formulation of the inactivated hepatitis A vaccine, Avaxim, was evaluated in 189 children, aged 18 months to 15 years in a monocentric, open trial. Two vaccinations were given six months apart. Enrollment was balanced within three age groups: 18 months to 3 years, 4-8 years and 9-15 years. Antibody titers were measured blindly by an independent laboratory using a modified radioimmunoassay. Two weeks after the first dose, seroconversion was achieved by 94.6, 94.3 and 96.4% of initially HAV-seronegative subjects (antibody titre <20 mIU/ml) in each age group (youngest to oldest, respectively), with corresponding geometric mean titre concentrations (GMC) of 72.2, 54.3 and 47.1 mIU/ml. Just before the booster dose, the seroconversion rate was 100% in all groups, and the corresponding GMC values were 163, 169 and 111 mIU/ml. All groups included, a 22.6-fold rise in GMC from prebooster levels was observed four weeks after the booster dose. An explanatory analysis suggested a tendency for higher antibody levels in younger children at all vaccination time points. Local reactions were noted in 18.2% of the vaccinees after the first dose and in 8.5% after the booster dose. The rates of systemic reactions were 23.8% after the first dose and 11.4% after the booster dose. Overall, this trial demonstrated the good safety and immunogenicity profile of this vaccine in children aged 18 months to 15 years of age.

Repertoire of antibodies against type 1 poliovirus in human sera.

A blocking-ELISA procedure was used to quantify antibodies in sera of humans immunized with poliovirus vaccines. Titers determined by this method demonstrated an excellent correlation with the results of neutralization test. Testing of serum potency with a panel of type 1 poliovirus strains altered antigenically was used to evaluate the composition of polyclonal sera with respect to the epitope specificity of constituent antibodies. Paratope profiles of various polyclonal sera determined by this new method differed, depending on the type of vaccine used for immunization. Antibodies induced in response to inactivated poliovirus vaccine (IPV) contained antibodies directed primarily against antigenic site 1, while sera from recipients of the oral poliovirus vaccine (OPV) contained antibodies to site 3. Antibodies to antigenic sites 2 and 4 were minor constituents in both types of sera. Pre-immunization sera had paratope profiles similar to OPV-induced antisera, allowing the discrimination between antibodies induced by IPV and maternal antibodies. The new method may be useful for analyzing results of clinical trials and to compare immunity induced by different poliovirus vaccines.

Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS®) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio®) given as a booster dose at 6 years of age

This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Non-inferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%), and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age.