Luc Hessel

Long-term Follow-up of Swedish Children Vaccinated With Acellular Pertussis Vaccines at 3, 5, and 12 Months of Age Indicates the Need for a Booster Dose at 5 to 7 Years of Age

OBJECTIVES. The purpose of this work was to evaluate the long-term effectiveness of vaccination with acellular pertussis vaccines at 3, 5, and 12 months of age. METHODS. Clinical follow-up of reported culture- and polymerase chain reaction–confirmed cases of pertussis was initiated during October 1997 in most of Sweden (except Gothenburg and environs). The study population included 90% of Swedish children born during 1996 or later (ie, who received diphtheria-tetanus-acellular pertussis vaccines at 3, 5, and 12 months of age) and children who had participated in a large pertussis vaccine trial in 1993–1996. Age-specific incidences were estimated using reported culture- or polymerase chain reaction–confirmed pertussis from October 1997 to September 2004 in areas covered by enhanced surveillance. In addition, annual overall and age-specific incidences of pertussis throughout Sweden before and after introduction of acellular pertussis vaccines were estimated. RESULTS. The overall incidence of notified culture- and polymerase chain reaction–confirmed pertussis dropped from 113 to 150 per 100 000 during 1992–1995 to 11 to 16 per 100 000 during 2001–2004. In areas of enhanced surveillance, the incidence of pertussis was 31 per 100 000 person-years after 2 doses and 19 per 100 000 person-years after the third dose at 12 months of age. The age-specific incidence remained low for ∼5 years after the third dose but increased in children aged 6 to 8 years, becoming 32 and 48 per 100 000 person-years, respectively. The highest incidence occurred among infants who were unvaccinated or had received only 1 dose of diphtheria-tetanus-acellular pertussis vaccine. CONCLUSIONS. The increased incidence among 7- to 8-year-olds (ie, mainly acellular pertussis vaccine–vaccinated children) suggests waning of vaccine-induced protection from pertussis. Along with a concomitant increase in incidence among infants, most likely infected by older siblings, these data suggest a booster dose of acellular pertussis vaccine is warranted from 5 to 7 years of age.

Declining pertussis incidence in Sweden following the introduction of acellular pertussis vaccine

Acellular pertussis vaccines were introduced nation-wide in Sweden in 1996, 17 years after the withdrawal of whole-cell pertussis vaccine from the childhood immunisation schedule. We report national data on age specific incidence of culture-confirmed Bordetella pertussis for 1986-2000, and clinical follow-up for 3 years (October 1997-September 2000) in children born in 1996-2000 and from children born in 1993-1994 who had participated in a trial of pertussis vaccines. The annual incidence of culture-confirmed B. pertussis was 89-150 per 100,000 before introduction of acellular pertussis vaccines and has dropped to 17-26 per 100,000. The data suggest that unimmunised infants and children who have received only one dose of pertussis vaccine were provided some protection. The decline is most obvious from the second dose onwards and remained stable for 4-5 years after the third dose in the absence of any booster dose. The first signs of waning immunity were observed at 6-7 years of age in the trial cohort. The short-term benefits reflect high vaccination coverage and high initial efficacy. The full impact of the acellular pertussis vaccination programme in infants remains to be established.

Immunogenicity and safety of a 23-valent pneumococcal polysaccharide vaccine in healthy children and in children at increased risk of pneumococcal infection.

Splenectomized children as well as those suffering from nephrotic syndrome or recurrent asthmatic bronchitis have an increased susceptibility to systemic pneumococcal infections compared to healthy children. To determine the immunogenicity and safety of a 23-valent pneumococcal polysaccharide vaccine (PPV), 119 children (21 healthy, 26 splenectomized children, 48 with nephrotic syndrome and 24 with recurrent asthmatic bronchitis), aged 2-18 years, received one subcutaneous injection of a 23-valent PPV. Anti-capsular antibodies (Ab) to types 6B, 9V, 14, 18C, 19F and 23F were measured by ELISA before and 4 weeks after immunization. In all cases the adverse reactions were mild and transient, consisting of local pain and/or erythema or swelling in 41% and fever above 38.5 degrees C in 2% of the children. The healthy children responded well to vaccination with a mean fold increase (FI) of 2.6 in postvaccination Ab titers compared to prevaccination titers. The combined geometric mean Ab concentrations in the high-risk children were significantly lower than those of healthy children both before and after vaccination. However, the combined geometric mean FI were not significantly different between high-risk and healthy children. These results indicate that PPV is immunogenic and safe in high-risk as well as in healthy Korean children.

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.

Current issues in adolescent immunization.

Based on the December 2006 Fondation Mérieux International Scientific Symposium, the current state of adolescent immunization is reviewed with a focus on the policy and programmatic issues that impact the acceptability, initiation, and successful implementation. Key questions are identified with proposed strategies to help achieve successful adolescent immunization programs. The role of current vaccines targeted to adolescents, such as those directed against invasive meningitis, pertussis, and the human papillomavirus, is reviewed as well as their role in rejuvenating interest in adolescent immunization, and more importantly, adolescent health as a whole.

Impact of osmolality on burning sensations during and immediately after intramuscular injection of 0.5 ml of vaccine suspensions in healthy adults.

A randomised placebo controlled double-blind cross-over trial was performed on twenty healthy adults to assess the effect of osmolality (300,600,850 and 1100 mOsm) on local tolerance of an intramuscular injection (0.5 ml) of five suspensions containing the same components as the excipients of a combined Diphtheria-Tetanus-acellular Pertussis-inactivated Poliomyelitis-Haemophilus influenzae type b paediatric vaccine (DtacP-IPV-Hib, PENTAVAC). The results did not show any dose-effect relationship between burning or pain sensations and the different osmolalities tested. Although mild and not clinically relevant, these sensations seemed to occur more frequently following injection of an isotonic saline solution (P<0.05). Thus, the osmolality of vaccine like suspensions does not appear to be a potential cause of local pain or burning sensation after their administration.

Lot-to-Lot Consistency of a Combined Hexavalent Diptheria-Tentanus-Acellular-Pertussis, Hepatitis B, Inactivated Polio and Haemophilus b Conjugate Vaccine, Adminstered to Healthy Chilean Infants at 2, 4 and 6 Months of Age

Objectives: To assess the safety, immunogenicity and lot consistency of a liquid hexavalent combined vaccine (DTaP-IPV-PRP~T-HBs, HEXAVAC®) (Sanofi-Pasteur MSD, France) administered to infants at 2, 4, and 6 months of age.Methods: A total of 1028 infants were vaccinated with one of 3 vaccine lots, in a randomized, double-blind fashion. Equivalence testing was used to compare post-vaccination seroprotection/seroconversion rates and geometric mean titers (GMTs) for each antigen between the three lots. Blood samples were drawn before vaccination and one month after the third dose. Local and systemic adverse events were monitored for 3 days following each injection.Results: Equivalence between lots was demonstrated for all antigens, on post-dose 3 seroprotection/seroconversion rates and GMTs. Reported rates of local and systemic adverse events tended to increase with subsequent doses. Altogether, 11.8% of the infants reported at least one adverse local event (mainly redness and induration/swelling) after the first dose and 36.1% after the third dose. Systemic adverse events (mainly irritability and fever) were reported by 39.2% of the infants after the first dose and by 57.5% after the third one.Conclusion: Three separate lots of the liquid hexavalent combined vaccine induced consistently protective antibody responses against all antigens. These results and the well established clinical tolerability of this combined vaccine make it suitable for primary immunization of infants at 2, 4, and 6 months of age.

The contribution of vaccine manufacturers to the establishment of vaccination policies

AimThis paper seeks to analyse the contribution of vaccine manufacturers to the establishment of immunisation policies.Subjects and methodsThe recent evolution of the role of industry from product development to post-licensure studies is reviewed in detail.ResultsThe primary responsibility of vaccine manufacturers has always been to develop vaccines and demonstrate their safety and efficacy. However, with the development of new vaccines it appears that vaccine manufacturers are expected to go beyond this role and to provide policy-makers with additional information required to support the establishment of optimal vaccination policies. This includes conducting extensive post-licensure risk management plans as part of follow-up measures to the initial marketing authorisation. Manufacturers are also requested to generate information on the epidemiology of the disease to be prevented as well as health-economics data and to assess the expected impact of the vaccine in the population. This requires additional in-house skills, external collaborations, not to mention considerable financial investment.ConclusionOver the recent decades new functions and departments have been created to address all the technical aspects leading to the introduction and adoption of new vaccines, such as risk management, epidemiology, policy affairs, and outcome research. Nevertheless such activities cannot be properly conducted or managed without an active partnership between the private sector and national or international public heath or academic institutions.

From clinical research to vaccination policy: 25 years experience in vaccinology.

I started learning epidemiology, biostatistics and preventive medicine while teaching it. In 1985, they suggested to me to follow the applied field epidemiology training course for EIS officers of the US CDC that Dr. Charles Mérieux had just started to organize in France for international students. This was an eye-opener to my future life. Spending three weeks in the exceptional environment of the Fondation Mérieux in “Les Pensières,” the private resort of Dr. Charles Mérieux in Annecy, France with a group of “students,” most of them experienced public health professionals, coached by Michael Gregg, Virgil Peavy and Nancy Binkin from the CDC, was a unique experience. I remember this Sunday morning when the door of the old barn, refurbished in a class room, opened and Charles Mérieux introduced us as “his students” to his friend Jonas Salk who was visiting him. These were the exact two visionaries who created the term “vaccinology” in the 1970s to define vaccination in its medical, technological, economic, socio-cultural, bioethical and geopolitical context. I did not know that five years later I would be involved with Salk in the early phase of the development of the first inactivated HIV vaccine, and would spend the rest of my professional life working in vaccinology. In fact, a couple of weeks later I was contacted by Michel Cadoz a professor of infectious diseases and former colleague of François Denis at the University of Dakar, Senegal, who had recently joint the vaccine industry. He asked me to join the department of clinical research he had just created. All my academic mentors in public health strongly supported that I took this opportunity, at least for a sabbatical year, to extend my professional experience and establish international relationships. This sabbatical is still ongoing.