[Influenza, an eternal problem]. / La grippe, une menace eternelle.

Influenza remains a serious disease in humans and animals (primarily poultry). Since influenza is caused by a virus that both undergoes continuous antigenic change and possesses an animal reservoir, it will be quite difficult to avoid any future pandemics and an eradication of the disease is likely to be impossible. It is now clear, for instance, that the avian viruses may jump into the human population. Are we heading towards another influenza pandemic? One cannot discount that eventuality and one should be cautious while trying to produce new specific drugs as well as efficient vaccines that eventually cannot be discounted, and various precautions must be taken in the production of new specific drugs and vaccines.

The use of combination vaccines has improved timeliness of vaccination in children.

BACKGROUND: In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been combined with diphtheria, tetanus and acellular pertussis vaccines. We examined whether the use of combination vaccines has improved the timing of these vaccinations. METHODS: Vaccination information was obtained from representative nationwide telephone interviews about 2701 children born from 1996 through 2003 in Germany. We assessed up-to-date vaccination as the percentage of children vaccinated by 3, 5 and 15 months for the first dose, full primary series and full immunization, respectively. We compared results over periods when different combination vaccines were used. We also compared median age at first dose, full priming and full immunization for children receiving different types of combination vaccines. RESULTS: During the study period, monovalent vaccines were replaced by higher-valent combination vaccines. With the change from mono- to 4-, 5- and 6-valent vaccines, up-to-date vaccination increased for Hib, polio and HBV. Median age at immunization improved by 0.5 month for Hib, 0.4 month for polio and 0.9 month for HBV at the first dose and 2.2 months for Hib, 3.2 months for polio and 1.4 months for HBV at full immunization when comparing hexavalent with monovalent vaccines. Median age for 4-5-valent vaccines was intermediate. The difference between monovalent and 6-valent vaccines remained significant after stratifying/adjusting for the effect of birth cohorts. CONCLUSION: Combination vaccines are usually advocated for reducing the number of injections. In Germany, however, the use of combination vaccines has also significantly improved timeliness of immunizations.

[Mercury in vaccines]. / Le mercure et les vaccins.

Thiomersal, also called thimerosal, is an ethyl mercury derivative used as a preservative to prevent bacterial contamination of multidose vaccine vials after they have been opened. Exposure to low doses of thiomersal has essentially been associated with hypersensitivity reactions. Nevertheless there is no evidence that allergy to thiomersal could be induced by thiomersal-containing vaccines. Allergy to thiomersal is usually of delayed-hypersensitivity type, but its detection through cutaneous tests is not very reliable. Hypersensitivity to thiomersal is not considered as a contraindication to the use of thiomersal-containing vaccines. In 1999 in the USA, thiomersal was present in approximately 30 different childhood vaccines, whereas there were only 2 in France. Although there were no evidence of neurological toxicity in infants related to the use of thiomersal-containing vaccines, the FDA considered that the cumulative dose of mercury received by young infants following vaccination was high enough (although lower than the FDA threshold for methyl mercury) to request vaccine manufacturers to remove thiomersal from vaccine formulations. Since 2002, all childhood vaccines used in Europe and the USA are thiomersal-free or contain only minute amounts of thiomersal. Recently published studies have shown that the mercury levels in the blood, faeces and urine of children who had received thiomersal-containing vaccines were much lower than those accepted by the American Environmental Protection Agency. It has also been demonstrated that the elimination of mercury in children was much faster than what was expected on the basis of studies conducted with methyl mercury originating from food. Recently, the hypothesis that mercury contained in vaccines could be the cause of autism and other neurological developmental disorders created a new debate in the medical community and the general public. To date, none of the epidemiological studies conducted in Europe and elsewhere support this assumption. Although any effort should be made to avoid useless exposure of vaccinees to a potentially toxic compound, it should be emphasized that 1) public communication on this issue has led to a decrease in the hepatitis B vaccination coverage of children born to HBs Ag positive mothers in the US; 2) this issue was not really relevant in France where until 2002, apart from two hepatitis B vaccines, all childhood vaccines were thiomersal-free, and 3) in developing countries using multidose vaccine vials, moving to thiomersal-free vaccines in unidose presentations would represent such an incremental cost that millions of children would no more have access to vaccination. Therefore the World Health Organisation still recommends the use of thiomersal-containing vaccines as part of the expanded programme of immunisation.

Rational approach to selection and clinical development of TB vaccine candidates.

A rational process is clearly needed and can be extremely helpful for selection, assessing and advancing TB vaccine candidates from entry into preclinical and clinical development and for advancing candidates from early safety and immunogenicity clinical trials to proof-of-concept and pivotal efficacy trials. A joint effort between Aeras and the Tuberculosis Vaccine Initiative has focused on the development of objective criteria for a number of key general vaccine characteristics which can be assessed at critical stages of development. In order to maximize development efficiency, increase likelihood of success, and optimize use of scarce resources, this process includes establishment of gates for moving TB vaccine candidates through progressive development stages based on meeting the established criteria for specific vaccine candidates.

Pandemic influenza vaccines: meeting the supply, distribution and deployment challenges.

An influenza pandemic will place an enormous strain on the world's vaccine production, distribution and administration systems. Following a pandemic declaration, industry's priority will be to deliver as much vaccine in as short a timeframe as possible. In respect to this challenge, manufacturers have successfully developed antigen-sparing strategies and significantly increased production capacity, with further growth planned assuming ongoing rising demand for seasonal vaccines. The combination of these factors has the potential to closer meet global needs for vaccine supply than ever before through increased availability of pandemic and pre-pandemic vaccines. The demonstration of cross-clade reactivity with H5N1 viruses makes the concept of pre-pandemic stockpiling and vaccination a reality for this subtype. Ensuring these vaccines are made available in a timely fashion to those who need them will present significant challenges. For local authorities, national governments and international organisations this means defining vaccine allocation and procurement processes as well as strengthening, and where necessary establishing, the critical health systems and infrastructure required for vaccine deployment. For vaccine producers this means addressing the technical and logistical issues associated with supply. This includes working with regulators to streamline key procedures, including generic labelling and batch release, while establishing flexibility in supply formats, including bulk and finished products, to maximise the speed of delivery. Similarly, the deployment of large quantities of vaccines in an emergency situation requires appropriate transport infrastructure and the distribution of associated medical supplies. As well as addressing these issues, specific consideration must be given to the logistics and storage aspects associated with stockpiling pre-pandemic vaccines. Finally, mutually agreed contractual arrangements between manufacturers and governments or international institutions represent the best approach toward addressing supply challenges and assisting vaccine producers meet national and international demand. To be effective, these contracts should be based on accurate forecasts, clearly defined vaccination strategies and the capabilities of public health infrastructure.

Influenza vaccine supply: building long-term sustainability.

Influenza represents a public health paradox. The virus is responsible for significant death, disease and economic loss. However, despite the availability of safe and efficacious vaccines, uptake is poor. While policy makers increasingly recognize the value of annual immunization, and vaccine supply is increasing, further efforts are required to implement existing vaccination recommendations and drive the long-term demand that supports supply sustainability. This is equally important for pandemic vaccine supply, which will rely on the same production plants and manufacturing approaches. Technological advances and capacity expansions now offer the prospect of billions of doses of vaccine in the event of a pandemic, and the availability of pre-pandemic vaccines for stockpiling and pre-emptive use. As a result, vaccination strategies utilizing pre-pandemic vaccines, combined with vaccines matched to a pandemic strain once available, offer for the first time a viable approach for mitigating an influenza pandemic.

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.

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 approximately 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.

Lot-to-lot consistency of a combined hexavalent diptheria-tetanus-acellular-pertussis, hepatitis B, Inactivated polio and haemophilus B conjugate vaccine, administered to healthy chilean infants at two, four and six months of age.

OBJECTIVES: To assess the safety, immunogenicity and lot consistency of a liquid hexavalent combined vaccine (DTaP-IPV-PRP approximately T-HBs, HEXAVAC) (Sanofi-Pasteur MSD, France) administered to infants at two, four and six months of age. METHODS: A total of 1028 infants were vaccinated with one of three 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 three 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 two, four and six months 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.

A liquid hexavalent combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type B and hepatitis B: review of immunogenicity and safety.

To reduce the number of injections needed to comply with paediatric vaccination requirements, a liquid, hexavalent vaccine (DTaP-IPV-PRP-T-HBs; Hexavac; Aventis Pasteur MSD) has been developed for primary and booster vaccination of infants and toddlers. In extensive clinical studies, Hexavac has been shown to be highly immunogenic. Seroconversion or seroprotective titres of antibodies against all antigens were achieved in the majority of infants following a primary series of three doses administered at 1-2-month intervals from 2 months of age. Hexavac also induced immunologic memory, as evidenced by the anamnestic response to booster vaccination at 12-18 months of age. These responses were comparable with those seen following concomitant administration of Pentavac (DTaP-IPV//PRP-T) and monovalent hepatitis B vaccine (H-B-Vax II), and were also within the ranges observed for other relevant licensed vaccines. Clinical studies comparing the immunogenicity of Hexavac administered at either 2, 3 and 4 months or 2, 4 and 6 months demonstrated that it can be used by either vaccination schedule. A further study also supported the use of primary doses of Hexavac at 3 and 5 months with a booster at 12 months of age. Hexavac demonstrated a good reactogenicity and tolerability profile. The most frequently reported adverse events after both primary and booster doses were local reactions of redness and swelling/induration and a systemic response of mild fever, irrespective of the vaccine used for priming. Hexavac provided immunity against six important childhood diseases with a single injection at each visit.