Acellular pertussis vaccines: new preparation. Better tolerated but less active?

(1) In France SmithKline Beecham market a three-component acellular pertussis vaccine in the form of a tetravalent vaccine and a pentavalent vaccine. Pasteur M/erieux MSD also market in France a two-component acellular pertussis vaccine in the form of a tetravalent vaccine and a pentavalent vaccine. (2) The two pentavalent vaccines are indicated for an early booster injection at age 16-18 months; the two tetravalent vaccines are indicated for a late booster injection at age 11-13 years. (3) The published assessment file on these vaccines is limited. (4) Immunological studies show that the acellular pertussis valency does not reduce the antigenicity of the valencies with which it is combined (diphtheria, tetanus and poliomyelitis), although there is some doubt regarding the Haemophilus influenzae tybe b valency. (5) In the absence of direct comparisons with the cellular pertussis vaccine available in France in tetravalent or pentavalent vaccines, indirect evidence and data from a trial comparing the acellular two-component vaccine with the cellular vaccine (Vaxicoq degrees ) marketed in France (combined with diphtheria and tetanus valencies) suggest that clinical protection is slightly lower after primary vaccination with the two acellular vaccines. (6) In children, acellular pertussis vaccines are globally better tolerated than the cellular pertussis vaccine. (7) In adolescents, a small study has shown that the three-antigen acellular pertussis vaccine is relatively well tolerated. But the acellular vaccine was released too recently onto the international market to know the precise incidence of rare and severe adverse effects. (8) The new French vaccination schedule for pertussis now includes a booster between 11 and 13 years. Only long-term epidemiological follow-up can show if routine vaccination of adolescents against pertussis will have an impact on the incidence of pertussis in infants and adults. (9) The incidence of Haemophilus b meningitis must continue to be monitored.     

DTaP(5)-IPV-Hib vaccine (Pediacel®)

Pediacel? is a fully liquid formulation of a diphtheria, tetanus, five-component acellular pertussis, inactivated poliovirus and Haemophilus influenzae type b combination vaccine, which does not require reconstitution. Both vial and prefilled syringe presentations of Pediacel? are available for use in the EU. In active-controlled clinical trials, primary and/or booster vaccination with Pediacel? was highly immunogenic, eliciting strong and sustained serologic responses against all its component toxoids/antigens when administered according to a variety of different schedules. In particular, pivotal studies showed that Pediacel? was generally similar and/or noninferior to reconstituted pentavalent and hexavalent diphtheria, tetanus, and acellular pertussis-based combination vaccines in terms of the seroprotection rates elicited against the diphtheria, tetanus, poliovirus, and Haemophilus influenzae type b components that these products have in common, as well as in terms of the seroresponse/booster response rates elicited against the acellular pertussis components that these products have in common. Differences in immune responses between Pediacel? and these vaccines were considered unlikely to be clinically significant. There was no clear evidence of clinically relevant changes in the immunogenicity of Pediacel? (or the coadministered vaccine) when given concomitantly with meningococcal group C conjugate, pneumococcal conjugate, or hepatitis B vaccines in clinical studies. Pediacel? was generally well tolerated and demonstrated low reactogenicity in clinical trials. It had an adverse event profile generally similar to that of other combination vaccines based on diphtheria, tetanus and acellular pertussis vaccine, including Infanrix?-IPV+Hib and Infanrix? hexa.     

Experiences with acellular pertussis vaccine in Japan and epidemiology of pertussis

In 1975, with two successive cases of death shortly after whole cell pertussis vaccine, administration of pertussis vaccine was temporarily suspended. The vaccine was soon resumed, but setting the vaccination age at over two years for group vaccination. This caused the fall in pertussis vaccine acceptance rates until 1980, resulting in a nationwide epidemic of pertussis infection, with the peak of the epidemic in 1979. Acellular pertussis vaccine was developed and introduced in 1981, since then the coverage rate with the three-time pertussis vaccination have retained the levels of more than 80%. The number of cases of pertussis infection decreased steadily since 1980 and in 1985, the number of total pertussis patients was as low as those observed before 1974. However, incidence of pertussis patients aged less than 2 year remained higher. Dramatical decrease in side effects of pertussis vaccination was observed after the elevation of the age of the vaccination at mass immunization clinic to two years. Side effects has decreased further after the introduction of acellular pertussis vaccine.     

Acellular pertussis vaccines for use among infants and young children

Pertussis is still one of the most common vaccine-preventable childhood diseases in developed countries. Infants, particularly those < 6 months, are the most susceptible and those who suffer the greatest disease burden and mortality. In the 1970s, concerns about the reactogenicity of whole-cell vaccines led to a decrease in vaccine coverage and later the re-emergence of the disease in many countries. The advent of acellular vaccines in recent years has constituted an important advance in the acceptance of this immunisation and consequently the control of the disease. The efficacy of acellular pertussis vaccines is approximately 59 - 93%, similar to whole-cell vaccines, but all available data confirm the substantial improvement in safety of the new vaccines. With the licensure of acellular pertussis vaccines and combined vaccines containing them, pertussis immunisation has become significantly developed. Furthermore, the possibility of continuing to vaccinate adolescents and adults with new diphtheria, tetanus, and pertussis (dTap) vaccines is an important step in achieving control and elimination of the disease.     

Acellular pertussis vaccines for use among infants and young children

Pertussis is still one of the most common vaccine-preventable childhood diseases in developed countries. Infants, particularly those < 6 months, are the most susceptible and those who suffer the greatest disease burden and mortality. In the 1970s, concerns about the reactogenicity of whole-cell vaccines led to a decrease in vaccine coverage and later the re-emergence of the disease in many countries. The advent of acellular vaccines in recent years has constituted an important advance in the acceptance of this immunisation and consequently the control of the disease. The efficacy of acellular pertussis vaccines is ～ 59 – 93%, similar to whole-cell vaccines, but all available data confirm the substantial improvement in safety of the new vaccines. With the licensure of acellular pertussis vaccines and combined vaccines containing them, pertussis immunisation has become significantly developed. Furthermore, the possibility of continuing to vaccinate adolescents and adults with new diphtheria, tetanus, and pertussis (dTap) vaccines is an important step in achieving control and elimination of the disease.     

Which strategy for pertussis vaccination today?

Pertussis (whooping cough) remains an epidemic disease responsible for infant and child morbidity and mortality, and is perceived as a serious public health problem. Since the widespread use of whole-cell pertussis vaccines in the 1940s, vaccination programs have varied greatly between countries. National specificity is a function of several factors. The most important are: vaccine efficacy and tolerability;vaccine coverage and distribution; and vaccine acceptance by parents and professionals. During the 1970s, Sweden, England, Wales and Japan provided contrasting examples of the attitude of health authorities to the use of whole-cell vaccines. The increase in pertussis incidence was noted as a consequence of active opposition to this vaccine. The re-emergence of pertussis in the 1990s, in countries with high vaccination coverage and increased incidence of disease in individuals >15 years and <6 months of age, has drawn attention to the role of booster doses of pertussis vaccines and their introduction into regular vaccination programs. The use of acellular vaccines for booster doses for adolescents and adults would seem unambiguous because of their decreased reactogenicity, although the exact schedule has yet to be established. The choice between the two kinds of vaccines is more difficult for primary courses, where safety and efficacy profiles are similar, and the attitude towards acellular vaccines varies from country to country. In this case, the strategy adopted results from the national history of pertussis infection and from the quality of the available whole-cell vaccine. Two contrasting examples are the US, where acellular vaccines were licensed for the primary series in the 1990s, and the UK, where whole-cell vaccines are exclusively used for primary immunization. The changing epidemiology of pertussis, and its local diversification, would suggest that at present it is difficult to define a single worldwide strategy with only one kind of vaccine and one schedule. In order to control pertussis incidence, each country should continue to determine the best national vaccination program established in very close relation to the past and present epidemiological situation and available healthcare resources.     

Diphtheria-tetanus-acellular pertussis vaccine adsorbed (Triacelluvax; DTaP3-CB): a review of its use in the prevention of Bordetella pertussis infection

DTaP3-CB (Triacelluvax) is an acellular pertussis (aP) vaccine containing 3 antigens from purified Bordetella pertussis bacteria combined with diphtheria and tetanus toxoids (DT). In addition to purified filamentous haemagglutinin and pertactin, DTaP3-CB contains pertussis toxin which has been genetically rather than chemically detoxified. As shown in randomised, double-blind clinical trials in infants, DTaP3-CB elicits an immune response similar to or greater than that of whole cell (DTwP) vaccines. Results of a large multicentre study comparing DTaP3-CB with 12 acellular and 1 DTwP vaccine indicate that DTaP3-CB, like all acellular vaccines, induces variable immune responses to different pertussis antigens; however, antibody titres to pertussis toxin are normally higher after immunisation with the genetically detoxified vaccine than with other 3- or 4-component vaccines. When given as a fourth or fifth booster dose, DTaP3-CB produced a significant immune response in infants primed with 3 doses of either a DTaP or DTwP vaccine. Virtually all infants immunised with DTaP3-CB had a serological response to diphtheria and tetanus toxoids. Data from 2 very large efficacy studies indicate that DTaP3-CB has high and long lasting protective efficacy against culture-confirmed pertussis which is greater than that of a 2-component vaccine (DTaP2-SB) and the whole cell DTwP-CON vaccine after a 3-, 5- and 12-month immunisation schedule and after a 2-, 4- and 6-month schedule with the DTwP-CON vaccine. However, the DTwP-CON whole cell vaccine has been noted for its low immunogenicity in 1 study and low efficacy and immunogenicity in another study. On the other hand, DTaP3-CB vaccine has similar efficacy to DTaP3-SB (after immunisation at 2, 4 and 6 months), DTaP5-CON and DTwP-EVANS against culture-confirmed pertussis with > or =21 days cough in infants immunised according to a 3-, 5- and 12-month schedule. Infants immunised with DTaP3-CB experienced significantly fewer adverse events such as pain, redness, swelling and irritability than infants given DTwP. DTaP3-CB has a similar tolerability profile to other acellular vaccines and is associated with similar rates of local tenderness, irritability, fever (> or =40 degrees C) and persistent crying. Comparative trials have shown that infants immunised with DTaP3-CB had a lower incidence of pain at the site of injection and fever (> or =38 degrees C) compared with other acellular vaccines, although this may have little clinical significance. Concomitant administration of DTaP3-CB with hepatitis B, oral polio or Haemophilus influenzae type B vaccines did not affect the immunogenicity of these other paediatric vaccines. CONCLUSION: Data from clinical trials with DTaP3-CB vaccine indicate that this vaccine induces high and long lasting efficacy. It is at least as efficacious as most whole cell vaccines and generally similar in efficacy to the most efficacious acellular pertussis vaccines containing 3 or more pertussis antigens. DTaP3-CB is better tolerated than whole cell vaccines and has a similar tolerability profile to other acellular vaccines; the possible lower risk of severe adverse events remains to be confirmed. The low reactogenicity of DTaP3-CB is likely to make it well tolerated and therefore well accepted for the immunisation of infants, thereby enabling wider implementation of vaccination programmes.     

Acellular pertussis vaccines: maybe slightly less effective, but better tolerated

(1) With the exception of an American vaccine, whole-cell pertussis vaccines, including the preparation marketed in France, have an efficacy of 90 to 95%. Systemic and local reactions are frequent and can be severe. Cellular vaccines do not seem to cause permanent brain lesions or sudden infant death. (2) Four acellular pertussis vaccines are marketed in France: two have two antigenic components and two have three components. (3) The efficacy of the best acellular pertussis vaccines does not exceed 85% after primary vaccination. Clinical protection may be shorter-lived with acellular than with cellular vaccines. (4) Systemic and local adverse effects, both mild and severe, are significantly less frequent with acellular vaccines.     

百日咳黏着素研究进展

百日咳黏着素(pertactin,PRN)是所有有毒力的百日咳杆菌产生的一种非纤毛性凝集原,存在于菌体外膜上,属于自主转运蛋白.它能产生保护水平的抗体,已经成为百日咳组分疫苗的重要抗原成分.近年来许多疫苗接种率较高的国家均有百日咳发病率增高的报告,其中一个因素就是百日咳杆菌的一些抗原(百日咳毒素、PRN、凝集原)型别的转换导致疫苗保护效果的下降.此文就PRN的分子结构、生物学特征、流行病学及纯化工艺方面作一综述.     

DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa™): A Guide to Its Use in Infants

Infanrix hexa?, a diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis, and Haemophilus influenzae type b (Hib) conjugate vaccine, is indicated for primary and booster vaccination of infants. Available clinical data from more than a decade of experience with the vaccine indicate that primary and booster vaccination with Infanrix hexa? is a safe and useful option for providing protection against the common childhood diseases of diphtheria, tetanus, poliomyelitis, pertussis, hepatitis B, and disease caused by Hib.     

Combined acellular pertussis vaccines: new indication. No tangible benefit in primary vaccination

(1) Two acellular pertussis vaccines included in pentavalent combinations are available in France. Their use was initially restricted to booster injections. This restriction has now been lifted, meaning that the two products can be used for primary vaccination. (2) The initial assessment files, which mainly concerned primary vaccination, showed that the acellular pertussis vaccines had fewer mild side effects than the cellular vaccine, but there was no evidence that they were as effective. (3) Some epidemiological studies with fairly short follow-up (about 2 years), conducted in various countries, suggest that the acellular vaccines confer clinical protection. There are no data comparing the bi- and tri-antigenic acellular vaccines marketed in France. (4) For the time being, the whole-cell pertussis vaccine remains the standard.     

无细胞百日咳疫苗抗体活性持久性监管研究

目的：比较不同类型无细胞百日咳疫苗免疫小鼠后诱导的抗体应答及其持久性。方法：将来自于3家企业,采用2种不同工艺生产的无细胞百日咳疫苗（组分苗和共纯化苗）按一定比例稀释后分别给3组小鼠皮下接种,0.5 mL/只,于第4周加强免疫,剂量与初免疫相同。于免疫后第4周、第5周、第8周、第12周、第17周、第30周、第40周、第50周和第65周取血,分离血清,检测小鼠血清中抗百日咳抗体IgG水平（抗-PT和抗-FHA）和PT的中和抗体水平,并对其结果进行分析比较。结果：两类疫苗组检测结果比较,在免疫后第30周之前,两组之间抗-PT和抗-FHA水平无显著性差异;但在30周之后,两组之间抗-PT和抗-FHA水平有显著性差异（P < 0.05）,组分苗组抗体水平高于共纯化苗组。中和抗体方面,组分苗组中和抗体水平高于共纯化苗组,两组比较有显著性差异（P < 0.05）。结论：两种类型的百日咳疫苗免疫小鼠后均能诱导产生体液免疫应答,组分苗组的抗体持久性（包括百日咳抗体IgG和百日咳PT中和抗体）强于共纯化苗组;且百日咳IgG抗体与中和抗体之间具有一定的相关性。     

Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine, adsorbed (Boostrix®): a review of its properties and use as a single-dose booster immunization

Reduced-antigen, combined diphtheria, tetanus and three-component acellular pertussis vaccine (Tdap; Boostrix?) is indicated for booster vaccination against diphtheria, tetanus and pertussis in individuals from age four years onwards in Europe and from age 10 years onwards in the US. Compared with infant formulations used for primary vaccination, Tdap contains reduced quantities (10-50%) of all toxoids and antigens, which are adsorbed to either ≤0.39?mg/dose (US licensed formulation) or 0.5?mg/dose (rest-of-world formulation) of aluminium adjuvant. The reduced antigen content is designed to avoid the increasing reactogenicity historically seen with the fourth and fifth doses of infant vaccine. This article reviews the immunogenicity, protective efficacy and reactogenicity of Tdap booster administered to children, adolescents and adults, including those aged ≥65 years. In clinical trials, a single booster dose of Tdap induced seroprotective levels of antibodies to diphtheria and tetanus toxoids in virtually all children and adolescents, and in a high proportion of adults and elderly individuals at approximately 1 month post-vaccination irrespective of their vaccination history. In all age groups, seropositivity rates for antibodies against pertussis antigens were ≥90% (including in unvaccinated adolescents), and booster response rates were high. Tdap was safely co-administered with other common vaccines without significantly affecting the immune responses. The immunogenicity and reactogenicity profiles of booster doses of Tdap were generally similar to those of infant diphtheria-tetanus-whole-cell pertussis vaccine and infant diphtheria-tetanus-acellular pertussis vaccine in children aged 4-6 years, and infant diphtheria-tetanus vaccine in older children. In adolescents and adults, the immunogenicity and reactogenicity of Tdap were generally similar to those of reduced-antigen diphtheria-tetanus vaccine, reduced-antigen diphtheria-tetanus-five-component acellular pertussis vaccine and reduced-antigen acellular pertussis vaccine. Therefore, Tdap is suitable as a booster in place of these vaccines, including tetanus toxoid vaccine in the management of tetanus-prone wounds in adults. The quantity of aluminium adjuvant in Tdap did not markedly affect the immunogenicity or reactogenicity of the vaccine. Seropositivity rates for antibodies against pertussis toxin had begun to decline by 5 years after a booster dose of Tdap in adolescents/adults, and a subsequent booster dose 10 years later was generally as immunogenic as the initial booster and was well tolerated. Tdap was safe and well tolerated in all age groups. Local injection-site reactions were the most common adverse events. Most adverse events were of mild or moderate intensity and transient; there were few serious vaccination-related adverse events. Thus, Tdap is highly immunogenic, with low reactogenicity, in all age groups and appears suitable for targeted and/or repeat Tdap boosters in children, adolescents, adults and elderly individuals as part of immunization strategies that may prove beneficial in further limiting the burden of pertussis.     

脑膜炎球菌疫苗的研究和开发现状

流行性脑脊髓膜炎(流脑)是一个世界性公共卫生问题,发病率和死亡率都较高.此文从细菌遗传学特征、流脑的流行趋势、疫苗供应现状、可供选择的候选疫苗及其筛选方法等方面讨论了脑膜炎球菌疫苗(特别是B群脑膜炎球菌疫苗)的研究和开发现状.     

The future of the immunisation schedule: recommendations of a workshop

The Ministry of Health convened a workshop in June 1998 on the future of the immunisation schedule. Your comments are invited on the recommendations of the workshop. PRINCIPLES BEHIND THE SCHEDULE: Improve on-time immunisation coverage as the priority. Reaching the last 20% will cost at least as much as the first 80% and is vital to achieve the aims of the immunisation programme (disease elimination and improved control). Obtain regular secure coverage data, derived from a tracking system that ensures children are followed up. Assess compliance with early childhood centre immunisation checks at entry and improve if necessary. Establish an expert committee to advise on the immunisation schedule and policies. Keep the schedule as simple as possible. Accept that vaccines are not generic and future schedule recommendations may be vaccine-specific. Involve providers in the process of change. PROPOSED CHANGES: Move the second dose of measles-mumps-rubella vaccine from age 11 years to around five years. Consider moving the third visit from five to four months to achieve earlier protection against pertussis. Consider adding a fifth dose of pertussis vaccine. Change to acellular pertussis vaccine, once suitable vaccines are available. Change to inactivated polio vaccine, once suitable vaccines are available. Consider omitting the fourth dose of polio vaccine. Consider introducing an adult immunisation schedule with fewer adult tetanus-diphtheria boosters.     

Booster vaccination at 6-8 years of age with a reduced antigen content dTpa-IPV vaccine is immunogenic and safe after priming with whole-cell pertussis vaccine

Pertussis vaccines containing reduced amounts of antigen have been considered primarily for use in adolescents and adults to date. We evaluated a reduced antigen content combined diphtheria tetanus acellular pertussis and inactivated polio vaccine (dTpa-IPV) in 6-8 years old children in Taiwan, who had received 4 doses of DTPw (combined diphtheria, tetanus, whole cell pertussis vaccine) and OPV (oral polio vaccine). One month after the booster dose, seroprotection rates and vaccine response rates to all antigens were at least 98.8%, and significant increases in antibody concentrations were observed. Booster vaccination was associated with minor local reactions and systemic symptoms. Symptoms of severe intensity did not occur, with the exception of local pain. The dTpa-IPV vaccine was immunogenic and well tolerated in 6-8 years old children and offers an alternative to the current use of tetanus and diphtheria vaccine and OPV in Taiwan, addressing the established need for repeated booster vaccinations against pertussis at the same time.     

Economic evaluation of an extended acellular pertussis vaccine program for adolescents in Québec, Canada

OBJECTIVE: Pertussis is a frequent cause of cough illness in adolescents. In Canada, immunization against pertussis in public programs has been restricted to children under 7 years of age. The purpose of this analysis was to estimate the health and economic impact of an additional booster dose of the acellular vaccine in adolescents in Québec. METHOD: We performed a cost-effectiveness analysis, based on a predictive spreadsheet dynamic model following a cohort of 90,929 adolescents in Québec from the age of 14 years over a 10-year period from the Québec Ministry of Health (MOH) and societal (SOC) perspectives. The model was used to compare costs (2003 values) and benefits of an adolescent vaccination program (AVP), including a diptheria, tetanus, and acellular pertussis (dTacp) vaccine administered at age 14 years, with current practice. RESULTS: From the MOH perspective, a booster vaccination of dTacp at age 14 years via the AVP would produce a yearly additional expected cost of Can dollars 1.06 per adolescent with an incremental cost-effectiveness ratio (ICER) of Can dollars 480 per pertussis case avoided based on a 10-year period. When outcomes are discounted at 3%, the ICER rises to Can dollars 527 per discounted pertussis case avoided. From the SOC perspective, the AVP would cost Can dollars 0.83 per adolescent per year with an additional cost per avoided pertussis case of Can dollars 377 (Can dollars 414 per additional discounted case of pertussis avoided). Over the 10-year period, 2012 non-discounted cases of pertussis would be prevented with approximately two hospital admissions averted. CONCLUSION: This study suggests that administering a booster dose of dTacp at age 14 years to replace the diptheria and tetanus vaccination will slightly increase the economic burden from MOH and SOC perspectives; however, the number of pertussis cases and the number of hospital admissions will decrease.     

第一代无细胞百日咳疫苗毒性国家参考品制备工艺的研究

目的筛选无细胞百日咳疫苗毒性国家参考品的最佳生产工艺。方法选用百日咳CS菌株(编号58003),对不同的培养方式进行比较研究,选择最佳毒性国家参考品的生产工艺。结果该参考品经过不同培养方式比较后,确定了最终生产工艺,将培养的百日咳菌加入保护剂后分装制备成冻干品。结论该生产工艺制备的样品含有较强的毒性,同时能进行规模生产,满足了毒性国家参考品各项检测指标的要求。     

无细胞百日咳疫苗特异性毒性检测方法现状及展望

 百日咳毒素是百日咳杆菌重要的保护性抗原,经化学方法脱毒成为百日咳类毒素后制成的无细胞百日咳疫苗（acellular pertussis vaccine,APV）具有残余毒性和毒性逆转的可能性,所以建立特异性毒性检测方法对于保证APV的安全性是十分必要的。此文就国内外APV特异性毒性检测方法的现状做一综述,并结合近几年国外研究的毒性检测新方法进行展望。     

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 (DTaP(2Fr)) obtained after primary series of immunizations were compiled from 75 study groups comprising 36 clinical trials or vaccination programs conducted between 1987 and 2006. DTaP(2Fr) 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 aP(2Fr) antigens. The immune responses to the PT and FHA antigens of the DTaP(2Fr) vaccine used in the Sénégal 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 DTaP(2Fr) vaccine is accompanied by effectiveness in controlling pertussis disease in the areas where it is used on a large scale with good vaccination coverage.