用于Hib结合疫苗生产的新型候选菌株的评价

目的 观察b型流感嗜血杆菌(Haemophilus influenzae type b,Hib)760705株在连续传代过程中的稳定性.方法 将Hib 760705株工作种子批菌种连续传代,对第5、第8、第10代Hib培养物进行全面检测,包括培养特性(细菌培养、卫星试验)、染色镜检、生化反应,以检测第5、第8、第10代...     

用于Hib结合疫苗生产的新型候选菌株的评价

目的 观察b型流感嗜血杆菌(Haemophilus influenzae type b,Hib)760705株在连续传代过程中的稳定性.方法 将Hib 760705株工作种子批菌种连续传代,对第5、第8、第10代Hib培养物进行全面检测,包括培养特性(细菌培养、卫星试验)、染色镜检、生化反应,以检测第5、第8、第10代Hib的生物学特性.同时采用血清凝集试验和聚合酶链反应荚膜分型方法进行b型荚膜多糖稳定性检测.结果 Hib 760705株工作种子批培养物在连续传代过程中具有典型的细菌学特性,能够稳定地产生b型荚膜多糖.结论 Hib 760705株有明确的来源和背景,可以稳定传代,具备作为Hib结合疫苗生产用候选菌株的条件.     

DTaP-IPV/Hib vaccine (Pentacel)

The combination vaccine diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus and Haemophilus b conjugate (tetanus toxoid conjugate) vaccine (DTaP-IPV/Hib), which has been exclusively used in Canada for more than 10 years, is the first DTaP-based vaccine approved in the US that includes both poliovirus and Haemophilus influenzae type b (Hib) antigens. In clinical trials, the combined DTaP-IPV/Hib vaccine induced high immunogenecity against all of the vaccine antigens, including Hib. Administration of the DTaP-IPV/Hib vaccine as a four-dose series in infants provided high levels of seroprotection against diphtheria and tetanus toxoids, poliovirus types 1, 2, and 3, and Hib polyribosyl-ribitol-phosphate capsular polysaccharide conjugated to tetanus toxoid (PRP-T). Immune responses produced after doses 3 and 4 of DTaP-IPV/Hib vaccine were noninferior to those seen with separately administered DTaP, inactivated poliovirus, and Hib vaccines, apart from those against PRP-T in one study. Seroconversion rates for the five pertussis components in DTaP-IPV/Hib vaccine were noninferior to those seen in infants receiving the separately administered vaccines. A serology bridging study showed the noninferiority of four doses of DTaP-IPV/Hib vaccine to three doses of a DTaP vaccine in terms of seroconversion rates for filamentous hemagglutinin and fimbriae 2 and 3, but not pertactin. There were no clinically relevant changes in the immunogenicity of DTaP-IPV/Hib when coadministered with pneumococcal-7-valent-CRM197 vaccine or measles, mumps, and rubella vaccine and varicella zoster vaccine at 15 months. The tolerability profile of DTaP-IPV/Hib vaccine was generally similar to that of separately administered DTaP, IPV, and Hib vaccines.     

Haemophilus influenzae type b (Hib) vaccine: an effective control strategy in India

Haemophilus influenzae type b (Hib) is an encapsulated, non-motile and non-spore-forming Gram-negative coccobacillus which causes severe pneumonia, meningitis and other life threatening illnesses. Hib disease affects almost exclusively (95%) children aged less than 5 years throughout the world. The mean age of onset is 6-24 months after which it declines gradually until age 5 years. The World Health Organization (WHO) estimates that Hib is responsible for 3 million cases of serious illnesses and approximately 386,000 deaths worldwide each year in children aged under 5 years. In the latest position paper on Hib vaccine, WHO recommended the inclusion of Hib conjugate vaccines in all routine infant immunization programs without waiting for local disease-burden data. The WHO and the Global Alliance for Vaccine Immunization (GAVI) have been working to expand supplies of Hib vaccine, reduce vaccine cost, and assist especially low-income countries with vaccine introduction. Hib vaccine is safe, highly effective and readily available in the market. Hib vaccine has been shown to be > 95% efficacious in diverse populations around the world. Globally, hundreds of millions of doses of Hib vaccine have been administered in the last 2 decades. More than 160 countries are using Hib vaccine in national immunization programmes and around 25 countries planning to introduce. Hib vaccination fits into the India's national immunization schedule.     

Kinetics of antibody response to Haemophilus influenzae type b vaccines. Pennridge Pediatric Associates.

Serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b (Hib) are effective in preventing or ameliorating invasive disease caused by this human pathogen. Polysaccharide and conjugate (saccharide covalently linked to protein carrier) vaccines have been developed which stimulate the production of such antibodies. The polysaccharide-specific antibody concentrations in the sera of vaccine-na?ve adults and toddlers on days 1, 3, 7, 14 and 28 following immunisation with one dose of the Hib polysaccharide vaccine (PRP, polyribosylribitol phosphate) or an oligosaccharide-CRM197 conjugate vaccine (HbOC, HibTITER) were determined. Antibody responses occurred within 7 days of immunisation with the maximum response usually occurring 14 days post-immunisation, irrespective of vaccine or subject age. In this small study, a significant transient decline in pre-existing antibodies was observed only in the groups receiving the polysaccharide vaccine and not in the groups receiving HbOC vaccine. Because of the small magnitude of antigen-specific antibody decline and its transient nature, it is unlikely that this observation has clinical significance.     

Vaccines against polysaccharide antigens

Encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae serogroup B (Hib) are a major cause of disease worldwide. Vaccine development against these organisms has targeted their capsular polysaccharides (CPS), as anti-capsular antibodies often protect against disease. The capsular polysaccharide vaccines that have been available against these organisms are neither immunogenic nor protective in young children and certain immunocompromised individuals. In general, polysaccharide (PS) antigens elicit a T-independent immune response, characterized by lack of memory, and poor immunogenicity at the extremes of life. Efforts to overcome the poor immunogenicity of CPS vaccines have led to development of conjugate vaccines. By conjugating CPS to carrier proteins it is possible to induce a T-dependent immune response against these antigens. Although conjugate vaccines have been successful against Hib disease, their applicability to multi-serotype/serogroup pathogens like the pneumococcus or the meningococcus is questioned. As a result, alternative vaccines including (1) surface proteins conserved across serotypes/serogroups, (2) peptides that mimic PS antigens and (3) DNA vaccines are presently under investigation. This review will highlight the potential and limitations of both CPS and CPS-conjugate vaccines against encapsulated bacteria as well as alternative strategies against PS antigens.     

冻干b型流感嗜血杆菌结合疫苗稳定性研究

目的 对以乳糖作为稳定剂的b型流感嗜血杆菌(Haemophilus influenzae type b,Hib)结合疫苗冻干剂型进行稳定性研究.方法 选取3批冻干Hib结合疫苗,分别于2～8℃保存42个月,20～25℃保存7个月,37℃保存5周.并于考察期内对疫苗进行外观检查、检测回收率(KD ＜0.2)、游离多糖含量...     

Antibody response of pneumococcal vaccine: need for booster dosing?

The approved pneumococcal vaccine comprises purified capsular polysaccharide of 23 stereotypes that account for more than 90% of the invasive pneumococcal infections in the USA. It induces adequate anti-polysaccharide IgG antibody levels to most or all of the component polysaccharide antigens in immunocompetent adults. Elderly adults respond about equally well to vaccination as do younger adults. Pneumococcal antibody declines over time, often below 1 month post-vaccination levels, and sometimes about to pre-primary vaccination levels. Second doses of vaccine satisfactorily boost antibody levels in healthy adults, but not in immunocompromised adults or children. The rate of antibody decline differs for the differing capsular stereotypes. In time, pneumococcal antibody wanes in all healthy persons perhaps increasing their risk of serious pneumococcal disease. Elderly and high risk persons face the highest risk of death from invasive pneumococcal disease, supporting the proposition that for these groups revaccination with pneumococcal vaccine at regular intervals may provide the needed increased measure of protection.     

Infectious diseases in day-care centers: transmission and approaches to prevention

Child day care is used increasingly by both single-parent and two-parent families. With the growth in numbers of children receiving day care outside the home comes a greater awareness of the potential for disease transmission. Epidemiologic patterns of spread of such diseases as Hemophilus influenzae type b, hepatitis A, diarrheal diseases, and cytomegalovirus are changing with respect to attendance at a day-care center. Not only is this a problem for the staff and children who attend a center, but it also may be a public health concern as these diseases could spread to households and the community at large. This review will identify those transmissible infectious agents frequently found in children who attend day-care centers with an emphasis on approaches to prevention and methods for decreasing secondary spread.     

Bacterial meningitis: the impact of vaccination

Acute bacterial meningitis remains an important cause of morbidity and mortality in children. Children <2 years of age are particularly susceptible to infection with encapsulated bacteria due to their immature response to polysaccharide antigens. Conjugate vaccines, which induce T cell memory, can provide immunological protection for these children. The Haemophilus influenzae type b (Hib) conjugate vaccine was the first such vaccine to become available. The efficacy of the vaccine has been quoted as being 98%. Its introduction was followed by a dramatic decrease in the incidence of all invasive Hib disease, including meningitis. This reduction was in part due to the ability of these vaccines to reduce nasopharyngeal carriage of the organism and thereby induce herd immunity. Different Hib vaccines use a variety of protein carriers and differ in their immunogenicity and efficacy. The most suitable vaccine needs to be determined according to the local epidemiology of Hib disease. Commercial combination vaccines may lead to lower antibody levels. A recent increase in the incidence of Hib disease in the UK highlights the importance of continued surveillance and the need for booster vaccinations to ensure continued protection. Conjugate vaccines to Streptococcus pneumoniae and Neisseria meningitidis have been developed. The introduction of a pneumococcal conjugate vaccine in the US has led to a decrease in the rate of infection by nearly 60% in children <5 years of age. A reduction in pneumococcal carriage may also modify disease epidemiology. The UK introduced the conjugate meningococcal C vaccine into its infant schedule with a corresponding reduction in N. meningitidis group C disease. A recent decrease in the effectiveness of the vaccine, however, suggests a booster may be necessary in the future. Our present understanding of the immunology of conjugate vaccines is far from complete. Developed countries have introduced conjugate vaccines into their immunisation schedules to prevent bacterial meningitis; however, their high cost precludes their use in many developing countries. Progress needs to be made in order to get these highly effective vaccines to those areas that need them.     

Pneumococcal conjugate vaccine (Prevnar; PNCRM7): a review of its use in the prevention of Streptococcus pneumoniae infection

PNCRM7 (Prevnar) is a pneumococcal vaccine containing seven capsular polysaccharide antigens from the bacterium Streptococcus pneumoniae, each of which is conjugated to diphtheria protein [cross-reactive material (CRM(197))]. CRM(197) is an inert but immunogenic variant of diphtheria toxoid that is also used as a carrier molecule in one Haemophilus influenzae type b conjugate vaccine. Unlike the 23-valent unconjugated pneumococcal vaccines, PNCRM7 elicits a T cell-dependent response and thus protects young children against pneumococcal disease. The immunogenicity of PNCRM7 has been demonstrated in both healthy children aged <2 years and older children in high-risk groups. Two randomized, double-blind trials conducted in the US demonstrated that all PNCRM7 serotypes were immunogenic in healthy infants and young children when compared with a control vaccine. A booster dose of PNCRM7 elicited an anamnestic response to all seven serotypes. Data from a large, randomized, double-blind study conducted in California (US) have confirmed the protective efficacy of PNCRM7 against invasive pneumococcal disease (e.g. bacteremia, meningitis) caused by serotypes included in the vaccine. The vaccine efficacy in the per-protocol analysis was 97.4% and its efficacy against invasive disease caused by any pneumococcal serotype in the intent-to-treat (ITT) analysis was 89.1%. Indeed, a postlicense surveillance study (n = 211,565) showed that the introduction and routine use of PNCRM7 was associated with a marked reduction in invasive pneumococcal disease in children <5 years of age. In addition, the US trial and another randomized, double-blind trial conducted in Finland, showed that PNCRM7 vaccine efficacy against all otitis media episodes was between 6 and 7%. PNCRM7 vaccine was generally well tolerated and had a similar local and systemic adverse events profile to other pediatric vaccines. The most common local adverse event associated with PNCRM7 administration was inflammation at the injection site, and the most common systemic adverse effect was febrile illness (> or =38 degrees C) that usually resolved without treatment. The limited available pharmacoeconomic data suggest that PNCRM7 could be cost effective depending, in part, on the manufacturer's list price of the vaccine. Results of the base case analysis in a US study showed a cost-effectiveness ratio for PNCRM7 of US dollars 80,000 per life-year saved from a societal perspective compared with US dollars 176,000 from a healthcare payer perspective, assuming a nondiscounted list price of US dollars 58 per dose (1997 costs). Concomitant administration of PNCRM7 vaccine with hepatitis B, oral polio, meningococcal oligosaccharide protein conjugate or H. influenzae type b vaccines did not affect the immunogenicity of these pediatric vaccines to a clinically relevant extent. CONCLUSION: PNCRM7 vaccine will be of great benefit to those societies that have active immunization programs implemented. In infants and vulnerable children throughout the world, PNCRM7 vaccine has the potential to reduce the mortality and morbidity rates associated with S. pneumoniae infections. In developed countries, the vaccine will be of particular benefit in preventing disabling infections but its impact in developing countries will be more pronounced with the potential to greatly reduce mortality.     

A new DTPw-HBV/Hib vaccine: immune memory after primary vaccination and booster dosing in the second year of life

The response to booster vaccination at 15-18 months of age and the presence of immune memory in 10-month old children, primed with a new combined diphtheria-tetanus-hepatitis B-whole cell pertussis vaccine extemporaneously mixed with Haemophilus influenzae type b-tetanus toxoid conjugate (DTPw-HBV/Hib) from new antigen sources and containing 2.5 microg polyribosyl-ribitol-phosphate (PRP) was assessed. Primary vaccination with the new DTPw-HBV/Hib vaccine was immunogenic and of comparable tolerability to commercially available Tritanrix HepB/Hiberix. Children were boosted with DTPw-HBV, DTPw-HBV/Hib or separate DTPw-HBV+Hiberix. Immune memory was assessed through administration of 10 microg PRP polysaccharide. Anti-PRP antibody GMCs increased substantially after the challenge in DTPw-HBV/Hib-primed subjects indicating the presence of immune memory. One month after the booster dose, 100% of subjects had seroprotective antibody concentrations against PRP, diphtheria and tetanus, >95% were seroprotected against hepatitis B, > or =94.0% had a pertussis booster response. Substantial increases in antibody GMCs against all antigens were observed. Swelling >20 mm was the most common Grade 3 solicited symptom reported (up to 26.0% of subjects). Fever >39.5 degrees C was uncommon (>2.5%). Eleven large swelling reactions were reported; none involved an adjacent joint. One serious adverse event occurred that was considered unrelated to vaccination. This new DTPw-HBV/Hib vaccine with new vaccine components and 2.5 microg PRP induced effective priming against Hib evidenced by a vigorous anamnestic response on exposure to PRP polysaccharide. The booster dose was immunogenic and the safety profile was acceptable. Combined DTPw-HBV and DTPw-HBV/Hib vaccines using new vaccine antigen sources will promote continued supply of combined DTPw-based vaccines to global mass vaccination campaigns.     

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

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 11000 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.     

Advances in pneumococcal vaccines: advantages for infants and children

The introduction of Haemophilus influenzae type b (Hib) vaccine into the universal immunisation schedules of many industrialised countries and the subsequent remarkable decline in the incidence of invasive Hib disease has further highlighted the impact of invasive pneumococcal diseases. Streptococcus pneumoniae is now the leading cause of bacterial meningitis in children in many settings and a leading cause of vaccine-preventable bacterial disease in children worldwide.The currently marketed 23-valent pneumococcal polysaccharide vaccine provides large serotype coverage at a relatively low cost. However, it is not efficacious in young children. Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive disease in infants and young children, with favourable safety and immunogenicity profiles. These vaccines have also shown efficacy in reducing cases of non-invasive disease (i.e. otitis media), nasopharyngeal acquisition of vaccine-specific serotypes of S. pneumoniae, and protection against pneumococcal disease caused by resistant strains. However, PCV contains a limited number of pneumococcal serotypes and, given adequate ecological pressure, replacement disease by non-vaccine serotypes remains a threat, particularly in areas with very high disease burden. Furthermore, although capsular-specific antibodies have been shown to be highly protective, it remains unclear what concentration of these serotype-specific antibodies protect against disease and, more recently, it has become clear that opsonic activity and avidity of these antibodies are more critical determinants of protection than concentration. Therefore, monitoring disease burden and defining immune correlates of protection after widespread use of conjugate vaccines are crucial for the evaluation of these new generation vaccines. Furthermore, a need exists to develop pneumococcal vaccines with lower cost and larger serotype coverage.Development of one or more protein vaccines that might be easier and, thus, less expensive to manufacture, and which might provide protection against multiple serotypes, is in progress. This article reviews the current state of pneumococcal disease and pneumococcal vaccines in clinical use.     

Conjugate vaccines

Conjugate vaccines extend the vaccinal prevention for children to more diseases. Conjugating the capsular polysaccharide to a carrier protein transforms a T-independent antigen in a T-dependent, allowing protection of the children (before 2 years of age) against Haemophilus influenzae type b, meningococcal C and pneumococcal infections. This article reviews the 3 conjugate vaccines and their results with focus on some questions: antigens interference in the immunological response, serological subrogate for protection, herd immunity and replacement of circulating serotypes.     

The safety of 7-valent pneumococcal conjugate vaccine

Streptococcus pneumoniae is one of the most important bacterial pathogens of young children. Currently, there are several conjugate vaccines against S. pneumoniae in various stages of laboratory development, clinical evaluation or currently licensed. Heptavalent pneumococcal conjugate vaccine (Wyeth Lederle; PCV-7) is the only currently approved pneumococcal conjugate vaccine indicated against invasive pneumococcal disease for children younger than two years of age. Safety studies have shown that the PCV-7 is acceptably safe when administered alone, simultaneously with other childhood vaccines or in combination with Haemophilus influenzae type b conjugate vaccines. In addition, PCV-7 vaccine was generally safe and immunogenic among infants infected with HIV and those with sickle cell disease. Surveillance studies to monitor the serotype distribution in invasive pneumococcal disease is important to determine that PCV-7 continues to be the optimal vaccination for prevention of pneumococcal invasive disease.     

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.     

DTPa-HBV-IPV/Hib vaccine (Infanrix hexa)

Primary vaccination of infants with diphtheria-tetanus-acellular pertussis-hepatitis B recombinant (adsorbed)-inactivated poliomyelitis-adsorbed conjugated Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib; Infanrix hexa)-inactivated poliomyelitis-absorbed conjugated Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) refers to Infanrix hexa trade mark.) provided high levels of seroprotection against diphtheria toxoid, tetanus toxoid, poliovirus 1, 2 and 3, pertussis antigens (pertussis toxoid, filamentous haemagglutinin and pertactin), hepatitis B virus surface antigen and H. influenzae polyribosyl-ribitol-phosphate (PRP) antigen. Most infants (97%) had anti-PRP levels >/=0.15 micro g/mL after a booster dose at 18 months. Primary vaccination with the DTPa-HBV-IPV/Hib vaccine produced a similar immune response to that with two different pentavalent plus monovalent vaccine combinations. Coadministration of DTPa-HBV-IPV/Hib vaccine and a heptavalent pneumonococcal conjugate vaccine resulted in a high level of seroprotection and was well tolerated. Primary or booster vaccination with DTPa- HBV-IPV/Hib vaccine was well tolerated. Commonly reported local adverse reactions included redness, pain and swelling. Systemic symptoms were usually mild to moderate, and included fussiness, fever, restlessness and sleepiness.     

测定b型流感嗜血杆菌结合疫苗游离多糖的脱氧胆酸钠沉淀法的建立

 目的  建立测定b型流感嗜血杆菌（Haemophilus influenzae type b,Hib）结合疫苗游离多糖的脱氧胆酸钠（sodium deoxycholate,DOC）沉淀法。 方法   在一定的酸性条件下,用1%DOC沉淀分离Hib结合疫苗中的结合多糖和游离多糖,测定上清和沉淀的多糖含量,并对该法进行验证。 结果   DOC沉淀法的标准曲线具有可靠的线性,决定系数＞0.999。该法的准确性和精密度良好,多糖加样回收率为103%~108%,相对标准差均<10%。 结论   建立的DOC沉淀法可用于Hib结合疫苗中的游离多糖测定。     

A new vaccine concept: polysaccharide conjugate vaccines]

Polysaccharide-based vaccines such as the vaccines against Neisseiria meningitidis group A and C or Streptococcus pneumoniae have proved their efficacy in children and adults. Nevertheless they induce B cell mediated immunological response and therefore fail to protect infants. In the eighties appeared a new concept of Polysaccharide based vaccine for infants: Polysaccharide conjugate vaccines. Coupling polysaccharide to carrier protein transforms the T-independent antigen into T-dependant antigen. The first conjugate vaccines for the prevention of infections caused by Haemophilus influenzae type b were a success, with a 95% efficacy. A worldwide vaccination program might lead to the eradication of that bacterial disease. New vaccines are currently under development, the next conjugate vaccine should be one against Streptococcus pneumoniae. First published clinical data are very promising and confirmed the potential of the polysaccharide conjugate vaccine approach against bacterial infections.