b型和不可分型流感嗜血杆菌疫苗的研究进展

流感嗜血杆菌(Hi)是常见的条件致病菌,可引起脑膜炎、肺炎、中耳炎、败血症和会厌炎等疾病,其中,b型流感嗜血杆菌(Hib)和不可分型流感嗜血杆菌(NTHi)所致感染最为常见.疫苗接种是预防其感染最有效的手段.本文简述了Hib疫苗的发展、应用及NTHi候选疫苗的研究现状,为疾病的防治和疫苗的研发提供参考.     

Pneumococcal conjugate vaccine for young children

Pneumococcal disease is a common cause of morbidity and mortality in the pediatric population. Pneumococcal infections, which account for most serious bacterial disease in infancy and early childhood, are a major cause of acute otitis media, sinusitis, pneumonia, bacterial meningitis, and bacteremia. Streptococcus pneumoniae is the causative agent in a large percentage of these infections, although other microorganisms also play a role. The recent emergence of drug-resistant strains has provided a strong incentive for preventing pneumococcal infections by vaccination. However, the capsular polysaccharide pneumococcal vaccines used to immunize adults are neither immunogenic nor protective in young children due to poor antibody responses. Therefore, research has focused on development of additional immunogenic pneumococcal vaccines to provide long-term immunity in children < 2 years of age. The most promising approach has been the development of a protein-polysaccharide conjugate vaccine for the seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) that most commonly cause infections in childhood. An effective conjugate vaccine that protects against these serotypes has the potential to prevent 85 percent of bacteremia episodes, 83 percent of meningitis episodes, and 65 percent of otitis media cases in the U.S. among children younger than 6 years. The Food and Drug Administration (FDA) recently approved the first protein-polysaccharide conjugate vaccine to prevent invasive pneumococcal diseases in infants and toddlers < 2 years of age. This conjugated vaccine against pneumococcus uses the same technology as the successful vaccine against Haemophilus influenzae type b. It consists of an immunogenic but inert protein coupled covalently to the polysaccharide coat of the selected strains of pneumococci. The conjugated antigen induces a more powerful, T-cell-based immune response in infants, which is developed by the time they are 2 months of age. Some important questions regarding this vaccine for children < 2 years of age: Is the vaccine safe? Is it immunogenic? Is it efficacious in preventing invasive pneumococcal disease and controlling otitis media? FINDINGS: Results of three randomized double-blind trials designed to evaluate the safety and immunogenicity of this vaccine in healthy children < 2 years of age were reported within the last three years. The studies found that the vaccine is safe and highly immunogenic for all seven serotypes. The most recent study, involving over 37,000 young children, also evaluated the vaccine's efficacy, and reported that the vaccine is highly effective in preventing invasive disease and has had an impact on otitis media. CONCLUSIONS: The heptavalent pneumococcal conjugate vaccine is safe and highly effective in preventing pneumococcal meningitis and bacteremic pneumonia in young children < 2 years of age; it is less effective in preventing otitis media. Based on the results of three well-designed studies demonstrating the vaccine's safety, immunogenicity, and efficacy, the vaccine is safe and effective for active immunization of children < 2 years of age against invasive disease caused by seven Streptococcus pneumoniae serotypes included in the vaccine. At this time, there is no clear medical consensus regarding its safety and efficacy for control of otitis media in children < 2 years of age. This application has not been evaluated by the FDA. The pneumococcal conjugate vaccine should be considered experimental, and has not been shown to be safe or efficacious for Streptococcus pneumoniae disease other than that caused by the serotypes included in the vaccine and for invasive infection, such as bacteremia or meningitis, caused by other microorganisms.     

Pneumococcal otitis media and pneumococcal vaccines, a historical perspective

Although pneumococcal otitis media was recognized in the 19th century, the illness stimulated little interest in prophylaxis until recently. Whole cell vaccines of killed pneumococci, developed to prevent pneumonia, were replaced by vaccines of capsular polysaccharides following demonstration of their antigenicity in adults. Failure of the latter to stimulate antibodies in infants and young children and demonstration of the efficacy of capsular polysaccharide-protein conjugate vaccines in preventing infection with Hemophilus influenzae type b has led to the development of polyvalent pneumococcal polysaccharide-protein conjugate vaccines. Preliminary studies have shown them to be highly effective in preventing invasive pneumococcal disease in the first 2 years of life, and studies of their impact on otitis media are currently in progress.     

不可分型流感嗜血杆菌疫苗研究进展

不可分型流感嗜血杆菌(non-typeable haemophilus influenzae,NTHi)可导致多种感染性疾病,如鼻窦炎、中耳炎、结膜炎、脑膜炎、菌血症等。随着b型流感嗜血杆菌疫苗的应用,NTHi逐渐成为侵袭性及非侵袭型流感嗜血杆菌病的主要病原体,因此目前亟待研究一种安全有效的疫苗来预防NTHi的感染。本文主要针对近年来的一些热点候选抗原及已进行临床试验的疫苗做一综述,为后续的疫苗研制提供依据。     

Immunization of preterm infants with GSK’s hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine: A review of safety and immunogenicity

BackgroundInfants with history of prematurity (<37 weeks gestation) and low birth weight (LBW, <2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed.MethodsHere we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK’s hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials.ResultsAt least 92.5% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13–30% of medically stable infants with history of prematurity developed apnea after vaccination with GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens.ConclusionGSK’s hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age.     

Maternal immunization with Haemophilus influenzae type b vaccines in different populations

Haemophilus influenzae type b (Hib) vaccines provide an excellent model for maternal immunization because effective vaccines are readily available and the vaccines are safe and reliable, and markers of efficacy have been established and standardized. Studies of polysaccharide and conjugate Hib vaccines administered to pregnant women and women of childbearing ages are reviewed in this paper. The type of vaccine has been shown to be important in increasing transplacental passage of maternal antibody. The timing of vaccine during pregnancy is also important in the transfer of this antibody. The total amount of IgG antibody in the mother, as well as the isotype class and subclass of IgG antibody, influences the final levels of antibody in the neonate. Placental integrity has been shown to be important in the active transport of antibody from mother to fetus. The impact of increased levels of Hib antibody in infants at the time of primary immunization with Hib does not appear to interfere with vaccine efficacy, although higher antibody levels in infants at the time of immunization may result in lower total antibody levels following all doses of vaccine. Principles observed in these studies have potential application against other important neonatal pathogens.     

Maternal immunization with pneumococcal 9-valent conjugate vaccine and early infant otitis media

A randomized trial of an investigational 9-valent pneumococcal conjugate vaccine (PCV-9) or placebo given to pregnant women during the last trimester to prevent early infant otitis media (OM) was conducted. All infants received Prevnar^® at 2, 4, 6, and 12 months. Clinic and adverse event records were reviewed to identify OM. Variables significantly related to acute OM by age 6 months (p < 0.05) were: vaccine group (9 valent or placebo), sibling history of tympanostomy tubes, upper respiratory infection, and number of clinic visits by 6 months. Infant OM rates were similar between 6 and 12 months (58% and 56%). Results suggested that immunizing pregnant women with PCV-9 increased infants’ risk of acute OM in the first 6 months of life, and this correlated with decreased infant antibody responses to their infant Streptococcus pneumoniae vaccine serotypes, but did not influence antibody responses to 3 other serotypes two of which were in maternal vaccine (types 1 and 5) and one was a control (type 7F). Explanations for these results include dampening of infant antibody production by high levels of passively acquired maternal pneumococcal antibodies and/or altered B lymphocyte immune responses in infants exposed to these specific polysaccharide antigens in utero.     

The impact of administration of conjugate vaccines containing cross reacting material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-analysis of randomised controlled trials

BackgroundProtein-polysaccharide conjugate vaccines such as Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccine, induce immunological memory and longer lasting protection than plain polysaccharide vaccines. The most common proteins used as carriers are tetanus toxoid (TT) and cross reacting material-197 (CRM), a mutant form of diphtheria toxoid. CRM conjugate vaccines have been reported to suppress antibody responses to co-administered Hib-TT vaccine.MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials in which infants were randomised to receive meningococcal or pneumococcal conjugate vaccines along with Hib-TT. Trials of licensed vaccines with different carrier proteins were included for group C meningococcal (MenC), quadrivalent ACWY meningococcal (MenACWY), and pneumococcal vaccines.ResultsTwenty-three trials were included in the meta-analyses. Overall, administration of MenC-CRM in a 2 or 3 dose schedule resulted in a 45% reduction in Hib antibody concentrations (GMR 0.55, 95% CI 0.49–0.62). MenACWY-CRM boosted Hib antibody responses by 22% (GMR 1.22, 95% CI 1.06–1.41) whilst pneumococcal CRM conjugate vaccines had no impact on Hib antibody responses (GMR 0.91, 95% CI 0.68–1.22).ConclusionsThe effect of CRM protein-polysaccharide conjugate vaccines on Hib antibody responses varies greatly between vaccines. Co-administration of a CRM conjugate vaccine can produce either positive or negative effects on Hib antibody responses. These inconsistencies suggest that CRM itself may not be the main driver of variability in Hib responses, and challenge current perspectives on this issue.     

Brief review of the clinical effectiveness of PREVENAR against otitis media

Pre-licensure trials in Finnish and US infants demonstrated that PREVENAR was associated, respectively, with a 6% (95% CI, -4% to 16%) and an 8.9% (95% CI, 5.8-11.8%) overall reduction in clinical AOM incidence. Long-term follow-up of these cohorts revealed that there was an approximately 10-50% vaccine efficacy against recurrent otitis media or for the prevention of tympanostomy tube placement. In surveillance reports from the USA that followed infants with serious AOM, generalized PREVENAR vaccination led to an important fall in the incidence of pneumococcal otitis media, particularly for cases that would have been frequent or would have been refractory to antibiotic treatment. The rate of pneumococcal MEF isolates fell by 39% for severe otitis media [McEllistrem MC, Adams JM, Patel K, Mendelsohn AB, Kaplan SL, Bradley JS, et al. Acute otitis media due to penicillin-nonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2005;40(12):1738-44], by 42%, among persistent or treatment-resistant otitis media [Casey JR, Pichichero ME, Changes in frequency and pathogens causing acute otitis media in 1995-2003. Pediatr Infect Dis J 2004;23(9):824-8 [see comment]] and by 66% among severe otitis media cases or from 'otitis-prone' children [Block SL, Hedrick J, Harrison CJ, Tyler R, Smith A, Findlay R, et al. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J 2004;23(9):829-33 [see comment]].     

The impact of pneumococcal conjugate vaccines on otitis media-can we extrapolate to pneumonia?

Pneumococcal conjugate vaccines (PCVs) have significant efficacy in preventing acute otitis media caused by vaccine-type pneumococcal serotypes. This article questions whether experiences with pneumococcal otitis can be applied to pneumococcal pneumonia, and examines whether PCVs have a class effect, meaning do different PCVs offer equivalent protection against the same outcome of pneumococcal disease. While PCVs appear to have a class effect in general, variability in serotype-specific antibody concentrations makes extrapolation from one vaccine to another difficult. Antibody concentrations or measurements of antibody functionality may provide a means to anticipate a predicted outcome in pneumococcal pneumonia for certain emergent vaccine candidates.     

Assessing vaccine efficacy for the prevention of acute otitis media by pneumococcal vaccination in children: a methodological overview of statistical practice in randomized controlled clinical trials

Acute otitis media (AOM) is the most common bacterial infectious disease among children. Vaccination is proposed to prevent otitis and several clinical trials were performed to assess the efficacy of pneumococcal vaccines. The way vaccine efficacy is analysed varies among trials. However, the clinical meaning of an estimate of vaccine effect and its statistical test depends on the applied statistical method. We aim to bring the meaning and validity of statistical trial results to the attention of researchers. We consider all methodological approaches for analysing vaccine efficacy applied in pneumococcal vaccination trials included in a recent Cochrane Review. We demonstrate how different methods address different scientific questions on the effect of vaccination, how they can complement each other and why some methods can produce misleading results.     

Acute otitis media in the era of effective pneumococcal conjugate vaccine: will new pathogens emerge?

The immunogenicity of pneumococcal conjugate vaccine (PCV) in young infants and its serotype-specific efficacy in otitis media (OM) results in a modest reduction in total episodes of OM and a more substantial reduction in disease due to the most frequent pneumococcal serotypes. Since PCV will only prevent disease due to the most common serotypes, concerns about potential changes in the microbiology of OM have emerged. Insight into potential changes can be obtained from reviewing middle ear and nasopharyngeal isolates from studies of antimicrobial prophylaxis and bacterial polysaccharide immune globulin for prevention of OM and PCV for prevention of invasive pneumococcal disease, respectively. In children receiving PCV, a shift in serotypes of SP colonizing the nasopharynx has been observed. Since non-vaccine serotypes are already present in the community as the etiology of acute purulent OM, it is predictable that these non-vaccine serotypes will become more common especially in children less than two years of age.     

Pneumococcal vaccine efficacy for mucosal pneumococcal infections depends on Fcgamma receptor IIa polymorphism

IgG2 antibodies are the main antibody subclass produced after pneumococcal polysaccharide vaccination. For these antibodies to be effective, interaction with FcgammaIIa receptors on phagocytic cells is necessary. FcgammaRIIa displays a functional polymorphism with either a histidine (H) or arginine (R) at position 131. Interaction of IgG2 antibodies depends on the H131 allele, whereas this interaction is low to absent with the R131 allele. We tested the clinical efficacy of combined pneumococcal conjugate and pneumococcal polysaccharide vaccination according to FcgammaIIa-H/R131 genotype in a randomized double blind placebo controlled vaccination trial in children with a history of acute otitis media. We found a decisive role for the FcgammaIIa-H/R131 polymorphism on the clinical vaccine efficacy of combined pneumococcal conjugate and polysaccharide vaccinations. RR homozygotes showed a significant increase in recurrence of acute otitis media after pneumococcal vaccinations. This cannot be explained by differences in the pneumococcal specific antibody response or differences in nasopharyngeal pneumococcal carriage, but may be explained by less efficient interaction of FcgammaRIIa with polysaccharide-induced IgG2 anti-pneumococcal antibodies in RR homozygotes. Our data show that the genetic make-up of individuals or populations under study should be considered while evaluating vaccine efficacy trials.     

Clinical inquiries. Which vaccinations are indicated after splenectomy?

Immunization against encapsulated bacterial pathogens decreases the incidence of post-splenectomy sepsis. Pneumococcal, meningococcal, and Haemophilus influenzae (Hib) vaccinations are indicated for patients after splenectomy. These immunizations should be given at least 14 days before a scheduled splenectomy, or given after the fourteenth postoperative day (strength of recommendation [SOR]: A, based on systematic review of RCTs for the pneumococcal vaccine; SOR: B, based on systematic review of clinical trials for meningococcal and Hib vaccines).     

Maternal immunisation in developing countries

Maternal immunisation could help to prevent the 2-3 million neonatal and early infant deaths that occur in the developing world each year. Determining the causes of neonatal and early infant deaths in developing countries is difficult as most occur at home. However, it is likely that at least half are due to infections, several of which might be prevented by maternal immunisation. Even in poor countries with few health facilities, a high percentage of pregnant women attend an antenatal clinic at least once during pregnancy. Thus, an effective delivery system for maternal immunisation already exists and, because of the success of maternal tetanus immunisation, this approach to the prevention of serious illness or death in young infants is widely accepted by the general population. However, the high prevalence of HIV and malaria found in pregnant women in some parts of the developing world, especially sub-Saharan Africa, could have an effect on the efficacy of maternal immunisation as both of these infections adversely affect placental function. Nevertheless, the potential of maternal immunisation to prevent early infant deaths in developing countries needs to be fully explored. The incidence of pneumococcal infections is high in many developing countries and about 25% of these infections occur at an age before protection could be anticipated following vaccination with a pneumococcal conjugate vaccine in infancy. Thus, a strong case can be made for a trial of the effectiveness of maternal immunisation with a pneumococcal vaccine in preventing serious illness or death in young infants in developing countries.     

Molecular characterisation of pneumococcal serotype 16F: Established predominant carriage and otitis media serotype in the 7vPCV era

Young Australian Aboriginal children in remote communities experience very high rates of pneumococcal carriage and otitis media. Prior to introduction of the 7-valent pneumococcal conjugate vaccine (7vPCV, Prevenar), serotype 16F was an important type found in nasal and ear discharge swabs. Since commencement of pneumococcal immunisation for Aboriginal infants in 2001, 16F has become the predominant established serotype in carriage and otitis media in young Aboriginal children. BOX typing and multi-locus sequence typing revealed a diverse population of serotype 16F strains, and evidence of potential capsule switching from a vaccine serotype 4 to a serotype 16F.     

Hib vaccine introduced in The Gambia

Acute respiratory infection (ARI) is the most common infectious cause of childhood death in Africa. Most deaths from ARI are caused by bacteria, including Haemophilus influenzae type b (Hib). Hib is also the most common bacterial cause of meningitis, except in those areas with outbreaks of meningococcal disease. Up to 40% of infants with meningitis die, and many of the survivors have permanent deafness and brain damage. Until recently, however, early diagnosis and treatment was the only defence against these infections. The newly developed Hib conjugate vaccines have been shown to be effective against Hib meningitis and pneumonia, and are now routinely used in infants in more than 25 countries around the world. A study of the efficacy of the vaccine in The Gambia's Western Region in 1993-95 showed that it was 95% effective in preventing meningitis and bloodstream infection, and 100% effective in preventing pneumonia. Hib vaccine was introduced this year in The Gambia as a routine immunization for children, to be given in the same injection as DTP at 2, 3, and 4 months of age. A 1-year study is underway to evaluate the impact of the vaccine upon disease. Trials are now underway for new pneumococcal and meningococcal vaccines which may be ready for wider use within 5-10 years.     

肺炎球菌疫苗及其应用

肺炎球菌可引起肺炎、脑膜炎、败血症、中耳炎等疾病,在2岁以下婴幼儿和老年人中发病率最高。实践证明,接种肺炎疫苗是安全、有效、经济的预防手段。本文介绍了肺炎球菌疫苗的发展及其免疫程序、免疫效果和应用,旨在为肺炎球菌疫苗在国内的推广应用提供参考。     

A phase 3 clinical trial of MINHAI PCV13 in Chinese children aged from 7 months to 5 years old

BackgroundPneumococcus lead to various kinds of invasive disease such as pneumonia, otitis media, meningitis, bacteremia and so on. It has been a great threat to children under 5. A new 13-valent pneumococcal conjugate vaccine (PCV13) with carrier tetanus toxoid and diphtheria toxoid was developed by MINHAI, aiming to prevent pneumococcus infection. In this study, we reported the safety and immunogenicity of MINHAI PCV13 in Chinese children aged from 7 months to 5 years old.MethodsA randomized, double-blinded, parallelized phase III clinical trial was operated in 900 participants. Haemophilus influenzae type B conjugate vaccine (Hib) served as negative control. PCV13 and Hib were intramuscular injected to participants at a ratio of 2:1. Local and systemic adverse events (AEs) and severe adverse events (SAEs) were recorded to evaluate the safety of PCV13. Blood samples were collected before and after immunization for the detecting of serotype-specific anti-polysaccharide immunoglobulin (Ig)G and opsonophagocytosis assay (OPA). The proportion of IgG concentration ≥ 0.35 μg/mL (IgG positive rate), IgG geometric mean concentration (GMC), OPA geometric mean titer (GMT), and other indicators were analyzed to evaluate the immunogenicity of PCV13.ResultsDuring the study period, no PCV13 associated SAE happened. Incidences of several AEs in PCV13 groups were higher than the Hib groups, but most of them were mild or moderate. For all 13 serotypes, IgG and OPA indicators of the PCV13 groups were generally superior to the Hib groups, and the differences were mostly statistically significant, which indicates that MINHAI PCV13 can effectively induce pneumococcal specific antibody.ConclusionThe study demonstrates that MINHAI PCV13 has sufficient immunogenicity and safety in Chinese children aged from 7 months to 5 years old.Clinical trial registration: NCT02494999.     

The impact of vaccines on pneumonia: key lessons from Haemophilus influenzae type b conjugate vaccines

This article explores key lessons learned from vaccination with Haemophilus influenzae type b (Hib) conjugate vaccine and how these lessons may provide insight into the impact of emergent pneumococcal vaccines against pneumonia. The worldwide value of Hib vaccination for reducing Hib disease burden and carriage is reviewed. Using comparisons of data for pneumococcus versus Hib, the article concludes that epidemiological and biological differences between these pathogens will complicate efforts to use results from the Hib vaccine experience to predict outcomes following pneumococcal conjugate vaccine introduction.