A Phase II,randomized, immunogenicity and safety study of a quadrivalent meningococcal conjugate vaccine,MenACYW-TT,in healthy adolescents in the United States

BackgroundMenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for use in individuals ≥6 weeks of age. We evaluated the safety and immunogenicity of MenACYW-TT when compared to a licensed quadrivalent conjugate meningococcal vaccine (Menveo®; MCV4-CRM; GlaxoSmithKline, Italy), and when co-administered with tetanus, diphtheria, acellular pertussis (Tdap) and human papilloma virus (HPV4) vaccines in healthy meningococcal vaccine-naïve adolescents (10–17 years old) in the United States of America.MethodsIn this pivotal Phase II, open-label, multicenter study, 1715 participants were randomized to receive MenACYW-TT, MCV4-CRM, MenACYW-TT co-administered with Tdap and HPV4, or Tdap and HPV4 vaccines alone (NCT02199691).The primary objective was to evaluate whether antibody responses to MenACYW-TT antigens were non-inferior to antibody responses after MCV4-CRM administration. Meningococcal antibody titers were determined using human complement serum bactericidal assay (hSBA) with titers measured at baseline, and 30 days post vaccination (D30). A vaccine seroresponse was defined as baseline titers <1:8 with post-vaccination titers ≥1:8 or baseline titers ≥1:8 with a ≥4-fold increase at post-vaccination. Safety data were collected up to six months post-vaccination.ResultsNon-inferiority was demonstrated for MenACYW-TT vs MCV4-CRM (primary endpoint), and for MenACYW-TT co-administered with Tdap and HPV4 vs MenACYW-TT alone (secondary endpoint). The vaccine seroresponse rate was higher with MenACYW-TT than with MCV4-CRM, for each serogroup: A: 75.6% vs 66.4%; C: 97.2% vs 72.6%; W: 86.2% vs 66.6%; Y: 97.0% vs 80.8%. The safety profiles of MenACYW-TT, MCV4-CRM, and Tdap and HPV4 vaccines, administered with or without MenACYW-TT, were comparable. There were no vaccine-related serious adverse events.ConclusionsThe MenACYW-TT vaccine was well tolerated and generated an immune response that was non-inferior to the licensed MCV4-CRM vaccine. Immunogenicity and safety profiles were comparable when MenACYW-TT was administered with or without Tdap and HPV4 vaccines in meningococcal vaccine-naïve adolescents.     

3β-羟基-5-雄甾烯-17-酮-丁二酸酯人工抗原的合成

目的 合成3β-羟基-5-雄甾烯-17-酮-丁二酸酯(5-烯雄甾酯)人工抗原.方法 以N,N-二环己基碳二亚胺和N-羟基琥珀酰亚胺为催化剂,采用活性酯法将5-烯雄甾酯与牛血清白蛋白偶联.结果 产物经元素分析、质谱和红外光谱确定,合成得到每个BSA载体连接6个半抗原小分子的人工抗原.结论 采用琥珀酸酐衍生化5-烯雄甾酯,活性酯法合成抗原,产率高、副产物少.     

Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children

Although it is well known that pneumococcal conjugate vaccines provide cross-protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes.     

Vaccines for low-income countries

Low-income countries typically lag behind industrialised nations, where the introduction of new vaccines is commonly tailored to the pressures of the commercial market. Happily in recent years this paradigm has started to change with the introduction of a univalent meningococcal A conjugate vaccine that is specifically targeted for the prevention of epidemic meningitis in Africa. The declaration of the 2010s as a New Decade of Vaccines, together with Millennium Development Goals 4 and 5, provide a strong mandate for a new approach to the development of vaccines for low-income countries, so that there has never been a more exciting time to work in this field. This review considers the opportunities and challenges of developing these new vaccines in the context of innovations in vaccinology, the need to induce protective immunity in the populations at risk and the requirement for strong partnership between the countries that will use these vaccines and different elements of the vaccine industry.     

Capacity of serotype 19A and 15B/C Streptococcus pneumoniae isolates for experimental otitis media: Implications for the conjugate vaccine

Non-vaccine Streptococcus pneumoniae serotypes are increasingly associated with disease. We evaluated isolates of the same sequence type (ST199) but different serotypes (15B/C, 19A) for growth in vitro, and pathogenic potential in a chinchilla otitis media model. We also developed a quantitative PCR (qPCR) assay to quantitatively assess each isolate, circumventing the need for selectable markers. In vitro studies showed faster growth of serotype 19A over 15B/C. Both were equally capable of colonization and middle ear infection in this model. Serotype 19A is included in new conjugate vaccine formulations while serotype 15B/C is not. Non-capsular vaccine targets will be important in disease prevention efforts.     

甲型副伤寒结合疫苗的制备及其免疫原性研究

目的 研制预防沙门菌属A组甲型副伤寒沙门菌感染的多糖蛋白结合疫苗。方法 通过对甲型副伤寒沙门菌尼泊尔株NTP-6的发酵培养，热酚水法提取脂多糖（LPS），酸水解脱毒，纯化出有效的型特异O-SP抗原；然后用CDAP对O-SP活化、ADH衍生后，在EDAC的缩合作用下，结合到破伤风类毒素TT上，制备出甲型副伤寒结合疫苗。用含2．5μg多糖甲型副伤寒结合疫苗免疫小鼠，以LPS为包被抗原，用间接ELISA法测定血清抗甲型副伤寒LPS IgG抗体；并测定血清多糖抗体的补体介导杀菌活性；在小鼠和豚鼠体内观察甲型副伤寒结合疫苗的安全性。结果甲型副伤寒结合疫苗第2次免疫NIH后，小鼠血清抗甲型副伤寒LPS IgG抗体平均几何滴度（GMT）均较第1次有4倍以上升高，第3次免疫后，有明显的加强效应；抗体的补体介导杀菌活性效价达1：1280以上；小鼠和豚鼠体内甲型副伤寒结合疫苗安全性良好。结论 成功建立了甲型副伤寒结合疫苗的制备工艺；制备的甲型副伤寒结合疫苗有良好的免疫原性，并具有明显的加强效应；刺激的血清多糖抗体有较高的补体介导杀菌活性效价；安全性达到人用生物制品相关要求。     

Prospects and challenges with introduction of a mono-valent meningococcal conjugate vaccine in Africa

Epidemic meningococcal meningitis is a priority disease for prevention and control in Africa. The current World Health Organization (WHO) approach to the control of meningitis epidemics is based on early detection of cases and emergency vaccination of the population at risk with meningococcal polysaccharide (PS) vaccines. But this is a tall order for the developing nations of Africa where experts operate from an ineffective health system. Although the widespread use of meningococal polysaccharide vaccines has had a major and much appreciated public health impact on the disease it has not prevented epidemics of this dreaded infection. The current partnership between WHO and the PATH aims to develop, evaluate and introduce an appropriate and affordable meningococcal conjugate vaccine that could potentially provide for a means of preventing epidemic meningitis caused by N. meningitidis group A. In this paper, we review the prospects and challenges facing the introduction of the mono-valent conjugate vaccine in Africa.     

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children

Background

Pneumococcal polysaccharide vaccine (PPV) is used in children at high risk of IPD. PPV is generally not considered to induce immunologic memory, whereas pneumococcal conjugate vaccines (PCVs) elicit protective antibody responses in infants and induce immunologic memory. Little is known about the characteristics of immune responses to PCV in children who previously received PCV and PPV in series.

Objective

To characterize immune responses to 13-valent pneumococcal CRM₁₉₇ conjugate vaccine (PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in children vaccinated in infancy with 9-valent pneumococcal–meningococcal C-CRM₁₉₇ conjugate combination vaccine (PCV9-MnCC), followed by a toddler dose of PCV9-MnCC or 23-valent pneumococcal polysaccharide vaccine (PPV23).

Methods

Children (n = 89) who received PCV9-MnCC in infancy and PPV23 or PCV9-MnCC at age 12 months in a previous (2002–2003) study were vaccinated at age 7.5 years with PCV13; groups PPV23/PCV13 (n = 50) and PCV9/PCV13 (n = 39). Immunoglobulin (Ig)G antibodies, avidity, and opsonophagocytic activity (OPA) were measured before and at 1 and 4 weeks postvaccination.

Results

One week postvaccination, IgG levels increased significantly for all serotypes in both groups, and >97% of vaccinees achieved IgG ≥0.35 μg/ml 4 weeks after PCV13 vaccination. The PCV9/PCV13 group had higher IgG responses compared with the PPV23/PCV13 group. The upper limits of the 95% confidence intervals of the PPV23/PCV13:PCV9/PCV13 IgG geometric mean concentration ratios were <1.0 for serotypes 1, 4, 5, 9V, 18C, and 23F at 1 week. OPA and avidity results supported these findings.

Conclusions

PPV23 vaccination of toddlers may compromise subsequent responses to pneumococcal conjugate vaccines. The clinical relevance of this finding is unclear.     

叶酸偶联白蛋白纳米粒的制备工艺研究

采用去溶剂化法制备普通白蛋白纳米粒 ,利用叶酸活性酯在微碱性条件下与白蛋白纳米粒表面的氨基反应 ,制得叶酸偶联白蛋白纳米粒。采用葡聚糖凝胶柱色谱法及紫外分光光度法验证偶联是否成功 ,并测定叶酸偶联的程度。通过葡聚糖凝胶柱色谱法可以清楚地看到叶酸偶联白蛋白纳米粒与未反应的叶酸活性酯完全分离 ,叶酸偶联白蛋白纳米粒与叶酸白蛋白机械混合物的胰蛋白酶水解液在 35 8nm处的紫外吸收图谱基本一致 ,说明叶酸已经成功地偶联于白蛋白纳米粒的表面。纳米粒形态圆整 ,平均粒径为 6 6 nm。叶酸偶联白蛋白纳米粒制备成功 ,作为叶酸受体表达丰富的多种肿瘤细胞的主动靶向给药的潜在途径 ,值得进一步的关注和研究     

The impact of the changing pneumococcal national immunisation program among older Australians

Australia has a universal infant pneumococcal conjugate vaccination program and until recently a universal pneumococcal polysaccharide vaccine program for non-Indigenous adults aged ≥65 years and Indigenous adults aged ≥50 years. We documented the impacts of infant and adult vaccination programs on the epidemiology of invasive pneumococcal disease (IPD) in Indigenous and non-Indigenous adults.IPD notifications from the National Notifiable Disease Surveillance System were analysed from 2002 to 2017, grouped by age, vaccine serotype group and Indigenous status. Since the universal funding of infant and elderly pneumococcal vaccination programs in January 2005, total IPD decreased by 19% in non-Indigenous adults aged ≥65 years but doubled in Indigenous adults aged ≥50 years. Vaccine uptake was suboptimal in both groups but lower in Indigenous adults. IPD due to the serotypes contained in the pneumococcal conjugate vaccines (PCV) except for serotype 3 declined markedly over the study period but were replaced by non-PCV serotypes. Serotype 3 is currently the most common in older adults. In the populations eligible for the adult 23-valent pneumococcal polysaccharide vaccine (23vPPV) program, IPD rates due to its exclusive serotypes increased to a lower extent than non-vaccine types. In 2017, non-vaccine serotypes accounted for most IPD in the older population eligible for the 23vPPV program, while it's eleven exclusive serotypes accounted for the majority of IPD in younger adults.Infant and adult pneumococcal vaccination programs in Australia have shaped the serotype-specific epidemiology of IPD in older adults. IPD remains a significant health burden for the Indigenous population. Herd immunity impact is clear for PCV serotypes excluding serotype 3 and serotype replacement is evident for non-PCV serotypes. The adult 23vPPV immunisation program appears to have partially curbed replacement with IPD due to its eleven exclusive serotypes, highlighting a potential benefit of increasing adult 23vPPV coverage in Australia.