Effects of the thermal denaturation of Sabin-derived inactivated polio vaccines on the D-antigenicity and the immunogenicity in rats

The efficacy of a Sabin-derived inactivated polio vaccine (sIPV) can be evaluated by measuring the immunogenicity and the contents of D-antigens, which induce the neutralizing antibodies. The immunogenic potency test in rats was done as a national assay in Japan. The two manufacturers of sIPV in Japan have performed both assays since development, and there is no clear discrepancy between the results obtained in the two assays. To further know the relationship between the two assays, we analyzed the effects of the heat treatment of sIPV on the D-antigenicity and the immunogenicity. We observed that the marginal D-antigen that remained after the thermal treatment was capable of inducing relatively high neutralizing antibodies in rats. This indicates that the measurement of the D-antigen contents as part of the quality control of sIPV is more sensitive and appropriate to detect denatured vaccines.     

A study of the immunogenicity of smallpox vaccines

The authors report on a series of tests to determine the immunogenic properties of smallpox vaccines of varying degrees of infectivity. Rabbits were immunized with serial dilutions of the vaccines and challenged twenty days later with intradermal neurovaccine or testicular vaccine, with injection of testicular vaccine into the testes, or with intracerebral neurovaccine. It was possible to demonstrate a correlation between the infectivity of the immunizing vaccine and the degree of immunity conferred, as shown by the serum antibody level and by the reaction to the challenge inoculation. It also appears that the immunogenicity of the vaccines is determined not only by the number of active virus particles they contain but also by their virulence, the more virulent giving greater immunity in smaller doses. Unduly virulent vaccines, however, may give rise in humans to severe and painful reactions.     

Lysed BCG vaccines. 2. The effect of lysis on the immunogenicity and allergenicity of BCG vaccines

The authors have attempted to prepare lysed BCG vaccines retaining the protective antigens of the BCG cell wall and yet eliciting in experimental animals limited sensitivity to the tuberculin substances, the advantage sought being to retain the usefulness of the tuberculin following vaccination as an indicator of superinfection.     

精制Vero细胞狂犬病疫苗的研制及免疫学效果观察

目的　以Vero细胞为基质，研制新一代精制Vero细胞狂犬病疫苗。方法　以CTN-1V10为生产毒株，以＜150代Vero细胞为培养基质，采用转瓶旋转培养，按不同时间收获病毒液，经过澄清、浓缩、纯化、灭活制成精制Vero细胞狂犬病疫苗。从以此工艺制备的疫苗中选取一批做为免疫学效果观察的受试疫苗。按暴露后免疫程序接种63人，其中受试疫苗接种33人，法国维尔博狂犬病疫苗接种30人，观察不良反应和测定中和抗体。结果　新研制的精制Vero细胞狂犬病疫苗各项指标完全符合WHO的有关质量要求。两种疫苗全程免疫后中和抗体阳转率均为100%，中和抗体受试组为11.94IU/ml;维尔博疫苗对照组为11.69IU/ml。结论　精制Vero细胞狂犬病疫苗不但制造工艺合理，而且副反应轻微，免疫原性良好。     

Impact of maternal and pre-existing antibodies on immunogenicity of inactivated rotavirus vaccines

Rotavirus (RV) is a major pathogen causing severe diarrhea in infants and children aged less than 5 years. Vaccination is an economically feasible and effective strategy to prevent rotavirus infections. However, immune efficacy of live vaccines could be interfered by maternal antibodies and pre-existing antibodies of children. To develop an inactivated rotavirus vaccine (IRV), we had previously isolated a wild-type human rotavirus strain ZTR-68-A (G1P[8]) from the fecal samples of infants having severe diarrhea in a region endemic for the presence of this pathogen. In our present study, we assessed whether the presence of maternal and pre-existing antibodies in newborn BALB/c mice affected the immunogenicity of IRV administered to these animals. Our results indicate that maternal antibodies, generated from either vaccine immunization or rotavirus infection, showed partial influence with the immune responses generated by two doses of IRV vaccination. Increasing the number of immunizations can significantly improve the titer of serum neutralizing antibody and a seroconversion rate of up to 100%. In newborn mice, single-virus infection did not elicit detectable levels of serum neutralizing antibodies. After an IRV vaccination, the immune responses of these mice remained unaffected, with no significant differences in titers compared with those of control-group mice. In summary, choosing a suitable immunization dose and dosing frequency is essential for the immune effectiveness of IRV. The results of this study will provide animal experimental support for the IRV clinical research in future.     

Composition of gut microbiota and its influence on the immunogenicity of oral rotavirus vaccines

The introduction of oral rotavirus vaccines (ORVVs) has led to a reduction in number of hospitalisations and deaths due to rotavirus (RV) infection. However, the efficacy of the vaccines has been varied with low-income countries showing significantly lower efficacy as compared to high-income countries. The reasons for the disparity are not fully understood but are thought to be multi-factorial. In this review article, we discuss the concept that the disparity in the efficacy of oral rotavirus vaccines between the higher and lower socio-economical countries could be due the nature of the bacteria that colonises and establishes in the gut early in life. We further discuss recent studies that has demonstrated significant correlations between the composition of the gut bacteria and the immunogenicity of oral vaccines, and their implications in the development of novel oral RV vaccines or redesigning the current ones for maximum impact.     

成年人连续三批次流感裂解疫苗接种的安全性、免疫原性观察

目的 评价流感裂解疫苗安尔来福TM的安全性和免疫原性,考核疫苗生产工艺的稳定性.方法 采用随机双盲设对照的临床试验设计,试验疫苗为连续三个批次的安尔来福TM,以进口疫苗为对照.受试者为566名18～60岁健康成年人,按照4个年龄层随机分配到4个试验组,疫苗含甲1型、甲3型和乙型流感病毒抗原各15 μg.免疫程序为1针,接种后进行30 min即时反应观察以及24、48、72 h的随访观察,免疫前及免疫后第21天采血,将成对血清设盲后进行血凝抑制(HI)抗体检测.结果 受试者以轻度不良反应为主,各试验组发热反应发生率为1.4%～2.8%,组间差异无统计学意义.4个组3个型别HI抗体阳转率均≥80.3%,GMT增长倍数≥11.1,抗体保护率≥93.4%.三个批次安尔来福TM3个型别的HI抗体阳转率、GMT增长倍数及血清抗体保护率均超过欧盟及美国FDA标准.结论 连续三批次安尔来福TM具有良好的免疫原性和安全性,疫苗生产工艺稳定.     

The immunogenicity of single and combination DNA vaccines against tuberculosis

DNA immunization is a promising new approach for the development of novel tuberculosis vaccines. In this study, the immune responses following the administration of single and combination tuberculosis DNA vaccines were evaluated. Single DNA vaccines encoding the MPT-63 and MPT-83 tuberculosis antigens evoked partial protection against an aerogenic challenge with M. tuberculosis Erdman in the mouse model of pulmonary tuberculosis. Immunization with a multivalent combination DNA vaccine (containing the ESAT-6, MPT-64, MPT-63, and KatG constructs) generated immune responses that indicated an absence of antigenic competition since antigen-specific cell-mediated and humoral responses were detected to each component of the mixture. More importantly, the combination vaccine elicited a strong protective response relative to the protection evoked by live BCG vaccine.     

Comparison of immunogenicity and safety between two paediatric TBE vaccines

TBE vaccination strategies capable of inducing strong paediatric immunogenicity and acceptable reactogenicity are still under evaluation. This single-blind, multi-center, randomized, controlled, phase III clinical study compared the immunogenicity and safety of the two paediatric TBE vaccines available in Europe (FSME-IMMUN^® Junior and Encepur^® Children) following administration of two doses of either vaccine in 303 children aged 1–11 years. Regardless of immunological test or viral antigen used, immunological responses were consistently higher in children vaccinated with FSME-IMMUN^® Junior than those vaccinated with Encepur^® Children. FSME-IMMUN^® Junior is also non-inferior to Encepur^® Children, with respect to NT seropositivity rates (p < 0.0001). Systemic reaction rates were low and similar between the vaccines. However, among children aged 7–11 years, local reactions were significantly higher after the first (p < 0.01) and second (p < 0.001) vaccination with Encepur^® Children than with FSME-IMMUN^® Junior, affecting half the children in the former group: 22.4% and 10.2% with FSME-IMMUN^® Junior vs. 49.0% and 51.0% for Encepur^® Children.     

The distinct impact of maternal antibodies on the immunogenicity of live and recombinant rotavirus vaccines

A high titre of maternal antibodies is one of the possible factors associated with decreased rotavirus vaccine efficacy in low-income countries where rotavirus-associated morbidity and mortality are high. Although some studies show a negative correlation between maternal antibody levels and seroconversion after vaccination, withholding breastfeeding does not improve rotavirus vaccine efficacy. Different types of recombined vaccines were developed as an alternative to produce higher protection in developing areas. In previous studies, we found that recombinantly expressed, truncated VP4* can stimulate high titres of neutralizing antibodies and can confer protection against rotavirus infections and rotavirus-induced diarrhoea. In this study, the impact of maternal antibodies on live and recombinant rotavirus vaccines (VP4*) was evaluated in a mouse model. Dams were infected orally with murine rotavirus 7 days after delivery to mimic a natural rotavirus infection in infants and to evaluate the separate effects of trans-placentally acquired and milk-acquired maternal antibodies, pups were half exchanged. After immunization with live rotavirus, both the neutralizing antibody and IgA antibody responses were inhibited by maternal antibodies, especially by milk antibodies; however, the neutralizing antibody responses after immunization with recombinant VP4* were enhanced. In addition, the in vitro incubation of VP4* with immune sera of rotavirus could also enhance the immune responses could also enhance the immune responses. Our finding provides a basis for the development of non-replicating vaccines to address the problem of live attenuated vaccines in low- and middle-income countries.     

Effect of vesicle size on tissue localization and immunogenicity of liposomal DNA vaccines

The formulation of plasmid DNA (pDNA) in cationic liposomes is a promising strategy to improve the potency of DNA vaccines. In this respect, physicochemical parameters such as liposome size may be important for their efficacy. The aim of the current study was to investigate the effect of vesicle size on the in vivo performance of liposomal pDNA vaccines after subcutaneous vaccination in mice. The tissue distribution of cationic liposomes of two sizes, 500 nm (PDI 0.6) and 140 nm (PDI 0.15), composed of egg PC, DOPE and DOTAP, with encapsulated OVA-encoding pDNA, was studied by using dual radiolabeled pDNA-liposomes. Their potency to elicit cellular and humoral immune responses was investigated upon application in a homologous and heterologous vaccination schedule with 3 week intervals. It was shown that encapsulation of pDNA into cationic lipsomes resulted in deposition at the site of injection, and strongest retention was observed at large vesicle size. The vaccination studies demonstrated a more robust induction of OVA-specific, functional CD8+ T-cells and higher antibody levels upon vaccination with small monodisperse pDNA-liposomes, as compared to large heterodisperse liposomes or naked pDNA. The introduction of a PEG-coating on the small cationic liposomes resulted in enhanced lymphatic drainage, but immune responses were not improved when compared to non-PEGylated liposomes. In conclusion, it was shown that the physicochemical properties of the liposomes are of crucial importance for their performance as pDNA vaccine carrier, and cationic charge and small size are favorable properties for subcutaneous DNA vaccination.     

国产与进口流行性腮腺炎联合疫苗(MMR)免疫原性与安全性系统评价

目的比较国产与进口含流行性腮腺炎成分的联合疫苗(MMR)接种后的抗体阳转率和副反应发生率,评价二者免疫学效果和安全性的差异,为应对流行性腮腺炎高发病率的情况,甄选安全性强、高效能和经济适用的流行性腮腺炎疫苗提供依据。方法全面收集国内外已发表的研究数据,对国产麻疹风疹腮腺炎联合疫苗(MMR)与进口联合疫苗(MMR)在免疫原性和安全性上进行系统差异性比较。结果经纳入和排除标准筛选,最终提取6篇关于含流行性腮腺炎疫苗成分的国产联合疫苗(MMR)与进口联合疫苗(MMR)免疫原性的文献资料,以接种后腮腺炎抗体阳性率为分析指标,结果显示:国产MMR接种组和进口MMR接种组的抗体阳性率差异无统计学意义[RR=0.99,95%CI(0.96,1.03),P=0.671];入选的5篇文献报告了含腮腺炎疫苗成分的国产MMR组和进口MMR组接种后副反应发生率,研究发现:国产MMR接种组和进口MMR接种组在副反应发生率上差异无统计学意义[RR=1.05,95%CI(0.87,1.27),P=0.620]。结论在选择联合疫苗预防腮腺炎疾病时,国产MMR和进口MMR具有相同的优势,国产MMR在免疫原性和免疫安全性方面和进口疫苗无明显差异。     

成人型非免疫规划疫苗延迟接种安全性和有效性分析及接种建议

处理好疫苗安全接种和延迟接种之间的关系,是当前预防接种工作的重点和难点。现就中国常用成人型非免疫规划疫苗延迟接种进行安全性和有效性分析,同时做出具体接种建议,以期更好的对该类疫苗科学使用和发挥预防作用提供循证依据。     

戊型肝炎疫苗和乙型肝炎疫苗联合接种的安全性及免疫原性研究

目的 分析戊型肝炎（戊肝）疫苗和乙型肝炎（乙肝）疫苗联合接种（联合接种）的安全性及免疫原性。方法 2015年9月至2016年12月在北京市朝阳区招募18~60岁健康受试者720人,将符合纳入标准的受试者随机化分为3组：联合接种（联合接种）组、乙肝疫苗接种组和戊肝疫苗接种组。3组均按照0、1、6个月程序接种,比较联合接种与单独接种的安全性及全程免疫1个月后的免疫原性。结果 接种疫苗的受试者共601人（戊肝疫苗接种组150人,乙肝疫苗接种组159人,联合接种组292人）。联合接种组的局部不良反应有疼痛（25.0%,73/292）、红（12.7%,37/292）、瘙痒（9.2%,27/292）、硬结（8.9%,26/292）、肿（8.2%,24/292）,全身不良反应有发热（7.2%,21/292）、头痛（5.8%,17/292）、肌肉痛（5.5%,16/292）、疲倦乏力（3.4%,10/292）。联合接种组除局部疼痛发生率高于单独接种组以外,其余不良反应与单独接种组均无明显差异,3组均无严重不良反应。全程接种1个月后,联合接种组的HBsAb阳转率、抗体几何平均浓度（GMC）非劣效于乙肝疫苗接种组（94.2%比93.8%,611.6 WU/ml比745.1 WU/ml）,HEV IgG抗体阳转率、GMC非劣效于戊肝疫苗接种组（98.8%比100.0%,11.0 WU/ml比18.0 WU/ml）。结论 联合接种具有良好的安全性和免疫原性,建议肝炎易感人群联合接种戊、乙肝疫苗,更好地保护肝脏。     

Evaluation of safety and immunogenicity of feline vaccines with reduced volume

A non adjuvanted vaccine against feline herpesvirus, feline calicivirus, feline panleucopenia and feline leukemia has been formulated in reduced volume (0.5 ml) with the same antigen content as the conventional 1 ml presentation. This paper reports studies evaluating the safety and the immunogenicity of this reduced volume vaccine in comparison with the conventional volume vaccine. The safety of both vaccines was evaluated in a small sized laboratory trial. It was further tested in a randomized controlled field trial on a total of 398 cats. Immediate and delayed local and systemic adverse events were monitored after vaccination. The immunogenicity of each vaccine was also checked by serological antibody responses against the vaccines antigens during the laboratory trial.These studies showed that the 0.5 ml vaccine was well tolerated in cats, inducing less local events, while keeping the same immunogenicity as the corresponding 1 ml vaccine. Reducing the volume of the vaccine is a way to improve the convenience of administration and to help following vaccination guidelines with the aim of reducing the incidence of adverse events following vaccination.     

Assessment of the stability and immunogenicity of meningococcal oligosaccharide C-CRM197 conjugate vaccines

In this stability study, meningococcal C-CRM(197) conjugate vaccines from two different manufacturers that differ in oligosaccharide chain length, number of conjugation sites, conjugation chemistry, manufacturing process and formulation were used. Both the bulk concentrated and final fill preparations were incubated at -20, 4, 23, 37 or 55 degrees C for 5 weeks or subjected to ten cycles of freeze-thawing. The structural stability, hydrodynamic size and integrity of the treated vaccines were monitored by size exclusion chromatography (FPLC-SEC), high performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD) and fluorescence spectroscopy techniques. The data showed that the structural stability of the oligosaccharide chains and of the protein carrier varied between the two conjugates. The experimental immunogenicity was not severely affected by repeated freeze-thawing, incubation at -20 or 4 degrees C, but one developed conformational changes in the protein carrier when incubated at 23 degrees C or above, although the integrity of the oligosaccharide structure was maintained. This was not associated with any reduction in primary IgG or IgM antibody responses to meningococcal C polysaccharide. In the other conjugate vaccine, exposure to 55 degrees C resulted in the release of a substantial proportion of free saccharide that was accompanied by significant reduction in both IgG and IgM antibody responses to immunisation in the model system. In conclusion, the two meningococcal C-CRM(197) conjugate vaccines were stable when stored at the recommended temperatures, although their structural stability and subsequent immunogenicity were influenced by their conjugation chemistry and formulation.     

Delivery methods to increase cellular uptake and immunogenicity of DNA vaccines

DNA vaccines are ideal candidates for global vaccination purposes because they are inexpensive and easy to manufacture on a large scale such that even people living in low-income countries can benefit from vaccination. However, the potential of DNA vaccines has not been realized owing mainly to the poor cellular uptake of DNA in vivo resulting in the poor immunogenicity of DNA vaccines. In this review, we discuss the benefits and shortcomings of several promising and innovative non-biological methods of DNA delivery that can be used to increase cellular delivery and efficacy of DNA vaccines.     

Optimization of epitope processing enhances immunogenicity of multiepitope DNA vaccines

Experimental DNA vaccines comprised of multiple minimal cytotoxic T lymphocytes (CTL) epitopes can effectively induce broad CTL responses; however, such constructs frequently exhibit significant variation in epitope immunogenicity. Antigenicity assays utilizing human cells transfected with one such multiepitope construct revealed that the epitopes with poor immunogenicity were inefficiently processed in transfected cells. Compilation of a database of 94 epitope/flanking region combinations, for which immunogenicity was measured experimentally, revealed that the type of residue immediately following the carboxyl-terminus of the epitope exerted a prominent effect on immunogenicity. Experiments utilizing a variety of HBV-specific vaccine constructs demonstrated epitope immunogenicity could be modulated by the insertion of a single amino acid and the effect on immunogenicity could be ascribed to modulation of processing efficiency. These findings demonstrate that multiepitope DNA vaccines can be engineered to enhance CTL immunogenicity by increasing processing efficiency.     

Safety and immunogenicity of adenovirus-vectored nasal and epicutaneous influenza vaccines in humans

The increasing number and density of the human population, the emergence of lethal influenza strains, and the potential use of designer influenza virus as a bioweapon, collectively highlight a critical need for more rapid production of influenza vaccines and less invasive means of delivery. We have developed a nonreplicative adenovirus-vectored influenza vaccine that can be produced without the prerequisite of growing influenza virus. This new class of vaccines can be administered as a nasal spray or skin patch by personnel without medical training. We report here that adenovirus-vectored nasal and epicutaneous influenza vaccines were well tolerated by human volunteers. The nasal vaccine was more potent than its epicutaneous counterpart under the adjuvant-free experimental condition. These results provide the foundation for further human testing of needleless vectored vaccines as promising alternatives to current vaccines.