Clinical evaluation to determine the appropriate paediatric formulation of a tick-borne encephalitis vaccine

Two dose-finding studies and one open label safety study with a paediatric FSME-IMMUN^® formulation were conducted in children and adolescents aged 1–15 years (N = 3697). The 1.2 μg antigen dose was identified as the optimal dose, inducing high seroconversion rates following the primary vaccination series. Adolescents (aged 12–15 years) vaccinated with the optimal paediatric dose (1.2 μg) attained similarly high seroprotective rates to adults (aged 16–35 years) vaccinated with the 2.4 μg formulation of FSME-IMMUN^®. We concluded that the FSME-IMMUN^® paediatric vaccine formulation is safe and highly immunogenic, not only for children <12 years, but also for adolescents <16 years.     

Antibody response following administration of two paediatric tick-borne encephalitis vaccines using two different vaccination schedules

Two paediatric tick-borne encephalitis vaccines, Encepur Children and FSME-IMMUN Junior, are used widely in Europe. This study compared the immunogenicity and safety of both vaccines, administered using the conventional (Days 0, 28, and 300) or accelerated (Days 0, 14, and 300) schedule and evaluated whether a third dose of Encepur Children can complete a primary vaccination course initiated with FSME-IMMUN Junior. A total of 334 children 1 to < 11 years of age were enrolled in this Phase IV randomized, controlled, single-blind, multi-centre trial. All subjects, irrespective of study arm, received Encepur Children as the third dose on Day 300. The percentage of subjects with antibody titres > or = 10, as determined by neutralization test (NT), was assessed and local and systemic reactions were monitored and solicited. Within both the conventional and accelerated schedules, the proportion of subjects achieving an NT > or = 10 was higher in the group that received Encepur Children, compared with the group that received FSME-IMMUN Junior, at Days 42 and 300 (conventional schedule Day 300, P < 0.001 Encepur Children versus FSME-IMMUN Junior; accelerated schedule Days 42 and 300, P<0.001 Encepur Children versus FSME-IMMUN Junior). The third dose of Encepur Children led to a substantial increase in the proportion of subjects in the FSME-IMMUN Junior groups achieving NT > or = 10. Overall, >95% of all children achieved NT > or = 10, on completion of the primary vaccination course. Encepur Children provides an immune response, measured by neutralizing TBE antibodies, that is superior to FSME-IMMUN Junior and can successfully be used to complete a primary vaccination course initiated with FSME-IMMUN Junior. Both vaccines were well tolerated, with comparable safety profiles; no vaccine-related serious adverse events were reported.     

Prevention of tick-borne encephalitis by FSME-IMMUN vaccines: review of a clinical development programme

The need for highly effective tick-borne encephalitis (TBE) vaccines has increased globally due to a variety of factors including climate, social, economic and demographic changes, which are thought to have promoted the expansion of the endemic region of TBE viruses. The first TBE vaccine, FSME-IMMUN^® Inject, was introduced in the 1970s and has been continually improved since then to enhance both its safety and immunogenicity. The current formulation was established in 2001 and is marketed as FSME-IMMUN^®. This review summarizes findings of the clinical development programme since 2001 regarding determination of the optimal dose, conventional and rapid vaccination schedules, vaccination in adults, the elderly and special patient populations, safety, immunogenicity, and immunopersistence in adults and children, comparison of FSME-IMMUN^® with another commercially available TBE vaccine as well as post-marketing vaccination outcome. This successful research programme demonstrated the strong immunogenicity and continued safety of the FSME-IMMUN^® vaccine, which is further confirmed by the performance reported under field conditions.     

Immunogenicity and safety of IXIARO (IC51) in a Phase II study in healthy Indian children between 1 and 3 years of age

For adults the standard administration of the Japanese encephalitis vaccine IXIARO^® is two injections of 6 μg in a 28-day interval. Immunogenicity and safety of 3 and 6 μg of IXIARO^® compared to JenceVac™ were investigated in 60 healthy Indian children aged between 1 and 3 years. JE specific neutralizing antibodies were measured at baseline and 28 days after the first and second vaccination. On Day 56 SCR of the 3 and 6 μg IXIARO^® and the JenceVac™ group were 95.7%, 95.2% and 90.9%, respectively, and GMT were 201, 218 and 230, respectively, both without statistically significant difference between the three groups. Local and systemic tolerability were captured in a diary 7 days post-vaccination. No apparent difference was seen in the safety profile between the vaccines. These first immunogenicity and safety data in children are promising and support the use of a 3 μg dose in children below the age of three for further development of IXIARO^® in the paediatric population.     

MF59-adjuvanted influenza vaccine (FLUAD) in children: Safety and immunogenicity following a second year seasonal vaccination

After priming with two intramuscular doses of MF59^®-adjuvanted (Sub/MF59) or split influenza vaccines during the 2006/07 season, 89 healthy children received a third booster dose of the respective vaccine (2007/08 Northern Hemisphere formulation) approximately 1 year later, and were followed up for 6 months post-third injection. Immunogenicity was evaluated on 81 of them by a hemagglutination inhibition (HI) assay before and 3 weeks after vaccination.     

Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-naive adults

Currently, more than half of the world's population has no immunity against smallpox variola major virus. This phase I double-blind, randomized trial was conducted to compare the safety and immunogenicity of two clonally derived, cell-culture manufactured vaccinia strains, ACAM1000 and ACAM2000, to the parent vaccine, Dryvax^®. Thirty vaccinia-naïve subjects were enrolled into each of three groups and vaccines were administered percutaneously using a bifurcated needle at a dose of 1.0 × 10⁸ PFU/mL. All subjects had a primary skin reaction indicating a successful vaccination. The adverse events, 4-fold neutralizing antibody rise and T cell immune responses were similar between the groups.     

Comparison of two commercial vaccines against visceral leishmaniasis in dogs from endemic areas: IgG,and subclasses,parasitism, and parasite transmission by xenodiagnosis

Background

The incidence of zoonotic canine visceral leishmaniasis (CVL) would decrease if dogs were effectively vaccinated; however, additional data on the efficacy of canine vaccines are required for their approved preventative use.

Purpose

To prospectively evaluate vaccination outcomes using two products commercially available in Brazil, with respect to adverse reactions (reactogenicity), humoral response, disease signs, parasitism, and parasite infectiousness in naturally exposed pet dogs in an endemic area of visceral leishmaniasis (VL).

Methods

From 2010 to 2012, healthy dogs were vaccinated with Leishmune^® (50 animals) or Leish-Tec^® (50 animals). Each dog was examined to identify clinical signs during peri- and post-vaccination procedures every 2 months for 11 months to identify the presence of parasites or parasite DNA in splenic samples using culturing or PCR, respectively. Levels of anti-Leishmania IgG, IgG1, and IgG2 were quantified in sera by ELISA and infectiousness was assessed by xenodiagnosis.

Results

Adverse effects occurred in 2.2% (1/45) and 13.0% (6/46) of the animals in the Leishmune^® and Leish-Tec^® groups, respectively. IgG levels peaked on the 21st day following the first dose of Leishmune^® and on the 21st day after the second dose of Leish-Tec^®. The final seropositivity rate for IgG was 32.5% (13/40) and 30.9% (13/42) in the Leishmune^® and Leish-Tec^® groups, respectively. The Leishmune^® group presented higher levels of IgG1 and IgG2 compared to the Leish-Tec^® group (p < 0.001), and ELISA reactivity in both vaccinated groups was significantly lower (p < 0.001) than in infected positive control dogs. Parasitism was observed in 12.2% (5/41) of the Leishmune^® group, and 7.9% (3/38) of the Leish-Tec^® group, with xenodiagnostic transmission rates of Leishmania to Lutzomyia longipalpis of 5.1% (2/39), and 5.4% (2/37), respectively.

Conclusions

No significant differences were observed in dogs vaccinated with Leishmune^® or Leish-Tec^®, with respect to LVC clinical aspects, parasitism, IgG seropositivity, or dog infectiousness. The Leishmune^®-vaccinated animals presented higher levels of IgG, IgG1, and IgG2. The animals vaccinated with Leish-Tec^® exhibited adverse reactions with greater frequency and severity.     

Quantitative comparison of the cross-protection induced by tick-borne encephalitis virus vaccines based on European and Far Eastern virus subtypes

Tick-borne encephalitis virus (TBEV) is a flavivirus of wide geographic distribution and the causative agent of tick-borne encephalitis (TBE), an infection of the central nervous system. TBE has the highest incidence rate in Russia, where locally produced as well as Western European vaccines for the prevention of TBE are available. The Western European vaccines are based on TBE viruses that belong to the European subtype, while the Russian vaccines are based on Far Eastern subtype viruses. The question of to which extent vaccination with a vaccine based on the European subtype is effective in protecting against the heterologous Far Eastern virus subtype - and vice versa - has not been answered conclusively. Here we immunized mice with TBE vaccines based on European and Far Eastern subtype viruses, and used an unbiased hybrid virus test system to determine cross-neutralizing antibody titers and cross-protective efficacy. All vaccines tested elicited cross-protective responses against the heterologous strains, similar to those induced against the respective homologous vaccine strains. These data, therefore, fully support the use of TBE vaccines in geographic regions where virus subtypes heterologous to the vaccine strains are prevalent.     

Phase 3 trial evaluating the immunogenicity and safety of a three-dose BioThrax regimen for post-exposure prophylaxis in healthy adults

Background

This study was conducted to support licensure of a post-exposure prophylaxis indication for BioThrax^® (anthrax vaccine adsorbed) concurrent with antimicrobials for individuals exposed to aerosolized anthrax spores.

Methods

The immunogenicity and safety of a three-dose regimen (0, 2, and 4 weeks) of BioThrax administered subcutaneously (SC) were evaluated in 200 healthy adults 18–65 years of age. Toxin-neutralizing antibody (TNA) was expressed as 50% neutralization factor (NF₅₀) at predetermined time points through Day 100. Safety was assessed by physical examinations, vital signs, solicited local and systemic reactions using web-enabled subject diaries, in-clinic solicited reactions, and unsolicited adverse events (AEs).

Results

The prospectively defined success criteria for the primary and secondary endpoints were met. This required the lower bound of the 95% confidence interval (CI) for the proportion of subjects with a TNA NF₅₀ value to be greater than 40% at Day 63 (primary), Day 70 (secondary) and Days 63–100 (secondary). At Day 63, 71% of subjects achieved a TNA NF₅₀ threshold value ≥0.56, with a lower bound of the 95% CI ≥40% (64%). The percentage of subjects achieving a TNA NF₅₀ threshold value ≥0.56 at Day 70 was 58% (95% CI: 50%, 65%), and the mean value on Days 63–100 (inclusive) was 53% (95% CI: 41%, 55%). The threshold TNA NF₅₀ value of 0.56 was developed from previous rabbit challenge and human immunogenicity studies. No related serious AEs occurred during the study, and no subjects withdrew from the study because of an AE. Tenderness and pain at the injection site were recorded most often in subject diaries following vaccination.

Conclusions

BioThrax, administered as three SC doses at 0, 2, and 4 weeks, was well tolerated. The prospectively defined success criteria for TNA levels on Days 63, 70, and 63–100 were achieved.     

国内外儿童用联合疫苗免疫原性、安全性和社会价值

联合疫苗含有两种或多种抗原,研究认为接种联合疫苗后能预防多种疾病,同时可减少接种次数。本文对国内外儿童用联合疫苗,如无细胞百白破疫苗（DTaP）、麻疹-风疹-腮腺炎疫苗（MMR）等免疫原性和安全性进行综述,并从儿童家长、预防接种工作者和卫生服务方面进行社会价值探究,为我国推动联合疫苗研发和使用提供决策证据。研究发现,联...     

Comparison of immunogenicity and safety of licensed Japanese encephalitis vaccines: A systematic review and network meta-analysis

IntroductionAnnually more than 100,000 Japanese encephalitis (JE) cases and 25,000 deaths worldwide are caused by JE virus infection. More than 15 JE vaccines are currently in use worldwide. It is unknown whether any of the vaccines is superior to the others in terms of immunogenicity and safety.MethodsFour databases were systematically searched for randomised controlled trials that compared two or more types of JE vaccines. Vaccines were classified into four classes: inactivated mouse brain-derived (oldest class), inactivated Vero cell, live chimeric, and live attenuated. Network meta-analysis was used to generate mixed effect estimates against inactivated mouse brain-derived vaccines for seroconversion, and against placebo for adverse event (AE) and severe adverse event (SAE).Results23 studies (38,496 participants) were included. All newer vaccine classes had better immunogenicity, the difference was statistically significant for inactivated Vero cell (OR = 2.98; 95 %CI: 1.02–8.65) and live chimeric (OR = 5.93; 95 %CI: 1.73–20.32) vaccines. Inactivated mouse-derived vaccines had the highest odds for AEs (OR = 2.27; 95 %CI: 1.59–3.23), the odds of AE of newer vaccines was not different to placebo. There was no difference in SAEs across vaccine classes.ConclusionsAll newer JE vaccines have comparable safety profiles, live chimeric and inactivated Vero cell vaccines are the most immunogenic among the newer vaccine classes.     

Effectiveness of TBE vaccination in southern Germany and Latvia

BackgroundTick-borne encephalitis (TBE) is a vaccine-preventable disease which may cause long-term sequelae and even death. The data on the long-term effectiveness of TBE vaccines are limited. Additionally, the vaccination schedule is complex which in part contributes towards sub-optimal uptake in TBE-endemic areas. The current ecological study measures vaccine effectiveness (VE) in two European countries.MethodsTBE VE was measured from 2007 to 2018 in Latvia and Southern German states by age group, vaccination history, and schedule compliance. TBE cases and vaccination history were obtained from the public health agencies for Latvia and the southern German federal states of Bavaria and Baden-Wuerttemberg. Cases were “within schedule” if a TBE infection was diagnosed within the time interval preceding the next scheduled dose and “outside schedule” if the diagnosis occurred after the next scheduled dose. Vaccine uptake was estimated via representative nationwide surveys.ResultsVE after 2, 3, and ≥4 doses was high in both countries at 97.2%, 95.0%, and 95.4% for southern Germany, and 98.1%, 99.4%, and 98.8% for Latvia while within- schedule, and only showed marginal differences outside schedule at 90.6%, 89.9%, and 95.6% for southern Germany, and 97.4%, 98.4%, and 99.0% for Latvia regardless of age groups.ConclusionsIn both countries, VE after two and three primary doses within-schedule was very high in all age groups. Once receiving booster doses, high VE continued to be observed even in persons with extended intervals since the last dose received, suggesting that longer and more flexible booster intervals may be considered for sustainable long-term protection.     

The current perspective on tick-borne encephalitis awareness and prevention in six Central and Eastern European countries: report from a meeting of experts convened to discuss TBE in their region

Tick-borne encephalitis (TBE) is a potentially life-threatening disease in humans and is caused by a flavivirus spread by infected ticks (Ixodes ricinus and Ixodes persulcatus). TBE is endemic across much of Central and Eastern Europe and the incidence is increasing, with numbers estimated to be as many as 8755 cases per year. The reasons for this increase are multi-faceted and may involve improvements in diagnosis and reporting of TBE cases, increases in recreational activities in areas inhabited by infected ticks and changes in climatic conditions affecting tick habitats. Vaccination is the most effective method of preventing TBE; following a successful nationwide vaccination campaign in Austria, the annual number of TBE cases fell to about 10% of those reported in the pre-vaccination era.This report describes the findings of a group of leading experts from six Central and Eastern European countries who convened to discuss TBE in their region during the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) Nice, France, 4-8 May 2010.     

Kinetics of the immune response after primary and booster immunization against tick-borne encephalitis (TBE) in adults using the rapid immunization schedule

A total of 222 adult subjects aged 19–51 years were enrolled in this multi-center, phase III study to evaluate immunogenicity and safety of the first booster immunization with a new tick-borne encephalitis (TBE) vaccine. This was an extension study that followed subjects who had received primary immunization 12–18 months previously with either the new or formerly licensed TBE vaccine according to the rapid immunization schedule (i.e. on Days 0, 7 and 21). Compared to the levels of primary immunization, prior to first booster, neutralizing TBE antibodies (geometric mean titers, GMTs) of both vaccination groups had remained on a high level and were far above the detection limit of the neutralization test used. All subjects showed a sharp increase of TBE antibodies following the booster. The booster was well tolerated by the subjects. Conclusion: These results in terms of both immunogenicity and safety indicate that the TBE vaccination with this new TBE vaccine can be used effectively and safely in adults. A long lasting immunity can be concluded from the strong immune response following the first booster.     

Tick borne encephalitis (TBE)-vaccination coverage and analysis of variables associated with vaccination,Sweden

To estimate the tick borne encephalitis (TBE)-vaccination coverage in the greater Stockholm region, we sent a questionnaire to a randomized sample of 8000 individuals in 2013. Fifty-three percent of all respondents (n = 4307) reported being vaccinated against TBE at least once. Reasons for not vaccinating included: no perceived risk (28.6%), too expensive (25.6%), did not have the time or opportunity (23%) and worried about vaccine side-effects (20.5%). Multiple logistic regression revealed that the probability of being vaccinated was higher among those who reported ≥2 weeks outdoor exposure in a known high risk area (OR 4.13 95% CI 3.54–4.81) and in individuals ≥60 years of age compared to all other age groups (OR 0.67 95% CI 0.55–0.81). A high net household income was associated with a higher probability of being vaccinated (OR 2.10 95% CI 1.6–2.73). Being born outside Europe was negatively correlated (OR 0.57 95% CI 0.39–0.83). Based on our findings the estimated TBE-incidence in the unvaccinated regional population was 8.5-12/100,000 which is comparable with high endemic areas as the Baltic region and Central Europe. We suggest targeted vaccination and reimbursement strategies in high-endemic areas of Sweden. Our results indicate a need for improved public information about TBE.     

A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available

Genus flavivirus comprises many important human pathogens causing public health problems worldwide. Some flavivirus infections are characterized by a relatively high mortality rate and/or high sequelae rate in survivors. Because most flavivirus life cycles are maintained between arthropod vectors and amplifying/reservoir hosts in the absence of humans, eradication of flaviviruses might be extremely difficult. Flavivirus vaccine development is considered a reasonable method to prevent flavivirus infections. Some vaccines have been successfully developed, but others have not, regardless of much effort. This review article describes currently available flavivirus vaccines against yellow fever, Japanese encephalitis, and tick-borne encephalitis. In addition, the current status of dengue and West Nile virus vaccine development is reviewed and problems regarding their development are discussed.     

Development of a simple and high-yielding fed-batch process for the production of influenza vaccines

A robust and reliable GMP-compatible fed-batch process was successfully developed for the production of recombinant hemagglutinin (rHA) proteins by expresSF^® cells. The feeding solution, feeding strategy as well as the cell density at infection were optimized to maximize the final rHA production yields without affecting the existing rHA recovery protocol and downstream process. A simple and stable feeding solution was formulated and a rational feeding regimen designed to yield, depending on the rHA baculovirus used, between 2- and 3-fold enhancements in volumetric rHA production with increased specific productivity compared to the batch culture. Recombinant HA from fed-batch cultures could be simply recovered following cell lysis and purified through chromatographic steps. Overall, the increased rHA yield was maintained throughout the whole process. The performance, reproducibility and scalability of the fed-batch process was successfully demonstrated in 12 bioreactor runs of 2- and 10-L working volume using five different rHA encoding baculoviruses.     

The safety of ONRAB in select non-target wildlife

ONRAB^® is a recombinant human adenovirus type 5 (HAd5) with the rabies glycoprotein gene incorporated into its genome. ONRAB^® has been used in Canada as an oral rabies vaccine in target wildlife species such as: red fox (Vulpes vulpes), raccoon (Procyon lotor), and striped skunk (Mepthis mephitis). We evaluated the safety of ONRAB^® in non-target wildlife species likely to contact the vaccine baits during oral rabies vaccine campaigns in the United States. We investigated the effects of oral inoculation of high titer ONRAB^®, approximately ten times the dose given to target species, in wood rats (Neotoma spp.), eastern cottontail rabbits (Sylvilagus floridanus), Virginia opossums (Didelphis virginiana), eastern wild turkeys (Meleagris gallopavo silvestri), and fox squirrels (Sciurus niger). We performed real-time polymerase chain reaction (PCR) on fecal swabs, oral swabs, and tissues, including lung, liver, kidney, small intestine, large intestine, and when appropriate nasal turbinates, to detect ONRAB^® DNA from inoculated animals. By seven days post-inoculation, turkeys, opossums, and cottontails had all stopped shedding ONRAB^® DNA. One wood rat and one fox squirrel still had detectable levels of ONRAB^® DNA in fecal swabs 14 days post-inoculation. Real-time PCR analysis of the tissues revealed some ONRAB^® DNA persisting in certain tissues; however, there were no significant gross or histologic lesions associated with ONRAB^® in any of the species studied. Our results suggest that many non-target species are not likely to be impacted by the distribution of ONRAB^® as part of oral rabies vaccination programs in the United States.     

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。     

Genetic conjugation of components in two pneumococcal fusion protein vaccines enhances paediatric mucosal immune responses

Streptococcus pneumoniae colonises the upper respiratory tract and can cause pneumonia, meningitis and otitis media. Existing pneumococcal conjugate vaccines are expensive to produce and only protect against 13 of the 90+ pneumococcal serotypes; hence there is an urgent need for the development of new vaccines. We have shown previously in mice that pneumolysin (Ply) and a non-toxic variant (Δ6Ply) enhance antibody responses when genetically fused to pneumococcal surface adhesin A (PsaA), a potentially valuable effect for future vaccines. We investigated this adjuvanticity in human paediatric mucosal primary immune cell cultures. Adenoidal mononuclear cells (AMNC) from children aged 0–15 years (n = 46) were stimulated with conjugated, admixed or individual proteins, cell viability and CD4+ T-cell proliferative responses were assessed using flow cytometry and cytokine secretion was measured using multiplex technology.Proliferation of CD4+ T-cells in response to PsaAPly, was significantly higher than responses to individual or admixed proteins (p = 0.002). In contrast, an enhanced response to PsaAΔ6Ply compared to individual or admixed proteins only occurred at higher concentrations (p < 0.01). Evaluation of cytotoxicity suggested that responses occurred when Ply-induced cytolysis was inhibited, either by fusion or mutation, but importantly an additional toxicity independent immune enhancing effect was also apparent as a result of fusion. Responses were MHC class II dependent and had a Th1/Th17 profile. Genetic fusion of Δ6Ply to PsaA significantly modulates and enhances pro-inflammatory CD4+ T-cell responses without the cytolytic effects of some other pneumolysoids. Membrane binding activity of such proteins may confer valuable adjuvant properties as fusion may assist Δ6Ply to deliver PsaA to the APC surface effectively, contributing to the initiation of anti-pneumococcal CD4+ T-cell immunity.