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Objectives The 4CMenB vaccine confers protection against serogroup B invasive meningococcal disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, we now have data on its effectiveness and impact. We have exhaustively reviewed all the evidence gathered in the real world since the vaccine was licensed. Results Data from 7 countries provide evidence of effectiveness and impact in different settings and age groups, including national/regional immunisation programmes, observational studies, and outbreak control. The administration of at least 2 doses of 4CMenB reduced IMD by 50–100% in individuals from 2 months to 20 years of age. Estimation of the effectiveness of the vaccine in fully vaccinated cohorts ranged from 59 to 100%. The real-world safety profile of 4CMenB corresponded with the data from the clinical trials undertaken prior to its licensing. Conclusion MenB IMD is a rare but potentially fatal disease, with unpredictable epidemiology. The data on the effectiveness and impact data of 4CMenB support its use in the prevention of IMD. The results underline the importance of directly protecting the groups most at risk: infants/young children and adolescents. Direct protection through systematic immunisation in infancy (with salvage in young children) and systematic immunisation in adolescents could constitute the preferred model for the control of MenB disease. A Video Abstract linked to this article is available on Figshare: https://doi.org/10.6084/m9.figshare .

espanolObjetivos 4CMenB es una vacuna que confiere proteccion frente a la enfermedad meningococica invasiva por el serogrupo B (EMI por MenB). Autorizada en todo el mundo a partir de los datos de inmunogenicidad y seguridad, disponemos ahora de datos de su efectividad e impacto. Hemos revisado de manera exhaustiva toda la evidencia recopilada en el mundo real desde su autorizacion. Resultados Los datos de 7 paises aportan evidencia de efectividad e impacto en diferentes entornos y grupos de edad, incluidos programas de inmunizacion nacionales/regionales, estudios observacionales y control de brotes. La administracion de al menos 2 dosis de 4CMenB redujo la enfermedad meningococica invasiva (EMI) por MenB en un 50-100% en personas de 2 meses a 20 anos. Las estimaciones de la efectividad vacunal en las cohortes completamente vacunadas oscilaron entre el 59 y el 100%. El perfil de seguridad de 4CMenB en el mundo real se correspondio con los datos de los ensayos clinicos previos a su autorizacion. Conclusion La EMI por MenB es una enfermedad poco frecuente pero potencialmente mortal, con una epidemiologia imprevisible. Los datos sobre efectividad e impacto de 4CMenB respaldan su uso para la prevencion de la EMI. Los resultados subrayan la importancia de la proteccion directa de los grupos con mayor riesgo: lactantes/ninos pequenos y adolescentes. La proteccion directa a traves de la inmunizacion sistematica en los lactantes (con rescate de los ninos pequenos) y la vacunacion sistematica en la adolescencia podrian constituir la modalidad preferida para el control de la enfermedad por MenB. En Figshare encontrara un resumen en video relacionado con este articulo: https://doi.org/10.6084/m9.figshare. EnglishObjectives The 4CMenB vaccine confers protection against serogroup B invasive meningococcal disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, we now have data on its effectiveness and impact. We have exhaustively reviewed all the evidence gathered in the real world since the vaccine was licensed. Result Data from 7 countries provide evidence of effectiveness and impact in different settings and age groups, including national/regional immunisation programmes, observational studies, and outbreak control. The administration of at least 2 doses of 4CMenB reduced IMD by 50-100% in individuals from 2 months to 20 years of age. Estimation of the effectiveness of the vaccine in fully vaccinated cohorts ranged from 59 to 100%. The real-world safety profile of 4CMenB corresponded with the data from the clinical trials undertaken prior to its licensing. Conclusion MenB IMD is a rare but potentially fatal disease, with unpredictable epidemiology. The data on the effectiveness and impact data of 4CMenB support its use in the prevention of IMD. The results underline the importance of directly protecting the groups most at risk: infants/young children and adolescents. Direct protection through systematic immunisation in infancy (with salvage in young children) and systematic immunisation in adolescents could constitute the preferred model for the control of MenB disease.

Serogroup B meningococci (MenB) remain a prominent cause of invasive meningococcal disease (IMD). The protein-based multicomponent 4CMenB and the bivalent MenB-FHbp are the only currently available vaccines against MenB-caused IMD. Efficacy studies are not possible, due to the low incidence of IMD. Therefore, the vaccines' immunogenicity has been evaluated against several target strains chosen to quantify complement-mediated killing induced by each vaccine component in the serum bactericidal antibody assay. However, due to the wide genetic diversity and different expression levels of vaccine antigens across MenB strains, vaccine performance may differ from one strain to another. Here, we review the methods used to predict MenB strain coverage for 4CMenB and MenB-FHbp. Phenotypic assays such as the meningococcal antigen typing system (MATS, 4CMenB-specific) and the flow cytometric meningococcal antigen surface expression assay (MEASURE; MenB-FHbp-specific) were developed. Genomic approaches are also available, such as genetic MATS (gMATS) and the Bexsero antigen sequence type (BAST) scheme, both 4CMenB-specific. All methods allow tentative predictions of coverage across MenB strains, including that afforded by each vaccine antigen, and are rapid and reproducible. Real-world data on vaccine effectiveness are needed to confirm predictions obtained by these methods.

The multicomponent meningococcal serogroup B vaccine, 4CMenB, has demonstrated effectiveness in preventing invasive MenB disease in infants and in controlling MenB outbreaks. The need for/timing of additional booster doses is not yet established. We reviewed eight studies that evaluated antibody persistence and booster following primary 4CMenB vaccination of infants, children, adolescents, and young adults. Putative seroprotective hSBA titers for ≥1 vaccine antigen were maintained by 76–100% of children 24–36 months after priming during infancy and in 84–100% after priming in the second year of life. hSBA levels were higher in vaccinees at 4 and 7.5 years following priming during adolescence than in vaccine-naïve individuals of a similar age. Antibodies persisted at higher levels to NHBA and NadA than to PorA or fHbp. Booster vaccination induced robust anamnestic responses, demonstrating effective priming by 4CMenB across age-groups. These data can inform decision-making to optimize vaccination strategies.

This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.

Meningococcal disease is rare, easily misdiagnosed, and potentially deadly. Diagnosis in the early stages is difficult and the disease often progresses extremely rapidly. In North America, the incidence of invasive meningococcal disease (IMD) is highest in infants and young children, with a secondary peak in adolescents, a population predominantly responsible for the carriage of disease. Neisseria meningitidis serogroup B (MenB) accounts for a large proportion of meningococcal disease in North America, with documented outbreaks in three universities in the United States (US) during 2008–2013. Vaccination is the most effective way to protect against this aggressive disease that has a narrow timeframe for diagnosis and treatment. 4CMenB is a multi-component vaccine against MenB which contains four antigenic components. We describe in detail the immunogenicity and safety profile of 4CMenB based on results from four clinical trials; the use of 4CMenB to control MenB outbreaks involving vaccination at two US colleges during outbreaks in 2013–2014; and the use of 4CMenB in a Canadian mass vaccination campaign to control the spread of MenB disease. We discuss the reasons why adolescents should be vaccinated against MenB, by examining both the peak in disease incidence and carriage. We consider whether herd protection may be attained for MenB, by discussing published models and comparing with meningitis C (MenC) vaccines. In conclusion, MenB vaccines are now available in the US for people aged 10–25 years, representing an important opportunity to reduce the incidence of IMD in the country across the whole population, and more locally to combat MenB outbreaks.

Having previously demonstrated the feasibility of administering A/H5N1 and seasonal influenza vaccine antigens in an MF59-adjuvanted tetravalent formulation, we now report on long-term antibody persistence and responses to a booster dose of a combined seasonal-pandemic, tetravalent influenza vaccine in adults. The primary objective was the evaluation of responses to a booster dose of tetravalent influenza vaccine containing seasonal (A/H1N1, A/H3N2, and B) and avian (A/H5N1, clade 2) influenza virus strains administered to 265 healthy 18- to 40-year-old volunteers 1 year after priming with one or two clade 1 A/H5N1 doses. Secondary objectives were assessment of reactogenicity, safety, and antibody persistence 1 year after priming with a combined seasonal-pandemic, tetravalent vaccine. Responses to seasonal strains met all European licensure criteria; seroprotection rates were 94 to 100%, 100%, and 61 to 90% for A/H1N1, A/H3N2, and B strains, respectively. Anamnestic responses were observed against homologous and heterologous A/H5N1 strains whether priming with one or two A/H5N1 doses, with a monovalent A/H5N1 vaccine, or with a tetravalent vaccine. A single dose of MF59-adjuvanted A/H5N1 vaccine given alone or as part of a fixed combination with a seasonal influenza vaccine was sufficient to prime adult subjects, resulting in robust antigen-specific and cross-reactive antibody responses to heterologous booster immunization 1 year later. These data support the feasibility of incorporating prepandemic priming into seasonal influenza vaccination programs. (This study has been registered at clinicaltrials.gov under registration no. NCT00481065.)

Seasonal influenza causes clinical illness and hospitalization in all age groups; however, conventional inactivated vaccines have only limited efficacy in young children. MF59(®), an oil-in-water emulsion adjuvant, has been used since the 1990s to enhance the immunogenicity of influenza vaccines in the elderly, a population with waning immune function due to immunosenescence. Clinical trials now provide information to support a favorable immunogenicity and safety profile of MF59-adjuvanted influenza vaccine in young children. Published data indicate that Fluad(®), a trivalent seasonal influenza vaccine with MF59, was immunogenic and well tolerated in young children, with a benefit/risk ratio that supports routine clinical use. A recent clinical trial also shows that Fluad provides high efficacy against PCR-confirmed influenza. Based on the results of clinical studies in children, the use of MF59-adjuvanted vaccine offers the potential to enhance efficacy and make vaccination a viable prevention and control strategy in this population.

Systemic safety surveillance is an essential component of vaccination programmes to elucidate the full safety profile of a vaccine and to detect previously unrecognized adverse reactions that might be related to new vaccines. This article summarizes the spontaneous adverse drug reactions (ADR) from approximately 12 million administered doses of the pandemic MF59-adjuvanted H1N1v vaccine (Focetria®, Novartis Vaccines and Diagnostics) from the mass vaccination programmes in Europe.All ADR reports from October 2009 to March 2010 were included in the analyses and classified according to Medical Dictionary for Regulatory Activities. Adverse events of special interest were compared with pooled spontaneous case reports for seasonal influenza vaccines, and signal detection analyses were performed.In the reporting period we received a total of 5315 pandemic vaccine ADR reports, of which 19.9% were serious. The reporting rate was higher after H1N1 pandemic vaccines, i.e. 44.3 cases/100.000 doses, than for seasonal influenza vaccines covering the same time period, i.e. 1.7 cases/100.000 doses. The majority of reports included expected local and systemic postvaccination reactions. Rates for adverse events of special interest, for example, Guillain-Barré syndrome, anaphylaxis, and convulsions showed no signs of disproportionality between the pandemic and the seasonal vaccines. There were 36 deaths reported after use of the pandemic vaccine; however, no evidence for a causal relationship with the vaccine was found.The analyses of the spontaneously reported adverse events support the good safety profile of the MF59-adjuvanted H1N1v pandemic influenza vaccine.

OBJECTIVE: This study evaluated the immunogenicity, safety, and tolerability of a MF59-adjuvanted H5N1 vaccine in a population 6 months through 17 years of age. METHODS: Healthy subjects 6 to RESULTS: A total of 335 subjects received the H5N1 vaccine, and 137 subjects received the seasonal vaccine. Rates of seroprotection (HI titer of ≥40) against the H5N1 vaccine antigen were 97% for children 6 to 36 months and 3 to 9 years of age and 89% for older children. All subjects seroconverted in the SRH assay. Microneutralization titers of ≥40 were achieved by 99% of subjects, and ≥98% of subjects, respectively. Local reactions, particularly injection site pain in older children, were common, generally mild to moderate in nature, and transient and resolved spontaneously. Up to 5% of participants. There were no vaccine-related serious adverse events in either group. CONCLUSIONS: In this pediatric population, MF59-adjuvanted H5N1 vaccine was highly immunogenic, had a good safety profile, reactogenicity comparable with that of an adjuvanted seasonal influenza control vaccine.

Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross- reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non-adjuvanted pre-pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre-pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross- reactive immunogenicity. MF59 � , the first oil-in-water emulsion

Objective To demonstrate the safety and immunogenicity of intradermal rabies pre-exposure prophylaxis with purified chick embryo cell vaccine (PCECV) in schoolchildren age 5 to 8 years in Thailand. Study design In a randomized, open-label, phase II clinical trial, 2 or 3 intradermal doses of 0.1 mL PCECV (Rabipur®) were administered to 703 schoolchildren on days 0 and 28 or on days 0, 7, and 28. In 206 children, 2 simulated post-exposure booster doses were given 1 year after the primary vaccination series. Rabies virus– neutralizing antibody (RVNA) titers were determined by the rapid fluorescent focus inhibition test. Results In school-age children in Thailand, a pre-exposure immunization regimen of 3 intradermal doses of PCECV produced adequate immune responses. After primary vaccination, all subjects developed RVNA titers ≥0.5 IU/mL and demonstrated a rapid increase in RVNA titer after 2 simulated post-exposure booster immunizations 1 year after the primary vaccination series. No serious adverse drug reactions occurred. Conclusions Rabies pre-exposure immunization with PCECV is safe and immunogenic, and its implementation could save the lives of many children in rabies-endemic areas.

Tick-borne encephalitis (TBE) is caused by an arthropod-borne virus, belonging to the family of Flaviviridae. In case of disease, which can lead to neurological sequelae or even fatal outcomes, only symptomatic treatment is available. TBE can be prevented by vaccination. Various primary immunization schedules have been developed. To identify the most suitable schedule, the present randomised, controlled study was designed to provide data on the immune response elicited by four different immunization schedules obtained by ELISA and by neutralization test (NT). A total of 398 healthy subjects agedor =12 years were randomised to vaccination according to either the rapid schedule (Group R, vaccination on days 0, 7 and 21), the conventional schedule (Group C, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M, vaccination on days 0, 21 and 300) or the accelerated conventional schedule (Group A, vaccination on days 0, 14 and 300). Within 3 weeks (i.e. by day 21) antibody levels were higher in Group R and Group A than in Group M and Group C. Group R and Group C both had higher titres on days 42, 180 and 300, than Group A and Group M. The rapid schedule thus combines the advantages of fast protection and of high titres over the observation period of 300 days.

Millions of vaccine doses are wasted each year due to a lapse in recommended storage conditions. Maintaining the cold chain for vaccines is both expensive and difficult, especially in developing countries. The present study investigated the safety and immunogenicity of a single dose of the conjugated meningococcal Group C vaccine, Menjugate, stored for 6 months at room temperature (25+/-2 degrees C, N=250) or at 2-8 degrees C (N=250) when administered to 12-23 months toddlers. In the two respective groups, 87 and 88% of toddlers reached bactericidal antibodies titers of at least 1:8. The immunogenicity of Menjugate stored at room temperature was not inferior to that stored at 2-8 degrees C. The safety profile and immunogenicity of the vaccine was not influenced by the storage condition.

Renal transplant recipients are at greater risk of infection from influenza than healthy individuals, due to therapeutic immunosuppression. Influenza can result in severe complications such as pneumonia, bacterial infections or even graft loss in these patients. However, immunosuppression impairs the efficacy of conventional influenza vaccines. A total of 116 adult (aged 18–64 years) renal transplant recipients were randomised to receive a single intramuscular injection of MF59-adjuvanted influenza vaccine (FLUAD®; n =60) or a conventional subunit influenza vaccine (Agrippal®; n =56). Safety and immunogenicity of both groups were assessed. Increases in geometric mean titres of antibody from pre- to post-immunisation were notably higher in the MF59-adjuvanted vaccine group for all three influenza antigens. Seroprotection rates were greater in the MF59-adjuvanted vaccine group, particularly for the A/H3N2 antigen (84% for the adjuvanted vaccine group versus 56% for the conventional vaccine group). Both vaccines were safe and well tolerated. It therefore seems reasonable to preferentially administer this adjuvanted vaccine over conventional vaccines in this immunocompromised population.

A total of 222 adult subjects, all of whom received primary immunization according to the rapid immunization schedule in a preceding clinical trial with either a new (i.e. polygeline free) or formerly licensed (i.e. polygeline containing) TBE vaccine were invited for extension studies. The subjects received the first booster immunization with the new TBE vaccine at 12 to 18 months after primary immunization. Subsequently, a total of 191 of the 222 subjects could be enrolled in a serological follow-up one year after the booster immunization. Neutralizing TBE antibody titers were determined prior to, 21 days after and approximately 12 months after booster immunization. Prior to first booster immunization, TBE antibodies (GMTs) had remained on a high level and were far above the detection limit of the neutralization test used. All subjects of the per protocol population who were primarily immunized with the new TBE vaccine formulation and all but one subject of the control group were still seropositive prior to the booster. All subjects showed a sharp increase of TBE antibodies following the booster immunization. Within the 12 months follow-up period, neutralizing TBE antibody titers remained on a high level. The booster vaccination was well tolerated by the subjects. Only very few febrile reactions (< 1%) none higher than 38.5 degrees C were reported. No serious or unexpected adverse events related to vaccination were reported. These successful results in terms of both immunogenicity and safety indicate that TBE vaccination with this new TBE vaccine can be used safely in adults. A long lasting immunity can be concluded from the strong immune response following the booster immunization.

A total of 3,559 children aged 1-11 years were enrolled in two clinical studies to evaluate immunogenicity and safety of a new pediatric tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer. Immunogenicity was evaluated in the rapid immunization schedule (Days 0, 7, and 21) from sera collected at baseline and on Day 42 post-immunization by in vitro TBE virus neutralization test. All subjects analyzed achieved levels of TBE antibodies to fulfil the definition of seroconversion or a four-fold increase in antibody titres from baseline. The frequency of solicited post-immunization reactions ranged from 1 to 32% for reported local reactions and from 1 to 14% for systemic reactions. Overall, this can be regarded as expected for an inactivated, aluminium-adjuvanted, TBE vaccine. There was no indication for any new safety issues. An acceptably low number of febrile reactions above 38 degrees C with the highest frequency after first immunization (i.e. 15% and 5% in children aged 1-2 and 3-11 years, respectively), mainly below 39 degrees C, was reported. The results of both studies clearly show that TBE vaccination with this new TBE vaccine formulation can be achieved with a high degree of safety in children from 1 to 11 years of age.

Immunogenicity and safety of a booster dose of an MF59-adjuvanted H5N1 vaccine containing 7.5 μg A/turkey/Turkey/1/2005-like (clade 2.2) H5N1 hemagglutinin, given approximately 18 months after primary vaccination with a heterologous strain, were evaluated. The booster vaccine was well tolerated and induced a robust, cross-reactive immune response.

The equivalence and interchangeability of Purified Chick Embryo Cell Culture Rabies Vaccine (PCECV) to Human Diploid Cell Culture Rabies Vaccine (HDCV) and the immunogenicity of a reduced post-exposure regimen with PCECV was investigated. Statistical analyses revealed no difference (P

Pulmonary emphysema is very uncommon in children in the first decade of life. The few cases documented in the literature were all due to alpha1-antitrypsin deficiency. We present the case of a 6-year-old white boy with chronic cough and dyspnea on exertion. Lung biopsy showed panacinar type emphysema with patent airways and diffuse hyperplasia of pulmonary neuroendocrine cells revealed after immunostaining for bombesin, a peptide produced by these cells. We speculate that idiopathic diffuse hyperplasia of bombesin-producing pulmonary neuroendocrine cells may contribute to the pathogenesis of unusual COPD in childhood.

Primary immunization with two doses of MF59 (®) -adjuvanted A/H5N1 influenza vaccine has been shown to be highly immunogenic and well tolerated in children and adolescents. Assessment of long-term antibody persistence after priming, and the effects of a one-year booster dose in children and adolescents was needed.This study assessed homologous and heterologous antibody responses to a one-year booster dose of MF59-adjuvanted A/H5N1 influenza vaccine in previously primed children.Twelve months after primary vaccination, persistent, homologous, seroprotective HI antibody titers (≥ 40) were observed in 46%, 26% and 30% of toddlers, children and adolescents; following booster vaccination, seroprotection rates increased to 99%, 98% and 91%, respectively. All toddlers and children, and 99% of adolescents achieved MN antibody titers ≥ 40. Cross-reactive A/H5N1 antibodies were detected in 94-98% of subjects after booster vaccination.Twelve months after primary vaccination, toddlers, children and adolescents received a single booster dose of the same A/H5N1 vaccine. Paired sera were collected before and three weeks after booster vaccination. Homologous antibody responses against the A/Vietnam/1194/2004 vaccine strain were measured by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization (MN) assays. Heterologous antibody responses against A/Indonesia/5/2005 and A/Anhui/1/2005 strains were assessed by MN assay only.Two priming doses of MF59-adjuvanted A/H5N1 vaccine resulted in homologous and heterologous antibody responses which persisted for up to one year after immunization. A one-year booster dose was highly immunogenic, generating high homologous and cross-reactive A/H5N1 antibody titers.

Proactive priming before the next pandemic could induce immune memory responses to novel influenza antigens. In an open-label study, we analyzed B cell memory and antibody responses of 54 adults who received 2 7.5-μg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 (H5N1) vaccine. Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 (H5N3) vaccine during 1999–2001. The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals. However, at day 21 after boosting, MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects. The immune memory was rapidly mobilized by a single vaccine administration and resulted in high titers of neutralizing antibodies to antigenically diverse clade 0, 1, and 2 H5N1 viruses already at day 7. In general, postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects. Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine, most notably in early induction and duration of cross-reacting antibody responses. After 6 months, high titers of cross-reactive antibody remained detectable among MF59-primed subjects. We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly. These results suggest that pre-pandemic vaccination strategies should be considered.

Immune responses to vaccination are tested in clinical trials. This process usually requires years especially when immune memory and persistence are analyzed. Markers able to quickly predict the immune response would be very useful, particularly when dealing with emerging diseases that require a rapid response, such as avian influenza. To address this question we vaccinated healthy adults at days 1, 22, and 202 with plain or MF59-adjuvanted H5N1 subunit vaccines and tested both cell-mediated and antibody responses up to day 382. Only the MF59-H5N1 vaccine induced high titers of neutralizing antibodies, a large pool of memory H5N1-specific B lymphocytes, and H5-CD4+T cells broadly reactive with drifted H5. The CD4+response was dominated by IL-2+IFN-γ−IL-13−T cells. Remarkably, a 3-fold increase in the frequency of virus-specific total CD4+T cells, measurable after 1 dose, accurately predicted the rise of neutralizing antibodies after booster immunization and their maintenance 6 months later. We suggest that CD4+T cell priming might be used as an early predictor of the immunogenicity of prepandemic vaccines.

Background Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed. Methods and Findings Healthy adults aged 18–60 and >60 years (n = 313 and n = 173, respectively) were randomized (1∶1) to receive two primary and one booster injection of 7.5 μg or 15 μg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 μg and 15 μg doses were comparable. The rates for seroprotection (HI>40; SRH>25mm2; MN ≥40) after the primary vaccination ranged 72–87%. Six months after primary vaccination with the 7.5 μg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 μg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations. Conclusions Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs. Trial Registration ClinicalTrials.gov NCT00311480

The standard serological methods present limitations for the measurement of immunity against H5N1 influenza strains. The hemagglutination inhibition (HI) assay lacks sensitivity and requires standardization, while the viral micro-neutralization (MN) assay needs handling of live virus. We produced pseudoparticles expressing hemagglutinin from clades 1 or 2 H5N1 in order to measure neutralizing antibodies in human sera after prime-boost vaccination with plain or MF59-adjuvanted H5N1 clade 1 subunit vaccines. Titers measured by pseudoparticle neutralization (PPN) assay significantly correlated with those measured by HI, single radial haemolysis or MN, with a PPN titer of 1:357 corresponding to an MN titer of 1:80. Notably, results from the PPN assay, confirm that MF59-H5N1 vaccine induces potent and long-lasting neutralizing antibody responses not only against the vaccine strain, but also against several heterologous clade 2 strains. Overall, the PPN assay represents a valid alternative to conventional serological methods for the evaluation of H5N1 vaccine immunogenicity.

The authors report on an open-label study of an MF59-adjuvanted vaccine against avian influenza. The findings indicate that priming subjects with H5 antigen induces a rapidly mobilized, long-lastin...

Once considered a local health issue confined to certain regions in Russia and Central and Eastern Europe, tick-borne encephalitis (TBE) is now considered an international health concern, and the most important and widespread viral disease transmitted by ticks in Europe. The number of reported TBE cases continues to increase in many endemic regions, and new foci have been identified. Increases in travel, access to high-risk areas, and the pursuit of leisure activities within TBE-endemic areas are placing more people at risk of TBE. Travellers from non-endemic regions are often unaware of the risk of acquiring TBE and therefore many travellers are not protected against TBE. Active immunization is the most effective way to avoid TBE and its potentially life-threatening sequelae. After a tick bite, no post-exposure treatment including active/passive vaccination is available or recommended in the immunologically naive patient. Available vaccines have undergone a series of modifications and improvement in both composition (with special formulations for children) and schedules to further enhance the safety of immunization and to meet the needs of vaccinees. Efforts to develop internationally recognized recommendations for TBE vaccination for travellers are underway.

Tick-borne encephalitis (TBE) is an important, vaccine-preventable arthropod-borne disease, causing severe illness in children too. In order to evaluate the immune response to different licensed primary immunization schedules, a total of 294 children aged 1 to 11 years of age were enrolled in a randomized, controlled, multi-center trial. The subjects were vaccinated with the pediatric formulation of a TBE vaccine (Encepur children) according to the conventional schedule (Group C; N = 73, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M; N = 139, vaccination on days 0, 21 and 300), or the rapid schedule (Group R; N = 82, vaccination on Days 0, 7 and 21). Antibody titers as measured by neutralization-test (NT) and ELISA were determined on Days 0, 42, 180, 300, and 321. The demographic data of the study groups were similar. Most subjects (97%-100%) reached an NT titer of at least 1:10 on Day 42. On Day 42, the highest NT geometric mean titers (GMTs) were reached in Group C. In Group C and Group M, titers declined up to Day 300. Until Day 300, the highest NT-GMTs were maintained in Group R, notably without a decline compared to Day 42. Group M reached titers similar to Group R on Day 42, but these titers declined by 50% up to Day 180. Similar to the NT, on Day 42 highest geometric mean concentrations (GMCs) as measured by ELISA across all groups were reached in Group C. In all groups, titers declined until Day 300. On Day 300, GMC ELISA of Group R was higher compared to Group C and Group M. To conclude, the rapid immunization schedule in children not only provides fast protection but also leads to stable titers as measured by NT for at least 300 days after vaccination.

ecent cases of human rabies imported to Eu-rope by travelers visiting India and Morocco demonstrate the relevance and value of receiving proper education regarding rabies prevention, in-cluding both preexposure vaccination and postex-posure prophylaxis, prior to leaving for canine rabies – endemic countries. 1,2 This is especially rele-vant for travelers planning on visiting countries in Asia and Africa where the majority of human rabies cases occur. 3 Modern cell culture vaccines recommended by the World Health Organization (WHO), including purifi ed chick embryo cell vac-cine (PCECV), purifi ed Vero cell rabies vaccine, and human diploid cell rabies vaccine (HDCV), provide a safe means by which travelers can be pro-tected in the event of exposure to rabies virus. These vaccines have been licensed for several decades, but there are limited published data regarding the length of time after a person has received his or her primary rabies vaccination, for which they will continue to develop an anamnestic response after a booster dose of rabies vaccine has been adminis-tered. 4,5 The vaccination recommendations for a person who has been vaccinated previously with a cell culture rabies vaccine and is subsequently exposed to a rabid animal include the administra-tion of two booster doses of vaccine (one dose on day 0 and the other on day 3) without the adminis-tration of rabies immunoglobulin (RIG). However, the limited amount of available data has led to some confusion regarding booster recommendations in previously vaccinated persons who are subse-quently exposed to rabid animals. 6,7 To determine how long individuals would be able to mount an anamnestic response after primary vac-cination, we contacted all veterinarians who had ini-tially received PCECV as students enrolled in a clinical trial initiated in 1986. 8 The veterinarians who agreed to participate in this booster study veri-fi ed and confi rmed that they had not received a rabies booster vaccination for 14 years since the clin-ical trial was completed, and all agreed to provide their serum samples for serological evaluation before and after receiving a booster dose of rabies vaccine. In the initial clinical trial conducted in 1986, 78 individuals were vaccinated with either HDCV or PCECV intramuscularly or intradermally as a pri-mary three-dose series. 8 In 1988, 68 of the 78 subjects received a single 1.0 mL of PCECV in tramuscularly. After the booster dose in 1988, the mean titer for subjects who received intradermal dosage initially was 1,106 (range: 270 – 6,800) and for subjects who received intramuscular dosage for their initial series was 1,859 (range: 1,100 – 9,500). For comparison purposes, a reciprocal titer of 1:25 is approximately equal to a titer of 0.5 IU/mL. Fourteen years later, 15 of those who initially received PCECV and a dose of intramuscular booster 1 year after their primary se-ries and who had not received any additional rabies vaccination since the 1988 booster were enrolled in this study. After approval of the study by the ethics committee and obtaining informed consent from the subjects, a blood sample was obtained and a single

Currently, two intradermal (ID) regimens for rabies post-exposure prophylaxis (PEP) are recommended by WHO and used in countries where approved by national authorities: the Thai Red Cross (TRC) two-site ID regimen and the eight-site ID regimen. Besides these WHO recommended schedules, a new economical four-site ID regimen was evaluated that reduces the cost of PEP by up to 80%, when compared with the standard intramuscular Essen regimen, reduces the number of visits required for the patients when compared with the TRC regimen, and is more convenient than the eight-site regimen. To determine the immunogenicity of the ID four-site PEP regimen (4-0-2-0-1-1), 180 healthy volunteers were randomized to receive 0.1 mL volumes of PCECV or PVRV administered ID over both left and right shoulders and both deltoid regions on day 0, both deltoid regions on day 7 and over one deltoid region on days 30 and 90. Regardless of the vaccine, every subject developed rabies virus neutralizing antibody (RVNA) titers above 0.5 IU/mL by day 14, as determined by rapid fluorescent focus inhibition test (RFFIT) using a homologous test system. Two weeks after the last dose of vaccine, RVNA titers were all above 0.5 IU/mL (day 104). Geometric mean titers were similar throughout the study period. Both vaccines were well tolerated. These results demonstrate that a new four-site ID PEP regimen is a cost-effective and convenient alternative to IM (Essen or Zagreb) or ID (TRC or eight-site) regimens, especially using a 1 mL vial of vaccine (PCECV).

To determine the minimum vaccine potency per intradermal dose required to elicit an adequate immune response using the Thai Red Cross (TRC) regimen (2-2-2-0-1-1), healthy volunteers received 0.1 mL volumes of PCECV containing decreasing amounts of antigen. Subjects also received HRIG to evaluate potential interference with antibody production. Results indicated that when each 0.1 mL intradermal dose of PCECV contained antigen corresponding to 0.32 IU per intramuscular dose, every subject had titers above 0.5 IU/mL by day 14. These results confirm that the current World Health Organization (WHO) recommendations for vaccine potency (2.5 IU per intramuscular dose) are sufficient for use in the Thai Red Cross intradermal regimen.

Purified chick embryo cell rabies vaccine (PCECV) administered as 0.1 ml intradermally according to the Thai Red Cross (TRC) regimen could reduce the cost of PEP by up to 84% when compared to the traditional five-dose Essen regimen. To confirm the efficacy of 0.1 ml of PCECV using the TRC regimen, a clinical trial was conducted in 113 patients presenting with category III exposures from confirmed rabid animals at two bite referral centres in the Philippines. Patients were monitored monthly for 1 year after exposure. PCECV was well tolerated, no vaccine-related serious adverse events occurred and all patients were alive 1 year after their initial exposure.

In order to evaluate the need for further booster immunizations, 222 subjects aged 20-52 years, who had received the first booster dose with a new tick-borne encephalitis (TBE) vaccine in a preceding study, were invited for a serological follow-up. A total of 191 and 182 adult subjects were analyzed for the persistence of neutralizing TBE antibodies at 1 and 2 years following the first booster immunization, respectively. Both serological follow-ups revealed high levels of neutralizing TBE antibodies in more than 99% of subjects. Although an expected decline of the respective geometric mean titers (GMTs) was noted after booster immunization, the titers were still far above the values noted after primary immunization at the 2-year follow-up. The kinetic curve clearly indicates a longer persistence of neutralizing TBE antibodies than currently expected. To conclude, these results suggest that the administration of a further booster dose 3 years after the first one (according to current recommendations) does not seem to be necessary in this study population.

Haemophilus influenzae type b (Hib) infection remains a major public health problem in the developing world. We evaluated the safety and immunogenicity of a new PRP-CRM197 conjugate Hib vaccine (Vaxem Hib, Chiron Vaccines), compared with the HibTITER vaccine (Wyeth-Lederle Vaccines), following the World Health Organisation (WHO)'s accelerated schedule which allows 4-week intervals between doses.A phase II, observer-blind, multicentre, randomised, controlled, non-inferiority study.In total, 331 babies were immunised with either Vaxem Hib (N = 167) or HibTITER (N = 164) vaccine at 6, 10 and 14 weeks of age, in parallel with oral polio, diphtheriatetanus-pertussis and hepatitis B vaccines. Post-immunisation reactions were recorded after each immunisation and at follow-up visits. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assays (ELISAs) before and 1 month after the third immunisation.Overall, there was no significant difference in the anti-PRP levels between the two groups. One month after the third immunisation, 76% of vaccinees in the Vaxem Hib group and 70% in the HibTITER group had anti-PRP antibody titresor = 1.0 microgram/ml, while 96% of the Vaxem Hib group and 90% of the HibTITER group demonstrated anti-PRP antibody titresor = 0.15 microgram/ml. The geometric mean titre at day 90 was 3.77 micrograms/ml for the Vaxem Hib and 3.0 micrograms/ml for the HibTITER groups. Although the Vaxem Hib vaccine produced more redness (6% versus 1%; p = 0.006) and swelling (5% versus 1%, p = 0.037), overall it was well tolerated compared with the HibTITER vaccine. There was no significant difference in vaccine-related elevated temperature (or = 38 degrees C) between the two groups (p = 0.11).Both vaccines showed comparable safety and immunogenicity profiles when administered to South African babies at 6, 10 and 14 weeks of age.

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.

The aim of this study was to evaluate the effectiveness of the influenza vaccine used at the Proelmed Medical Center, Poland during the influenza season 1998-1999. The study randomised patients attending the Proelmed Medical Center, Poland to receive influenza vaccination or not. Volunteers were monitored for the following 6 months by interviews at which systemic and local symptoms were recorded. 193 volunteers were randomised to receive influenza vaccine and 206 to the control group. In the vaccinated group, 7 cases (3.7%) of influenza were recorded, compared to 59 cases (28.6%) in the unvaccinated group. Respiratory disease other than influenza occurred in 29.5% of the vaccinated group and 34.5% of the unvaccinated group. Vaccinated patients had a total of 62 days off sick due to influenza, compared to 467 days for the unvaccinated patients. No unexpected adverse events were reported. The influenza vaccine used is highly efficacious in protecting against influenza infection leading to absenteeism from work, and has a good safety profile.

Background: The elderly are at a higher risk of morbidity and mortality associated with influenza infection than younger adults, but get less protection from conventional vaccination. Objective: We conducted a meta-analysis of all available data from clinical trials in the elderly on a recently introduced MF59-adjuvanted influenza vaccine to determine its immunogenicity and safety in subjects with underlying chronic disease who are at highest risk of influenza infection. Methods: Data on immunogenicity and safety from 3,600 subjects immunized with either the MF59-adjuvanted or conventional comparator influenza vaccine in 13 clinical trials were analyzed by disease history. Geometric mean haemagglutination inhibition titres (GMTs) and differences between the vaccine groups were compared using two-way analysis of variance. Differences between vaccine groups in the percentages with post-immunization reactions were assessed using chi-squared test and Fischer’s exact test. Results: At 28 days the adjuvanted:comparator GMT ratio for the A/H3N2 antigen was 1.18 in healthy elderly subjects and 1.43 in elderly subjects with chronic disease (p = 0.004). The respective GMT ratios were 1.17 versus 1.37 for the B antigen (p = 0.065) and 1.10 versus 1.17 for the A/H1N1 antigen (p = 0.41). Although post-immunization reactions were more common in the group receiving the adjuvanted vaccine, these were predominantly mild and transient, and none were serious. Conclusions: The MF59-adjuvanted influenza vaccine is more immunogenic in elderly subjects than conventional non-adjuvanted influenza vaccines and especially so in those with chronic disease. Therefore, since its safety profile is clinically acceptable, this adjuvanted vaccine represents an excellent option for influenza immunization of elderly subjects at highest risk of complications.

Objective: To investigate the immunogenicity of and tolerance towards the preservative-free inactivated influenza vaccine Begrivac®. Methods: In this prospective, single-centre, non-controlled study, efficacy was evaluated by the change in influenza antibody titre from baseline to 21 days following vaccination. The safety variables included post-injection reactions and adverse events. Blood samples were taken on day 21 and the antibody titre assayed by haemagglutination inhibition test. Results: All three of the European efficacy requirements for influenza vaccines are satisfied by the new preservative-free vaccine described in this report. The mean geometric increase in titre and the proportion of vaccination responders were greater in patients of the adult group than in the elderly. Thus for strain A/Beijing/262/95 66% of subjects seroconverted and 28% showed a significant increase in antibody titre (total 94%), compared to a total of 45 patients (76%) in the elderly group. For strain A/Sydney/5/97 the corresponding figures were total 55 (90%) adult and 47 (80%) elderly, and for B/Beijing/184/93 46 (75%) adult and 31 (53%) elderly. Sixty four subjects (53%) reported adverse events, mainly local reactions at the injection site such as pain, erythema and induration, and systemic reactions such as headache and fatigue. Conclusions: The absence of preservative in this novel vaccine preparation does not have any detectable impact on its efficacy or safety and tolerability profile.

In a prospective, controlled, randomized, multicenter study the immunogenicity and tolerance of a single vaccination (day 0) and two (day 0, 28) booster vaccinations against diphtheria were compared in subjects who had received their last diphtheria vaccination more than 10 years ago. 415 subjects received the first booster vaccination, and 203 were vaccinated twice. The geometric mean diphtheria antitoxin concentration after the first booster (day 28) was 2.354 I.U./ml, and after the second booster (day 56) 2.238 I.U./ml. Prior to the first vaccination 48.9% of the subjects had a diphtheria antitoxin level below 0.1 I.U./m; after the first and second boosters 95.4% and 97.5% of subjects, respectively, showed a level of at least 0.1 I.U./ml. A clear serological effect of a second booster 4 weeks after the first one could not be demonstrated.