The Diverse Spectrum of Invasive Meningococcal Disease in Pediatric and Adolescent Patients: Narrative Review of Cases and Case Series.

INTRODUCTION: Invasive meningococcal disease (IMD) is a potentially life-threatening disease caused by Neisseria meningitidis infection. We reviewed case reports of IMD from newborns, infants, children, and adolescents, and described the real-life clinical presentations, diagnoses, treatment paradigms, and clinical outcomes. METHODS: PubMed and Embase were searched for IMD case reports on patients aged ≤ 19 years published from January 2011 to March 2023 (search terms "Neisseria meningitidis" or "invasive meningococcal disease", and "infant", "children", "paediatric", pediatric", or "adolescent"). RESULTS: We identified 97 publications reporting 184 cases of IMD, including 25 cases with a fatal outcome. Most cases were in adolescents aged 13-19 years (34.2%), followed by children aged 1-5 years (27.6%), children aged 6-12 years (17.1%), infants aged 1-12 months (17.1%), and neonates (3.9%). The most common disease-causing serogroups were W (40.2%), B (31.7%), and C (10.4%). Serogroup W was the most common serogroup in adolescents (17.2%), and serogroup B was the most common in the other age groups, including children aged 1-5 years (11.5%). The most common clinical presentations were meningitis (46.6%) and sepsis (36.8%). CONCLUSIONS: IMD continues to pose a threat to the health of children and adolescents. While this review was limited to case reports and is not reflective of global epidemiology, adolescents represented the largest group with IMD. Additionally, nearly half of the patients who died were adolescents, emphasizing the importance of monitoring and vaccination in this age group. Different infecting serogroups were predominant in different age groups, highlighting the usefulness of multivalent vaccines to provide the broadest possible protection against IMD. Overall, this review provides useful insights into real-life clinical presentations, treatment paradigms, diagnoses, and clinical outcomes to help clinicians diagnose, treat, and, ultimately, protect patients from this devastating disease.

Meningococcal B Immunisation in Adults and Potential Broader Immunisation Strategies: A Narrative Review.

Recombinant vaccines against invasive meningococcal disease due to Neisseria meningitidis serogroup B (MenB) have shown substantial impact in reducing MenB disease in targeted populations. 4CMenB targets four key N. meningitidis protein antigens; human factor H binding protein (fHbp), Neisserial heparin binding antigen (NHBA), Neisseria adhesin A (NadA) and the porin A protein (PorA P1.4), with one or more of these expressed by most pathogenic MenB strains, while MenB-FHbp targets two distinct fHbp variants. While many countries recommend MenB immunisation in adults considered at high risk due to underlying medical conditions or immunosuppression, there are no recommendations for routine use in the general adult population. We reviewed the burden of MenB in adults, where, while incidence rates remain low (and far lower than in young children < 5 years of age at greatest risk), a substantial proportion of MenB cases (20% or more) is now observed in the adult population; evident in Europe, Australia, and in the United States. We also reviewed immunogenicity data in adults from clinical studies conducted during MenB vaccine development and subsequent post-licensure studies. A 2-dose schedule of 4CMenB generates hSBA titres ≥ 1:4 towards all four key vaccine target antigens in up to 98-100% of subjects. For MenB-FHbp, a ≥ fourfold rise in hSBA titres against the four primary representative test strains was observed in 70-95% of recipients following a 3-dose schedule. While this suggests potential benefits for MenB immunisation if used in adult populations, data are limited (especially for adults > 50 years) and key aspects relating to duration of protection remain unclear. Although a broader adult MenB immunisation policy could provide greater protection of the adult population, additional data are required to support policy decision-making.

A comprehensive review of clinical and real-world safety data for the four-component serogroup B meningococcal vaccine (4CMenB).

INTRODUCTION: Neisseria meningitidis causes invasive meningococcal disease and, globally, significant morbidity, with serogroup B (MenB) being the most common cause of endemic disease and outbreaks in several regions. Extensive use of the four-component serogroup B meningococcal vaccine (4CMenB; Bexsero, GSK) and its inclusion in immunization programs in several countries have generated substantial safety data during the 9 years since its first authorization in 2013. AREAS COVERED: 4CMenB safety data from clinical trials and post-marketing surveillance studies (2011 to 2022), and spontaneously reported adverse events of medical interest from the GSK global safety database. We discuss these safety findings in relation to the benefit of 4CMenB vaccination and implications for further enhancing vaccine confidence. EXPERT OPINION: 4CMenB has been consistently well tolerated across clinical trials and post-licensure surveillance studies, despite a higher incidence of fever reported in infants than with other pediatric vaccines. Surveillance data have not identified any significant safety issues, consistent with an acceptable safety profile of 4CMenB. These findings highlight the need to balance the risk of relatively common, transient, post-immunization fever with the benefit of affording protection that reduces the risk of uncommon but potentially fatal meningococcal infection.

The four-component serogroup B meningococcal vaccine 4CMenB (Bexsero®, GSK) was licensed in 2013 and has acquired substantial safety evidence through clinical trial and real-world data. Availability of real-world and clinical 4CMenB safety evidence is important to help address vaccination hesitancy. This comprehensive review of safety data, from 9 years of 4CMenB use including recent data from the real world, shows no significant safety issues in a variety of age groups. Data show that transient fever may occur after vaccination. Invasive meningococcal disease, although rare, can be life-threatening. Abundant safety data from this review can help reassure individuals and healthcare providers on the use of 4CMenB.

Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.

OBJECTIVES: 4CMenB is a broadly protective vaccine against invasive meningococcal capsular group B disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, effectiveness and impact data are now available. We comprehensively reviewed all available real-world evidence gathered from use of 4CMenB since licensure. RESULTS: Data from 7 countries provide evidence of effectiveness and impact across different healthcare settings and age-groups, including national/regional immunization programs, observational studies and outbreak control. At least 2 4CMenB doses reduced MenB IMD by 50%-100% in 2-month to 20-year-olds depending on length of follow-up. Estimates of vaccine effectiveness in fully vaccinated cohorts ranged from 59%-100%. The safety profile of 4CMenB administered in real-world settings was consistent with pre-licensure clinical trial data. CONCLUSION: MenB IMD is an uncommon but life-threatening disease with unpredictable epidemiology. The substantial body of data demonstrating 4CMenB effectiveness and impact supports its use in IMD prevention. The results reinforce the importance of direct protection of the highest risk groups; infants/young children and adolescents. Direct protection via routine infant immunization with catch-up in young children and routine adolescent vaccination could be the preferred option for MenB disease control. A Video Abstract linked to this article is available on Figshare: https://doi.org/10.6084/m9.figshare.14546790.

Methods to evaluate serogroup B meningococcal vaccines: From predictions to real-world evidence.

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.

Persistence of the immune response after 4CMenB vaccination, and the response to an additional booster dose in infants, children, adolescents, and young adults.

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.

Del genoma de un patógeno a una vacuna efectiva: la vacuna de cuatro componentes frente a los meningococos del serogrupo B / From a pathogen's genome to an effective vaccine: the four-component meningococcal serogroup B vaccine

La enfermedad meningocócica invasiva (EMI), causada por la bacteria Neisseria meningitidis, supone una mortalidad y morbilidad significativas. La incidencia de la enfermedad alcanza el máximo entre lactantes <1 año y niños pequeños en todo el mundo. En Europa, el serogrupo B de N. meningitidis es responsable de más del 50 % de todos los casos de EMI, mientras que en Latinoamérica la mayoría de los casos de EMI se deben a los serogrupos B o C. El desarrollo de una vacuna efectiva frente al serogrupo B ha supuesto un reto para los investigadores a lo largo de más de medio siglo. Los polisacáridos capsulares del serogrupo B no eran antígenos vacunales apropiados, y el éxito de las vacunas de vesículas de la membrana externa (OMV) se limitaba a las cepas bacterianas homólogas. La vacunología inversa permitió desarrollar una vacuna meningocócica de 4 componentes que incluía tres antígenos novedosos y las OMVs (4CMenB). Cada componente de la vacuna posee una diana distinta. La vacuna 4CMenB ha sido autorizada basándose en datos de inmunogenicidad y seguridad, debido a que la baja incidencia de la enfermedad impide la realización de estudios de eficacia clínica. El análisis de anticuerpos bactericidas en suero con complemento humano (hSBA) mide los anticuerpos funcionales del suero de los sujetos vacunados (es decir, la inmunogenicidad vacunal) y constituye un correlato de protección aceptado. La cobertura de cepas vacunales se ha evaluado tanto mediante el análisis de la hSBA, como mediante otro método más conservador denominado Sistema de Tipificación de Antígenos Meningocócicos (MATS). Desde 2013, se han recogido datos de efectividad en vida real de 4CMenB. La vacuna resultó efectiva en el control de brotes de Norteamérica y los datos recientes de introducción de la vacuna en el programa nacional de vacunación de lactantes del Reino Unido, han revelado una efectividad vacunal del 82,9 % tras las dos primeras dosis, junto a un perfil de seguridad aceptable

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target.4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i. e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile

Optimizing the timing of 4CMenB vaccination in adolescents and young adults based on immune persistence and booster response data.

INTRODUCTION: Meningococcal disease has an incidence peak spread over several years during adolescence and young adulthood in the United States. Meningococcal serogroup B (MenB) vaccines have been introduced relatively recently and may help protect individuals in these age groups. Currently there is insufficient long-term experience to determine the duration of disease protection after any MenB vaccine. Understanding antibody persistence after primary vaccination and responses to booster can help inform MenB vaccination strategies and optimize disease prevention. Areas covered: Four studies in adolescents/young adults vaccinated with meningococcal B vaccine 4CMenB were reviewed with the aim to compare findings across studies and draw key learnings. The studies varied by geographic location, population characteristics, and timing of antibody measurement relative to primary vaccination. Expert opinion: Antibody persistence data for 4CMenB are substantial, extending 7.5 years post-primary vaccination. Vaccination at age 16-18 years may help protect adolescents throughout their highest age-based risk period. Similar robust responses to a single booster dose were observed 4 and 7.5 years after primary vaccination. In outbreak settings it is beneficial to have received prior vaccination; residual circulating antibodies may provide protection, and a single dose induces booster responses within 7 days, which is quicker than administration of a 2-dose series to vaccine-naïve individuals.

Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study.

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.

Multicomponent meningococcal B vaccination (4CMenB) of adolescents and college students in the United States.

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.

Combined administration of MF59-adjuvanted A/H5N1 prepandemic and seasonal influenza vaccines: long-term antibody persistence and robust booster responses 1 year after a one-dose priming schedule.

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.).

Homologous and heterologous antibody responses to a one-year booster dose of an MF59(®) adjuvanted A/H5N1 pre-pandemic influenza vaccine in pediatric subjects.

BACKGROUND: 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. OBJECTIVES: 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. RESULTS: 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. SUBJECTS AND METHODS: 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. CONCLUSIONS: 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.

Effective influenza vaccines for children: a critical unmet medical need and a public health priority.

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.

Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults.

OBJECTIVE: We performed a phase II randomized, controlled, open-label, single-center study (Centros de Estudios de Infectología Pediátrica, Colombia) to examine the feasibility of combined administration of seasonal and MF59-adjuvanted A/H5N1 influenza vaccines using extemporaneous mixing or simultaneous administration. METHODS: The primary objective of the study was to assess the immunogenicity of seasonal influenza and A/H5N1 vaccines using European licensure criteria (Committee for Medicinal Products for Human Use [CHMP]); the secondary objective was to assess vaccine reactogenicity and safety. RESULTS: In 401 healthy 18-40-year-old subjects, both vaccines were immunogenic in all settings; the vaccine for seasonal influenza met all CHMP criteria, unaffected by coadministration of A/H5N1 vaccine in separate or mixed injections. Likewise, the immunogenicity of A/H5N1 vaccine was unaffected by seasonal influenza vaccination, with hemagglutination inhibition seroprotection rates of 28%-40% after 1 dose and 67%-80% after 2 doses, sufficient to meet CHMP criteria. Solicited local and systemic adverse events were mainly mild to moderate. No vaccine-related serious adverse events were reported during the study period. CONCLUSIONS: These data demonstrate that seasonal and MF59-adjuvanted A/H5N1 influenza vaccines can be given as a mixed injection or by simultaneous separate injections without affecting immunogenicity or safety, supporting the feasibility of incorporating prepandemic MF59-adjuvanted A/H5N1 vaccines into seasonal influenza vaccination programs and the development of tetravalent influenza vaccines, including pandemic strains. Clinical Trials Registration. NCT00481065.

Passive surveillance of adverse events of an MF59-adjuvanted H1N1v vaccine during the pandemic mass vaccinations.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The analyses of the spontaneously reported adverse events support the good safety profile of the MF59-adjuvanted H1N1v pandemic influenza vaccine.

Immunogenicity and safety of MF59-adjuvanted H5N1 influenza vaccine from infancy to adolescence.

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 <36 months, 3 to <9 months, and 9 to <18 years of age were assigned randomly to receive 2 doses of either a MF59-adjuvanted H5N1 vaccine (7.5 µg/dose) or a MF59-adjuvanted trivalent seasonal influenza control vaccine (15 µg/dose for each antigen). Immunogenicity against the A/Vietnam/1194/2004-like vaccine strain was measured before and 3 weeks after the 2-dose primary series, through hemagglutination inhibition (HI), single radial hemolysis (SRH), and microneutralization. Local and systemic reactions were recorded. 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.

A heterologous MF59-adjuvanted H5N1 prepandemic influenza booster vaccine induces a robust, cross-reactive immune response in adults and the elderly.

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.

Pseudoparticle neutralization is a reliable assay to measure immunity and cross-reactivity to H5N1 influenza viruses.

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.