Astrid Borkowski

Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial.

BACKGROUND Antigen sparing is regarded as crucial for pandemic vaccine development because worldwide influenza vaccine production capacity is limited. Adjuvantation is an important antigen-sparing strategy. We assessed the safety and immunogenicity of a recombinant H5N1 split-virion vaccine formulated with a proprietary adjuvant system and investigated whether it can induce cross-reactive immunity. METHODS Two doses of an inactivated split A/Vietnam/1194/2004 NIBRG-14 (recombinant H5N1 engineered by reverse genetics) vaccine were administered 21 days apart to eight groups of 50 volunteers aged 18-60 years. We studied four antigen doses (3.8 microg, 7.5 microg, 15 microg, and 30 microg haemagglutinin) given with or without adjuvant. Blood samples were collected to analyse humoral immune response. Adverse events were recorded up through study day 51. Safety analyses were of the whole vaccinated cohort and immunogenicity analyses per protocol. This trial is registered with the ClinicalTrials.gov, number NCT00309634. FINDINGS All eight vaccine formulations had a good safety profile. No serious adverse events were reported. The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature. The adjuvanted formulations were significantly more immunogenic than the non-adjuvanted formulations at all antigen doses. At the lowest antigenic dose (3.8 microg), immune responses for the adjuvanted vaccine against the recombinant homologous vaccine strain (A/Vietnam/1194/2004 NIBRG-14, clade 1) met or exceeded all US Food and Drug Administration and European Union licensure criteria. Furthermore, 37 of 48 (77%) participants receiving 3.8 microg of the adjuvanted vaccine seroconverted for neutralising antibodies against a strain derived by reverse genetics from a drifted H5N1 isolate (A/Indonesia/5/2005, clade 2). INTERPRETATION Adjuvantation conferred significant antigen sparing that could increase the production capacity of pandemic influenza vaccine. Moreover, the cross-clade neutralising antibody responses recorded imply that such a vaccine could be deployed for immunisation before a pandemic.

Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children

BACKGROUND The efficacy of inactivated influenza vaccines is known to be poor in infants and young children. METHODS We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay. RESULTS Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups. CONCLUSIONS Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).

Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant.

Background: Children have high morbidity and hospitalization rates from seasonal influenza. Meta-analyses suggest that conventional inactivated influenza vaccines are of low efficacy in young children, making vaccines that induce greater and broader immune protection in this vulnerable population a medical priority. Adjuvanted influenza vaccines may offer a solution. Subjects and Methods: Unprimed healthy children (6 to <36 months) were enrolled in an observer-blinded study and randomly assigned to receive 2 doses of MF59-adjuvanted vaccine (Sub/MF59, n = 130) or nonadjuvanted split vaccine (split, n = 139); subgroups of these (n = 43 and 46, respectively) received a booster dose 1 year later. Safety and clinical tolerability were assessed after each dose. Hemagglutination inhibition antibody titers were measured against influenza A and B strains included in the formulation of the vaccines and against mismatched strains. Results: Clinical tolerability and safety were generally comparable between vaccine groups, though some transient, mild solicited reactions were more frequent in the Sub/MF59 group. Postvaccination hemagglutination inhibition antibody titers to all 3 vaccine strains were significantly higher with Sub/MF59 than with split vaccine (all comparisons P < 0.001) after each of the 3 vaccine doses. In addition, Sub/MF59 induced significantly higher cross-reactivity against A/H3N2 and A/H1N1 mismatched strains. Conclusion: MF59-adjuvanted influenza vaccine was well tolerated in healthy young children after each of 3 doses and induced greater, longer-lasting, and broader immune responses than a nonadjuvanted split vaccine. The enhanced immunogenicity of the adjuvanted vaccine was most evident in very young children and for the B vaccine strain.

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. The Sub/MF59 influenza vaccine was safe and well tolerated following the booster vaccination. Pre-booster HI antibody titers were consistently higher in the Sub/MF59 group than in the comparator group, confirming significantly longer persistence of antibodies after priming with Sub/MF59 vaccine. Post-booster immune responses were significantly higher in the Sub/MF59 group compared with the split group, especially vs. the influenza B strain, which is epidemiologically relevant in the pediatric population. Altogether, these data further support the potential use of MF59-adjuvanted influenza vaccine as a safe and highly immunogenic influenza vaccine for young children.

Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study

Objective To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age. Design Observational study. Setting Secondary and tertiary educational institutions in the United Kingdom. Participants Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines. Intervention Serum obtained by venepuncture. Main outcome measures Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody. Results Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P<0.0001 for both comparisons). Within these age bands, no significant difference in geometric mean titres of bactericidal antibody between recipients of the different serogroup C meningococcal vaccines was seen. More than 70% of participants had received a vaccine from one manufacturer; in this cohort, geometric mean titres were higher in those immunised at aged 10 years or above than in those immunised before the age of 10. Conclusions Higher concentrations of bactericidal antibody are seen five years after immunisation with serogroup C meningococcal vaccine at age 10 years or above than in younger age groups, possibly owing to immunological maturation. This provides support for adolescent immunisation programmes to generate sustained protection against serogroup C meningococcal disease not only for the vaccine recipients but also, through the maintenance of herd immunity, for younger children.

The Magnitude of the Antibody and Memory B Cell Responses during Priming with a Protein-Polysaccharide Conjugate Vaccine in Human Infants Is Associated with the Persistence of Antibody and the Intensity of Booster Response

Rapid waning of anti-polysaccharide bactericidal Ab and vaccine effectiveness is observed following infant immunization with the serogroup C meningococcal (MenC) glycoconjugate vaccine. This is despite the demonstrable presence of immunological memory. Persistence of functional Ab, therefore, appears to be the key determinant of MenC conjugate vaccine effectiveness. Ab persistence is thought to depend in the short term on the survival of plasma cells generated during priming and in the longer term on the production of new Ab secreting cells from memory B cells. In this study, we found a strong association between the level of MenC-specific Ab and the frequency of memory B cells measured at 5 mo of age (1 mo after 3-dose primary immunization with MenC conjugate vaccine), and the persistence of functional Ab at one year of age. These findings suggest that these two parameters are good markers of B cell responses to priming and can be used as predictors of long term humoral immunity induced by glycoconjugate vaccines received in early infancy.

Serogroup C Meningococcal Glycoconjugate Vaccine in Adolescents: Persistence of Bactericidal Antibodies and Kinetics of the Immune Response to a Booster Vaccine More Than 3 Years after Immunization

BACKGROUND The persistence of protection from meningococcal disease following immunization with serogroup C meningococcal (MenC) glycoconjugate vaccines in infancy is short-lived. The duration of protective immunity afforded by these vaccines in other at-risk age groups (i.e., adolescents and young adults) is not known. We evaluated the persistence of bactericidal antibodies following immunization with a MenC glycoconjugate vaccine (MenCV) in adolescents and the kinetics of immune response to a meningococcal AC plain polysaccharide vaccine (MenPS) challenge or a repeat dose of MenCV. METHODS We conducted a randomized comparative trial of 274 healthy 13-15-year-olds from whom a total of 4 blood samples were obtained (prior to administration of a dose of MenPS or MenCV, again on 2 further occasions at varying times from days 2-7 after vaccination, and finally on day 28 after vaccination. The correlate of protection was a serum bactericidal assay titer > or = 8 (with a serum bactericidal assay using human complement). RESULTS A serum bactericidal assay using human complement titer > or = 8 was observed in 75% of participants at baseline (mean age, 14.5 years; mean time since routine MenCV vaccination, 3.7 years). No increase in serum bactericidal assay geometric mean titers was detected until day 5 after administration of MenPS. Geometric mean titers following administration of MenCV were significantly higher than those observed following administration of MenPS, at days 5, 7, and 28. CONCLUSIONS This study showed sustained levels of bactericidal antibodies for at least 3 years after immunization of adolescents with MenCV. After challenge of immunized adolescents with MenPS, there was no increase in serum bactericidal assay observed until day 5 after vaccination, indicating that immunological memory may be too slow to generate protection against this potentially rapidly invasive organism.

Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial

BACKGROUND Dose-sparing strategies and new production technologies will be necessary to produce adequate supplies of vaccines for pandemic influenza. One approach is to include adjuvant, which can reduce the amount of antigen required for immunization and stimulate cross-reactive responses to drifted variants of novel viruses. Dose-sparing studies of adjuvant, itself a finite resource, have not previously been reported for H5N1 vaccine development. METHODOLOGY/PRINCIPAL FINDINGS A total of 753 healthy 18-40-year-old adults were randomized to one of 12 groups (N approximately 60/group) to receive two intramuscular doses, 21 days apart, of 3.75, 7.5 or 15 microg of cell culture grown influenza A/H5N1 hemagglutinin (A/Indonesia/5/2005 (H5N1)/PR-8-IBCDC-RG2), each dose level formulated with 0%, 25%, 50% or 100% of the MF59 dose contained in licensed influenza vaccine. 752 subjects actually received one dose, and 695 a second dose. Serum hemagglutination inhibition and neutralizing antibody levels, were determined before and 21 days after each dose. Safety and reactogenicity were assessed by self-completed diary cards. Nonadjuvanted H5N1 formulations were poorly immunogenic, but antibody responses were significantly enhanced by all doses of MF59 for each antigen level. The 3.75 microg H5N1 containing 50% MF59 satisfied the European criteria for pandemic vaccine licensure. All formulations were well tolerated, although MF59 dose-dependent increases in the frequency of injection site pain were observed. The frequencies of injection site and systemic reactions were lower after receipt of the second dose of vaccine. No vaccine-related SAE was reported. CONCLUSIONS Dose-sparing of both antigen and adjuvant is possible without compromising immunogenicity, while improving reactogenicity and is a promising strategy that will expand the availability of vaccines for global control of pandemic influenza.

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.

Safety and immunogenicity of an MF59®-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly ☆

BACKGROUND The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59(®)-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine. METHODS Healthy adult (18-60 years, n=3372) and elderly (≥61 years, n=275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal(®)) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study. RESULTS Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15μg antigen for each component strain. CONCLUSIONS Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.