Comparison of the Immunogenicity and Safety of the Conventional Subunit,MF59-Adjuvanted,and Intradermal Influenza Vaccines in the Elderly

The influenza vaccination is known as the most effective method for preventing influenza infection and its complications in the elderly. Conventional subunit (Agrippal S1; Novartis), MF59-adjuvanted (Fluad; Novartis), and intradermal (IDflu15; Sanofi Pasteur) influenza vaccines are widely used throughout South Korea. However, few comparative studies evaluating the safety and immunogenicity of these vaccines are available. Prior to the beginning of the 2011-2012 influenza season, 335 healthy elderly volunteers randomly received one of three seasonal trivalent influenza vaccines, the conventional subunit, MF59-adjuvanted, or intradermal influenza vaccine. Serum hemagglutination-inhibiting antibody levels were measured at the time of vaccination and at 1 and 6 months after vaccination. Adverse events were recorded prospectively. A total of 113 conventional subunit, 111 MF59-adjuvanted, and 111 intradermal influenza vaccine volunteers were followed up during a 6-month postvaccination period. One month after vaccination, all three vaccines satisfied Committee for Medical Products for Human Use (CHMP) immunogenicity criteria for the A/H1N1 and A/H3N2 strains but not for the B strain. Compared with the subunit vaccine, the intradermal vaccine exhibited noninferiority, while the MF59-adjuvanted vaccine exhibited superiority. Furthermore, the MF59-adjuvanted vaccine was more immunogenic against the A/H3N2 strain than was the subunit vaccine up to 6 months postvaccination. The most common local and systemic reactions to the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines were pain at the injection site (7.1%, 10.8%, and 6.3%, respectively) and generalized myalgia (0.9%, 8.1%, and 5.4%, respectively). Local and systemic reactions were similar among the three vaccine groups. MF59-adjuvanted vaccine exhibited superior immunogenicity compared with a conventional subunit vaccine and had a comparable safety profile. For older adults, the MF59-adjuvanted vaccine is preferable for providing superior immunogenicity.     

Assessment of Antigen-Specific and Cross-Reactive Antibody Responses to an MF59-Adjuvanted A/H5N1 Prepandemic Influenza Vaccine in Adult and Elderly Subjects

Preparedness against an A/H5N1 influenza pandemic requires well-tolerated, effective vaccines which provide both vaccine strain-specific and heterologous, cross-clade protection. This study was conducted to assess the immunogenicity and safety profile of an MF59-adjuvanted, prepandemic influenza vaccine containing A/turkey/Turkey/01/2005 (H5N1) strain viral antigen. A total of 343 participants, 194 adults (18 to 60 years) and 149 elderly individuals (≥61 years), received two doses of the investigational vaccine given 3 weeks apart. Homologous and heterologous antibody responses were analyzed by hemagglutination inhibition (HI), single radial hemolysis (SRH), and microneutralization (MN) assays 3 weeks after administration of the first vaccine dose and 3 weeks and 6 months after the second dose. Immunogenicity was assessed according to European licensure criteria for pandemic influenza vaccines. After two vaccine doses, all three European licensure criteria were met for adult and elderly subjects against the homologous vaccine strain, A/turkey/Turkey/1/2005, when analyzed by HI and SRH assays. Cross-reactive antibody responses were observed by HI and SRH analyses against the heterologous H5N1 strains, A/Indonesia/5/2005 and A/Vietnam/1194/2004, in adult and elderly subjects. Solicited local and systemic reactions were mostly mild to moderate in severity and occurred less frequently in the elderly than in adult vaccinees. In both adult and elderly subjects, MF59-adjuvanted vaccine containing 7.5 μg of A/Turkey strain influenza virus antigen was highly immunogenic, well tolerated, and able to elicit cross-clade, heterologous antibody responses against A/Indonesia and A/Vietnam strains 6 weeks after the first vaccination.     

Comparison of the Long-Term Immunogenicity of Two Pandemic Influenza A/H1N1 2009 Vaccines,the MF59-Adjuvanted and Unadjuvanted Vaccines,in Adults

Since the first reports of the A/H1N1 virus in April 2009, the pandemic influenza virus spread globally and circulated for a long time. The primary method for the control of influenza is vaccination, but levels of influenza vaccine-induced antibody are known to decline rapidly during a 6-month period. In adults aged 18 to 64 years, we compared the long-term immunogenicity of two of the influenza A/H1N1 2009 monovalent vaccines, 3.75-μg MF59-adjuvanted vaccine and 15-μg unadjuvanted vaccine. The serum hemagglutinin inhibition (HI) titers were determined prevaccination and at 1, 6, and 10 months after vaccination. One hundred six (88.3%) of the 120 subjects were monitored for the entire 10-month period after receiving the influenza A/H1N1 2009 monovalent vaccine. There were 60 patients who received the unadjuvanted vaccine and 46 patients who received the MF59-adjuvanted vaccine. The seroprotection rates, seroconversion rates, and the geometric mean titer (GMT) folds fulfilled the criteria of the European Medicines Agency (EMA) for influenza A/California/7/2009 (H1N1) at 1 month after vaccination irrespective of the vaccine composition. Although the GMTs at 1 month postvaccination were somewhat higher in the unadjuvanted vaccine recipients than in the MF59-adjuvanted vaccine recipients, the difference was not significant (P = 0.29). The seroprotection rates at 6 and 10 months postvaccination were preserved above 70% but only in the MF59-adjuvanted vaccine recipients. In conclusion, low-dose MF59-adjuvanted influenza vaccine, even with 3.75 μg hemagglutinin antigen, might induce excellent long-term immunity that is comparable to the conventional dose of unadjuvanted vaccine among healthy adults aged 18 to 64 years.     

Adjuvanted Influenza Vaccine

black triangle Adjuvanted influenza vaccine is composed of 2 type A and 1 type B inactivated influenza subunits combined with an oil-and-water emulsion (MF59). Each dose contains 15microg haemagglutinin per strain. black triangle Adjuvanted influenza vaccine was immunogenic in elderly vaccinees and in younger adults after 1 to 3 consecutive annual injections. black triangle According to studies available to date, the adjuvanted vaccine was more immunogenic than the nonadjuvanted subunit or split virus vaccines and the virosomal vaccine for 1 to 3 of the 3 strains tested per injection. black triangle The immunogenic effect generally persisted for longer after the adjuvanted vaccine than the nonadjuvanted subunit vaccine in elderly recipients. black triangle The adjuvanted vaccine also appeared to be more effective than the nonadjuvanted subunit vaccine against antigenically different heterovariant strains in elderly vaccinees. black triangle The 28-day seroprotection rate in 4 studies was significantly greater after the adjuvanted vaccine for 1 or 2 of the 3 strains tested compared with the nonadjuvanted subunit vaccine and the virosomal vaccine and for 1 of 3 strains compared with the split virus vaccine. black triangle The incidence of systemic adverse events was generally low. Local reactions such as pain, erythema and induration occurred more frequently with the adjuvanted than the 2 nonadjuvanted or the virosomal vaccines; however, these were mild and transient.     

Serological responses in volunteers to inactivated trivalent subunit influenza vaccine: antibody reactivity with epidemic influenza A and B strains and evidence of a rapid immune response

A study of the immunogenicity of the inactivated trivalent subunit influenza vaccine for the 1989/90 season was performed in what proved to be an influenza epidemic year. One hundred student volunteers at The London Hospital Medical College participated in the study and the findings indicated that there was an excellent serological match between the epidemic strain of influenza A (H3N2) and the vaccine strain. Before vaccination, the geometric mean titre (GMT) to A/England/308/89, a representative H3N2 epidemic strain in the United Kingdom from the 1989/90 season, was 46. Post-vaccination the antibody levels rose and 99% of vaccinees had HI titres of greater than or equal to 40, the GMT being 131. The serological responses were also investigated against other circulating influenza A (H3N2 and H1N1) and B strains. Preliminary results of an evaluation of the rapidity of the immune response showed that in three of six subjects rises in HI antibody appeared within two days of vaccination.     

In vitro assessment of the allergenicity of novel MF59-adjuvanted pandemic H1N1 influenza vaccine produced in dog kidney cells

A licensed inactivated MF59-adjuvanted seasonal influenza vaccine (Optaflu) produced in canine kidney cells (MDCK 33016-PF) contained no egg proteins and did not trigger degranulation in rat basophilic leukemia (RBL) cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals. The cell-derived pandemic H1N1 influenza vaccine was also adjuvanted with the emulsion adjuvant MF59, and support for its similar safe use was sought. We sought to evaluate in vitro allergenicity of the MF59-adjuvanted cell-derived pandemic H1N1 influenza vaccine in subjects with dog allergy, with a mediator release assay. RBL-2H3 cells transfected with human Fcε receptor type 1 were sensitized with sera from adult dog-allergic subjects and stimulated with serial dilutions of pandemic H1N1 influenza vaccine and dog dander extract. β-N-hexosaminidase release (NHR) was used as a marker of RBL degranulation.. Median dog dander-specific IgE in 30 dog-allergic subjects was 27.7 kUA/L (range 10.1; > 100); and in 5 dog non-allergic subjects was < 0.35 kUA/L (UniCAP system). Median (range) maximum NHR in dog-allergic subjects was: pandemic H1N1 influenza vaccine 1.1% (0; 4.4) and dog dander 6.9% (0.7; 37.3), P < 0.001. In conclusion, MF59-adjuvanted pandemic H1N1 influenza vaccine produced in continuous canine kidney cells did not trigger degranulation in RBL cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals.     

Superior protection provided by a single dose of MF59-adjuvanted whole inactivated H5N1 influenza vaccine in type 1 diabetic mice

Vaccination is the preferred strategy for the prevention of influenza virus infection. Both H5N1 subunit and split vaccines have shown poor immunogenicity in clinical trials thus far. Therefore, it is urgent to develop more immunogenic and antigen-sparing H5N1 influenza vaccines as well as safe and effective adjuvants for humans, especially for immunocompromised people such as patients with diabetes mellitus. In this study, the protective effect of an MF59-adjuvanted inactivated whole-virion H5N1 vaccine was investigated in a type 1 diabetic mouse model. Mice (both healthy and diabetic) were immunized with a single dose of the inactivated vaccine, alone or adjuvanted with MF59 or Al(OH)₃. After four weeks, mice were challenged with a lethal dose of H5N1 virus. Antibody responses, survival rates, lung virus titers and body weight changes were tested. The results showed that addition of MF59 or Al(OH)₃ to the vaccine enhanced the antibody responses in both healthy mice and diabetic mice, but the MF59-adjuvanted groups showed higher antibody responses than the Al(OH)₃-adjuvanted groups. The addition of MF59 or Al(OH)₃ to the vaccine led to a conversion of the immune response from a Th1-biased response to an enhanced mixed Th1/Th2 profile. The MF59-adjuvanted inactivated whole-virion H5N1 vaccine provided superior protection in type 1 diabetic mice to either the vaccine alone or the vaccine adjuvanted with Al(OH)₃.     

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.     

Influenza vaccination in the elderly

Influenza vaccination of elderly people has been shown to be useful. All vaccine types are well tolerated by higher age group vaccinees. Actually, whole virus vaccine, split virus vaccine and subunit vaccine are used in the vaccination of the elderly. Some studies have suggested that the induction of serum influenza antibody production was reduced in elderly persons when compared with that elicited in younger persons. However, investigations on the protective efficacy of influenza vaccination in the elderly have demonstrated a clinical protection of 50% for preventing hospitalization.

Live attenuated influenza vaccine conferred protection similar to that obtained with a conventional subunit vaccine. A virosomal unilamellar trivalent hemagglutinin vaccine showed promising serological results compared with those obtained with a whole cell vaccine and with a subunit vaccine, respectively. The actual policy is to vaccinate persons 65 years of age and the groups that can transmit influenza to them. Each year's vaccine should contain three virus strains representing the influenza viruses that are likely to circulate in the upcoming winter.     

Impact of preexisting memory to seasonal A/H1N1 influenza virus on the immune response following vaccination against avian A/H5N1 virus

Cross‐protection against divergent strains of influenza virus is an objective of various vaccination approaches. B cells cross‐neutralizing several influenza A heterosubtypes have been isolated from cultured human memory B cells (MBCs) and plasmablasts early after influenza vaccination or infection. However, a systematic assessment of the frequency of MBCs and plasmablasts in the blood of healthy individuals is lacking. Here, we show that under resting conditions about 45% of human adults never vaccinated nor exposed to avian A/H5N1 influenza have detectable circulating MBCs cross‐reacting with H5N1. This proportion rises to 63.3% among subjects with a large pool of MBCs specific for seasonal H1N1 (i.e. frequency ≥1% of total IgG MBCs). Moreover, subjects with high baseline frequencies of H1N1‐specific MBCs had an expansion of H5N1‐specific MBCs producing H5‐neutralizing antibodies already after the first dose of an MF59‐adjuvanted H5N1 vaccine. These results suggest that H1N1‐specific MBCs contain a subset of cells cross‐reacting to H5. We propose that a proportion of human adults have a pool of H5/H1 cross‐reactive MBCs that contribute to the rapid rise of the antibody response to divergent influenza strains. This may have implications on vaccination strategies aimed at counteracting future influenza pandemics.     

MF59-adjuvanted subunit influenza vaccine: an improved interpandemic influenza vaccine for vulnerable populations

Influenza is a highly contagious respiratory disease associated with substantial morbidity and mortality in vulnerable populations, especially the elderly. Influenza viruses are unique in that they undergo small mutations and antigenic variation in their hemagglutinin and neuraminidase genes. Owing to the senescence of the immune system, the ability to mount novel immune responses may be particularly compromised in older people. Fluad (Novartis Vaccines), an MF59-adjuvanted subunit influenza vaccine, was formulated in order to achieve greater immunogenicity in those groups who need a higher protection than that brought about by conventional vaccines. This article summarizes the main characteristics of MF59-adjuvanted subunit influenza vaccine, the clinical effectiveness data that have been generated in recent years and future developments.     

Cross-Protective Immune Responses Elicited by Live Attenuated Influenza Vaccines

The desired effect of vaccination is to elicit protective immune responses against infection with pathogenic agents. An inactivated influenza vaccine is able to induce the neutralizing antibodies directed primarily against two surface antigens, hemagglutinin and neuraminidase. These two antigens undergo frequent antigenic drift and hence necessitate the annual update of a new vaccine strain. Besides the antigenic drift, the unpredictable emergence of the pandemic influenza strain, as seen in the 2009 pandemic H1N1, underscores the development of a new influenza vaccine that elicits broadly protective immunity against the diverse influenza strains. Cold-adapted live attenuated influenza vaccines (CAIVs) are advocated as a more appropriate strategy for cross-protection than inactivated vaccines and extensive studies have been conducted to address the issues in animal models. Here, we briefly describe experimental and clinical evidence for cross-protection by the CAIVs against antigenically distant strains and discuss possible explanations for cross-protective immune responses afforded by CAIVs. Potential barriers to the achievement of a universal influenza vaccine are also discussed, which will provide useful guidelines for future research on designing an ideal influenza vaccine with broad protection without causing pathogenic effects such as autoimmunity or attrition of protective immunity against homologous infection.     

Genetic and Antigenic Typing of Seasonal Influenza Virus Breakthrough Cases from a 2008-2009 Vaccine Efficacy Trial

Estimations of the effectiveness of vaccines against seasonal influenza virus are guided by comparisons of the antigenicities between influenza virus isolates from clinical breakthrough cases with strains included in a vaccine. This study examined whether the prediction of antigenicity using a sequence analysis of the hemagglutinin (HA) gene-encoded HA1 domain is a simpler alternative to using the conventional hemagglutination inhibition (HI) assay, which requires influenza virus culturing. Specimens were taken from breakthrough cases that occurred in a trivalent influenza virus vaccine efficacy trial involving >43,000 participants during the 2008-2009 season. A total of 498 influenza viruses were successfully subtyped as A(H3N2) (380 viruses), A(H1N1) (29 viruses), B(Yamagata) (23 viruses), and B(Victoria) (66 viruses) from 603 PCR- or culture-confirmed specimens. Unlike the B strains, most A(H3N2) (377 viruses) and all A(H1N1) viruses were classified as homologous to the respective vaccine strains based on their HA1 domain nucleic acid sequence. HI titers relative to the respective vaccine strains and PCR subtyping were determined for 48% (182/380) of A(H3N2) and 86% (25/29) of A(H1N1) viruses. Eighty-four percent of the A(H3N2) and A(H1N1) viruses classified as homologous by sequence were matched to the respective vaccine strains by HI testing. However, these homologous A(H3N2) and A(H1N1) viruses displayed a wide range of relative HI titers. Therefore, although PCR is a sensitive diagnostic method for confirming influenza virus cases, HA1 sequence analysis appeared to be of limited value in accurately predicting antigenicity; hence, it may be inappropriate to classify clinical specimens as homologous or heterologous to the vaccine strain for estimating vaccine efficacy in a prospective clinical trial.     

MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines

Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (≥10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines.     

Narcolepsy, 2009 A(H1N1) pandemic influenza,and pandemic influenza vaccinations: What is known and unknown about the neurological disorder,the role for autoimmunity,and vaccine adjuvants

The vaccine safety surveillance system effectively detected a very rare adverse event, narcolepsy, in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine made using the European inactivation/purification protocol. The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. However, additional investigations are needed to better understand what factor(s) in wild influenza infection trigger(s) narcolepsy in susceptible hosts. An estimated 31 million doses of European AS03-adjuvanted A(H1N1) pandemic vaccine were used in more than 47 countries. The Canadian AS03-adjuvanted A(H1N1) pandemic vaccine was used with high coverage in Canada where an estimated 12 million doses were administered. As no similar narcolepsy association has been reported to date with the AS03-adjuvanted A(H1N1) pandemic vaccine made using the Canadian inactivation/purification protocol, this suggests that the AS03 adjuvant alone may not be responsible for the narcolepsy association. To date, no narcolepsy association has been reported with the MF59®-adjuvanted A(H1N1) pandemic vaccine. This review article provides a brief background on narcolepsy, outlines the different types of vaccine preparations including the ones for influenza, reviews the accumulated evidence for the safety of adjuvants, and explores the association between autoimmune diseases and natural infections. It concludes by assimilating the historical observations and recent clinical studies to formulate a feasible hypothesis on why vaccine-associated narcolepsy may not be solely linked to the AS03 adjuvant but more likely be linked to how the specific influenza antigen component of the European AS03-adjuvanted pandemic vaccine was prepared. Careful and long-term epidemiological studies of subjects who developed narcolepsy in association with AS03-adjuvanted A(H1N1) pandemic vaccine prepared with the European inactivation/purification protocol are needed.     

Protection against influenza virus infection by intranasal administration of hemagglutinin vaccine with chitin microparticles as an adjuvant

Chitin in the form of microparticles (chitin microparticles, CMP) has been demonstrated to be a potent stimulator of macrophages, promoting T-helper-1 (Th1) activation and cytokine response. In order to examine the mucosal adjuvant effect of CMP co-administered with influenza hemagglutinin (HA) vaccine against influenza infection, CMP were intranasally co-administered with influenza HA vaccine prepared from PR8 (H1N1) virus. Inoculation of the vaccine with CMP induced primary and secondary anti-HA IgA responses in the nasal wash and anti-HA IgG responses in the serum, which were significantly higher than those of nasal vaccination without CMP, and provided a complete protection against a homologous influenza virus challenge in the nasal infection influenza model. In addition, CMP-based immunization using A/Yamagata (H1N1) and A/Guizhou (H3N2) induced PR8 HA-reactive IgA in the nasal washes and specific-IgG in the serum. The immunization with A/Yamagata and CMP resulted in complete protection against a PR8 (H1N1) challenge in A/Yamagata (H1N1)-vaccinated mice, while that with A/Guizhou (H3N2) and CMP exhibited a 100-fold reduction of nasal virus titer, demonstrating the cross-protective effect of CMP and influenza vaccine. It is suggested that CMP provide a safe and effective adjuvant for nasal vaccination with inactivated influenza vaccine.     

Protection against influenza virus infection by intranasal vaccine with surf clam microparticles (SMP) as an adjuvant

A safe and effective adjuvant is necessary to enhance mucosal immune responses for the development of an inactivated intranasal influenza vaccine. The present study demonstrated the effectiveness of surf clam microparticles (SMP) derived from natural surf clams as an adjuvant for an intranasal influenza vaccine. The adjuvant effect of SMP was examined when co-administered intranasally with inactivated A/PR8 (H1N1) influenza virus hemagglutinin vaccine in BALB/c mice. Administration of the vaccine with SMP induced a high anti-PR8 haemagglutinin (HA)-specific immunoglobulin A (IgA) response in the nasal wash and immunoglobulin G (IgG) response in the serum, resulting in protection against both nasal-restricted infection and lethal lung infection by A/PR8 virus. In addition, administration of SMP with A/Yamagata (H1N1), A/Beijing (H1N1), or A/Guizhou (H3N2) vaccine conferred complete protection against A/PR8 virus challenge in the nasal infection model, suggesting that SMP adjuvanted vaccine can confer cross-protection against variant influenza viruses. The use of SMP is suggested as a new safe and effective mucosal adjuvant for nasal vaccination against influenza virus infection.     

MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection

In preclinical studies, MF59 adjuvant offered improved protection against influenza virus challenge and significantly reduced the viral load in the lungs of challenged mice. In humans, MF59 is a safe and potent vaccine adjuvant that has been licensed in more than 20 countries (Fluad [Novartis Vaccines and Diagnostics Inc., MA, USA]). The safety profile of an MF59-adjuvanted vaccine is well established through a large safety database. MF59 adjuvant has had a significant impact on the immunogenicity of influenza vaccines in the elderly and in adults who are chronically ill. MF59 has also been shown to have a significant impact on the immunogenicity of pandemic influenza vaccines. MF59 allows for broader cross-reactivity against viral strains not included in the vaccine. MF59 has been shown to be more potent for both antibody and T-cell responses than aluminum-based adjuvants. MF59 has broad potential to be used as a safe and effective vaccine adjuvant for a wide range of vaccine types.     

Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion

AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.     

Immunogenicity, boostability, and sustainability of the immune response after vaccination against Influenza A virus (H1N1) 2009 in a healthy population

The emergence of a new influenza A virus (H1N1) variant in 2009 led to a worldwide vaccination program, which was prepared in a relatively short period of time. This study investigated the humoral immunity against this virus before and after vaccination with a 2009 influenza A virus (H1N1) monovalent MF59-adjuvanted vaccine, as well as the persistence of vaccine-induced antibodies. Our prospective longitudinal study included 498 health care workers (mean age, 43 years; median age, 44 years). Most (89%) had never or only occasionally received a seasonal influenza virus vaccine, and 11% were vaccinated annually (on average, for >10 years). Antibody titers were determined by a hemagglutination inhibition (HI) assay at baseline, 3 weeks after the first vaccination, and 5 weeks and 7 months after the second vaccination. Four hundred thirty-five persons received two doses of the 2009 vaccine. After the first dose, 79.5% developed a HI titer of ≥40. This percentage increased to 83.3% after the second dose. Persistent antibodies were found in 71.9% of the group that had not received annual vaccinations and in 43.8% of the group that had received annual vaccinations. The latter group tended to have lower HI titers (P=0.09). With increasing age, HI titers decreased significantly, by 2.4% per year. A single dose of the 2009 vaccine was immunogenic in almost 80% of the study population, whereas an additional dose resulted in significantly increased titers only in persons over 50. Finally, a reduced HI antibody response against the 2009 vaccine was found in adults who had previously received seasonal influenza virus vaccination. More studies on the effect of yearly seasonal influenza virus vaccination on the immune response are warranted.