Original Article
Trial of 2009 Influenza A (H1N1) Monovalent MF59-Adjuvanted Vaccine
N Engl J Med 2009; 361:2424-2435December 17, 2009
- Abstract
Background
The 2009 pandemic influenza A (H1N1) virus has emerged to cause the first pandemic of the 21st century. Development of effective vaccines is a public health priority.
Methods
We conducted a single-center study, involving 176 adults, 18 to 50 years of age, to test the monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine, in both MF59-adjuvanted and nonadjuvanted forms. Subjects were randomly assigned to receive two intramuscular injections of vaccine containing 7.5 μg of hemagglutinin on day 0 in each arm or one injection on day 0 and the other on day 7, 14, or 21; or two 3.75-μg doses of MF59-adjuvanted vaccine, or 7.5 or 15 μg of nonadjuvanted vaccine, administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay and a microneutralization assay on days 0, 14, 21, and 42 after injection of the first dose.
Results
The most frequent local and systemic reactions were pain at the injection site and muscle aches, noted in 70% and 42% of subjects, respectively; reactions were more common with the MF59-adjuvanted vaccine than with nonadjuvanted vaccine. Three subjects reported fever, with a temperature of 38°C or higher, after either dose. Antibody titers, expressed as geometric means, were higher at day 21 among subjects who had received one dose of MF59-adjuvanted vaccine than among those who had received one dose of nonadjuvanted vaccine (P<0.001 by the microneutralization assay). By day 21, hemagglutination-inhibition and microneutralization antibody titers of 1:40 or more were seen in 77 to 96% and 92 to 100% of subjects receiving MF59-adjuvanted vaccine, respectively, and in 63 to 72% and 67 to 76% of those receiving nonadjuvanted vaccine, respectively. By day 42, after two doses of vaccine, hemagglutination-inhibition and microneutralization antibody titers of 1:40 or more were seen in 92 to 100% and 100% of recipients of MF59-adjuvanted vaccine, respectively, and in 74 to 79% and 78 to 83% of recipients of nonadjuvanted vaccine, respectively.
Conclusions
Monovalent 2009 influenza A (H1N1) MF59-adjuvanted vaccine generates antibody responses likely to be associated with protection after a single dose is administered. (ClinicalTrials.gov number, NCT00943358.)
Media in This Article
Figure 1
Reverse Cumulative-Distribution Curves of Antibody Titers in Serum Samples Obtained on Days 14 and 42, According to Number and Timing of Vaccine Doses.Table 1
Baseline Characteristics of the Study Subjects, According to Vaccine Group.Article Activity
- Article
The emergence of the 2009 pandemic influenza A (H1N1) virus demonstrates the unpredictable nature of influenza.1 The virus has the potential to cause disease, death, and socioeconomic disruption,2,3 and modeling suggests that the effect of the virus can be reduced by immunization.4 The development of effective vaccines is a public health priority.
Traditional seasonal influenza vaccines are produced from reassortant vaccine strains grown in hens' eggs. However, demand for vaccine against the 2009 H1N1 virus will most likely exceed the supply if this method of manufacturing is solely used. Cell culture provides an additional platform for the manufacture of vaccines that may be more easily scaled up during periods of heightened demand.5-7
Serologic analysis suggests that after seasonal vaccination in children and young adults, there is little evidence of cross-reactive antibodies against the 2009 H1N1 virus,8 with no evidence of protection from the seasonal vaccine.9 The efficacy of conventional vaccines prepared from avian influenza strains is disappointingly low, even after two doses.10-14 The addition of oil-in-water–emulsion adjuvant enhances immunogenicity and induces cross-reactive antibodies against antigenically drifted variants.12-16 The use of such adjuvants in 2009 influenza A (H1N1) vaccines has been suggested by the World Health Organization.17
Vaccination programs for 2009 influenza A (H1N1) are under way, but the optimal formulation is unknown. The need for high-yield vaccine strains, limitations of the supply and production capacity of egg-based vaccines, and the possible requirement of two doses in some groups may delay an effective immunization program.
We present the clinical and immunogenicity profiles of the 7.5-μg dose of the monovalent influenza A/California/2009 (H1N1) MF59-adjuvanted surface-antigen vaccine, derived from cell culture, administered to adults 18 to 50 years of age. Two doses of 7.5 μg of MF59-adjuvanted vaccine were given concurrently on day 0 or were given 7, 14, or 21 days apart; or two doses of 3.75 μg of MF59-adjuvanted vaccine or 7.5 or 15 μg of nonadjuvanted vaccine were given 21 days apart. Our earlier report of the preliminary results is available at NEJM.org.
Methods
The study was designed by one academic author and one industry author; the academic author was responsible for managing the data and drafting the manuscript. The data were fully accessible and interpreted by all the authors, who vouch for the accuracy and completeness of the data and analyses. The U.K. Medicines and Healthcare Products Regulatory Agency and the Leicestershire, Rutland, and Northamptonshire Ethics Committee approved the study. University Hospitals Leicester was the main sponsor; the vaccine was manufactured by Novartis, who provided funding but had no role in the conduct of the study or in preparation of the manuscript.
Vaccine
The 2009 H1N1 vaccine virus (New York Medical College [NYMC] X-179A) was generated from the influenza A/California/7/2009 strain with the use of classical reassortant methods. The gene segments encoding the hemagglutinin, neuraminidase, and the polymerase PB1 were derived from the influenza A/California/7/2009 strain, with the remaining genes taken from the influenza A/PR8/8/34 virus used as a backbone for influenza vaccines. The strain was supplied by the Centers for Disease Control and Prevention and is a pandemic vaccine strain recommended for use in vaccine development. The seed virus was grown in Madin–Darby Canine Kidney (MDCK) cell culture by means of standard processes similar to those used for the development of Optaflu vaccines against interpandemic influenza. The vaccine was formulated and produced by Novartis (Marburg, Germany) as an inactivated surface-antigen H1N1 vaccine, with or without MF59 adjuvant, and was supplied in 0.5-ml prefilled single-dose syringes. Each MF59-adjuvanted vaccine contained 7.5 μg of H1 hemagglutinin, 9.75 mg of the squalene MF59, 1.175 mg of polysorbate 80, and 1.175 mg of sorbitan trioleate in buffer. Each nonadjuvanted vaccine contained 15 μg of H1 hemagglutinin in buffer. Hemagglutinin content in the final vaccine was initially determined by means of reverse-phase high-performance liquid chromatography, because single-radial diffusion reagents were unavailable. Subsequently, hemagglutinin content of the final product, determined by means of single-radial diffusion reagents, was approximately 20% lower than the estimated content. Vaccine was stored at 2 to 8°C until use.
Study Design
We conducted a single-center, phase 1, randomized study from July through September 2009 at Leicester Royal Infirmary (Leicester, United Kingdom). Subjects were screened for eligibility and provided written informed consent. (For eligibility criteria, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)
The first 75 subjects enrolled were randomly assigned, in a 1:1:1 ratio, to receive two doses of 7.5 μg of MF59-adjuvanted vaccine, either concurrently administered on day 0 (i.e., one injection of the vaccine containing twice the antigen and adjuvant content of a single vaccine) or administered in two doses, one at day 0 and the other at day 7, 14, or 21. Serum samples for antibody measurements were collected on days 0, 14, 21, and 28.
The next 101 subjects enrolled were randomly assigned, in a 1:1:1:1 ratio, to receive two doses of 7.5 or 3.75 μg of MF59-adjuvanted vaccine (for the latter dose, by administering half the contents of the adjuvanted-vaccine syringe for each), two 15-μg doses of nonadjuvanted vaccine, or two 7.5-μg doses of nonadjuvanted vaccine (by administering half the contents of the nonadjuvanted-vaccine syringe for each) — with one injection at day 0 and the other at day 21. Serum samples were collected on days 0, 14, 21, and 42.
The vaccine was administered by intramuscular injection into the deltoid muscle of the nondominant arm, or in both arms if both doses were given on day 0. Subjects were observed for 30 minutes after each injection, and for the next 7 days they recorded, in self-completed diaries, the severity of unsolicited and solicited local symptoms (pain, bruising, erythema, and swelling) and systemic symptoms (chills, malaise, muscle aches, nausea, and headache), oral temperature, and use of analgesics. Symptoms were graded as follows: none; mild, if they did not interfere with normal activities; moderate, if they resulted in interference with normal activities; and severe, if they prevented engagement in daily activities and necessitated medical attention. Adverse reactions were defined as any reaction that persisted beyond 7 days after vaccination. Serious adverse reactions were defined as any reaction that necessitated medical attention or hospitalization during the study period.
Laboratory Assays
Antibody responses were detected by means of microneutralization and hemagglutination-inhibition assays, according to standard methods,18,19 at the Centre for Infections, Health Protection Agency (London), and with the use of cell-culture X-179A H1N1 vaccine virus (see the Vaccine section above) and egg-grown NIBRG-121 virus — a reverse-genetic virus containing hemagglutinin and neuraminidase from the influenza A/California/7/2009 strain (see the Supplementary Appendix for details). Serum samples obtained from subjects were tested with the use of 1:2 serial dilutions. For hemagglutination-inhibition assays, serum samples were tested at an initial dilution of 1:8, and those that were negative for the antibody were assigned a titer of 1:4. Serum specimens were analyzed to determine absolute end-point titers. For microneutralization assays, serum samples were tested at an initial dilution of 1:10,20 and those that were negative were assigned a titer of 1:5. The final dilution was 1:320, and samples for which the end-point titers were greater were assigned a value of 1:640. Specimens were tested in duplicate, and the geometric mean values were used in analyses.
Statistical Analysis
The group sizes used are usual for phase 1 studies and were not based on power calculations. Data analysis was undertaken with the use of Stata software (version 9.2, StataCorp).
For solicited and unsolicited adverse reactions, the percentages of subjects (point estimates and 95% confidence intervals) with postvaccination reactions were based on the frequency and severity of the reported responses after vaccination. Exact (Clopper–Pearson) confidence intervals are reported for all proportional end points. We used a two-sided Fisher's exact test to compare proportions between vaccine groups. All reported P values are two-sided, with no adjustment for multiple testing; values of 0.05 or less were considered to indicate statistical significance.
For immunogenicity analyses, the geometric mean antibody titers at each time point were used. Geometric mean titers and 95% confidence intervals were computed by taking the exponent (log10) of the mean and of the lower and upper limits of the 95% confidence intervals of the log10-transformed titers. Geometric mean titers were compared between each pair of vaccine groups by means of one-way analysis of variance on the log10-transformed titers with Bonferroni correction for multiple pairwise comparisons, if appropriate. The proportions of subjects in whom seroconversion (a prevaccination hemagglutination-inhibition antibody titer ≤1:10 and a postvaccination titer ≥1:40 or a prevaccination titer ≥1:10 and an increase in the titer by a factor of four or more) or a hemagglutination-inhibition antibody titer of 1:40 or more was achieved were compared between each group with the use of a two-sided Fisher's exact test. Separate analyses were performed for the hemagglutination-inhibition and microneutralization assays. Because there are no established immune correlates for microneutralization, in that analysis we assessed the proportion of subjects who had seroconversion (an increase in the antibody titer by a factor of four or more) and a microneutralization titer of 1:40 or more.
Results
We enrolled 176 subjects. A total of 101 subjects received two 7.5-μg doses of MF59-adjuvanted vaccine (with the two doses administered concurrently at day 0 [in 25 subjects] or one dose at day 0 and one at day 7 [in 25 subjects], at day 14 [in 25 subjects], or at day 21 [in 26 subjects]). The other 75 subjects each received two doses of 3.75 μg of MF59-adjuvanted vaccine (25 subjects), or 7.5 or 15 μg of nonadjuvanted vaccine (25 subjects each), separated by 21 days (i.e., doses at day 0 and at day 21).
Both doses of vaccine were given in 175 of the 176 subjects (99%); 1 subject in the group receiving 15 μg of nonadjuvanted vaccine did not attend the second vaccination visit. In all, 322 of the 325 issued diary cards (99%) were returned. Serum samples were obtained from 175 of the 176 subjects (99%) and 97 of the 101 subjects (96%) from whom samples were required at days 21 and day 42, respectively, according to protocol. In addition, serum samples were obtained on day 14 from 166 of the 176 subjects (94%). Data from all 176 subjects were included in safety and immunogenicity analyses (see the Supplementary Appendix).
The median age was 33 years (range, 18 to 50); 65% of the subjects were women, 82% were white, and 37% had previously received seasonal influenza vaccine (Table 1Table 1
Baseline Characteristics of the Study Subjects, According to Vaccine Group.). The baseline characteristics were similar among the seven groups.Safety Analysis
Solicited local and systemic reactions during the first 7 days following any vaccine dose are shown in Table 2Table 2
Solicited Local and Systemic Adverse Effects within 7 Days after Receipt of Either Dose of MF59-Adjuvanted or Nonadjuvanted Vaccine, According to Vaccine Group.. Overall, 80% of subjects reported adverse reactions after either vaccine dose (73% after the first and 60% after the second). The frequency or severity of reactions did not increase after the second dose was received (see the Supplementary Appendix). All self-reported reactions were graded as mild or moderate and were generally self-limited, resolving within a 72-hour period. No dose–response relationship was observed for either vaccine type for any reaction.The most frequent local reaction after any vaccine was pain at the injection site, reported by 61% of subjects. Overall, pain was more frequent after injection of the MF59-adjuvanted vaccine than with nonadjuvanted vaccine (65% vs. 39%, P=0.003). In general, pain was not accompanied by redness, swelling, or bruising, although bruising was reported to be severe in one subject — affecting an area 20 mm in diameter — after the first dose, with resolution within 72 hours. No severe local reactions were reported.
The most frequent systemic reaction was muscle ache, reported by 40% of subjects. There was no significant difference in frequency or severity of systemic reactions after receipt of MF59-adjuvanted vaccine and those after receipt of nonadjuvanted vaccine, except in subjects who received two doses of MF59-adjuvanted vaccine on day 0, who reported a greater frequency of muscle ache than did subjects who received one dose of MF59-adjuvanted vaccine on day 0 (P=0.02). A total of 13% of subjects reported use of analgesics. Three subjects reported fever, defined as a temperature of 38°C or more (after the first dose in two subjects and after the second dose in the third), but none required antipyretic medication. No severe systemic reactions were reported.
Fifteen unsolicited adverse events were reported (see the Supplementary Appendix). After receiving MF59-adjuvanted vaccine, three subjects reported self-limiting diarrhea (that resolved within the 48-hour period after the first dose); one subject took over-the-counter loperamide. Three subjects reported coryza that resolved within 72 hours. One subject reported toothache that resolved after 5 days. One subject reported a transient itchy rash on the right forearm that resolved within 48 hours. After receiving nonadjuvanted vaccine, two subjects reported musculoskeletal pain that resolved after 48 hours. Two subjects reported coryza that resolved within 72 hours. One subject each reported diarrhea, itching, or sore throat that resolved within 48 hours.
A probable vaccine-related adverse reaction, reported after receipt of the 7.5 μg of MF59-adjuvanted vaccine, is described in the Supplementary Appendix. Briefly, this subject (who received two doses of the MF59-adjuvanted vaccine on day 0) reported a purpuric rash on the lower limbs on day 17, with resolution within 72 hours. Further questioning revealed that she had consulted with her family practitioner in May 2009 for an intermittent leg rash within the 12-month period before the study. Investigations including complete blood count and biochemical profile showed normal values, but an autoimmune profile was positive for antinuclear and extractable nuclear-antigen antibodies. She had not received medication, and this medical history was not known at enrollment. Follow-up for the rash included a normal complete blood count and biochemical profile. Results of autoimmune testing were unchanged from those in May 2009.
Immunogenicity against the 2009 H1N1 Virus
Antibody responses against the vaccine strain were detected by the hemagglutination-inhibition assay (titer >1:8) and the microneutralization assay (titer >1:10) before vaccination in 16% and 31% of subjects, respectively; this frequency was unrelated to age (P=0.72 by hemagglutination-inhibition assay and P=0.32 by microneutralization assay) or previous receipt of seasonal vaccine (P=0.14 and P=0.18, respectively).
There was no significant dose–response relationship regarding the geometric mean titers, at any postvaccination visit, for MF59-adjuvanted vaccine (P=0.71 by hemagglutination-inhibition assay and P=0.43 by microneutralization assay on day 14; P=0.63 and P=0.42, respectively, on day 21; and P=0.86 and P=0.75, respectively, on day 42) or for nonadjuvanted vaccine (P=0.74 and P=0.49, respectively, on day 14; P=0.99 and P=0.62, respectively, on day 21; and P=0.27 and P=0.88, respectively, on day 42).
On day 14, geometric mean titers, as measured with the use of hemagglutination-inhibition assay (Table 3Table 3
Antibody Responses as Measured with the Hemagglutination-Inhibition Assay, According to Vaccine Group.) and microneutralization assay (Table 4Table 4
Antibody Responses as Measured with the Microneutralization Assay, According to Vaccine Group.), were higher in subjects who received two 7.5-μg doses of MF59-adjuvanted vaccine by that time, as compared with those who had received one dose only (P=0.03 by hemagglutination-inhibition assay and P<0.001 by microneutralization assay). After the administration of one dose, the microneutralization antibody titers were greater in subjects who had received the MF59-adjuvanted vaccine than in those who had received nonadjuvanted vaccine (P<0.001).On day 21, microneutralization antibody titers were higher among subjects who had received two 7.5-μg doses of MF59-adjuvanted vaccine than among those who had received one dose only by that time (P=0.03). After one dose of either vaccine, the MF59-adjuvanted vaccine induced greater titers than nonadjuvanted vaccine (P<0.001 by microneutralization assay).
On day 42, after two doses of either vaccine, geometric mean titers were higher in groups receiving the MF59-adjuvanted vaccine than in those receiving the nonadjuvanted vaccine (P=0.007 by hemagglutination-inhibition assay and P<0.001 by microneutralization assay).
Table 3 shows the ratio of the antibody titer measured at each postvaccination visit and the titer measured at the prevaccination visit, and the percentages of subjects with seroconversion and with an antibody titer of 1:40 or more, as measured with the hemagglutination-inhibition assay.
There was no significant dose–response relationship regarding the rates of seroconversion with MF59-adjuvanted vaccine (P=0.78 by the hemagglutination-inhibition assay and P=1.00 by the microneutralization assay on day 14; P=0.29 and P=1.00, respectively, on day 21; and P=1.00 and P=1.00, respectively, on day 42) or with nonadjuvanted vaccine (P=0.23 and P=1.00, respectively, on day 14; P=0.23 and P=1.00, respectively, on day 21; and P=0.74 and P=1.00, respectively, on day 42). There was no significant difference in the rates of seroconversion between subjects who had a detectable prevaccination antibody titer and those who did not (day 14, P=0.46; day 21, P=0.61; and day 42, P=1.00). On day 14, the percentages of subjects with seroconversion and with an antibody titer of 1:40 or more were higher (P=0.007 and P=0.002, respectively) among subjects who had received two doses of the MF59-adjuvanted vaccine than among those who had received only one. On day 21, as compared with subjects who had received one dose of MF59-adjuvanted vaccine, those who had received two doses did not differ significantly in the percentage of subjects with seroconversion (P=0.06) but did have a greater percentage with an antibody titer of 1:40 or more (P=0.03). Although MF59-adjuvanted vaccine induced more seroconversions and antibody titers of 1:40 or more than nonadjuvanted vaccine at each postvaccination visit, the difference was not significant (day 14, P=0.22 and P=0.09, respectively; and day 21, P=0.07 and P=0.06, respectively). On day 42, after two vaccine doses, the percentages of subjects with seroconversion and an antibody titer of 1:40 or more were higher among the MF59-adjuvanted vaccine groups (P=0.05 and P=0.007, respectively) than among the nonadjuvanted vaccine groups.
Table 4 shows the ratio of the antibody titer measured at each postvaccination visit and the titer measured at the prevaccination visit, and the percentages of subjects with seroconversion and antibody titers of 1:40 or more, as measured with the microneutralization assay. On days 14 and 21, there were no significant differences between subjects who had received two doses of MF59-adjuvanted vaccine and those who had received one dose in the rate of seroconversion (day 14, P=0.20; and day 21, P=0.64) or in the percentage with titers of 1:40 or more (day 14, P=0.50; and day 21, P=1.00). On each postvaccination visit, the rate of seroconversion and the percentage of subjects with titers of 1:40 or more were greater after receipt of MF59-adjuvanted vaccine than after receipt of nonadjuvanted vaccine (day 14, P=0.02 and P=0.003, respectively; day 21, P=0.002 and P=0.001, respectively; and day 42, P=0.04 and P=0.001, respectively).
Figure 1Figure 1
Reverse Cumulative-Distribution Curves of Antibody Titers in Serum Samples Obtained on Days 14 and 42, According to Number and Timing of Vaccine Doses. shows the distribution of antibody titers at day 14 and day 42, according to vaccine group. At day 14, hemagglutination-inhibition titers of 1:32 or more were achieved in 84% of subjects receiving MF59-adjuvanted vaccine and in 77% of subjects receiving nonadjuvanted vaccine. Microneutralization titers of 1:40 or more were achieved in 94% subjects receiving MF59-adjuvanted vaccine and in 73% of subjects receiving nonadjuvanted vaccine. After two doses, at day 42, hemagglutination-inhibition titers of 1:32 or more were achieved in 100% of subjects receiving MF59-adjuvanted vaccine and in 87% of subjects receiving nonadjuvanted vaccine. Microneutralization titers of 1:40 or more were achieved in 100% subjects receiving MF59-adjuvanted vaccine and in 80% of subjects receiving nonadjuvanted vaccine.Responses against the NIBRG-121 virus were similar to those against the 2009 X-179A H1N1 vaccine virus, as measured by means of the hemagglutination-inhibition assay (see the Supplementary Appendix).
Discussion
Data from studies of other inactivated influenza vaccines suggest that hemagglutination-inhibition antibody titers of 1:40 or more provide partial protection, and this titer was achieved by most of the subjects given one dose, with or without adjuvant, in this clinical trial. Effective vaccination should reduce illness and virus transmission,4 although this may be challenging, as global demand for vaccine will probably exceed manufacturing capacity and will be met only by implementing a range of production approaches. Large-scale vaccine production with newly characterized viruses can be challenging if low egg growth limits the supply of antigen. Our vaccine was produced from a classical egg-derived seed virus propagated in a MDCK cell line.7,21 Cell-culture systems may provide a faster response and greater scale-up than egg production. Cell-culture seasonal influenza seed viruses also show better antigenic matching to clinical isolates than egg-passaged strains.5-8,21
Clinical experience with avian and human influenza A/H1N1–subunit vaccines in subjects who did not have detectable levels of preexisting antibody suggests that two doses are required to induce a hemagglutination-inhibition antibody titer of 1:40 or more.10-15,22,23 Traditionally, dosing intervals of 21 to 28 days are used, often delaying effective immunization. We evaluated rapid immunization schedules involving two doses of MF59-adjuvanted vaccines, since flexible dosing would be useful for authorities organizing immunizations. However, our data suggest that a single immunization against the 2009 pandemic influenza A (H1N1) virus would be sufficient to induce a hemagglutination-inhibition antibody titer of 1:40 or more.
Our findings add to observations that oil-in-water–emulsion adjuvants are well tolerated, with systemic reactogenicity similar to that of nonadjuvanted inactivated seasonal vaccines, but are associated with increased local pain at the site of administration.24 For avian subvirion vaccines, oil-in-water–emulsion adjuvants are important to induce long-lasting cross-reactive immunity.10,12-15 Although 2009 pandemic influenza A (H1N1) isolates are antigenically homogenous, induction of broadly cross-reactive antibodies would be a desirable characteristic of the first vaccines against the 2009 H1N1 virus, and serum samples obtained after the administration of candidate vaccines, either adjuvanted or nonadjuvanted, should be assessed against emerging antigenic variant strains. The addition of MF59 adjuvant to 2009 influenza A (H1N1) monovalent vaccine increases the speed and magnitude of the antibody response; however, nonadjuvanted vaccine also induced satisfactory immune responses, which is consistent with early reports of other 2009 H1N1 subunit vaccines.25 The 2009 H1N1 virus is antigenically distinct from recently circulating seasonal H1N1 strains, so the response to a single dose of vaccine suggests there may a greater degree of preexisting immunity in the population than expected. Sixteen percent of subjects had detectable prevaccination levels of hemagglutination-inhibition antibody, a finding that is consistent with results of seroepidemiologic studies.11 Although we excluded subjects with previous respiratory illnesses, asymptomatic infection with influenza A (H1N1) viruses cannot be ruled out, since local activity was present during the study.
Interpretation of immunogenicity data for the vaccine against the 2009 pandemic influenza A (H1N1) virus is complicated by a lack of recognized immune correlates. The insensitivity of hemagglutination-inhibition assays to some avian hemagglutinin has required that microneutralization assays, hemagglutination-inhibition assays involving horse erythrocytes, or single radial hemolysis be used.10,18,26 Because there is significant laboratory variation in testing,20 efforts to develop biologic standards for serologic assays of influenza A (H1N1) viruses are under way.
The safety and immunogenicity of these and alternative candidate vaccines against the 2009 H1N1 virus, including egg-derived, whole-virion, recombinant, and live-attenuated vaccines, must be assessed in high-risk populations, including children, the elderly, and other persons whose immunologic profiles may differ from those of young adults.8 In addition, the duration of antibody responses and their ability to be boosted after revaccination should be established to predict protection against future pandemic waves.
Finally, although seasonal influenza vaccines have an established safety profile, there are occasional case reports of unusual reactions, including vasculitis.24,27 MF59, a proprietary oil-in-water–emulsion adjuvant, was first licensed for use in seasonal influenza vaccines in 1997. Over 40 million doses have been delivered in Europe, and over 16,000 doses administered in clinical trials, with no excess reports of autoimmune conditions.28 It is important to ensure post-marketing surveillance during any mass use of a pandemic-virus vaccine, with or without adjuvant. These results may be useful for planning of immunization schedules, and comparison with other vaccine options as they become available.
Supported by grants from University Hospitals Leicester and Novartis Vaccines and Diagnostics.
Dr. Hoschler reports holding equity and stock options in Illumina; Dr. Nicholson, receiving consulting fees from Novartis Vaccines and GlaxoSmithKline and lecture fees from Baxter Vaccines; Dr. Groth, holding equity and stock options in Novartis; and Dr. Stephenson, receiving consulting fees from Novartis Vaccines and Sanofi Pasteur, lecture fees from Baxter Vaccines and Novartis Vaccines, and grant support from Hoffmann–La Roche, Novartis Vaccines, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.
Drs. Clark and Pareek contributed equally to this article.
A preliminary version of this article (10.1056/NEJMoa0907650) was published on September 10, 2009, at NEJM.org.
We thank the subjects who volunteered for the study; staff at University Hospitals of Leicester Infectious Diseases Research Unit, in particular, Sally Batham and Marie-jo Medina; Carolyn Maloney of the Department for Research and Development; Chris Cannaby of the Leicestershire Comprehensive Research Network Office; and the technical staff at the Health Protection Agency influenza laboratory for their assistance with serologic assessment.
Source Information
From the Infectious Diseases Unit, University Hospitals Leicester and Department of Inflammation, Infection and Immunity, University of Leicester, Leicester, United Kingdom (T.W.C., M.P., H.D., K.G.N., I.S.); the Respiratory Virus Laboratory, Health Protection Agency, London (K.H.); and Novartis Vaccines and Diagnostics, Siena, Italy (N.G.).
Address reprint requests to Dr. Stephenson at the Infectious Diseases Unit, Level 6, Windsor Bldg., Leicester Royal Infirmary, Leicester, United Kingdom, or at iain.stephenson@uhl-tr.nhs.uk.
- References
References
1
Global alert and response: Pandemic (H1N1) 2009. Geneva: World Health Organization, 2009. (Accessed November 25, 2009, at http://www.who.int/csr/disease/swineflu/en.)
2
Novel Swine-Origin Influenza A (H1N1) Virus Investigation TeamEmergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-2615
Full Text | Web of Science | Medline3
Perez-Padilla R ,de la Rosa-Zamboni D ,Ponce de Leon S , et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med 2009;361:680-689
Full Text | Web of Science | Medline4
Ferguson NM ,Cummings DA ,Fraser C ,Cajka JC ,Cooley PC ,Burke DS . Strategies for mitigating an influenza pandemic. Nature 2006;442:448-452
CrossRef | Web of Science | Medline5
Oxford JS ,Manuguerra C ,Kistner O , et al. A new European perspective of influenza pandemic planning with a particular focus on the role of mammalian cell culture vaccines. Vaccine 2005;23:5440-5449
CrossRef | Web of Science | Medline6
Audsley JM ,Tannock GA . Cell-based influenza vaccines: progress to date. Drugs 2008;68:1483-1491
CrossRef | Web of Science | Medline7
Szymczakiewicz-Multanowska A ,Groth N ,Bugarini R , et al. Safety and immunogenicity of a novel influenza subunit vaccine produced in mammalian cell culture. J Infect Dis 2009;200:841-848
CrossRef | Web of Science | Medline8
Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 2009;58:521-524
Medline9
Kelly H, Grant K. Interim analysis of pandemic influenza (H1N1) 2009 in Australia: surveillance trends, age of infection and effectiveness of seasonal vaccination. (Accessed November 25, 2009, at http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19288.)
10
Nicholson KG ,Colegate AC ,Podda A , et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001;357:1937-1943
CrossRef | Web of Science | Medline11
Treanor JJ ,Campbell JD ,Zangwill KM ,Rowe T ,Wolff M . Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006;354:1343-1351
Full Text | Web of Science | Medline12
Atmar RL ,Keitel WA ,Patel SM , et al. Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations. Clin Infect Dis 2006;43:1135-1142
CrossRef | Web of Science | Medline13
Stephenson I ,Nicholson KG ,Gluck R , et al. Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial. Lancet 2003;362:1959-1966
CrossRef | Web of Science | Medline14
Stephenson I ,Bugarini R ,Nicholson KG , et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005;191:1210-1215
CrossRef | Web of Science | Medline15
Leroux-Roels I ,Borkowski A ,Vanwolleghem T , et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007;370:580-589
CrossRef | Web of Science | Medline16
Galli G ,Hancock K ,Hoschler K , et al. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc Natl Acad Sci U S A 2009;106:7962-7967
CrossRef | Web of Science | Medline17
Global alert and response: WHO recommendations on pandemic (H1N1) 2009 vaccines. Geneva: World Health Organization, 2009. (Accessed November 25, 2009, at http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090713/en/index.html.)
18
Rowe T ,Abernathy RA ,Hu-Primmer J , et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 1999;37:937-943
Web of Science | Medline19
Ellis JS ,Zambon MC . Molecular investigation of an outbreak of influenza in the United Kingdom. Eur J Epidemiol 1997;13:369-372
CrossRef | Web of Science | Medline20
Stephenson I ,Heath A ,Major D , et al. Reproducibility of serologic assays for influenza virus A (H5N1). Emerg Infect Dis 2009;15:1252-1259
CrossRef | Web of Science | Medline21
Doroshenko A ,Halperin SA . Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines). Expert Rev Vaccines 2009;8:679-688
CrossRef | Web of Science | Medline22
Nicholson KG ,Tyrrell DA ,Harrison P , et al. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. J Biol Stand 1979;7:123-136
CrossRef | Medline23
Parkman PD ,Hopps HE ,Rastogi SC ,Meyer HM Jr . Summary of clinical trials of influenza virus vaccine in adults. J Infect Dis 1977;136:Suppl:S422-S430
CrossRef24
Wiselka MJ. Vaccine safety. In: Nicholson KG, Hay AJ, Webster RG, eds. Textbook of influenza. Oxford: Blackwell Publications, 1998:346.
25
Greenberg ME, Lai MH, Hartel GF, et al. Response after one dose of a monovalent influenza A (H1N1) 2009 vaccine — preliminary report. N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0907413.
26
Stephenson I ,Wood JM ,Nicholson KG ,Zambon MC . Sialic acid receptor specificity on erythrocytes affects detection of antibody to avian influenza haemagglutinin. J Med Virol 2003;70:391-398
CrossRef | Web of Science | Medline27
Mader R ,Narendran A ,Lewtas J , et al. Systemic vasculitis following influenza vaccination -- report of 3 cases and literature review. J Rheumatol 1993;20:1429-1431
Web of Science | Medline28
Schultze V ,D'Agosto V ,Wack A ,Novicki D ,Zorn J ,Hennig R . Safety of MF59 adjuvant. Vaccine 2008;26:3209-3222
CrossRef | Web of Science | Medline
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CrossRef2
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CrossRef3
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CrossRef9
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CrossRef12
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CrossRef13
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CrossRef15
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CrossRef17
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CrossRef19
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CrossRef24
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CrossRef25
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CrossRef29
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CrossRef30
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CrossRef31
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CrossRef32
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CrossRef33
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CrossRef34
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CrossRef35
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CrossRef36
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CrossRef37
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CrossRef38
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CrossRef39
Emanuele Montomoli, Simona Piccirella, Baharak Khadang, Elisa Mennitto, Roberto Camerini, Alfonso De Rosa. (2011) Current adjuvants and new perspectives in vaccine formulation. Expert Review of Vaccines 10:7, 1053-1061
CrossRef40
Katja Hoschler, Maria Zambon, Karl G Nicholson. (2011) Adjuvanted or whole-virion vaccine for 2009 influenza A (H1N1) – Authors' reply. The Lancet Infectious Diseases 11:7, 497-498
CrossRef41
Rajeev Dhere, Leena Yeolekar, Prasad Kulkarni, Ravi Menon, Vivek Vaidya, Milan Ganguly, Parikshit Tyagi, Prajakt Barde, Suresh Jadhav. (2011) A pandemic influenza vaccine in India: From strain to sale within 12 months. Vaccine 29, A16-A21
CrossRef42
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CrossRef43
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CrossRef44
Rino Rappuoli, Steven Black, Paul Henri Lambert. (2011) Vaccine discovery and translation of new vaccine technology. The Lancet 378:9788, 360-368
CrossRef45
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CrossRef46
S. Esposito, E. Meregalli, C. Daleno, L. Ghio, C. Tagliabue, A. Valzano, D. Serra, C. Galeone, A. Edefonti, N. Principi. (2011) An open-label, randomized clinical trial assessing immunogenicity, safety and tolerability of pandemic influenza A/H1N1 MF59-adjuvanted vaccine administered sequentially or simultaneously with seasonal virosomal-adjuvanted influenza vaccine to paediatric kidney transplant recipients. Nephrology Dialysis Transplantation 26:6, 2018-2024
CrossRef47
S. Khurana, N. Verma, J. W. Yewdell, A. K. Hilbert, F. Castellino, M. Lattanzi, G. Del Giudice, R. Rappuoli, H. Golding. (2011) MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines. Science Translational Medicine 3:85, 85ra48-85ra48
CrossRef48
Xavier Kurz, François Domergue, Jim Slattery, Andrej Segec, Agnieszka Szmigiel, Ana Hidalgo-Simon. (2011) Safety monitoring of Influenza A/H1N1 pandemic vaccines in EudraVigilance. Vaccine 29:26, 4378-4387
CrossRef49
J. Garcia-Sicilia, P. Gillard, A. Carmona, J.C. Tejedor, J. Aristegui, J.M. Merino, U. Behre, A. Caplanusi, T. Vaman, I. Dieussaert. (2011) Immunogenicity and safety of AS03-adjuvanted H1N1 pandemic vaccines in children and adolescents. Vaccine 29:26, 4353-4361
CrossRef50
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CrossRef51
E. C. Settembre, P. R. Dormitzer, R. Rappuoli. (2011) Learning from the 2009 H1N1 pandemic: prospects for more broadly effective influenza vaccines. Journal of Molecular Cell Biology 3:3, 144-146
CrossRef52
Cem Gabay, Michael Bel, Christophe Combescure, Camillo Ribi, Sara Meier, Klara Posfay-Barbe, Stéphane Grillet, Jörg D. Seebach, Laurent Kaiser, Werner Wunderli, Pierre-André Guerne, Claire-Anne Siegrist, . (2011) Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: A prospective, open-label, parallel-cohort, single-center study. Arthritis & Rheumatism 63:6, 1486-1496
CrossRef53
S. Brakemeier, B. Schweiger, N. Lachmann, P. Glander, C. Schonemann, F. Diekmann, H.-H. Neumayer, K. Budde. (2011) Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix(R)) in renal transplant recipients. Nephrology Dialysis Transplantation
CrossRef54
A. Ortqvist, I. Berggren, M. Insulander, B. de Jong, B. Svenungsson. (2011) Effectiveness of an Adjuvanted Monovalent Vaccine Against the 2009 Pandemic Strain of Influenza A(H1N1)v in Stockholm County, Sweden. Clinical Infectious Diseases 52:10, 1203-1211
CrossRef55
Bruce Y. Lee, Randy M. Stalter, Kristina M. Bacon, Julie H.Y. Tai, Rachel R. Bailey, Shanta M. Zimmer, Michael M. Wagner. (2011) Cost-Effectiveness of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Adult Hemodialysis Patients. American Journal of Kidney Diseases 57:5, 724-732
CrossRef56
Paula Garland, Hugues de Lavallade, Takuya Sekine, Katja Hoschler, Shiranee Sriskandan, Parind Patel, Stephen Brett, Kate Stringaris, Eva Loucaides, Katherine Howe, David Marin, Ed Kanfer, Nichola Cooper, Donald Macdonald, Amin Rahemtulla, Mark Atkins, Akila Danga, Dragana Milojkovic, Ian Gabriel, Ahmad Khoder, Abdullah Alsuliman, Jane Apperley, Katayoun Rezvani. (2011) Humoral and Cellular Immunity to Primary H1N1 Infection in Patients with Hematologic Malignancies following Stem Cell Transplantation. Biology of Blood and Marrow Transplantation 17:5, 632-639
CrossRef57
Gabriele Neumann, Yoshihiro Kawaoka. (2011) The first influenza pandemic of the new millennium. Influenza and Other Respiratory Viruses 5:3, 157-166
CrossRef58
Sven Meyer, Matti Adam, Brunhilde Schweiger, Corina Ilchmann, Christine Eulenburg, Edgar Sattinger, Hendrik Runte, Michael Schlüter, Tobias Deuse, Hermann Reichenspurner, Angelika Costard-Jäckle. (2011) Antibody Response After a Single Dose of an AS03-Adjuvanted Split-Virion Influenza A (H1N1) Vaccine in Heart Transplant Recipients. Transplantation 91:9, 1031-1035
CrossRef59
Pauline Verdijk, Nynke Y Rots, Wilfried AM Bakker. (2011) Clinical development of a novel inactivated poliomyelitis vaccine based on attenuated Sabin poliovirus strains. Expert Review of Vaccines 10:5, 635-644
CrossRef60
Ralf Dikow, Isabella Eckerle, Dorothea Ksoll-Rudek, Heidrun Hampel, Vedat Schwenger, Martin Zeier, Paul Schnitzler, Claudia Sommerer. (2011) Immunogenicity and Efficacy in Hemodialysis Patients of an AS03A-Adjuvanted Vaccine for 2009 Pandemic Influenza A(H1N1): A Nonrandomized Trial. American Journal of Kidney Diseases 57:5, 716-723
CrossRef61
Amel Chaabane, Karim Aouam, Nadia Ben Fredj, Adnen Toumi, Dorra Braham, Naceur A Boughattas, Mohamed Chakroun. (2011) Les vaccins anti A(H1N1) en Tunisie : efficacité et tolérance. Thérapie 66:3, 281-289
CrossRef62
L. Labriola, A. Hombrouck, C. Marechal, S. Van Gucht, B. Brochier, I. Thomas, M. Jadoul, P. Goubau. (2011) Immunogenicity of an adjuvanted 2009 pandemic influenza A (H1N1) vaccine in haemodialysed patients. Nephrology Dialysis Transplantation 26:4, 1424-1428
CrossRef63
L E Davidson, A-M Fiorino, D R Snydman, P L Hibberd. (2011) Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial. European Journal of Clinical Nutrition 65:4, 501-507
CrossRef64
Nancy F. Crum-Cianflone, Erik Iverson, Gabriel Defang, Patrick J. Blair, Lynn E. Eberly, Jason Maguire, Anuradha Ganesan, Dennis Faix, Christopher Duplessis, Tahaniyat Lalani, Timothy Whitman, Carolyn Brandt, Grace Macalino, Eugene V. Millar, Timothy Burgess. (2011) Durability of antibody responses after receipt of the monovalent 2009 pandemic influenza A (H1N1) vaccine among HIV-infected and HIV-uninfected adults. Vaccine 29:17, 3183-3191
CrossRef65
Massimiliano Fabbiani, Simona Di Giambenedetto, Michela Sali, Salvatore Farina, Paola Sansonetti, Enrica Tamburrini, Lorenzo Zileri Dal Verme, Giovanni Delogu, Andrea De Luca, David Kelvin, Roberto Cauda, Giovanni Fadda. (2011) Immune response to influenza A (H1N1)v monovalent MF59-adjuvanted vaccine in HIV-infected patients. Vaccine 29:16, 2836-2839
CrossRef66
Derek T O’Hagan, Rino Rappuoli, Ennio De Gregorio, Theodore Tsai, Giuseppe Del Giudice. (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Review of Vaccines 10:4, 447-462
CrossRef67
John E. O'Toole, Vincent C. Traynelis. (2011) Editorial. Journal of Neurosurgery: Spine1-5
CrossRef68
Benoît Baras, Leon de Waal, Koert J. Stittelaar, Valérie Jacob, Sandra Giannini, Edwin J.B. Veldhuis Kroeze, Judith M.A. van den Brand, Geert van Amerongen, James H. Simon, Emmanuel Hanon, Sally P. Mossman, Albert D.M.E. Osterhaus. (2011) Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets. Vaccine 29:11, 2120-2126
CrossRef69
Heng Liu, Laura Bungener, Wouter ter Veer, Beth-Ann Coller, Jan Wilschut, Anke Huckriede. (2011) Preclinical evaluation of the saponin derivative GPI-0100 as an immunostimulating and dose-sparing adjuvant for pandemic influenza vaccines. Vaccine 29:11, 2037-2043
CrossRef70
Sudhir Pai Kasturi, Ioanna Skountzou, Randy A. Albrecht, Dimitrios Koutsonanos, Tang Hua, Helder I. Nakaya, Rajesh Ravindran, Shelley Stewart, Munir Alam, Marcin Kwissa, Francois Villinger, Niren Murthy, John Steel, Joshy Jacob, Robert J. Hogan, Adolfo García-Sastre, Richard Compans, Bali Pulendran. (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470:7335, 543-547
CrossRef71
Liang, Xiao-Feng, Li, Li, Liu, Da-Wei, Li, Ke-Li, Wu, Wen-Di, Zhu, Bao-Ping, Wang, Hua-Qing, Luo, Hui-Ming, Cao, Ling-Sheng, Zheng, Jing-Shan, Yin, Da-Peng, Cao, Lei, Wu, Bing-Bing, Bao, Hong-Hong, Xu, Di-Sha, Yang, Wei-Zhong, Wang, Yu, . (2011) Safety of Influenza A (H1N1) Vaccine in Postmarketing Surveillance in China. New England Journal of Medicine 364:7, 638-647
Full Text72
Susanna Esposito, Laura Tagliaferri, Cristina Daleno, Antonia Valzano, Irene Picciolli, Francesca Tel, Giulia Prunotto, Domenico Serra, Carlotta Galeone, Anna Plebani, Nicola Principi. (2011) Pandemic influenza A/H1N1 vaccine administered sequentially or simultaneously with seasonal influenza vaccine to HIV-infected children and adolescents. Vaccine 29:8, 1677-1682
CrossRef73
Karl G Nicholson, Keith R Abrams, Sally Batham, Tristan W Clark, Katja Hoschler, Wei Shen Lim, Marie-Jo Medina, Jonathan S Nguyen-Van-Tam, Robert C Read, Fiona C Warren, Maria Zambon. (2011) Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial. The Lancet Infectious Diseases 11:2, 91-101
CrossRef74
Cécile L. Tremblay, Danielle Rouleau, Claude Fortin, Emil Toma, Mohamed Sylla, Lise Cyr, Serge Cote, Mariana Baz, John Sampalis, Lydie Trautman, Rafick-Pierre Sékaly, Guy Boivin. (2011) Immunogenicity and tolerability of an inactivated and adjuvanted pandemic H1N1 influenza vaccine, in HIV-1-infected patients. Vaccine 29:7, 1359-1363
CrossRef75
Ping Huang, Yuansheng Xu, Hanzhong Ni, Jing Zhong, Xin Zhang, Songnuan Tan, De Wu, Baoyun Qiu, Dawei Guan, Miaoheng Wen, Jin Yan, Yonghui Zhang. (2011) Linear B-cell epitope mapping of neuraminidases of the 2009 A H1N1 viruses based on immunoinformatics. Vaccine 29:6, 1278-1282
CrossRef76
Geert Leroux-Roels, Isabel Leroux-Roels. (2011) Head-to-head comparison of pandemic influenza vaccines. The Lancet Infectious Diseases 11:2, 74-75
CrossRef77
Valentina Parodi, Daniela de Florentiis, Mariano Martini, Filippo Ansaldi. (2011) Inactivated Influenza Vaccines. Drugs & Aging 28:2, 93-106
CrossRef78
M. Loebermann, G. Anders, G. Brestrich, C. Fritzsche, S. Klammt, D. Boršo, S. Frimmel, D. Riebold, E.C. Reisinger. (2011) Safety and immunogenicity of a trivalent single dose seasonal influenza vaccine containing pandemic A(H1N1) antigen in younger and elderly subjects: A phase III open-label single-arm study. Vaccine 29:6, 1228-1234
CrossRef79
G. L. Chen, Y.-F. Lau, E. W. Lamirande, A. W. McCall, K. Subbarao. (2011) Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine. Proceedings of the National Academy of Sciences 108:3, 1140-1145
CrossRef80
O. Manuel, M. Pascual, K. Hoschler, S. Giulieri, D. Alves, K. Ellefsen, P.-A. Bart, J.-P. Venetz, T. Calandra, M. Cavassini. (2011) Humoral Response to the Influenza A H1N1/09 Monovalent AS03-Adjuvanted Vaccine in Immunocompromised Patients. Clinical Infectious Diseases 52:2, 248-256
CrossRef81
Anneke Steens, Eleonora G Wijnans, Jeanne P Dieleman, Miriam CJM Sturkenboom, Marianne AB van der Sande, Wim van der Hoek. (2011) Effectiveness of a MF-59™-adjuvanted pandemic influenza vaccine to prevent 2009 A/H1N1 influenza-related hospitalisation; a matched case-control study. BMC Infectious Diseases 11:1, 196
CrossRef82
N. F. Crum-Cianflone, L. E. Eberly, C. Duplessis, J. Maguire, A. Ganesan, D. Faix, G. Defang, Y. Bai, E. Iverson, T. Lalani, T. Whitman, P. J. Blair, C. Brandt, G. Macalino, T. Burgess. (2011) Immunogenicity of a Monovalent 2009 Influenza A (H1N1) Vaccine in an Immunocompromised Population: A Prospective Study Comparing HIV-Infected Adults with HIV-Uninfected Adults. Clinical Infectious Diseases 52:1, 138-146
CrossRef83
Theodore F. TSAI. (2011) MF59® Adjuvanted Seasonal and Pandemic Influenza Vaccines. YAKUGAKU ZASSHI 131:12, 1733-1741
CrossRef84
A. Schuchat, B. P. Bell, S. C. Redd. (2011) The Science behind Preparing and Responding to Pandemic Influenza: The Lessons and Limits of Science. Clinical Infectious Diseases 52:Supplement 1, S8-S12
CrossRef85
A. Carvajal, P. García Ortega, M. Sáinz, V. Velasco, I. Salado, L.H. Martín Arias, J.M. Eiros, A. Pérez Rubio, J. Castrodeza. (2011) Adverse events associated with pandemic influenza vaccines: Comparison of the results of a follow-up study with those coming from spontaneous reporting. Vaccine 29:3, 519-522
CrossRef86
PengHui Yang, YueQiang Duan, Cheng Wang, Li Xing, Xiao Gao, Chong Tang, DeYan Luo, ZhongPeng Zhao, Weihong Jia, Daxin Peng, Xiufan Liu, Xiliang Wang. (2011) Immunogenicity and protective efficacy of a live attenuated vaccine against the 2009 pandemic A H1N1 in Mice and Ferrets. Vaccine 29:4, 698-705
CrossRef87
Day-Yu Chao, Kuang-Fu Cheng, Ying-Hen Hsieh, Tsai-Chung Li, Trong-Neng Wu, Chiu-Ying Chen, Chen-An Tsai, Jin-Hwa Chen, Hsien-Tsai Chiu, Jang-Jih Lu, Mei-Chi Su, Yu-Hsin Liao. (2011) Serological response and persistence in schoolchildren with high baseline seropositive rate after receiving 2009 pandemic influenza A(H1N1) vaccine. Vaccine 29:4, 617-623
CrossRef88
Philip R. Dormitzer, Grazia Galli, Flora Castellino, Hana Golding, Surender Khurana, Giuseppe Del Giudice, Rino Rappuoli. (2011) Influenza vaccine immunology. Immunological Reviews 239:1, 167-177
CrossRef89
Anna Kajaste-Rudnitski, Laura Galli, Silvia Nozza, Giuseppe Tambussi, Andrea Di Pietro, Gabriele Pellicciotta, Alessandro Monti, Paolo Mascagni, Matteo Moro, Elisa Vicenzi. (2011) Induction of protective antibody response by MF59-adjuvanted 2009 pandemic A/H1N1v influenza vaccine in HIV-1-infected individuals. AIDS 25:2, 177-183
CrossRef90
Susan L. Baldwin, Christopher B. Fox, Mark A. Pallansch, Rhea N. Coler, Steven G. Reed, Martin Friede. (2011) Increased potency of an inactivated trivalent polio vaccine with oil-in-water emulsions. Vaccine 29:4, 644-649
CrossRef91
Johannes M Luteijn, Helen Dolk, Gordon J Marnoch. (2011) Differences in pandemic influenza vaccination policies for pregnant women in Europe. BMC Public Health 11:1, 819
CrossRef92
Jason Ho, Susan Moir, Wei Wang, Jacqueline G Posada, Wenjuan Gu, Muhammad T Rehman, Robin Dewar, Colin Kovacs, Michael C Sneller, Tae-Wook Chun, Dean A Follmann, Anthony S Fauci. (2011) Enhancing effects of adjuvanted 2009 pandemic H1N1 influenza A vaccine on memory B-cell responses in HIV-infected individuals. AIDS 25:3, 295-302
CrossRef93
Hee Jin Cheong, Joon Young Song, Jung Yeon Heo, Ji Yun Noh, Won Suk Choi, Dae Won Park, Seong-Heon Wie, Woo Joo Kim. (2011) Immunogenicity and safety of influenza A (H1N1) 2009 monovalent inactivated split vaccine in Korea. Vaccine 29:3, 523-527
CrossRef94
Jodie McVernon, Terry Nolan. (2011) Panvax ® : a monovalent inactivated unadjuvanted vaccine against pandemic influenza A (H1N1) 2009. Expert Review of Vaccines 10:1, 35-43
CrossRef95
Nisreen Amayiri, Faris Madanat. (2011) Retrospective analysis of pediatric cancer patients diagnosed with the pandemic H1N1 influenza infection. Pediatric Blood & Cancer 56:1, 86-89
CrossRef96
Mark Jit, Deborah Cromer, Marc Baguelin, Julia Stowe, Nick Andrews, Elizabeth Miller. (2010) The cost-effectiveness of vaccinating pregnant women against seasonal influenza in England and Wales. Vaccine 29:1, 115-122
CrossRef97
Abdullah S. Madhun, Per Espen Akselsen, Haakon Sjursen, Gabriel Pedersen, Signe Svindland, Jane Kristin Nøstbakken, Mona Nilsen, Kristin Mohn, Åsne Jul-Larsen, Ingrid Smith, Diane Major, John Wood, Rebecca J. Cox. (2010) An adjuvanted pandemic influenza H1N1 vaccine provides early and long term protection in health care workers. Vaccine 29:2, 266-273
CrossRef98
Woolf T Walker, Saul N Faust. (2010) Monovalent inactivated split-virion AS03-adjuvanted pandemic influenza A (H1N1) vaccine. Expert Review of Vaccines 9:12, 1385-1398
CrossRef99
J. J. Strouse, M. E. Reller, D. G. Bundy, M. Amoako, M. Cancio, R. N. Han, A. Valsamakis, J. F. Casella. (2010) Severe pandemic H1N1 and seasonal influenza in children and young adults with sickle cell disease. Blood 116:18, 3431-3434
CrossRef100
Penghui Yang, Chong Tang, Deyan Luo, Zhongpeng Zhan, Li Xing, Yueqiang Duan, Weihong Jia, Daxin Peng, Xiufan Liu, Xiliang Wang. (2010) Cross-clade protection against HPAI H5N1 influenza virus challenge in BALB/c mice intranasally administered adjuvant-combined influenza vaccine. Veterinary Microbiology 146:1-2, 17-23
CrossRef101
Susanna Esposito, Emanuela D’Angelo, Cristina Daleno, Francesco Peia, Alessia Scala, Domenico Serra, Nadia Mirra, Carlotta Galeone, Nicola Principi. (2010) Immunogenicity, safety and tolerability of monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in patients with β-thalassemia major. Vaccine 28:50, 7825-7828
CrossRef102
Aristeidis Stavroulopoulos, Georgios Stamogiannos, Vasiliki Aresti. (2010) Pandemic 2009 influenza H1N1 virus vaccination: compliance and safety in a single hemodialysis center. Renal Failure 32:9, 1044-1048
CrossRef103
Hsiang-Chi Kung, Kuo-Chin Huang, Tsui-Mai Kao, Yi-Chien Lee, Feng-Yee Chang, Ning-Chi Wang, Yung-Ching Liu, Wen-Sen Lee, Hsing-Jin Liu, Chin-I Chen, Chien-Hui Chen, Li-Min Huang, Szu-Min Hsieh. (2010) A clinical study to assess the immunogenicity and safety of a monovalent 2009 influenza A (H1N1) vaccine in an area with low-level epidemics of pandemic influenza. Vaccine 28:45, 7337-7343
CrossRef104
Marc P. Girard, Jacqueline Katz, Yuri Pervikov, Laszlo Palkonyay, Marie-Paule Kieny. (2010) Report of the 6th meeting on the evaluation of pandemic influenza vaccines in clinical trials World Health Organization, Geneva, Switzerland, 17–18 February 2010. Vaccine 28:42, 6811-6820
CrossRef105
Hana El Sahly. (2010) MF59™ as a vaccine adjuvant: a review of safety and immunogenicity. Expert Review of Vaccines 9:10, 1135-1141
CrossRef106
Steven Black, Giovanni Della Cioppa, Anne Malfroot, Pantaleo Nacci, Uwe Nicolay, Michele Pellegrini, Etienne Sokal, André Vertruyen. (2010) Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: An integrated analysis. Vaccine 28:45, 7331-7336
CrossRef107
Julian W. Tang, Nandini Shetty, Tommy T.Y. Lam, K.L. Ellis Hon. (2010) Emerging, Novel, and Known Influenza Virus Infections in Humans. Infectious Disease Clinics of North America 24:3, 603-617
CrossRef108
Susana Chávez-Bueno, Terrence L. Stull. (2010) Pediatric Vaccines on the Horizon. The American Journal of the Medical Sciences 340:3, 226-231
CrossRef109
Jin Soo Shin, Seon Do Hwang, Hyun Soo Kim, Sung Whan Cho, Sang Heui Seo. (2010) Protection of Ferrets from Infection by Swine-Origin 2009 A (H1N1) Influenza Virus by the Inactivated Vaccine. Viral Immunology 23:4, 395-402
CrossRef110
Alfonso Carmona, Félix Omeñaca, Juan C. Tejedor, Jose M. Merino, Tejaswini Vaman, Ilse Dieussaert, Paul Gillard, Javier Arístegui. (2010) Immunogenicity and safety of AS03-adjuvanted 2009 influenza A H1N1 vaccine in children 6–35 months. Vaccine 28:36, 5837-5844
CrossRef111
Chun-Yi Lu, Pei-Lan Shao, Luan-Yin Chang, Yhu-Chering Huang, Cheng-Hsun Chiu, Yu-Chia Hsieh, Tzou-Yien Lin, Li-Min Huang. (2010) Immunogenicity and safety of a monovalent vaccine for the 2009 pandemic influenza virus A (H1N1) in children and adolescents. Vaccine 28:36, 5864-5870
CrossRef112
José María Navarro-Marí, José María Mayoral-Cortés, Mercedes Pérez-Ruiz, Jesús Rodríguez-Baño, Jordi Carratalá, Virtudes Gallardo-García. (2010) Infección en humanos por virus de la gripe A(H1N1): revisión al 30 de octubre de 2009. Enfermedades Infecciosas y Microbiología Clínica 28:7, 446-452
CrossRef113
Giovanna Orlando, Elena Pariani, Francesca Mazza, Elisabetta Tanzi, Paola Meraviglia, Erica Gianelli, Barbara Argenteri, Antonella Amendola, Massimo Galli, Giuliano Rizzardini, Alessandro Zanetti. (2010) Pandemic influenza vaccine in adult HIV-1-infected patients. AIDS 24:13, 2142-2143
CrossRef114
Ari Balofsky, Nancy Agmon-Levin, Yehuda Shoenfeld. (2010) The new H1N1 and HPV vaccines and old fears. Current Opinion in Rheumatology 22:4, 431-436
CrossRef115
Yuji Yasuda, Ryoya Komatsu, Kenji Matsushita, Taketsugu Minami, Yutaka Suehiro, Hiroshi Sawata, Noriko Nakura, Ralf K. Jaeger, Maria Lattanzi. (2010) Comparison of half and full doses of an MF59-adjuvanted cell culture-derived A/H1N1v vaccine in Japanese children. Advances in Therapy 27:7, 444-457
CrossRef116
Marc P. Girard, John S. Tam, Olga M. Assossou, Marie Paule Kieny. (2010) The 2009 A (H1N1) influenza virus pandemic: A review. Vaccine 28:31, 4895-4902
CrossRef117
Helena C. Maltezou. (2010) Novel (pandemic) influenza A H1N1 in healthcare facilities: Implications for prevention and control. Scandinavian Journal of Infectious Diseases 42:6-7, 412-420
CrossRef118
M Lamine Mbow, Ennio De Gregorio, Nicholas M Valiante, Rino Rappuoli. (2010) New adjuvants for human vaccines. Current Opinion in Immunology 22:3, 411-416
CrossRef119
Chonticha Klungthong, Piyawan Chinnawirotpisan, Kittinun Hussem, Thipwipha Phonpakobsin, Wudtichai Manasatienkij, Chuanpis Ajariyakhajorn, Kamonthip Rungrojcharoenkit, Robert V. Gibbons, Richard G. Jarman. (2010) The impact of primer and probe-template mismatches on the sensitivity of pandemic influenza A/H1N1/2009 virus detection by real-time RT-PCR. Journal of Clinical Virology 48:2, 91-95
CrossRef120
Roman Chlibek, Ioana Anca, Francis André, Mustafa Bakir, Inga Ivaskeviciene, Atanas Mangarov, Zsófia Mészner, Penka Perenovska, Roman Prymula, Darko Richter, Nuran Salman, Pavol Šimurka, Eda Tamm, Nataša Toplak, Vytautas Usonis. (2010) Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for 2009 pandemic influenza A(H1N1) vaccination. Vaccine 28:22, 3758-3766
CrossRef121
Julian W Tang, Nandini Shetty, Tommy Tsan-Yuk Lam. (2010) Features of the new pandemic influenza A/H1N1/2009 virus: virology, epidemiology, clinical and public health aspects. Current Opinion in Pulmonary Medicine 16:3, 235-241
CrossRef122
Regina Allwinn, Janina Geiler, Annemarie Berger, J. Cinatl, H. W. Doerr. (2010) Determination of serum antibodies against swine-origin influenza A virus H1N1/09 by immunofluorescence, haemagglutination inhibition, and by neutralization tests: how is the prevalence rate of protecting antibodies in humans?. Medical Microbiology and Immunology 199:2, 117-121
CrossRef123
E. C. Settembre, P. R. Dormitzer, R. Rappuoli. (2010) H1N1: Can a Pandemic Cycle Be Broken?. Science Translational Medicine 2:24, 24ps14-24ps14
CrossRef124
R. Gasparini, F. Schioppa, M. Lattanzi, M. Barone, D. Casula, M. Pellegrini, K. Veitch, N. Gaitatzis. (2010) Impact of prior or concomitant seasonal influenza vaccination on MF59-adjuvanted H1N1v vaccine (Focetria™) in adult and elderly subjects. International Journal of Clinical Practice 64:4, 432-438
CrossRef125
Elizabeth Miller, Katja Hoschler, Pia Hardelid, Elaine Stanford, Nick Andrews, Maria Zambon. (2010) Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study. The Lancet 375:9720, 1100-1108
CrossRef126
Kamran Khan, Ziad A. Memish, Aneesh Chabbra, Jessica Liauw, Wei Hu, David A. Janes, Jennifer Sears, Julien Arino, Michael Macdonald, Felipe Calderon, Paulo Raposo, Christine Heidebrecht, Jun Wang, Angie Chan, John Brownstein, Michael Gardam. (2010) Global Public Health Implications of a Mass Gathering in Mecca, Saudi Arabia During the Midst of an Influenza Pandemic. Journal of Travel Medicine 17:2, 75-81
CrossRef127
Tao Jiang, XiaoPing Kang, Yongqiang Deng, Hui Zhao, Xiaofeng Li, Xuedong Yu, Man Yu, Ede Qin, Qingyu Zhu, Yinhui Yang, Chengfeng Qin. (2010) Development of a real-time RT-PCR assay for a novel influenza A (H1N1) virus. Journal of Virological Methods 163:2, 470-473
CrossRef128
François Roman, Tejaswini Vaman, Beatrice Gerlach, Andre Markendorf, Paul Gillard, Jeanne-Marie Devaster. (2010) Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: Preliminary report of an observer-blind, randomised trial. Vaccine 28:7, 1740-1745
CrossRef129
Theodore Tsai, Moe H. Kyaw, Deborah Novicki, Pantaleo Nacci, Saroj Rai, Ralf Clemens. (2010) Exposure to MF59-adjuvanted influenza vaccines during pregnancy—A retrospective analysis. Vaccine 28:7, 1877-1880
CrossRef130
Arguedas, Adriano, Soley, Carolina, , Lindert, Kelly, . (2010) Responses to 2009 H1N1 Vaccine in Children 3 to 17 Years of Age. New England Journal of Medicine 362:4, 370-372
Full Text131
Xiao-Feng Liang, Hua-Qing Wang, Jun-Zhi Wang, Han-Hua Fang, Jiang Wu, Feng-Cai Zhu, Rong-Cheng Li, Sheng-Li Xia, Yu-Liang Zhao, Fang-Jun Li, Shao-Hong Yan, Wei-Dong Yin, Kang An, Duo-Jia Feng, Xuan-Lin Cui, Feng-Chun Qi, Chang-Jun Ju, Yu-Hui Zhang, Zhi-Jun Guo, Ping-Yu Chen, Ze Chen, Kun-Ming Yan, Yu Wang. (2010) Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet 375:9708, 56-66
CrossRef132
Zoltan Vajo, Ferenc Tamas, Laszlo Sinka, Istvan Jankovics. (2010) Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: a multicentre, randomised controlled trial. The Lancet 375:9708, 49-55
CrossRef133
D. Kumar, M. I. Morris, C. N. Kotton, S. A. Fischer, M. G. Michaels, U. Allen, E. A. Blumberg, M. Green, A. Humar, M. G. Ison, . (2010) Guidance on Novel Influenza A/H1N1 in Solid Organ Transplant Recipients†. American Journal of Transplantation 10:1, 18-25
CrossRef134
J.-F. RAHIER, Y. YAZDANPANAH, N. VIGET, S. TRAVIS, J.-F. COLOMBEL. (2010) Review article: influenza A (H1N1) virus in patients with inflammatory bowel disease. Alimentary Pharmacology & Therapeutics 31:1, 5-10
CrossRef135
Zuhal Gundogdu, Mualla Seyhogullari. (2010) Lymphadenitis as a Rare Side Effect of H1N1 Vaccine in a Child. Case Reports in Medicine 2010, 1-3
CrossRef136
Heath Kelly, Ian Barr. (2010) Large trials confirm immunogenicity of H1N1 vaccines. The Lancet 375:9708, 6-9
CrossRef137
Eric Plennevaux, Eric Sheldon, Mark Blatter, Mary-Kate Reeves-Hoché, Martine Denis. (2010) Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials. The Lancet 375:9708, 41-48
CrossRef138
Dina Pfeifer, Claudia Alfonso, David Wood. (2010) Defining the safety profile of pandemic influenza vaccines. The Lancet 375:9708, 9-11
CrossRef139
G. Del Giudice, K. J. Stittelaar, G. van Amerongen, J. Simon, A. D. M. E. Osterhaus, K. Stohr, R. Rappuoli. (2009) Seasonal Influenza Vaccine Provides Priming for A/H1N1 Immunization. Science Translational Medicine 1:12, 12re1-12re1
CrossRef140
Neuzil, Kathleen M., . (2009) Pandemic Influenza Vaccine Policy — Considering the Early Evidence. New England Journal of Medicine 361:25,
Full Text141
Lara A. Danziger-Isakov, Shahid Husain, Martha L. Mooney, Margaret M. Hannan. (2009) The Novel 2009 H1N1 Influenza Virus Pandemic: Unique Considerations for Programs in Cardiothoracic Transplantation. The Journal of Heart and Lung Transplantation 28:12, 1341-1347
CrossRef142
Brice E. Barefoot, Kathleen Athearn, Christopher J. Sample, Elizabeth A. Ramsburg. (2009) Intramuscular immunization with a vesicular stomatitis virus recombinant expressing the influenza hemagglutinin provides post-exposure protection against lethal influenza challenge. Vaccine 28:1, 79-89
CrossRef143
Denise J Jamieson, Margaret A Honein, Sonja A Rasmussen, Kitty F MacFarlane, Sonja J Olsen. (2009) Pregnancy and H1N1 infection – Authors' reply. The Lancet 374:9699, 1417-1418
CrossRef
