•A method to assess seasonal influenza vaccine dose distribution has been developed.•3 of 6 WHO regions account for 95% of all influenza vaccine doses distributed.•There is a downward trend in ...seasonal influenza vaccine dose distribution in EURO.•WHA influenza vaccination coverage targets have not been met by most countries.•Most countries are inadequately prepared for a global influenza pandemic.
There is no global monitoring system for influenza vaccination coverage, making it difficult to assess progress towards the 2003 World Health Assembly (WHA) vaccination coverage target. In 2008, the IFPMA Influenza Vaccine Supply International Task Force (IVS) developed a survey method to assess the global distribution of influenza vaccine doses as a proxy for vaccination coverage rates. The latest dose distribution data for 2014 and 2015 was used to update previous analyses. Data were confidentially collected and aggregated by the IFPMA Secretariat, and combined with previous IFPMA IVS survey data (2004–2013). Data were available from 201 countries over the 2004–2015 period. A “hurdle” rate was defined as the number of doses required to reach 15.9% of the population in 2008. Overall, the number of distributed doses progressively increased between 2004 and 2011, driven by a 150% increase in AMRO, then plateaued. One percent fewer doses were distributed in 2015 than in 2011. Twenty–three countries were above the hurdle rate in 2015, compared to 15 in 2004, but distribution was highly uneven in and across all WHO regions. Three WHO regions (AMRO, EURO and WPRO) accounted for about 95% of doses distributed. But in EURO and WPRO, distribution rates in 2015 were only marginally higher than in 2004, and in EURO there was an overall downward trend in dose distribution. The vast majority of countries cannot meet the 2003WHA coverage targets and are inadequately prepared for a global influenza pandemic. With only 5% of influenza vaccine doses being distributed to 50% of the world’s population, there is urgency to redress the gross inequities in disease prevention and in pandemic preparedness. The 2003WHA resolution must be reviewed and revised and a call issued for the renewed commitment of Member States to influenza vaccination coverage targets.
Abstract Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either ...plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978–2009, 33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years. For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93–1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40). Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events. This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges.
We introduce the antibody landscape, a method for the quantitative analysis of antibodymediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among ...pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.
•Serological and field studies with seasonal influenza vaccines were systematically retrieved for estimates of vaccine effectiveness, pre-seasonal immunity, and antigenic match state.•The impact of ...influenza B lineage mismatch on vaccine effectiveness was largest in trials with low pre-seasonal immunity (infants/young children). QIV would be beneficial in this age group.•In trials with large pre-seasonal immunity (elderly), effectiveness of TIV was similar for match and lineage mismatch. QIV can be used in this age group, although its gain over TIV is limited.
B lineage mismatch prompted introduction of quadri-valent influenza vaccines (QIV) with two influenza B viruses representing distinct antigenic lineages. To explore the impact on antibody induction and vaccine effectiveness predicted from antibody (VEab), we performed a systematic literature search on immunogenicity studies conducted to assess antibody superiority of QIV over trivalent influenza vaccine (TIV). Thirteen relevant articles described 31 trials from 2007 and 2013. Log-transformed GMT trial estimates and their variances were converted to clinical protection rates predicted from antibody (PRab). VEab estimates were calculated from pre- and post-vaccination PRab. Without specific pre-vaccination immunity, average VEab was 69% for match, and −4% for lineage mismatch. With increasing pre-vaccination seropositivity, mismatch impact declined to 2%. We also performed an umbrella literature search for randomised controlled trials and test-negative case-control trials with TIV, and estimated vaccine effectiveness against laboratory-confirmed influenza B (VEf). Sixty-eight eligible clinical articles described 110 season-trials from 1965 to 2012, covering seasons with B lineage match (n=52), lineage drift (n=15) and lineage mismatch (n=43). With no pre-vaccination antibody levels determined, we used chance of previous exposure to influenza B (Ppe) as pre-seasonal immunity measure. When Ppe was 0%, average VEf for matched seasons was 67%, and for mismatched seasons 35%, indicating a moderate, yet significant mismatch impact on VEf. With increasing Ppe, mismatch impact declined to 3%. Thus serological and field trials indicate that B lineage mismatch impact is negatively related to pre-seasonal immunity and that the gain of QIV over TIV most benefits infants and children not yet exposed to influenza B.
Influenza vaccination is becoming an increasingly important aspect of public health programs in developed and rapidly developing countries. In 2000, most of these countries had national ...recommendations to vaccinate elderly people and those with high-risk conditions. Levels of vaccine use, however, varied widely and several rapidly developing countries had higher levels than those seen in many developed countries. More than one-third of all influenza vaccinations occurred in countries outside North America, western Europe and Australia and New Zealand. With increasing vaccine use, all countries will be better prepared for the next pandemic. Nonetheless, those countries that use but do not produce influenza vaccine will find it difficult to obtain supplies of pandemic vaccine.
Since the 1940s, influenza vaccines are inactivated and purified virus or virus subunit preparations (IIV) administered by the intramuscular route. Since decades, attempts have been made to ...construct, as an alternative, attenuated live influenza vaccines (LIV) for intranasal administration. Presently, the most successful LIV is derived from the cold-adapted master strains A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 (AA-LIV, for Ann-Arbor-derived live influenza vaccine). It has been claimed that AA-LIV is more efficacious than IIV. In order to assess differences between the two vaccines with respect to systemic reactogenicity, antibody response, and efficacy, we performed a meta-analysis on eighteen randomised comparative clinical trials involving a total of 5000 vaccinees of all ages. Pooled odds ratios (AA-LIV versus IIV) were calculated according to the random effects model. The two vaccines were associated with similarly low frequencies of systemic vaccine reactions (pooled odds ratio: 0.96, 95% confidence interval: 0.74–1.24). AA-LIV induced significantly lower levels of serum haemagglutination inhibiting antibody and significantly greater levels of local IgA antibody (influenza virus-specific respiratory IgA assayed by ELISA in nasal wash specimens) than IIV. Yet, although they predominantly stimulate different antibody compartments, the two vaccines were similarly efficacious in preventing culture-positive influenza illness. In all trials assessing clinical efficacy, the odds ratios were not significantly different from one (point of equivalence). The pooled odds ratio for influenza A-H3N2 was 1.50 (95% CI: 0.80–2.82), and for A-H1N1, 1.03 (95% CI: 0.58–1.82). The choice between the two vaccine types should be based on weighing the advantage of the attractive non-invasive mode of administration of AA-LIV, against serious concerns about the biological risks inherent to large-scale use of infectious influenza virus, in particular the hazard of gene reassortment with non-human influenza virus strains.
Wegener's granulomatosis (WG) is a systemic vasculitis characterised by relapsing and remitting disease activity. Immunosuppressive drugs are used to control disease, but increase susceptibility to ...infection. Therefore, influenza vaccination should be considered in WG patients. This study was performed to assess the immunogenicity of influenza vaccination in WG patients.
A randomised, controlled trial was performed in WG patients with quiescent disease, defined as a Birmingham vasculitis activity score (BVAS) less than 2. Patients were randomly assigned to receive influenza vaccination (n = 49) or to participate as controls (n = 23). In addition, healthy controls (n = 49) were vaccinated. At entry and at 1 and 3-4 months after entry, antibody responses to vaccination were determined. Furthermore, disease activity was measured (BVAS), adverse effects were recorded and antineutrophil cytoplasmic autoantibody (ANCA) titres were determined.
WG patients achieved high seroprotection rates to all three influenza strains, comparable with healthy controls. Only the A/H1N1 strain patients had a lower seroconversion rate (p = 0.002) and geometric mean titre (p = 0.037) than controls. After 1 month, one control and one vaccinated WG patient had developed active disease. At 3-4 months, two additional control patients had developed active disease compared with none of the vaccinated patients (p = 0.099). Vaccination did not influence ANCA titres. Adverse effects did not differ between patients and healthy controls.
Influenza vaccination in WG patients with quiescent disease induced a sufficient antibody response.
NTR1130.
Serological parameters intend to describe antibody response to influenza vaccine in a population. However, there is uncertainty about the mathematical appropriateness and the biological or clinical ...meaning of conventionally used parameters. Theoretical considerations and exploration of a data-set of 16 studies with an inactivated (subunit) influenza vaccine involving 1176 adult subjects suggest the following conclusions.
In a population seronegative before vaccination, the post-vaccination geometric mean titre (post-GMT) is a meaningful immunological parameter adequately expressing antibody response after vaccination. The related protection rate (PR) is a good surrogate parameter for protection provided by a given vaccine, thus relevant to public health. However, in a population partially seropositive before vaccination (due to previous exposition to influenza antigens), the same parameters may, under certain conditions, seriously overestimate the antibody response, as they do not account for the pre-vaccination state.
Conventional attempts to address pre-vaccination antibody are associated with either loss of information (exclusion of seropositive subjects) or incomplete control of pre-vaccination state (mean fold increase (MFI), response rate (RR)). Although not devoid of theoretical limitations (heteroscedasticity), correction of post-GMT and PR by linear regression appears to provide better estimates of antibody response and vaccine immunogenicity.
Abstract Between 1982 and 2006, 76 clinical studies (including the annual update studies required for licensing in Europe) were performed with the trivalent inactivated subunit influenza vaccine ...Influvac® . In all, 6415 subjects were vaccinated, of whom 5034 were eligible for safety evaluation and 4534 for efficacy evaluation. Treatment-emergent adverse events occurred in 13.7% of subjects. Transient mild-to-moderate local and systemic reactions occurred in up to half of subjects. Post-marketing surveillance confirmed the well-established safety profile reported for inactivated influenza vaccines. All three serological criteria for immunogenicity of the Committee for Medicinal Products for Human Use (CHMP) were met for all three virus strain (sub)types in healthy adults, elderly (over 60 years), nursing home residents, and those at high risk of influenza-related complications. In an additional trial in children aged 3–12 years, all three CHMP criteria for adults were met for all three virus strains. Influvac® is thus immunogenic and safe, and is a suitable vaccine to combat the annually recurring medical and economic burden of influenza epidemics.
Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza ...vaccines. There are two influenza vaccines available for elderly subjects: Fluad
® (Chiron) and Invivac
® (Solvay Pharmaceuticals). The present clinical study was a randomized, endpoint-blind, parallel group study in elderly subjects aged 61 years and older to investigate the safety and immunogenicity of these vaccines as compared to a standard influenza vaccine Invivac
® (Solvay Pharmaceuticals). The three vaccines had similar immunogenicity results, whereas the tolerability profile of Invivac was better as compared to Fluad.
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