Wegener's granulomatosis patients show an adequate antibody response to influenza vaccination.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Influenza vaccination in WG patients with quiescent disease induced a sufficient antibody response. TRIAL REGISTRATION NUMBER: NTR1130.

Rationale for two influenza B lineages in seasonal vaccines: A meta-regression study on immunogenicity and controlled field trials.

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.

Protection against influenza after annually repeated vaccination: a meta-analysis of serologic and field studies.

BACKGROUND: According to common recommendations, influenza vaccination should be performed annually. It has been suggested that vaccination in previous years reduces vaccine efficacy in the long term. OBJECTIVE: To determine whether the protection of influenza vaccine decreases when vaccination is repeated annually. METHODS: Articles published between 1966 and 1997 were selected from MEDLINE. The end point for field studies was the influenza-related morbidity or mortality during influenza outbreaks (resulting in field protection rates). The end point for serologic studies was exceeding a protective postvaccination hemagglutination-inhibition titer (serologic protection rates). Protection rate differences between groups with single and multiple vaccinations were subjected to meta-analysis. RESULTS: Seven field studies (including 13 trials) supported the hypothesis that protection in multiple-vaccination groups is at least as good as that in single-vaccination groups. Ten trials with 5117 observations could be subjected to meta-analysis. The pooled protection-rate difference was close to 0 (1.1%; 95% confidence interval, -0.2% to 2.4%), thus detecting no difference between single or multiple vaccination. Twelve serologic studies (including 53 trials) showed heterogeneous results: 9 trials were significantly in favor of single vaccination, and 7 were in favor of multiple vaccination, but in most cases, there was no significant difference between the 2 vaccination groups. The pooled serologic protection-rate difference from 52 trials (12341 observations) was again close to 0 (1.7%; 95% confidence interval, -1.3% to 4.8%). CONCLUSIONS: We did not detect any evidence for a decreasing protection with annually repeated influenza vaccination. Annual vaccination should not be discouraged in populations at risk.

Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers.

In 14 clinical studies, various efficacy and safety aspects of a new virosomal influenza vaccine (Invivac) were assessed in 2865 subjects. The virosomal influenza vaccine fully complies with the Committee for Proprietary Medicinal Products (CPMP) requirement for immunogenicity of influenza vaccines. In particular, in a subset of subjects with low pre-vaccination titers (thus those persons who actually need protection by a vaccine), between 76 and 99% of subjects (dependent on age, health status and vaccine components) achieved protective hemagglutination inhibiting (HI) antibody titers after vaccination with the virosomal influenza vaccine. Acceptable frequencies of well-known local and systemic reactions were observed in healthy adults and risk subjects in clinical studies and in a post-marketing study population. These reactions were transient and generally not severe, and did not cause major inconvenience. In conclusion, Invivac is an efficacious and safe vaccine for the protection against influenza in healthy and chronically ill adult subjects. The vaccine is especially efficacious in subjects with low pre-vaccination immunity.

Seroprotection rate, mean fold increase, seroconversion rate: which parameter adequately expresses seroresponse to influenza vaccination?

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.

Influenza vaccines. A reappraisal of their use.

The medical and economic burden associated with annual influenza activity is well known and well documented. Yearly updated influenza vaccines are available to combat the disease and its consequences. In many countries, less than half of the high risk patients are being vaccinated, despite recommendations to do so by national health authorities. Scientific evidence on the safety, tolerance, efficacy and effectiveness of currently existing inactivated influenza vaccines unambiguously demonstrates the favourable benefit/risk ratio of influenza immunisations for high risk patients and strongly suggests an economic benefit of influenza immunisation programmes. Because of both the successful world-wide efforts of the WHO to optimise the chance of an adequate antigenic match between vaccine and epidemic strains each year and the available scientific data about the inactivated influenza vaccines, influenza immunisations should be offered annually to high risk patients. On the basis of the available evidence, offering a vaccination to such patients should be considered an ethical obligation.

Haemagglutination-inhibiting antibody to influenza virus.

The results of the haemagglutination-inhibiting (HI) antibody test for influenza virus antibody in human sera closely match those produced by virus neutralization assays and are predictive of protection. On the basis of the data derived from 12 publications concerning healthy adults, we estimated the median HI titre protecting 50% of the vaccinees against the virus concerned at 28. This finding supports the current policy requiring vaccines to induce serum HI titres of > or = 40 to the vaccine viruses in the majority of the vaccinees. Unfortunately similar studies are scanty for the elderly, the group most at risk of influenza. There still remain many unsolved technical problems with the HI assay and we recommend that these problems be studied and the virus neutralization test as a predictor of resistance to influenza be assessed. Although the studies on this issue often give conflicting results, they generally show that HI antibody responses to influenza vaccination tend to diminish with increasing age, when health is often compromized. Advanced age in itself seems not to be an independent factor in this process. However, even in completely healthy elderly individuals the response to vaccination with an antigenically new virus may be strongly reduced compared with younger vaccinees.

Comparison of Serology and Reactogenicity between Influenza Subunit Vaccines and Whole Virus or Split Vaccines: A Review and Meta-Analysis of the Literature.

Currently three different inactivated influenza vaccine types are available: whole virus (WV), split (SPL) and subunit (SU) vaccines. Physicians and patients at risk for influenza complications may wonder whether there are important differences between the vaccine types with respect to antibody induction (serology) and adverse effects (reactogenicity). A literature review (1975 to 1995) was performed to evaluate the serology and reactogenicity of SU vaccines in comparison with either split or whole virus vaccines. 22 publications with randomised allocation were identified describing a total of 5416 serological observations, 2858 observations of local reactions, and 2990 observations of systemic reactions. Subjects included those from all age groups from children to the elderly. Absolute protection and reaction rate differences (RD) were calculated for the comparisons SU vs SPL or SU vs WV vaccine. These were subjected to a method of meta-analysis, resulting in pooled rate differences and their 95% confidence intervals. With the exception of the comparison SU vs WV vaccine in subjects born after 1957 and unexposed to the reappearing H1N1 subtype after 1977, no evidence was found to suggest relevant differences in seroresponse among the three currently available inactivated influenza vaccine types. Although insufficient data were available in the meta-analysis for vaccines in children for whom specific recommendations concerning these vaccines exist, adverse events after administration of any of the three vaccine types were generally mild and transitory; however, SU vaccines were associated with a lower frequency of local and systemic reactions.

Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-analysis.

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.

Trivalent inactivated subunit influenza vaccine Influvac: 25-Year experience of safety and immunogenicity.

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.

The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad in elderly subjects.

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.

Clinical experience with inactivated, virosomal influenza vaccine.

Current available influenza vaccines are safe and effective in preventing influenza. Nevertheless, there is a need for influenza vaccines with improved efficacy in the elderly. This need is underscored by both the observation that influenza has a major clinical and economic impact in the elderly and the fact that currently available vaccines are generally less effective in elderly than in younger subjects. 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. A novel antigen-presenting strategy to overcome impaired immune responses is the use of virosomes. Previously, data on safety and reactogenicity have been published regarding the use of virosomal influenza vaccines. Data from three recent clinical trials are presented here. The first of these was a comparative study of a virosomal vaccine and a conventional subunit vaccine in "at-risk" adults with underlying chronic illness. The virosomal vaccine demonstrated comparable tolerability to the subunit vaccine, with about 98% of patients reporting tolerability to be good or very good. The vast majority of adverse events reported were mild to moderate in severity. With both vaccine types, mean HI titres decreased with age for both the A-H1N1 and B influenza virus strains, but for the A-H3N2 strain (the most virulent of the three strains), mean HI titres did not decrease with age, suggesting a better response with the virosomal vaccine when compared to the subunit vaccine. All three studies explored the long-term persistence of antibodies after vaccination with virosomal influenza vaccines. Immunogenicity declined over time but remained high at 4, 6 and 12 months post-vaccination compared to baseline, indicating that adequate seroprotection is achievable for the duration of the influenza season. Virosomal vaccines may induce better immunity in elderly subjects and may be more effective in reducing morbidity and mortality in this age group.

Influenza immunization policies in Europe and the United States.

Influenza vaccination policies of 28 European countries were compared with those of the US Immunization Practices Advisory Committee. Twenty-four of 28 (86%) European countries had immunization policies for influenza. European and US recommendations were in complete agreement concerning immunization of those with heart and lung disease. Within Europe there was 81-86% agreement concerning immunization of the elderly, irrespective of their health status, and patients with diabetes, renal dysfunction and immunosuppression, and 71% agreement concerning those in residential care and occupational groups that can transmit influenza to high-risk patients. Unlike the US, 62-71% of European countries did not target those with haemoglobinopathies, children and teenagers taking salicylates or household members of those at high risk. Few recommendations were endorsed by relevant medical or patient organizations. The observed variation in vaccination policies in Europe and North America possibly reflect uncertainties concerning risks from influenza and benefits from vaccination, and differences in public health systems and attitudes towards preventive medicine.

Immunogenicity and reactogenicity of influenza subunit vaccines produced in MDCK cells or fertilized chicken eggs.

A tissue culture method using MDCK cells grown under serum-free conditions was developed to produce an inactivated influenza subunit vaccine. The first clinical data suggest it to be equal to the conventional egg-derived influenza subunit vaccine. In a double-blind controlled trial, 2 groups (n = 57 each) of adult volunteers were immunized with experimental bivalent influenza subunit vaccine derived from either MDCK cells or hens' eggs. Each vaccine contained 15 microg of hemagglutinin of influenza A/Taiwan/1/186 (H1N1) and 15 microg of hemagglutinin of B/Panama/45/90. No clinically relevant adverse reactions were observed in either vaccine group, and the incidence of systemic and local vaccine reactions was comparable in both groups. Standard hemagglutination inhibition antibody titers were determined using both MDCK- and egg-derived test antigens. The data reveal that both vaccines are safe and well-tolerated and meet the criteria for immunogenicity as stated in the European Community's "Harmonisation of Requirements for Influenza Vaccines."

Influvac: a safe Madin Darby Canine Kidney (MDCK) cell culture-based influenza vaccine.

Influenza vaccine production technology based on large scale cell culture technology has been developed. From the characterization of the continuous cell line MDCK as well as drug safety studies we conclude that this cell line and the cell culture system are suitable for biological production. The Down Stream Process (DSP) of the virus-containing harvest fluids guarantees sufficient inactivation of influenza viruses and adequate removal or inactivation of putative adventitious or endogenous viruses, mycoplasma or bacteria. Our data indicate that the tissue culture-based production technology is feasible.

Influenza vaccination in 2000: recommendations and vaccine use in 50 developed and rapidly developing countries.

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.

Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies.

In order to determine whether there is a difference between genders in reported adverse reactions to inactivated influenza vaccine, a computerized database of serological studies was investigated. A standardized questionnaire was used to evaluate vaccine reactogenicity. A total of 1,800 vaccinees in 14 studies were analyzed separately for two age groups ( < 60 and > or = 60 years of age). Females reported significantly more local reactions than males. The pooled odds ratio for the outcome measure "any local reaction" was 0.32 (95% confidence interval, 0.26-0.40, significant) and 0.54 (95% Cl, 0.41-0.70, significant) for young and elderly adults, respectively. Similar results were obtained for the outcome measure "any systemic reaction." Previous exposure to influenza or influenza vaccine had no influence on reactogenicity. There were no gender differences in sero-responses. In conclusion, gender should be regarded as a predictor of reported reactions to influenza vaccine in both young and elderly adults and should be addressed in future study designs.

Antibody induction by influenza vaccines in the elderly: a review of the literature.

Conflicting results have been reported concerning the association between high age and response to influenza vaccines. Some authors have found a reduced response in aged subjects, others have found no difference or even better results as compared with younger control subjects. Seventeen papers were selected from international literature published in the period 1968-1988 for a review of the anti-haemagglutinin-IgG sero-response following vaccination: among 30 cases in which vaccine components could be studied independently, ten revealed a better immune response in young subjects than in the elderly, four found more favourable results in the elderly, and 16 could not detect any significant between-group-differences, the latter most probably because of a high type-2-error. Nine of these 16 cases tended to favour young subjects. These results were relativated by the finding that each paper had at least one of three methodological limitations: (1) the failure to exclude subjects with illnesses or using drugs influencing the immune system, (2) the failure to exclude subjects with previous vaccinations against influenza, (3) the failure to exclude subjects with high prevaccination antibody titres. The direction of these biases is such that failure to address any one issue will lead to an underestimate of the response of aged subjects. In view of the failure to control these biases, it was not surprising that the papers reviewed presented a heterogeneous picture. Thus, the association between high age per se and response to influenza vaccines, if any, has not yet been established. Suggestions are made for future studies in which admission criteria should control health state and previous exposure to influenza antigens.