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Biomedical subjects

A M Palache

Publications and source records attributed to A M Palache.

At least 19 recordsLinked to original sources
PubMed2006

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.

Adjuvants, Immunologic↗
PubMed2005

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.

Adolescent↗
PubMed2004

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.

Adult↗
PubMed2004

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.

Adolescent↗
PubMed2003

Non-responders to egg grown influenza vaccine seroconvert after booster immunization with MDCK cell grown vaccine.

We have investigated whether 'at risk' subjects who did not respond serologically during a pre-study vaccination with a commercial egg grown influenza sub-unit vaccine would respond to a subsequent vaccination with either a single dose of MDCK cell grown influenza vaccine or a standard egg grown influenza vaccine containing the same virus strains. We studied 48 non-responder subjects with a mean age 67.5, range: 34-82 years. In this non-responder group the increased immune response that was detected after boosting with an MDCK cell derived vaccine response was variable and relatively modest, except for the A/Texas strain in the vaccine. The proportion of subjects, with an HI titre of >/=40 (protective antibody titre) increased from 50 to 83% (A/Texas strain), from 13 to 25% (B/Harbin strain) and from 38 to 46% (A/Wuhan strain). In comparison a booster vaccination with egg-derived influenza vaccine resulted in an increase immune response with an HI antibody titre >/=40 for two of the three strains, namely from 17 to 58% for the B/Harbin strain and from 8 to 33% for the A/Wuhan strain.

Adult↗
PubMed2003

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.

Developed Countries↗
PubMed2003

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.

Antibodies, Viral↗
PubMed2002

Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis.

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.

Adaptation, Physiological↗
PubMed2001

Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity.

Local mucosal IgA antibodies play a central role in protection of the respiratory tract against influenza virus infection. Therefore, new-generation influenza vaccines should aim at stimulating not only systemic, but also local antibody responses. Previously, we demonstrated that the recombinant B subunit of the Escherichia coli heat-labile toxin (LTB) is a potent adjuvant towards nasally administered influenza subunit antigen. Here, we investigated the protection conferred by LTB-supplemented influenza subunit antigen given intranasally (i.n.) or intramuscularly (i.m.) to mice. Both i.n. and i.m. immunization with subunit antigen and LTB completely protected the animals against viral infection. Protection upon i.n. immunization was associated with the induction of antigen-specific serum IgG and mucosal IgA, whereas protection upon i.m. immunization correlated with strong serum and mucosal IgG, but not IgA responses. We conclude that LTB-supplemented influenza subunit antigen, given either i.n. or i.m, induces protective antibody-mediated mucosal immunity and thus represents a promising novel flu vaccine candidate.

Adjuvants, Immunologic↗
PubMed2000

Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly.

The success of influenza vaccination depends largely on the antigenic match between the influenza vaccine strains and the virus strains actually circulating during the season. In the past, this match has proved to be satisfactory in most seasons. In the 1997/1998 season, however, hemagglutination inhibition (HI) assays with ferret antisera indicated a considerable mismatch between the H3N2 vaccine component and the most prevalent epidemic influenza A(H3N2) virus. The results from antigenic analyses using pre- and postvaccination serum samples from volunteers of various ages, including residents of nursing homes who were more than 60 years of age, were in good agreement with the results obtained with ferret antisera. Homologous serum antibody responses to the H3N2 vaccine component as well as the cross-reactivity of the induced antibodies to the epidemic H3N2 strain, declined with increasing age of the vaccinees. As a consequence of these two effects, 84% of the vaccinees over 75 years of age did not develop HI antibody titers >/= 40 against the major H3N2 virus variant of 1997/1998, suggesting that they were not protected against infection with this virus variant. These findings support the current policy of the World Health Organization (WHO), which is to base worldwide influenza virus surveillance on results predominantly obtained by antigenic analyses of influenza virus isolates with ferret antisera in HI tests. If an antigenic mismatch is observed, the protective efficacy of the vaccine, especially for the elderly, may be insufficient. The observations also support the current policy to include the elderly in serologic efficacy trials.

Adult↗
PubMed1999

Characterization of high-growth reassortant influenza A viruses generated in MDCK cells cultured in serum-free medium.

In the present study reassortant influenza A viruses of both the H1N1 and H3N2 type were generated in Madin Darby Canine Kidney cells grown in the absence of fetal bovine serum (MDCK-SF1 cells). To this end, MDCK-SF1 cells were simultaneously infected with one of the high-growth laboratory strains A/Puerto Rico/8/34 (H1N1) or A/Hong Kong/2/68 (H3N2) and recent H3N2 and H1N1 vaccine strains, respectively. Reassortant viruses obtained from these mixed infections were genetically characterized by RT-PCR and restriction enzyme analysis and their growth properties were compared to those of the corresponding field strains. Reassortant H3N2 viruses inherited the matrix and polymerase pa gene whilst H1N1 reassortant viruses inherited the matrix and polymerase pbl gene of the high-growth parent. Reassortant viruses generally gave higher viral yields, as measured by a haemagglutination assay, than their wild type counterparts. The procedure followed results in the generation of high-growth reassortant viruses in weeks. The use of MDCK-SF1 cells together with these reassortants for generating influenza virus antigens can significantly speed up the vaccine production procedure.

Animals↗
PubMed1999

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.

Antibodies, Viral↗
PubMed1999

Generation and characterization of reassortant influenza A viruses propagated in serum-free cultured MDCK-SF1 cells.

The replacement of embryonated chicken eggs by tissue culture cells for the production of influenza vaccines is likely to take place in the near future. Vaccines have already been produced in Madin Darby Canine Kidney (MDCK) cells (Brands et al, in this issue) and extensively tested in phase III trials in humans (Palache et al, in this issue) and it seems a matter of time before such vaccines will become available. For this reason, the generation of high-growth reassortants of influenza A virus strains in MDCK cells has been examined. Influenza A virus reassortants of the field strains A/Taiwan/1/86, A/Johannesburg/82/96 and A/Shenzhen/227/95 (all H1N1) were generated in serum-free cultured MDCK-SF1 cells by dual infection with A/Hong Kong/2/68 (H3N2), a strain selected for its high-growth phenotype. These reassortant viruses all contained at least the matrix gene of A/Hong Kong/2/68 which apparently correlates with an improvement of the viral yield.

Animals↗
PubMed1999

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.

Animals↗
PubMed1998

The plea against annual influenza vaccination? 'The Hoskins' Paradox' revisited.

Three papers by Hoskins and collaborators published in The Lancet in the 70s, have been challenging the common policy to annually vaccinate people at risk with inactivated influenza virus vaccine. From an analysis of a vaccination campaign in adolescent pupils of a boarding school and four influenza outbreaks in the period 1970-76, Hoskins et al. concluded that annually repeated vaccinations would not confer protection against epidemic influenza in the long-term ('Hoskins' Paradox'). A review of the papers revealed, however, that most of the study subjects were not consequently vaccinated every year and that most of the presented data were, therefore, not relevant for the problem of annually repeated influenza vaccination. When applying strict definitions of single vaccination (immunised immediately prior to the epidemic, but not in the years before) and multiple vaccination (immunised immediately prior to the epidemic, and also in the year(s) before), only two of four epidemics (A/England/42/72 (H3N2) in 1972/73 and A/Port Chalmers/1/73 (H3N2) in 1973/74) could be evaluated: in one case, no negative effect of repeated vaccination could be detected, in the second case, the attack rate difference between groups with single and multiple vaccination was of borderline significance. Data on two other epidemics (B/Hong Kong/8/73 in 1973/74 and A/Victoria/3/75 (H3N2) in 1975/76) could not be interpreted because of incomplete vaccination strategies. In conclusion, Hoskins' Paradox cannot be substantiated by Hoskins' own data. Considering other published data on the subject, it is suggested that no negative effect of annually repeated vaccination on protection against epidemic influenza exists.

Adolescent↗
PubMed1997

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."

Adolescent↗
PubMed1997

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.

Health Policy↗