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  • #16
    Re: Swine flu vaccines, adjuvants, equity, safety

    Because of the changing nature of viruses, and the rapidity by which a 'new' product must be made annually, the fact remains (and is likely to remain) that the burden of proof for safety testing for influenza vaccines is far lighter than any other area of pharmaceutical medicine. It is no good to have to undergo year long safety evaluations, when by the time they were completed, the nature of the virus and vaccine will have fundamentally changed. Adjuvant use was not extensively considered until the world faced an imminent H5N1 pandemic, and as a consequence, in my opinion, thier use and the evaluation of their use has been rushed. We may not have time to answer these questions in a hurry, right now - but even if corners are cut NOW, then manufacturers should still undertake full safety testing of adjuvants as soon as possible to guide future decisions. this is not the last pandemic situation we will face.

    Adjuvant safety testing has been restricted to its use in association with specific vaccines. To echo Tropical's comments I would like to see globally applicable, full safety testing and clinical trials of adjuvant given ALONE and in isolation as well as with specific vaccines, with a longer term ADR follow up than the 7 day (or at maximum 30 day) standard that it applied wjhen it is used with influenza vaccines. This would help to answer the basecase inherent safety questions of adjuvant use. As far as I have been able to discover, this has never been done.

    Such testing then needs to be followed up by widespread trials of adjuvanted influenza vaccine using age specific groups and including target vaccine populations i.e those with underlying health conditions.

    It will be impossible to carry out such testing with every influenza vaccine in view of its changeability and costs - but it would make current levels of testing more adequate, if each adjuvant has at least been properly and thoroughly investigated as a single entity. As to why the EU has seen fit to approve these vaccines and the US has not, all I would say is that IMHO 'the hurdle' for proof of efficacy and safety has been set at a very low level in the EU, and US requirements are more stringent. I find it a cause for concern that the US should be considering lowering its standards to accomodate adjuvant vaccines - and if it does so, I hope it is temporary and with long term conditions applied, so that the current emergency situation can be met.

    the probability is that adjuvants will be both safe and effective for the vast majority. the point of such detailed safety testing should be to throw up which population groups should be contra-indicated, and which practices (such as multiple anitgenic challenges, perhpas) should be avoided. Even if the powers that be decide that the world cannot afford to wait for answers to these questions now, it is important that manufacturers should not be exempted from investigating throroughly (i.e include up to one year's follow up looking for ADRs) in the future.

    Comment


    • #17
      Re: Swine flu vaccines, adjuvants, equity, safety

      Swine flu vaccines, adjuvants, equity, safety: more discussion

      Category: Infectious disease Influenza treatment Pandemic preparedness Swine flu Vaccines
      Posted on: September 8, 2009 6:15 AM, by revere


      As we expected, yesterday's vaccine piece provoked a lot of discussion, almost all of it thoughtful and pertinent. Since we've already said we might be wrong, we thought we'd take some time to respond, using it as a way to keep thinking things through on our end. Writing is thinking and thinking is needed in this situation.


      Over at FluTrackers.com (an excellent flu forum like Flu Wiki with highly informed people) there were a number of lengthy responses, most of them on the negative side. Since these folks follow events closely their opinions are also worth following closely. In addressing them I will also summarize the gist of yesterday's post, which represents the Reveres' joint opinion at this point.


      1. We have been somewhat skeptical of the efficacy of influenza vaccination in the past. However reviewing the literature (we dealt with a good summary in this post recently) we have come to the conclusion that the vaccine works sufficiently that it is an important public health measure. Its efficacy varies but, depending upon the group, probably lies somewhere between 30% and 70%. In the case of a good match to a virus to which most of the population has no natural immunity, we believe 70% to be a good estimate considering the groups most at risk. This means that compared to an unvaccinated group, the vaccinated group will have 70% fewer infections. It means that 30% of those vaccinated who are exposed will still get the flu. Flu vaccine isn't even close to 100% effective like DPT or MMR. But even 30% reduction in infection in a pandemic is a Big Deal in terms of demands on services, lost work time and productivity, pain and suffering, and of course, mortality, so we don't think using the high end of efficacy makes much difference.


      So that's the first point that may separate us from others. We think the vaccine will work and we base that on experience with seasonal vaccine where numerous randomized clinical trials have been done (see the Basta-Halloran review we linked above; here it is again). Take a look at it and make up your own mind about this. If you don't think the vaccine will work, then there's no reason to get it. We think it will work (based on our review of the science) and that it will make a big difference to how well communities who use it sufficiently will get through whatever might come next.


      2. Safety, adjuvanted or unadjuvanted. Yesterday's post pointed out that it is not feasible to assure the advance safety of any product being consumed or administered to tens or hundreds of millions of people. No advance testing is possible for relatively rare adverse events that would still be numerous when that many people are exposed. But the mathematics of the adverse events versus the risks from flu, even if it is only the virulence of seasonal flu, is so overwhelmingly in favor of vaccination that we don't think this is a hard call. True, there are various guesses that have to be made about how many people are infected, what the CFR will be, how well the vaccine will work, etc., and while we tried to be pretty conservative in most of them (we did use a high end number for vaccine efficacy because we thought the data for similarly placed populations merited it, but even if we'd used the lowest efficacy vaccines come out far ahead), and you might differ with some of them. At least you know what we assumed. But the major point is this. If you want to wait for assurances of safety, then you better have a definition of "safety" that is determinable ahead of time or you are just saying you won't accept any vaccine. And for most of the rare events people talk about (e.g., Guillian-Barre Syndrome) there is no way to test for it in advance.



      A related point was that there is no reason to trust vaccine manufacturers as they have a dismal record for honesty and probity. We agree and have complained bietterly about Big Pharma many times. But accepting this argument also means we reject essentially the entire modern pharmacopoeia since these folks also make all the other vaccines, antibiotics, hand sanitizers, etc., etc. We've argued frequently that influenza vaccines (and probably other vaccines) should be made by a regionalized network of international vaccine institutes outside the market system. We didn't do that. So we are stuck with Big Pharma. It is what it is.


      3. The adjuvant question. Two weighty objections to our advocacy of adjuvants have been advanced, one at FluTrackers and one by Jody Lanard here. They are slightly different but we will take them together. Vibrant62 at FluTrackers observes that the safety of adjuvants has been tested more often in the older age groups (where the immune response is more sluggish and adjuvants are more needed), not well tested in the young age groups. Vibrant62 suggests the decision doesn't have to be "all or nothing" but we could use unadjuvanted vaccine for some age groups (or pregnant women) and adjuvanted vaccine for others. Let's assume this is economically feasible (i.e., that two different vaccine could be made and distributed efficiently). If children and young adults really, on average, react quite differently to a particular adjuvant, then this will be seen in the safety and efficacy trials, unless it is rare, in which case we are in the same box we were earlier regarding trade-off with the benefit. There has been quite a lot of experience with adjuvants and influenza virus and also some with this particular virus. I will refer you to the excellent post by Vincent Racaniello at Virology Blog. Before giving my full answer to this, though, I want to address Jody Lanard's objections, since my answer is the same to both.


      Jody Lanard and Peter Sandman are among the most experienced and thoughtful practitioners of risk communication anywhere, so their views are of special significance. We usually agree, although not always. This seems to be one of the "not always" times. Jody's concern has to do with how the US public will react to the idea that a relatively untested vaccine will contain an even more untested additive, especially after the 1976 swine flu debacle where it is widely reported that the vaccine was worse than the disease (although not reported that one reason this is so is that the disease never got out of Fort Dix so there was no disease averted by the vaccine). This comes at a time of high anxiety about vaccines among certain segments of the population, some of it sincere, much of it fed by paranoid conspiracy theorists who see monsters under every bed. The bad behavior of Big Pharma and the demonizing by the Far Right Noise Machine of any health measure promoted by government adds to the problem. The result is that the anti-vaxxer movement is killing and disabling children. The fear is that a government program with an adjuvanted vaccine will pour gasoline on this fire:
      There is a great deal of undue -- but thoroughly unmitigated -- anti-vaccine feeling and fear in the U.S. The anti-vaccine activists and the vaccine-causes-autism activists are ready to roll with every flu vaccine Teachable Moment that comes along. The more traction they can get by encouraging doubt and skepticism about flu vaccine among parents, the more children will end up unvaccinated against the "usual" childhood diseases. So in the U.S., this is a really bad time to change the flu vaccine any more than necessary (a strain change is necessary, of course). (Jody Lanard in the Comment Thread of yesterday's post)
      In essence (and read the whole comment here), Dr. Lanard is saying it will backfire and make things worse. Instead of more people being vaccinated because of antigen sparing, fewer in the US will be vaccinated because parents will refuse the vaccine and it will have a spillover effect on other important childhood vaccination programs.


      I understand this point of view and it comes from what I consider an authoritative source. But here's where the question of "balance" that I discussed in yesterday's post comes in. Jody and I have struck different balances on this. For us, the principal point of using adjuvant is to increase the number of people in the world who can be vaccinated, not just the number of people in the United States. Most of the viral antigen is made outside the US. We are rich so we bought it up and now less rich countries can't get it. Our only entitlement to it is through the fact that the ability to live without influenza infection has become a commodity and the US has the means of exchange (money) to buy it. Adjuvants would make it more available to more people.


      I am opposed to mandatory vaccination, even though I believe vaccination is an important public health measure that will save millions of lives. But there isn't enough vaccine for everyone in the world, so if people in the US don't want it, then any unused stock (keeping a small reserve) should be released by a date certain (say January 15 for the sake of argument) and given to others. I believe this will doom many Americans to severe sickness and some to a fatal illness, but the compensation is that many others, children and adults, in poorer parts of the world will be saved. Their lives are worth no less than American lives. If someone in this country, for whatever reasons, doesn't wish to receive the vaccine, someone who wants it and needs it will be waiting.


      There are real imponderables and trade-offs here with no easy answers. It is clear that our answer is not the same as others who have followed the issue as assiduously as we have and who have great expertise. That doesn't make them right, or us right, or the US government's position right. And different governments are making different decisions. We may never know what the right thing to do was because we will be dealing with a counterfactual: what would the world have been like if we'd done X instead of Y?


      But the US is a big player in this high stakes game. It has ordered (and hence pre-empted for others) a lot of antigen, so it's something worth discussing. So we're discussing it.

      Comment


      • #18
        Re: Swine flu vaccines, adjuvants, equity, safety

        #17:
        * "3. The adjuvant question. Two weighty objections to our advocacy of adjuvants have been advanced, one at FluTrackers and one by Jody Lanard here. They are slightly different but we will take them together. Vibrant62 at FluTrackers observes that the safety of adjuvants has been tested more often in the older age groups (where the immune response is more sluggish and adjuvants are more needed), not well tested in the young age groups. Vibrant62 suggests the decision doesn't have to be "all or nothing" but we could use unadjuvanted vaccine for some age groups (or pregnant women) and adjuvanted vaccine for others. Let's assume this is economically feasible (i.e., that two different vaccine could be made and distributed efficiently). If children and young adults really, on average, react quite differently to a particular adjuvant, then this will be seen in the safety and efficacy trials, unless it is rare, in which case we are in the same box we were earlier regarding trade-off with the benefit. There has been quite a lot of experience with adjuvants and influenza virus and also some with this particular virus. I will refer you to the excellent post by Vincent Racaniello at Virology Blog. Before giving my full answer to this, though, I want to address Jody Lanard's objections, since my answer is the same to both."
        ...
        ** "We may never know what the right thing to do was because we will be dealing with a counterfactual: what would the world have been like if we'd done X instead of Y?"
        **
        The WHO position is also to gather and find the most valuable and viable solution, based on the expertise of international scientific teams/professionals.

        So, the right thing to do, is to demand that the best option be vigorously suggested and sci. proved by the WHO, and than can be further implemented by the countries.


        *
        Is it the number of involved non-elderly people of various ages in the MF59 (EU aproved) adjuvant screening study enaugh balanced, that we can said at least that it is safe to use adjuvants at least in the age group 40-65, or not?

        Could we said that the ok registration of squalene/MF59 adjuvanted Fluad flu vacc., 2006. year, as already used seasonal flu vaccine in EU, is not due to less stringent safety laws than in US?

        Does the above already used adjuvanted vaccine, from the released scientific published trials, safe enaugh for the non-elderly age groups, at least for the senior adults from 30/40-65 years?



        _____________

        Probably, after there was other published results trials, but here we have an excerpt from an public doc about, here at FT, Vibrant62 given link of MF59 usage study, Fluad, pdf:
        http://www.flutrackers.com/forum/att...2&d=1251745072


        Sorry for the poor formated excerpted text:

        ____
        from one additional sticky link:

        http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_PMC&li nkpos=1&log$=citedinpmcarticles&logdbfrom=pubmed

        1: Clin Vaccine Immunol. 2006 Sep;13(9):1010-3.

        Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene.


        <!--AuthorList-->Del Giudice G, Fragapane E, Bugarini R, Hora M, Henriksson T, Palla E, O'hagan D, Donnelly J, Rappuoli R, Podda A.

        Research Center, Novartis Vaccines, Via Fiorentina 1, 53100 Siena,

        Italy. giuseppe_del_giudice@chiron.com

        "Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of noncontrolled and nonvalidated assays, a claim was made that antisqualene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Using a validated enzyme-linked immunosorbent assay for the quantitation of immunoglobulin G (IgG) and IgM antibodies against squalene, we demonstrated that antisqualene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers. In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 emulsion adjuvant."
        ___

        From the pdf doc text:


        http://www.flutrackers.com/forum/att...2&d=1251745072

        ...
        The nonclinical testing of MF59TM consists of research studies
        performed to explore its mechanism of action, ‘adjuvanticity’, and
        ability to enhance protection in challenge models. GLP (Good Laboratory
        Practice) tolerability and toxicology studies have also been
        conducted to fulfil regulatory requirements. Several publications
        describe the enhancement of immunogenicity of a variety of antigens
        adjuvanted with MF59TM in animals [33,28–30,11], whereas
        the results of Novartis’ GLP toxicology studies performed to fulfil
        global health authority requirements for clinical testing or product
        approvals have not been published, to date.

        ___
        ...
        Histopathology
        findings were generally limited to inflammatory responses at the
        injection site. Thesewere of lowseverity andwere partially to fully
        resolved by the end of a 7- to 14-day recovery period. Consistent
        systemic treatment-related findings in animals treated with antigen
        plus MF59TM included increases in fibrinogen levels and slight
        increases in globulin
        . These findings are consistent with administration
        of adjuvanted vaccine formulations.
        ...
        ___
        ...
        To evaluate whether antibodies against squalene are produced,
        an analysis using very sensitive and specific assays, developed at
        theWalter Reed Army Institute of Research, USA [5,35], were used.
        Serum samples taken from individuals before and at various times
        after immunization with MF59TM-adjuvanted influenza vaccine or,
        as a control, with influenza vaccines without adjuvantswere tested.
        The results of these assays show that:
        IgG and IgM antibodies against squalene were detectable at
        very low levels already before immunization with MF59TMadjuvantedinfluenza
        vaccines in the vastmajority of young, adult,
        and elderly individuals
        .
        • Immunization with MF59TM-adjuvanted vaccines did not induce
        any change in the levels of serum anti-squalene antibodies
        .
        • The level of anti-squalene antibodies detectable in the sera of
        subjects immunized with vaccines adjuvanted or not adjuvanted
        with MF59TM was similarly low [36].
        Data obtained with sera fromsubjects fromdifferent geographic
        areas were similar (USA,Western and Eastern Europe) [36].
        Taken together, these data showthat theMF59TM adjuvant squalene
        is not associated with the production of specific antibodies
        (Fig. 2). These antibodies may well represent low-avidity antibodies
        naturally occurring in healthy individuals, and their serum titres
        are not influenced by immunization with MF59TM-adjuvanted vaccines.
        ___
        ...
        Extensive clinical immunogenicity and safety data on various
        MF59TM-adjuvanted vaccine antigens have been generated in
        clinical trials over the last 15 years. The data show that MF59TMadjuvanted
        antigens elicit a strong antibody response, and are safe
        and generally well tolerated [4]. The clinical findings are instrumental
        in the understanding of the adjuvanticity of MF59TM, and
        more importantly of the safety of this compound.
        As an o/w emulsion, the MF59TM adjuvant is very fluid, and
        is expected to be well tolerated and to induce strong short-term
        immune responses as the oil content is very low (between 15 and
        25%
        ) [37]. Furthermore, the route of administration is important as
        it influences local reactogenicity and the immune response.
        Data have been generated across all age groups, including the
        elderly, younger adults, adolescents, and also newborn infants.
        Most experience has been gathered in conjunction with influenza vaccines with more than 14,000 individuals exposed in more than 30 phases 1–4 clinical studies [38,3,39–44]. Before registration in May 1997 Fluad&#174;, had been testedin 28 single- or double-blind,randomized,
        and controlled studies, 13 of which with a 4- to 6-month
        follow-up and 12 studies with a 4-week follow-up.
        24 of 30 studies enrolled elderly subjects (≥65 years).

        Fluad&#174; was tested for equivalence of antigenic content against the inactivated subunit comparator vaccine Agrippal&#174; (same antigenic content as Fluad&#174;, but without MF59TM adjuvant), in 20 studies, against Fluogen&#174;/Fluvirin&#174; in one study, against Fluzone&#174; in two studies, against Influvac&#174; in three studies, and against Flushield&#174; in two studies.
        ___
        ...
        30-26=6 (of 30) = NON-ELDERLY STUDIES)
        ___
        Table 2
        Clinical experience with MF59TM adjuvanted to different vaccine antigens [33]
        Antigen(s) Route of immunization Population Size database (N) Indicationa
        Influenza +MF59TM Intranasally Healthy adults 31 P
        Influenza +MF59TM IM Adults 460 P
        Influenza +MF59TM IM Elderly 11,462
        Influenza vaccine +MF59TM IM Children; adolescents 116 P
        HCVE2 +MF59TM IM Healthy adults 36 P
        Controls: MF59TM + buffer IM Healthy adults 12 P
        HCVE1E2MF59TM IM Healthy adults 48 P
        Controls: saline IM Healthy adults 12 P
        HCVE1E2MF59TM + CpG IM Healthy adults 48 P
        Controls: HCVE1E2MF59TM IM Healthy adults 12 P
        HBV+MF59TM IM Healthy adults 156 P
        HSV-2MF59TM (HSVMF59TM +MTP-PE adjuvant) IM HSV-seronegative and -seropositive
        subjects
        2,422 (104) P
        CMV antigens +MF59TM IM Seronegative volunteers: Incl. 15/500
        toddlers 30/500 seropositive volunteers
        500 P
        Influenza +MF59TM Intranasally Healthy adults 31 P
        Influenza +MF59TM IM Adults 460 P
        Influenza +MF59TM IM Elderly 11,462 P
        Influenza vaccine +MF59TM IM Children; adolescents 116 P
        HBV+MF59TM IM HBV-infected subjects 159 Th
        HBV+MF59TM + Lamivudine IM HBV-infected subjects 120 Th
        Controls: MF59TM + buffer IM HBV-infected subjects 99 Th
        HCVE1E2MF59TM &#177;pegylated Interferon + Ribavirin IM HCV-infected patients 48 Th
        a P = prophylactic; Th = immunotherapeutic
        ...
        5.3.3.6. Influenza vaccine. The US Advisory Committee on Immunization
        Practices produces a regularly updated rationale for
        vaccination against influenza [55]. The current version identifies 12
        categories of patients at high risk of complications from influenza.
        Annual vaccination against influenza is recommended for: (1) all
        persons, including school-aged children, who want to reduce the
        risk of becoming ill with influenza or of transmitting influenza
        to others; (2) all children aged 6–59 months (i.e., 6 months–4
        years); (3) all persons aged >50 years; (4) children and adolescents
        (aged 6months–18 years) receiving long-term aspirin therapy who
        therefore might be at-risk for experiencing Reye syndrome after
        influenza virus infection; (5) women who will be pregnant during
        the influenza season; (6) adults and children who have chronic pulmonary
        (including asthma), cardiovascular (except hypertension),
        renal, hepatic, haematological or metabolic disorders (including
        diabetes mellitus); (7) adults and children who have immunosuppression
        (including immunosuppression caused by medications
        or by human immunodeficiency virus; (8) adults and children
        who have any condition (e.g., cognitive dysfunction, spinal cord
        injuries, seizure disorders, or other neuromuscular disorders) that
        can compromise respiratory function or the handling of respiratory
        secretions or that can increase the risk for aspiration; (9) residents
        of nursing homes and other chronic-care facilities; (10) health-care
        personnel; (11) healthy household contacts (including children)
        and caregivers of children aged <5 years and adults aged >50 years,
        with particular emphasis on vaccinating contacts of children aged
        <6 months; and (12) healthy household contacts (including children)
        and caregivers of persons with medical conditions that put
        them at higher risk for severe complications from influenza.
        There is general agreement on the need to enhance the immunogenicity
        and efficacy of influenza vaccines, especially in adults
        approaching elderly age and in the elderly themselves, when the
        ability of the immune system to mount a strong and efficacious
        response decreases. MF59TM has been proven to strongly enhance
        the immunogenicity in mice, and other small animals, inducing
        antibody titres 5 to >100 times higher than those obtained in the
        absence of adjuvants [56]. Importantly, the enhancement of the
        immune response to an influenza subunit vaccine, mixed with
        MF59TM, was not affected by pre-existing immunity to the virus
        [57]. This observation is particularly important because immunization
        against influenza is routinely carried out every year and
        pre-existing immunity can negatively affect the efficacy of subsequent
        immunizations. In preclinical studies, MF59TM adjuvant
        offered improved protection against influenza virus challenge and
        significantly reduced the viral load in the lungs of challenged mice
        [58]. Clinical trials of the MF59TM-adjuvanted influenza vaccine are
        summarized in Table 2.

        ___
        ...
        3216 V. Schultze et al. / Vaccine 26 (2008) 3209–3222
        5.3.4. Special populations
        5.3.4.1. Adults (non-elderly).
        The overall database consists of 460 subjects aged 18–64 years who have received at least one immunization with Fluad&#174;; 104 of these subjects also received a second immunization.
        The pooled analysis includes data from 460 subjects vaccinated with Fluad&#174; and 453 subjects vaccinated with comparator vaccines (Agrippal&#174;, Fluzone&#174. Overall, these data show that post-immunization reactions, particularly local reactions, were more frequent in non-elderly adults than in elderly
        subjects.
        Compared to unadjuvanted vaccines, Fluad&#174; induced
        more local reactions, most of which, however, were mild and of
        short duration
        . In the Fluad&#174; group after the first injection pain
        was rated mild to moderate in 87%, 10% had none and 3% of subjects
        had severe pain; after the second injection pain was rated
        mild to moderate in 83%, 16% had no pain, and 1% had severe
        pain.
        A statistically significant increase in the incidence of injection
        site—warmth, chills, myalgia, and analgesic/antipyretic use,
        occurred in the Fluad&#174; group after the first injection, but not after
        the second
        . No longer lasting reactions were noted [38].
        5.3.4.2. Elderly subjects. The overall database for safety of Fluad&#174; and Fluad&#174;-like vaccines consists of 11,462 elderly subjects (≥65 years of age) who received at least one immunization with Fluad&#174;.
        The comparator vaccine group includes 6216 subjects who have
        received at least one dose of licensed comparator vaccine (e.g.,
        Flushield&#174;, Fluvirin&#174;, Influvac&#174;, Vaxigrip&#174.
        Immunization against influenza is normally administered every
        year due to the antigenic variability of the viruses responsible
        for seasonal epidemics. Therefore, the evaluation of a potential
        increased reactogenicity associated with repeated immunizations
        was part of this clinical program.
        This aspect is even more relevant
        for Fluad&#174;, since it contains MF59TM inducing a higher incidence
        of mild and transient local reactions
        compared to unadjuvanted
        vaccines.

        For this reason, several trials of this clinical program were
        ‘extended’ to the following influenza seasons to evaluate the safety
        of a second and a third immunization with Fluad&#174;.

        These data indicate that multiple immunizations (up to three)
        with Fluad&#174; were well tolerated (Table 3). Subjects enrolled in second
        and third immunization trials were predominantly those who
        did not experience local reactions to the first immunization.
        An
        ad hoc analysis showed that demographic characteristics and incidence
        of reactions in subjectswithdrawing from the first trialwere
        not different from those of subjects included in the extension trials.
        One phase 4, single-blind, randomized study to evaluate the
        safety and effectiveness of Fluad&#174; versus a licensed influenza vaccine
        (Influvac&#174 administered to elderly (≥65 years of age) subjects
        enrolled a total of 9194 subjects to receive Fluad&#174; vaccine, and 4550 subjects enrolled to receive the control vaccine (Influvac&#174.
        A total of 750 serious adverse events were observed in the Fluad&#174; group (i.e., 8.2%) versus 386 in the control (Influvac&#174 group (i.e., 8.5%).
        The rates of adverse events requiring a physician visit with onset
        between days 0 and 6 and of serious adverse events during the
        study period (October 1997 to April 1998) were low and similar to
        the non-adjuvanted control vaccine Influvac&#174;. Hospitalizations and
        deaths during local influenza season period (24 December 1997 to 4
        May 1998)were similar to the control vaccine. One SAEwas considered
        possibly related to Fluad&#174;. From this finding it can be derived
        that for Fluad&#174; the incidence rate of such AEs (i.e., both serious and
        possibly related) in the entire population does not exceed 0.05% (or
        1 in 1933 subjects).
        In the entire clinical database, only 3 SAEs were considered by
        the investigator to be related (exudative erythemamultiforme, Herpes
        Zoster, pancreatitis and cholangitis) to immunization [33].
        5.3.5. Other routes of administration of influenza vaccine
        The MF59TM-adjuvanted influenza vaccine was given
        intranasally to 31 subjects in a phase 1 study of healthy adults.
        The safety and immunogenicity was compared to unadjuvanted
        influenza vaccine (Agrippal&#174; and placebo). Neither local (sneezing,
        unpleasant taste, bloody nasal discharge) nor systemic reactions
        differed significantly between the treatment groups. No SAEs
        occurred in this study [59].
        5.3.6. Pediatric immunization
        Until recently, influenza vaccination in children was recommended
        only for individuals with medical conditions that could
        put them at higher risk from influenza infection, such as bronchial
        asthma. The Advisory Committee on Immunization Practices (ACIP)
        of the Centers for Disease Control and Prevention recommended
        use of trivalent inactivated influenza vaccine in all children 6–23
        months old, including healthy children with no chronic medical
        condition, beginning in the winter season of 2004–2005 based
        on increasing evidence of high morbidity from influenza infection
        in young children [60]. An increasing number of children in
        the United States are being vaccinated [61]. To achieve the goal
        of universal influenza immunization coverage for healthy children,
        health care professionals will need a greater understanding of
        the severity of influenza illness in this age group, coupled with
        an increased knowledge of indications for vaccine administration.
        One pediatric trial has compared the safety and immunogenicity
        of Fluad&#174; and unadjuvanted vaccines (Fluogen&#174;, Flushield&#174,
        in children and adolescents. In this study, performed in the USA,
        Fluad&#174; was compared to two other influenza vaccines licensed in
        the USA. A total of 116 subjects (9- to 17-year-olds)were vaccinated with Fluad&#174; and 100 subjects were vaccinated with comparator vaccines. The safety profile emerging from this trial was similar to that of older age groups with a moderately increased rate of pain, chills, malaise and headache in the Fluad&#174; group.

        A second randomized, observer-blind pediatric trial in children
        recently conducted in Finland [62] compared safety and immunogenicity of Fluad&#174; to a conventional Influenza split vaccine. A total of 130 healthy children (6–59 months of age) received 2 doses of Fluad&#174;. As with other clinical trials, local and systemic reactions were recorded for 7 days after each immunization, and all other AEs recorded throughout the entire study period with a followup period of 6 months. Both vaccines were equally well tolerated except for injection site swelling which was higher in the Fluad&#174; recipients.
        A third clinical study in children is ongoing to investigate safety
        and immunogenicity of amonovalent influenza vaccine, containing
        H5N1 antigen with MF59TM adjuvant [33].

        However, these clinical data are too limited to draw final conclusions
        on the pediatric indication of Fluad&#174;, which will require
        more extensive clinical investigation.
        ...
        ___
        5.4. Postmarketing experience
        The favourable safety data demonstrated in clinical trials are
        supported by postmarketing pharmacovigilance since first registration of Fluad&#174; in September 1997.

        Meanwhile, more than 27 million patients have received
        Fluad&#174; (or Fluad&#174;-like vaccines
        sold with other brand names
        such as Adiugrip&#174;, Addigrip&#174;, Prodigrip&#174;, Influpozzi&#174; Adiuvato,
        Gripguard&#174;, Chiromas&#174 during the past 9 years, most of which
        were administered to the elderly.

        Fluad&#174; is only licensed in the elderly, and a separate safety evaluation in children will be required, once the target population of
        immunization can be extended to children.
        Reports on suspected spontaneous ADRs after immunization
        with Fluad&#174; are collected on an ongoing basis.
        The Fluad&#174; pharmacovigilance database involves all individual
        ADR case reports, regardless of their causality. All reports from
        September 1997 (when Fluad&#174; was first marketed) to August 2006
        (before start of the 2006 influenza season) were included in this
        analysis. In order to ensure coherence and analysis of reported
        events, all were classified according to MedDRA.
        ...
        ___

        (ADVERSE EVENT)

        Atotal of 57%of case reportswere fromelderly vaccine recipients
        whowere 65 years or older, which is the target group for immunization
        (Fig. 4). Another 34% of cases were from adults (18–64 years),
        1% of cases were from adolescents and children
        , and 8% were cases
        of unreported age.
        ...
        5.4.1. Serious cases
        In total, 107 cases met at least one seriousness criterion, most
        often (64.8%) “hospitalization”, resulting in a reporting rate of 0.39
        serious cases per 100,000 doses sold
        . Of these, 34 cases were consideredpossibly
        relateddue to temporal or biological plausibility, or
        both, according to the company internal causality assessment. The
        AEs reported in these serious cases belonged to a variety of clinical
        entities.Most frequently reportedAEswere injection-site reactions,
        skin reactions and subcutaneous tissue disorders, neurological disorders
        (myelitis (n = 1), transverse myelitis (n = 1), Guillain-Barre&#180;
        syndrome (GBS) (n = 6), Personage Turner Syndrome (n = 1)), and
        respiratory symptoms. No new or uncommon trend of AEs
        (compared
        with company internal data on other influenza vaccines, like
        Agrippal&#174;, Begrivac&#174;, and Fluvirin&#174 or any signs of increased frequency
        of listed AEs have been identified.
        5.4.2. Fatal cases
        During the evaluation period, 13 cases of death in elderly
        patients, 68–91 years of age, were reported after use of Fluad&#174;.
        None of the death cases occurred in persons below 65 years of
        age.

        ...

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