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      Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination

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          Abstract

          Objective  Our studies aimed to measure the quality of antibody response to influenza vaccines in the elderly. The frequency of significant rise in hemagglutination inhibition (HAI) titer in the elderly is low and although annual vaccination reduces morbidity and mortality, better correlates of vaccine efficacy in the elderly are needed.

          Methods  We measured the amount and avidity of serum antibodies against native H3N2 influenza glycoproteins or denatured virus (unfoldons) in pre‐ and post‐vaccinated sera of 36 elderly subjects.

          Results  Eighty percent of subjects had high pre‐immunization antibody levels and only 13% showed ≥2fold increase after vaccination, but 33% showed ≥2fold increase in avidity. With increasing dosage there was a significant increase in avidity against unfoldons with 50% of subjects showing ≥2fold increase at the highest dose. Elderly subjects given subunit vaccine showed higher reactivity with unfoldons (78% of native) than younger subjects studied earlier who were given inactivated whole virus vaccine (19% of native).

          Conclusion  The clear inverse relationship between pre‐immunization antibody levels and antibody increase after vaccination implies that a major reason for the low frequency of antibody responses in elderly subjects is simply because they have high pre‐immunization antibody levels. Only low reactivity was observed with earlier viruses. The increased proportion and avidity of antibodies against unfoldons is of concern, as these are not protective, and vaccine developers need to be aware of the role of age or vaccine formulation in inducing anti‐unfoldon antibodies.

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          Most cited references28

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          Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine.

          Influenza A (H5N1) viruses could cause a severe worldwide epidemic, with high attack rates, large numbers of deaths and hospitalizations, and wide disruption. Effective vaccines against these viruses in humans are urgently needed. We conducted a multicenter, double-blind two-stage study involving 451 healthy adults 18 to 64 years of age who were randomly assigned in a 2:2:2:2:1 ratio to receive two intramuscular doses of a subvirion influenza A (H5N1) vaccine of 90, 45, 15, or 7.5 microg of hemagglutinin antigen or placebo. The subjects were followed for the safety analysis for 56 days. Serum samples obtained before each vaccination and again 28 days after the second vaccination were tested for H5 antibody by microneutralization and hemagglutination inhibition. Mild pain at the injection site was the most common adverse event for all doses of vaccine. The frequency of a serum antibody response was highest among subjects receiving doses of 45 microg or 90 microg. Among those who received two doses of 90 microg, neutralization antibody titers reached 1:40 or greater in 54 percent, and hemagglutination-inhibition titers reached 1:40 or greater in 58 percent. Neutralization titers of 1:40 or greater were seen in 43 percent, 22 percent, and 9 percent of the subjects receiving two doses of 45, 15, and 7.5 microg, respectively. No responses were seen in placebo recipients. A two-dose regimen of 90 mug of subvirion influenza A (H5N1) vaccine does not cause severe side effects and, in the majority of recipients, generates neutralizing antibody responses typically associated with protection against influenza. A conventional subvirion H5 influenza vaccine may be effective in preventing influenza A (H5N1) disease in humans. (ClinicalTrials.gov number, NCT00115986.). Copyright 2006 Massachusetts Medical Society.
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            Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review.

            Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older. We searched five electronic databases to December, 2004, in any language, for randomised (n=5), cohort (n=49), and case-control (n=10) studies, assessing efficacy against influenza (reduction in laboratory-confirmed cases) or effectiveness against influenza-like illness (reduction in symptomatic cases). We expressed vaccine efficacy or effectiveness as a proportion, using the formula VE=1-relative risk (RR) or VE*=1-odds ratio (OR). We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications, and deaths. In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against influenza-like illness was 23% (95% CI 6-36) and non-significant against influenza (RR 1.04, 0.43-2.51). Well matched vaccines prevented pneumonia (VE 46%, 30-58) and hospital admission (VE 45%, 16-64) for and deaths from influenza or pneumonia (VE 42%, 17-59), and reduced all-cause mortality (VE 60%, 23-79). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19, 0.02-2.01), influenza-like illness (RR 1.05, 0.58-1.89), or pneumonia (RR 0.88, 0.64-1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%, 12-38) and all-cause mortality (VE 42%, 24-55). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%, 21-33), respiratory diseases (VE* 22%, 15-28), and cardiac disease (VE* 24%, 18-30), and for all-cause mortality (VE* 47%, 39-54). In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest.
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              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.
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                Author and article information

                Journal
                Influenza Other Respir Viruses
                Influenza Other Respir Viruses
                10.1111/(ISSN)1750-2659
                IRV
                Influenza and Other Respiratory Viruses
                Blackwell Publishing Ltd (Oxford, UK )
                1750-2640
                1750-2659
                05 November 2007
                July 2007
                : 1
                : 4 ( doiID: 10.1111/irv.2007.1.issue-4 )
                : 147-156
                Affiliations
                [ 1 ]Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
                [ 2 ]Departments of Molecular Virology & Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
                Author notes
                [*]Gillian M. Air, Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Email: gillian-air@ 123456ouhsc.edu
                Article
                IRV017
                10.1111/j.1750-2659.2007.00017.x
                2367137
                18458742
                1224c18a-1317-4764-a58c-5c4a750ac90d
                History
                Page count
                Figures: 3, Tables: 1, Pages: 10
                Categories
                Original Articles
                Custom metadata
                2.0
                July 2007
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015

                Infectious disease & Microbiology
                elderly,ha inhibition,influenza virus,native and denatured antigen,serum antibodies

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