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1.  Heterovariant Cross-Reactive B-Cell Responses Induced by the 2009 Pandemic Influenza Virus A Subtype H1N1 Vaccine 
The Journal of Infectious Diseases  2012;207(2):288-296.
Background. The generation of heterovariant immunity is a highly desirable feature of influenza vaccines. The goal of this study was to compare the heterovariant B-cell response induced by the monovalent inactivated 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) vaccine with that induced by the 2009 seasonal trivalent influenza vaccine (sTIV) containing a seasonal influenza A virus subtype H1N1 (A[H1N1]) component in young and elderly adults.
Methods. Plasmablast-derived polyclonal antibodies (PPAb) from young and elderly recipients of A(H1N1)pdm09 vaccine or sTIV were tested for binding activity to various influenza antigens.
Results. In A(H1N1)pdm09 recipients, the PPAb titers against homotypic A(H1N1)pdm09 vaccine were similar to those against the heterovariant seasonal A(H1N1) vaccine and were similar between young and elderly subjects. The PPAb avidity was higher among elderly individuals, compared with young individuals. In contrast, the young sTIV recipients had 10-fold lower heterovariant PPAb titers against the A(H1N1)pdm09 vaccine than against the homotypic seasonal A(H1N1) vaccine. In binding assays with recombinant head and stalk domains of hemagglutinin, PPAb from the A(H1N1)pdm09 recipients but not PPAb from the sTIV recipients bound to the conserved stalk domain.
Conclusion. The A(H1N1)pdm09 vaccine induced production of PPAb with heterovariant reactivity, including antibodies targeting the conserved hemagglutinin stalk domain.
doi:10.1093/infdis/jis664
PMCID: PMC3532823  PMID: 23107783
influenza; vaccine; antibody; cross-reactivity
2.  Quantity, not quality, of antibody response decreased in the elderly 
The Journal of Clinical Investigation  2011;121(8):2981-2983.
The burden of disease during seasonal influenza epidemics is felt most keenly among the very young and the elderly. Although vaccination effectively protects children and young adults against infection, it has limited efficacy in elderly individuals. This has been linked to a reduced ability to induce a robust serum antibody response. In this issue of the JCI, Sasaki et al. identify some of the cellular and molecular deficits that underlie the reduced serum antibody response induced by influenza vaccination in elderly individuals. Importantly, they show that it is the quantity of the response, and not its quality, that needs to be improved if we are to enhance the success of influenza vaccination in this vulnerable population.
doi:10.1172/JCI58406
PMCID: PMC3148749  PMID: 21785210
3.  Systems Biology of Seasonal Influenza Vaccination in Humans 
Nature immunology  2011;12(8):786-795.
We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.
doi:10.1038/ni.2067
PMCID: PMC3140559  PMID: 21743478
4.  Age Affects Quantity but Not Quality of Antibody Responses after Vaccination with an Inactivated Flavivirus Vaccine against Tick-Borne Encephalitis 
PLoS ONE  2012;7(3):e34145.
The impairment of immune functions in the elderly (immunosenescence) results in post-vaccination antibody titers that are significantly lower than in young individuals. It is, however, a controversial question whether also the quality of antibodies declines with age. In this study, we have therefore investigated the age-dependence of functional characteristics of antibody responses induced by vaccination with an inactivated flavivirus vaccine against tick-borne encephalitis (TBE). For this purpose, we quantified TBE virus-specific IgG and neutralizing antibody titers in post-vaccination sera from groups of young and elderly healthy adults and determined antibody avidities and NT/ELISA titer ratios (functional activity). In contrast to the quantitative impairment of antibody production in the elderly, we found no age-related differences in the avidity and functional activity of antibodies induced by vaccination, which also appeared to be independent of the age at primary immunization. There was no correlation between antibody avidity and NT/ELISA ratios suggesting that additional factors affect the quality of polyclonal responses, independent of age. Our work indicates that healthy elderly people are able to produce antibodies in response to vaccination with similar avidity and functional activity as young individuals, albeit at lower titers.
doi:10.1371/journal.pone.0034145
PMCID: PMC3312914  PMID: 22461903
5.  Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates with Antibody Responses to Influenza Vaccination 
Science translational medicine  2013;5(176):176ra32.
Seasonal influenza vaccine protects 60 to 90% of healthy young adults from influenza infection. The immunological events that lead to the induction of protective antibody responses remain poorly understood in humans. We identified the type of CD4+ T cells associated with protective antibody responses after seasonal influenza vaccinations. The administration of trivalent split-virus influenza vaccines induced a temporary increase of CD4+ T cells expressing ICOS, which peaked at day 7, as did plasmablasts. The induction of ICOS was largely restricted to CD4+ T cells co-expressing the chemokine receptors CXCR3 and CXCR5, a subpopulation of circulating memory T follicular helper cells. Up to 60% of these ICOS+CXCR3+CXCR5+CD4+ T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-γ upon antigen stimulation. The increase of ICOS+CXCR3+CXCR5+CD4+ T cells in blood correlated with the increase of preexisting antibody titers, but not with the induction of primary antibody responses. Consistently, purified ICOS+CXCR3+CXCR5+CD4+ T cells efficiently induced memory B cells, but not naïve B cells, to differentiate into plasma cells that produce influenza-specific antibodies ex vivo. Thus, the emergence of blood ICOS+CXCR3+CXCR5+CD4+ T cells correlates with the development of protective antibody responses generated by memory B cells upon seasonal influenza vaccination.
doi:10.1126/scitranslmed.3005191
PMCID: PMC3621097  PMID: 23486778
6.  Plasmablast-derived polyclonal antibody response after influenza vaccination 
Journal of immunological methods  2010;365(1-2):67-75.
Conventional measurement of antibody responses to vaccines largely relies on serum antibodies, which are primarily produced by bone marrow plasma cells and may not represent the entire vaccine-induced B cell repertoire, including important functional components such as those targeted to mucosal sites. After immunization or infection, activated B cells differentiate into plasmablasts in local lymphoid organs, then traffic through circulation to the target sites where they further develop into plasma cells. On day 7 after influenza vaccination, a burst of plasmablasts, highly enriched for vaccine-specific antibody secreting cells, appears in the peripheral blood. This provides a unique window to the overall B cell response to the vaccine, without interference of pre-existing cross-reactive serum antibody. In this study we isolated B cells from volunteers on day 7 after immunization with the inactivated influenza vaccine and cultured them ex vivo to collect plasmablast-derived polyclonal antibodies (PPAb). The PPAb contained secreted IgG and IgA, which was approximately 0.2 ng per antibody secreting cell. Influenza-specific IgG and IgA binding activity was detected in PPAb at dilutions up to 105 by ELISA. The ratio of the titers of influenza-specific IgA to IgG by ELISA was 4-fold higher in PPAb than in day 28 post-vaccination sera, suggesting that vaccine-induced IgA is enriched in PPAb compared to sera. Functional activity was also detected in PPAb as determined by microneutralization and hemagglutination inhibition assays. In addition to bulk B cell cultures, we also cultured plasmablast subsets sorted by cell surface markers to generate PPAb. These results suggest that PPAb better reflects the mucosal IgA response than serum samples. Since PPAb are exclusively produced by recently activated B cells, it allows assessing vaccine-induced antibody response without interference from pre-existing cross-reactive serum antibodies and permits an assessment of antibody avidity based on antigen specific binding and antibody quantity. Therefore this assay is particularly useful for studying vaccine/infection-induced antibodies against antigens that might have previously circulated, such as antibody responses to rotavirus, dengue or influenza viruses in which cross-reactive antibodies against different virus serotypes/subtypes play a critical role in immunity and/or pathogenesis.
doi:10.1016/j.jim.2010.12.008
PMCID: PMC3039424  PMID: 21182843
Influenza virus; vaccines; antibodies; plasmablasts
7.  Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine 
Vaccine  2011;29(16):2865-2873.
A comparative analysis of antibody and cell-mediated immune responses was performed in ambulatory medically stable elderly and young adults who received the standard-dose of trivalent inactivated influenza vaccine, containing 15 μg of hemagglutinin (HA) per virus strain, or a high-dose vaccine containing 60 μg HA per virus strain. Among the elderly, the high dose vaccine induced greater HAI (hemagglutination inhibition) and virus neutralization antibody titers than the standard dose vaccine. These responses, however, did not achieve the magnitude of those induced by the standard dose vaccine in young adults. Vaccine-specific circulating T cells producing IFN-γ were detected in the elderly and young adults following immunization. However, there were no significant differences in the IFN-γ responses among groups. On the other hand, the standard dose vaccine in the elderly resulted in the highest proportion of complete non-responders who failed to elicit either an HAI or an IFN-γ response. This study provides further evidence that a higher dose vaccine for the elderly may result in enhanced immune responses which are predicted to improve protection although still of lower magnitude than those induced in younger healthier individuals.
doi:10.1016/j.vaccine.2011.02.017
PMCID: PMC3070775  PMID: 21352939
Influenza; vaccines; elderly; immune responses
8.  Effective influenza vaccines for children 
Seasonal influenza causes clinical illness and hospitalization in all age groups; however, conventional inactivated vaccines have only limited efficacy in young children. MF59®, an oil-in-water emulsion adjuvant, has been used since the 1990s to enhance the immunogenicity of influenza vaccines in the elderly, a population with waning immune function due to immunosenescence.
 
Clinical trials now provide information to support a favorable immunogenicity and safety profile of MF59-adjuvanted influenza vaccine in young children. Published data indicate that Fluad®, a trivalent seasonal influenza vaccine with MF59, was immunogenic and well tolerated in young children, with a benefit/risk ratio that supports routine clinical use. A recent clinical trial also shows that Fluad provides high efficacy against PCR-confirmed influenza. Based on the results of clinical studies in children, the use of MF59-adjuvanted vaccine offers the potential to enhance efficacy and make vaccination a viable prevention and control strategy in this population.
doi:10.4161/hv.18561
PMCID: PMC3426083  PMID: 22327501
children; influenza vaccine; immunogenicity; MF59 adjuvant
9.  Characterization of Plasmablasts in the Blood of HIV-Infected Viremic Individuals: Evidence for Nonspecific Immune Activation 
Journal of Virology  2013;87(10):5800-5811.
Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG+ plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA+ plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG+ plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection.
doi:10.1128/JVI.00094-13
PMCID: PMC3648153  PMID: 23487459
10.  Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination 
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.
doi:10.1111/j.1750-2659.2007.00017.x
PMCID: PMC2367137  PMID: 18458742
Elderly; HA inhibition; influenza virus; native and denatured antigen; serum antibodies
11.  Seasonal Inactivated Influenza Virus Vaccines 
Vaccine  2008;26(Suppl 4):D5-D9.
Inactivated influenza virus vaccines are the primary modality used for prevention of influenza. A system of annual identification of new strains causing illnesses, selections for vaccines, chick embryo growth, inactivation, processing, packaging, distribution and usage has been in place for decades. Current vaccines contain 15 µg of the HA of an A/H1N1, A/H3N2 and B strain and are given parenterally to induce serum anti-HA antibody for prevention of subsequent infection and illness from natural influenza. Reactogenicity is low and protection among healthy older children and adults is good; protection levels are generally lower in young children and the elderly. Needs include ensuring antigenic matches of vaccine and epidemic viruses each season, enhancing immunization rates, and providing new and improved vaccines and immunization approaches for the varied populations and circumstances globally.
doi:10.1016/j.vaccine.2008.05.076
PMCID: PMC2643340  PMID: 18602728
12.  Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine 
International Immunology  2012;24(3):175-182.
In order to develop predictive markers for a beneficial humoral immune response, we evaluated the in vivo and in vitro response to the pandemic (p)H1N1 vaccine in young and elderly individuals. We measured serum antibody response and associated this with the in vitro B-cell response to the vaccine, measured by activation-induced cytidine deaminase (AID). Both responses decrease with age and are significantly correlated. The percentage of switched memory B cells in blood, both before and after vaccination, is decreased with age. The percentage of switched memory B cells at t0 correlates with the hemagglutination inhibition response and therefore, we suggest that this may be used as a predictive marker for B-cell responsiveness. AID induced by CpG before vaccination also predicts the robustness of the vaccine response. Plasmablasts showed a trend to increase after vaccination in young individuals only. This report establishes molecular biomarkers of response, percentage of switched memory B cells and AID response to CpG, useful for identifying individuals at risk of poor response and also for measuring improvements in vaccines and monitoring optimal humoral responses.
doi:10.1093/intimm/dxr123
PMCID: PMC3621378  PMID: 22281510
Aging; B lymphocytes; biomarkers for vaccine response; immunoglobulin class switch recombination; pH1N1
13.  Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma 
British Journal of Cancer  2000;82(7):1261-1265.
Vaccination against influenza and Streptococcus pneumoniae is recommended for elderly and immunocompromised individuals. However, there is little information concerning the efficacy of vaccination in specific groups of patients. In this study, 52 patients underwent vaccination against influenza, S. pneumoniae and Haemophilus influenzae type b (Hib) as they attended hospital outpatient clinics. Serum was analysed prior to vaccination and 4–6 weeks afterwards. Antibody titres against S. pneumoniae and Hib were compared with reference values corresponding to the geometric mean titres of a healthy UK population. For influenza vaccination, haemagglutination inhibition (HI) titres were measured against three inactivated strains; a titre of ≥ 1/40 was considered protective. No patient had protective titres to all three antigens prior to vaccination and 41 patients (85%) had titres < 1/40 to all 3 strains. Post vaccination only 9/48 patients (19%) achieved protective antibody titres. Resistance to S. pneumoniae and response to Pneumovax II was also poor: prevaccination, 45 patients (93%) had suboptimal antibody titres and in 26/43 patients (61%) titres remained low post vaccination. Resistance to Hib and response to vaccination was comparable with the healthy adult UK population. These results question the practice of routine influenza and pneumococcal vaccination in myeloma patients. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.1088
PMCID: PMC2374477  PMID: 10755398
myeloma; influenza; Streptococcus pneumoniae; Haemophilus influenzae; vaccination
14.  Passive immune neutralization strategies for prevention and control of influenza A infections 
Immunotherapy  2012;4(2):175-186.
Although vaccination significantly reduces influenza severity, seasonal human influenza epidemics still cause more than 250,000 deaths annually. Vaccine efficacy is limited in high-risk populations such as infants, the elderly and immunosuppressed individuals. In the event of an influenza pandemic (such as the 2009 H1N1 pandemic), a significant delay in vaccine availability represents a significant public health concern, particularly in high-risk groups. The increasing emergence of strains resistant to the two major anti-influenza drugs, adamantanes and neuraminidase inhibitors, and the continuous circulation of avian influenza viruses with pandemic potential in poultry, strongly calls for alternative prophylactic and treatment options. In this review, we focus on passive virus neutralization strategies for the prevention and control of influenza type A viruses.
doi:10.2217/imt.11.167
PMCID: PMC3292042  PMID: 22339460
human monoclonal antibody; immunoprophylaxis; immunotherapy; influenza A virus; neutralizing antibodies
15.  Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study 
BMC Infectious Diseases  2010;10:134.
Background
Although seasonal influenza vaccine is effective in the elderly, immune responses to vaccination are lower in the elderly than in younger adults. Strategies to optimise responses to vaccination in the elderly include using an adjuvanted vaccine or using an intradermal vaccination route. The immunogenicity of an intradermal seasonal influenza vaccine was compared with that of an adjuvanted vaccine in the elderly.
Methods
Elderly volunteers (age ≥ 65 years) were randomised to receive a single dose of trivalent seasonal influenza vaccine: either a split-virion vaccine containing 15 μg haemagglutinin [HA]/strain/0.1-ml dose administered intradermally, or a subunit vaccine (15 μg HA/strain/0.5-ml dose) adjuvanted with MF59C.1 and administered intramuscularly. Blood samples were taken before and 21 ± 3 days post-vaccination. Anti-HA antibody titres were assessed using haemagglutination inhibition (HI) and single radial haemolysis (SRH) methods. We aimed to show that the intradermal vaccine was non-inferior to the adjuvanted vaccine.
Results
A total of 795 participants were enrolled (intradermal vaccine n = 398; adjuvanted vaccine n = 397). Non-inferiority of the intradermal vaccine was demonstrated for the A/H1N1 and B strains, but not for the A/H3N2 strain (upper bound of the 95% CI = 1.53) using the HI method, and for all three strains by the SRH method. A post-hoc analysis of covariance to adjust for baseline antibody titres demonstrated the non-inferiority of the intradermal vaccine by HI and SRH methods for all three strains. Both vaccines were, in general, well tolerated; the incidence of injection-site reactions was higher for the intradermal (70.1%) than the adjuvanted vaccine (33.8%) but these reactions were mild and of short duration.
Conclusions
The immunogenicity and safety of the intradermal seasonal influenza vaccine in the elderly was comparable with that of the adjuvanted vaccine. Intradermal vaccination to target the immune properties of the skin appears to be an appropriate strategy to address the challenge of declining immune responses in the elderly.
Trial registration
ClinicalTrials.gov: NCT00554333.
doi:10.1186/1471-2334-10-134
PMCID: PMC2895601  PMID: 20504306
16.  Towards universal influenza vaccines? 
Vaccination is the most cost-effective way to reduce the considerable disease burden of seasonal influenza. Although seasonal influenza vaccines are effective, their performance in the elderly and immunocompromised individuals would benefit from improvement. Major problems related to the development and production of pandemic influenza vaccines are response time and production capacity as well as vaccine efficacy and safety. Several improvements can be envisaged. Vaccine production technologies based on embryonated chicken eggs may be replaced by cell culture techniques. Reverse genetics techniques can speed up the generation of seed viruses and new mathematical modelling methods improve vaccine strain selection. Better understanding of the correlates of immune-mediated protection may lead to new vaccine targets besides the viral haemagglutinin, like the neuraminidase and M2 proteins. In addition, the role of cell-mediated immunity could be better exploited. New adjuvants have recently been shown to increase the breadth and the duration of influenza vaccine-induced protection. Other studies have shown that influenza vaccines based on different viral vector systems may also induce broad protection. It is to be expected that these developments may lead to more universal influenza vaccines that elicit broader and longer protection, and can be produced more efficiently.
doi:10.1098/rstb.2011.0102
PMCID: PMC3146782  PMID: 21893539
universal flu vaccines; influenza; seasonal flu vaccines
17.  Vaccination in the elderly 
Microbial biotechnology  2012;5(2):226-232.
Summary
There is a general consensus that the elderly do not respond as well to vaccination as the young, but robust studies are few and far between. Most refer to influenza vaccination, but even here, adequate immunological and clinical data are surprisingly thin on the ground. The meta‐analysis by Goodwin et al. from 2006 is still the most comprehensive that we have. They reviewed 31 antibody response studies comparing influenza vaccination efficacy in groups of elderly and younger adults. They reported that the adjusted odds ratio (OR) of responses in elderly versus young adults ranged from 0.24 to 0.59 for the three influenza antigens used in the vaccines. They concluded that rather than the estimated 70–90% clinical vaccine efficacy in younger adults, this figure was only 17–53% in the elderly, depending on which viruses were prevalent that year. They stated that ‘this highlights the need for more immunogenic vaccine formulations for the elderly’. How to achieve this? There are three areas where we may consider alterations to increase vaccine efficacy: (i) make the vaccine more potent; (ii) use adjuvants to enhance immunity; and (iii) apply immune modulators or other interventions to alter host immunity generally. We will consider these three options, focusing on influenza vaccination, in this mini‐review.
doi:10.1111/j.1751-7915.2011.00283.x
PMCID: PMC3815782  PMID: 21880118
18.  Prevention and control of influenza in persons with chronic obstructive pulmonary disease 
Despite recommendations for annual vaccination against influenza, more than half of patients with chronic obstructive pulmonary disease (COPD) in developed countries do not receive this vaccine. Influenza is characterized by its potentially of causing epidemics and by excess morbidity and mortality in patients with COPD and other chronic medical conditions. Good evidence of the efficacy, effectiveness, and cost-effectiveness of influenza vaccination underlines the recommendation of use in patients with COPD. Influenza vaccination could reduce influenza-related complications and exacerbations in patients with COPD, therefore reducing hospitalizations and deaths. Each year, all persons with COPD should be vaccinated with the inactivated trivalent influenza vaccine containing the most frequent two influenza A viral strains and one influenza B viral strain detected in the influenza season of the previous year. To achieve a 100% vaccination rate in patients with COPD, all patients with COPD registered in health insurance companies and attended in health centers and specialized clinics should be vaccinated during the immunization period (October–December). Antiviral therapies could be used as an adjunct to vaccination and to reduce influenza transmission in outbreaks. Antiviral therapies could reduce the duration and complications of influenza when administered within two days of the onset of illness. Research is necessary for new antiviral therapies that could prevent influenza with cost-effectiveness similar to the influenza vaccine.
PMCID: PMC2692112  PMID: 18044065
influenza vaccination; chronic obstructive pulmonary disease; vaccination program
19.  Novel Viral Vectored Vaccines for the Prevention of Influenza 
Molecular Medicine  2012;18(1):1153-1160.
Influenza represents a substantial global healthcare burden, with annual epidemics resulting in 3–5 million cases of severe illness with a significant associated mortality. In addition, the risk of a virulent and lethal influenza pandemic has generated widespread and warranted concern. Currently licensed influenza vaccines are limited in their ability to induce efficacious and long-lasting herd immunity. In addition, and as evidenced by the H1N1 pandemic in 2009, there can be a significant delay between the emergence of a pandemic influenza and an effective, antibody-inducing vaccine. There is, therefore, a continued need for new, efficacious vaccines conferring cross-clade protection—obviating the need for biannual reformulation of seasonal influenza vaccines. Development of such a vaccine would yield enormous health benefits to society and also greatly reduce the associated global healthcare burden. There are a number of alternative influenza vaccine technologies being assessed both preclinically and clinically. In this review we discuss viral vectored vaccines, either recombinant live-attenuated or replication-deficient viruses, which are current lead candidates for inducing efficacious and long-lasting immunity toward influenza viruses. These alternate influenza vaccines offer real promise to deliver viable alternatives to currently deployed vaccines and more importantly may confer long-lasting and universal protection against influenza viral infection.
doi:10.2119/molmed.2012.00147
PMCID: PMC3510293  PMID: 22735755
20.  Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic H1N1 2009 influenza virus in an age dependent manner 
The Journal of infectious diseases  2010;202(11):1634-1638.
Pre-existing antibodies to the hemagglutinin of pandemic A (H1N1) 2009 influenza virus (pH1N1) positively correlates with age. The impact of contemporary seasonal influenza vaccines on establishing immunity to other pH1N1 proteins is unknown. We measured serum antibodies to the neuraminidase of pandemic H1N1 (pNA) in adults prior to and after vaccination with seasonal trivalent inactivated influenza vaccines. Serum antibodies to pNA were observed in all age groups; however, vaccination elevated pNA antibodies in predominately the elderly. Therefore, contemporary seasonal vaccines likely contribute to reduction of pH1N1 associated disease in older individuals.
doi:10.1086/657084
PMCID: PMC2974032  PMID: 20979454
pandemic; neuraminidase; seasonal; antibodies
21.  Inactivated Seasonal Influenza Vaccines Increase Serum Antibodies to the Neuraminidase of Pandemic Influenza A(H1N1) 2009 Virus in an Age-Dependent Manner 
The Journal of Infectious Diseases  2010;202(11):1634-1638.
Levels of preexisting antibodies to the hemagglutinin of pandemic influenza A(H1N1) 2009 (hereafter pandemic H1N1) virus positively correlate with age. The impact of contemporary seasonal influenza vaccines on establishing immunity to other pandemic H1N1 proteins is unknown. We measured serum antibodies to the neuraminidase (NA) of pandemic H1N1 in adults prior to and after vaccination with seasonal trivalent inactivated influenza vaccines. Serum antibodies to pandemic H1N1 NA were observed in all age groups; however, vaccination elevated levels of pandemic H1N1 NA antibodies predominately in elderly individuals (age,⩾60 years). Therefore, contemporary seasonal vaccines likely contribute to reduction of pandemic H1N1-associated disease in older individuals.
doi:10.1086/657084
PMCID: PMC2974032  PMID: 20979454
22.  Influenza vaccination in the elderly. 
Postgraduate Medical Journal  1996;72(848):339-342.
There is overwhelming evidence for the clinical efficacy of the influenza vaccine, especially in the elderly with chronic disease, reducing mortality and hospital admissions. There is also evidence to suggest that the influenza vaccine may be beneficial in the healthy elderly. There is some evidence to suggest that the antibody response in the elderly to the vaccine may decrease with increasing age, although there are several confounding factors that have not been taken into account in many of these studies. That aside, even if antibody response is not as good as that in younger people, the evidence that vaccination saves lives and reduces morbidity in the elderly means that the vaccination should be offered to elderly patients at high risk and perhaps even to the elderly healthy population. Although vaccination of an elderly at-risk patient does not necessarily mean that that particular patient will mount an appropriate antibody response, a significant number of elderly patients will respond appropriately. Serious side-effects from vaccination are extremely rare and the more common side-effects are mild and self-limiting. Increasing the number of elderly people receiving the influenza vaccination will not only result in cost savings for the National Health Service in terms of reduced hospitalisation but, more significantly, the elderly will benefit in terms of reduced morbidity and mortality.
PMCID: PMC2398486  PMID: 8758010
23.  A Reduced-Dose Seasonal Trivalent Influenza Vaccine Is Safe and Immunogenic in Adult and Elderly Patients in a Randomized Controlled Trial 
With the recent pandemic of influenza A (H1N1) and vaccine shortages, there has been considerable interest in developing influenza vaccines with reduced doses, allowing for increased production capacity. Here we report a prospective, randomized, double-blind, single-center clinical trial of a reduced-dose whole-virion inactivated, adjuvanted influenza vaccine in adult and elderly volunteers. A total of 234 subjects, including 120 adults (18 to 60 years of age) and 114 elderly subjects (>60 years of age) were enrolled to receive either 6 μg or the conventional 15-μg dose of seasonal trivalent influenza vaccines. The subjects were followed for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition testing. The subjects developed antibody responses against the seasonal influenza A virus H1N1 and H3N2 strains, as well as the seasonal influenza B virus included in the vaccines. Single doses of 6 μg fulfilled licensing criteria for seasonal influenza vaccines. No significant differences in rates of seroconversion or seroprotection or in geometric mean titers were found between the two dosage levels. All adverse events were rare, mild, and transient. We found that the present reduced-dose vaccine is safe and immunogenic in healthy adult and elderly subjects and triggers immune responses that comply with licensing criteria.
doi:10.1128/CVI.05619-11
PMCID: PMC3294605  PMID: 22219315
24.  Immune Response to Pneumococcal Polysaccharides 4 and 14 in Elderly and Young Adults: Analysis of the Variable Light Chain Repertoire  
Infection and Immunity  2005;73(11):7477-7484.
Streptococcus pneumoniae is a human bacterial pathogen responsible for serious infections including pneumonia. The currently licensed polysaccharide vaccine provides 60 to 80% protection in young adults, but in the elderly the vaccine efficacy is drastically reduced despite normal antibody levels. We hypothesized that the reduced vaccine efficacy in the elderly results from altered variable gene family usage. We have analyzed the light chain gene usage in 20 young (20 to 30 years of age) and 20 elderly (65 to 86 years of age) adults in response to pneumococcal polysaccharide 4 (PPS4) and PPS14. We generated a variable light chain library using B cells specific for PPS4 and PPS14 from each vaccinated individual. We determined complete sequences and somatic mutation frequencies in all isolated variable light chain fragments. Six gene families, κ1, κ2, κ3, κ4, λ1, and λ3, were identified in response to PPS4 and PPS14 in both age groups. Comparison of young and elderly adults demonstrated significant differences in κ4, λ1, and λ3 gene usage in response to PPS4 and PPS14. With aging, there was a significant increase in κ4 gene usage and a significant decrease in λ1 and λ3 gene usage in response to both PPS4 and PPS14. Although both Vκ1 and Vλ3 gene products demonstrated extensive mutations, there was no age-related difference in mutational frequency per gene family. These findings suggest an age-related change in light chain gene usage in response to PPS4 and PPS14.
doi:10.1128/IAI.73.11.7477-7484.2005
PMCID: PMC1273897  PMID: 16239549
25.  Immunogenicity and Cross-Reactivity of 2009–2010 Inactivated Seasonal Influenza Vaccine in US Adults and Elderly 
PLoS ONE  2011;6(1):e16650.
The campaign of 2009–2010 Northern Hemisphere seasonal vaccination was concurrent with the 2009 H1N1 pandemic. Using a hemagglutination inhibition (HAI) assay, we evaluated the immunogenicity and cross-reactivity of 2009–2010 inactivated trivalent influenza vaccine (TIV) in US adult and elderly populations. Vaccination of TIV resulted in a robust boost on the antibody response of all subjects to seasonal A/Brisbane/59/2007 (H1N1) and A/Uruguay/716/2007 (H3N2) with over 70% of recipients reaching a seroprotective titer of 40. B/Brisbane/60/2008 was the least immunogenic among the three seasonal vaccine strains with <30% of TIV recipients reaching a seroprotective titer of 40. TIV vaccination also induced a moderate boost on the pandemic specific antibody responses. Twenty-four percent of adults and 36% of elderly reached a seroprotective HAI titer of 40 or more against pandemic A/South Carolina/18/2009 (H1N1) after receiving TIV compared to 4% and 7% at the beginning of vaccination, respectively. In addition, 22% of adults and 34% of elderly showed an increase of 4-fold or more in A/South Carolina/18/2009 specific HAI titers after TIV vaccination. The pandemic specific cross-reactive antibodies strongly correlated with the post-vaccination HAI titers against the seasonal H3N2 vaccine strain in all subjects.
doi:10.1371/journal.pone.0016650
PMCID: PMC3031605  PMID: 21304946

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