Serum cytokine levels and antibody response to influenza vaccine in the elderly

Cytokines play critical roles in regulating the antibody response to vaccines. We sought to understand the role of endogenous cytokines in the determination of antibody production in the elderly, a group of subjects known to have a lower response rate to vaccination. We found that in a healthy elderly group, only 52% of whom responded to the influenza vaccine, endogenous levels of interleukin 6 (IL-6), IL-10 and gamma interferon (IFNgamma) did not differ statistically significantly between responders and non-responders (responders: n = 27, IL-6 = 293 +/- 101 pg/ml, IL-10 = 882 +/- 240 pg/ml; nonresponders: n = 26, IL-6 = 223 +/- 71 pg/ml, P = 0.57, IL-10 = 445 +/- 148 pg/ml, mean +/- SE, P = 0.14, respectively, and undetectable IFNgamma). Serum levels of these three cytokines were not changed significantly four weeks after vaccination (P < 0.05 for IL-6 and P < 0.01 for IL-10). In addition, there were also no age-dependent differences in serum IL-6 and IL-10 levels.     

Immune response to live influenza vaccine

Priority data on the induction, by using a Russian live cold-adapted reassortant influenza vaccine (LIV), of the cellular and humoral immunity with regard for attenuation and genetic reassortment of vaccine stains as well as with regard for the age of vaccinated persons and the production of Th1 (IFNY, IL-2) and Th2 (IL-4) cytokine markers in vitro are presented. It was demonstrated in vivo that a pathogenic virus of the A group by far more actively induced the lymphocyte apoptosis as compared with attenuated genetically reassorted stains. Unlike the influenza pathogenic virus, the genetically attenuated and reassorted strain did not produce any negative effects on the induction of cellular immunity. A comparative study of the LIV immunogenic properties in vaccinated persons showed an advantage of LIV over inactivated influenza vaccine (IIV) in stimulating the cellular and local immunity in the elderly. Unlike IIV, LIV induced an active and balanced immune response developing due to Th1 and Th2 activation. LIV was found to stimulate well enough the production of IFN and IL-2 in both young and old persons.     

Time course study of the antigen-specific immune response to a PLGA microparticle vaccine formulation

Microparticle-based vaccine delivery systems are known to promote enhanced immune responses to protein antigens and can elicit T_H1-biased responses when used in combination with Toll-like receptor (TLR) agonists. It is important to understand the kinetics of the immune responses to microparticle-based protein vaccines in order to predict the duration of protective immunity and to optimize prime-boost vaccination regimens. We carried out a 10-week time course study to investigate the magnitude and kinetics of the antibody and cellular immune responses to poly(lactic-co-glycolic acid) (PLGA) microparticles containing 40 μg ovalbumin (OVA) protein and 16 μg CpG-ODN adjuvant (MP/OVA/CpG) in comparison to OVA-containing microparticles, soluble OVA plus CpG, or OVA formulated with Alhydrogel^® aluminum adjuvant. Mice vaccinated with MP/OVA/CpG developed the highest T_H1-associated IgG2b and IgG2c antibody titers, while also eliciting T_H2-associated IgG1 antibody titers on par with Alhydrogel^®-formulated OVA, with all IgG subtype titers peaking at day 56. The MP/OVA/CpG vaccine also induced the highest antigen-specific splenocyte IFN-γ responses, with high levels of IFN-γ responses persisting until day 42. Thus the MP/OVA/CpG formulation produced a sustained and heightened humoral and cellular immune response, with an overall T_H1 bias, while maintaining high levels of IgG1 antibody equivalent to that seen with Alhydrogel^® adjuvant. The time course kinetics study provides a useful baseline for designing vaccination regimens for microparticle-based protein vaccines.     

Impact of glycosylation on the immunogenicity of a DNA-based influenza H5 HA vaccine

Avian H5N1 influenza viruses isolated from humans in Hong Kong in 1997 were divided into two antigenic groups based on the presence or absence of a potential glycosylation site at amino acid residues 154-156 in the HA1 region of the viral hemagglutinin (HA) surface glycoprotein. To assess the impact of glycosylation on the immunogenicity of an HA-expressing DNA vaccine, a series of plasmid vaccine constructs that differed in the presence of potential glycosylation sites at amino acid residues 154-156, 165-167, and 286-288 were used to immunize BALB/c mice. Postvaccination serum IgG, hemagglutination inhibition, and neutralizing antibody titers as well as the morbidity and mortality following a lethal H5N1 viral challenge did not vary significantly among any of the experimental groups. We conclude that the glycosylation pattern of the influenza virus HA1 domain has little impact on the murine antibody response raised to a DNA vaccine encoding the H5 HA, thereby minimizing the concern that the pattern of glycosylation sites encoded by the vaccine match those of closely related H5 viruses.     

Antibody response to influenza vaccine in adults vaccinated with identical vaccine strains in consecutive years

Fifty seven hospital workers received influenza vaccine in November 2003, and the serum HI antibody titer was determined before, 2 and 4 weeks after the vaccination. Thirty seven were vaccinated in November, 2002 consecutively (the repeated vaccination group), and the remaining 20 had not been vaccinated in the previous year (the single vaccination group). Six of the repeated vaccination group received both influenza and hepatitis B vaccination in September, 2004 and the antibody responses were examined 2 weeks later. Two and four weeks after the 2003-vaccination, the HI antibody titers to A/H1N1, A/H3N2, and B in the repeated vaccination group were significantly lower than in the single vaccination group (P < 0.05). This phenomenon had no relation to the pre-vaccination HI antibody titer. The antibody response was low to repeated influenza vaccination, but normal to hepatitis B vaccine in six subjects who had a second vaccination in 2004, showing that this depressed response was influenza-specific. These results suggest that the decreased HI antibody response to repeated influenza vaccination was affected mainly by the previous vaccination per se rather than by the pre-existing antibody titer.     

Vaccine immune response and side effects with the use of acetaminophen with influenza vaccine.

The purpose of this study was to determine whether acetaminophen impairs the immune response to influenza vaccine. Influenza vaccine is an under-utilized preventive measure, partly because of the unfounded perception that fever and myalgias frequently follow vaccination. While acetaminophen may decrease these infrequent side effects, it may also alter the immune response to vaccination. We compare the effect of acetaminophen with placebo on the humoral immune response to the 1991-1992 commercially available influenza vaccine. We studied 60 healthy, elderly subjects from a geriatric clinic and 20 infirm, elderly subjects from a nursing home. The subjects were randomly assigned to receive placebo or acetaminophen (1,000 mg every 6 h) for 2 days. Acetaminophen did not depress or enhance the immune development of serum hemagglutination inhibition antibody to the three vaccine antigens. The systemic side effects of fever and myalgia were uncommon in both groups. The healthy elderly subjects mounted a significantly better immune response to the influenza virus A/Taiwan/1/86 (H1N1) vaccine strain than did the infirm elderly subjects (geometric mean titer, 115 versus 51; P = 0.003). The functional activity score obtained by using the chronic healthy evaluation component of the Acute Physiology and Chronic Health Evaluation system could be used to distinguish the healthy from the infirm elderly (scores of 1.27 versus 3.75, P < 0.001). Acetaminophen neither depressed nor enhanced the serum antibody response to the vaccine in the healthy and infirm elderly subjects studied.     

Characteristics of the immune response in children multiply inoculated with an inactivated influenza vaccine

The observations involved 1082 children ranging in ages from 11 to 14 years who had been annually given from one to four injections of inactivated chromatographic influenza vaccine. An additional group consisted of 242 children who after three years of vaccination with the inactivated vaccine were given a live influenza vaccine type A (H1N1) and A (H3N2) for children. The studies showed that the highest immunological effect in children was achieved after two years of vaccination with the inactivated influenza vaccine. No positive effect on the immune response in children was demonstrated by the addition of a live vaccine into the immunization schedule against the background of multiple immunizations with the inactivated one. Different types of responses in children to immunization against influenza were observed.     

Clinical and serological response in humans following immunization with gripax influenza vaccine

A commercial trivalent formol-inactivated influenza vaccine (Gripax) was tested. The vaccine consisted of equal amounts of A/England/321/77 (H₃N₂), B/Hong Kong/8/73, and A/USSR/99/177 (H₁N₁) strains. One hundred four females were injected intramuscularly. Eighty-eight (74.6%) were 17–24 yr old and 16 (15.4%) were 29–45 yr old. Seventy subjects were immunized with 1,200 IU, 24 with 1,680 IU, and 10 with 2,400 IU. A follow-up for adverse side effects was carried out during 72 hr following vaccination. There was no absence from work or school, nor did the subjects develop any systemic symptoms (fever and malaise). Local reactogenic effects were minor and included painless erythema and induration of low degree, which were observed in small numbers of the recipients and lasted for no more than 24–48 hr. Localized, axillary lymphadenopathy was noted in one subject. Seventy-four paired sera samples were tested for hemagglutination inhibition (HI) response. A highly reactive response to A/England and B/Hong Kong strains was observed, as evidenced by an at-least fourfold increase of titers. There was no significant change when a dose of 400 IU or more was given: An 83.6% and 89.4% response was, respectively, recorded for A/England and 69.0% and 73.6%, respectively, for B/Hong Kong. However, when the dose of A/USSR was increased, the response was significantly elevated from 56.0 to 84.2%. All the sera tested for neuraminidase inhibition antibody showed a satisfactory response. Regardless of the dose, a single administration of the vaccine sufficed to confer a high degree of immunity against the “old” circulating strains: 94–100% against A/England and 79–90.9% against B/Hong Kong. Immunization with 400 IU of the recent strain A/USSR conferred immunity in 50.9% of the cases, whilc the administration of a dose equal to or larger than 560 IU elicited a far higher rate of immunity-89.4%. The high quality of the vaccine is evidenced by the conversion rate from nonimmune to the immune state, as well as by the lack of undesirable side effects.     

The formation of an immune response in volunteers inoculated with a live recombinant influenza vaccine]

The capacity of a live influenza vaccine (LIV) to stimulate cytotoxic cells (ADCMC and NK) was studied in 49 volunteers and 56 patients with influenza. Experimental batches of LIV from influenza A and B viruses prepared by genetic recombination on the basis of cold-adapted attenuation donors were used. Type A and B LIV were shown to stimulate the cytotoxic cell-mediated and humoral immunity; the intensity of immune response, however, depended on the molecular genetic characteristics of the vaccine (genome structure, properties of the donor of attenuation), its biological activity and capacity of reproduction in tissues.     

Written disclosure of experiences with racial discrimination and antibody response to an influenza vaccine

This study examined whether Blacks who wrote about their experiences with racial discrimination in a laboratory-based disclosure intervention would show greater levels of antibody production in response to an influenza vaccine compared with Blacks who wrote about a neutral topic. Forty-seven participants were randomized to write about their thoughts and feelings around their experiences with racism, or to write about their schedule for the week. Participants wrote on the same topic during each of three 20-min sessions. Blood was drawn prior to the intervention and at 1 and 3 months postvaccination to assess antibody production. Participants in the racism disclosure group produced significantly less antibodies to 2 of 3 viral strains. Post hoc analysis suggests that participants who were unsure about whether their events were due to racism or due to other factors had reduced levels of antibody to 1 viral strain. The attributional ambiguity sometimes associated with racism may inhibit the benefits of disclosure interventions for these types of stressors.     

Time to peak serum antibody response to influenza vaccine.

The time to the appearance of a peak serum antibody response to influenza virus vaccine is not clearly defined. We compared the most commonly used time intervals described in the literature--4 and 6 weeks after vaccination. We studied 118 elderly patients from three different geographic sites. The 1992 to 1993 trivalent inactivated influenza virus vaccine containing influenza virus A/Beijing/353/89 (H3N2), influenza virus A/Texas/36/91 (H1N1), and influenza virus B/Panama/45/90 was used. No statistically significant differences were found at the 4- and 6-week intervals after vaccination.     

Association of cytokine genetic polymorphisms with the humoral immune response to recombinant vaccine against HBV in infants

The prevention of hepatitis B by vaccination is one the most efficient tools to avoid the transmission of the virus, although a considerable variability to the anti‐HBsAg antibody response has been described. Recently, polymorphisms of cytokine regulating genes have been described which seem to influence the immune response to various antigens. This article's objective was to evaluate the influence of cytokine genetic polymorphisms onto the humoral immune response to hepatitis B vaccine in infants. Vaccinated children were classified according to the level of anti‐HBsAg antibody titles. The genotyping for TNF (?308), TGFB1 (+869, +915), IL‐10 (?1082, ?819, ?592), IL‐6 (?174), and IFNG (+874) was accomplished by the PCR‐SSP technique. The TNF (?308) allele A presented a lower but not statistically significant frequency at 5% level in high responder patients (3.7% vs. 12.3%, P = 0.0919). The same was seen for the TNF (?308) genotype GA (7.4% vs. 24.5%, P = 0.0757). Further studies in other populations and evaluation of a greater number of individuals may contribute for a better understanding of the cytokine gene polymorphism influence in general and TNF polymorphism more specifically in the humoral immune response to the HBsAg vaccination in newborn children. J. Med. Virol. 82:929–933, 2010. © 2010 Wiley‐Liss, Inc.     

Restriction analysis of genome composition of live influenza vaccine

Live attenuated cold-adapted influenza vaccine (LIV) has been used in Russia for over 50 years and proved to be safe and effective. Currently, Russian reassortant LAIV is based on influenza AILeningrad/134/17/57 (H2N2) and B/USSR/60/69 Master Donor Viruses (MDVs) which are cold-adapted (ca), temperature-sensitive (ts), and attenuated (att), respectively. The MDVs are used to generate attenuated reassortant vaccine viruses containing the surface antigens of current wild type (wt) influenza A (HINI) and A (H3N2) viruses and wt influenza B virus. The ca/ts/att phenotype of these viruses limits replication in the upper respiratory tract. Reassortment typically yields numerous viruses with different genome constellations, rapid screening is needed to select proper vaccine viruses. In this study, screening of reassortant vaccine strains for live attenuated influenza vaccine generated from currently circulating influenza A and B viruses by RFLP assay is described.     

The delivery site of a monovalent influenza vaccine within the respiratory tract impacts on the immune response

Pulmonary vaccination is a promising immunization route. However, there still remains a crucial need to characterize the different parameters affecting the efficacy of inhaled vaccination. This study aimed at assessing the impact of antigen distribution within the respiratory tract on the immune response to a monovalent A/Panama/2007/99 H3N2 influenza split virus vaccine administered to BALB/c mice. Varying the administration technique allowed the targeting of the vaccine to different sites of the mouse respiratory tract, i.e. the nasal cavity, the upper or central airways, or the deep lung. This targeting was verified by using ovalbumin as a tracer compound. The immune responses generated following influenza vaccine administration to the different respiratory tract sites were compared to each other and to those elicited by intramuscular and peroral intragastric immunization. Delivery of the vaccine to the different respiratory regions generated systemic, local and cellular virus-specific immune responses, which increased with the depth of vaccine deposition, culminating in deep-lung vaccination. The latter induced virus-specific serum immunoglobulin G and neutralizing antibody titres as elevated as intramuscular vaccination, whereas the production of mucosal secretory immunoglobulin A was significantly superior in deep-lung-vaccinated animals. The analysis of cytokines secreted by mononuclear cells during an in vitro recall response indicated that deep-lung vaccination induced a local shift of the cellular immune response towards a T helper type 1 phenotype as compared to intramuscular vaccination. In conclusion, antigen distribution within the respiratory tract has a major effect on the immune response, with the deep lung as the best target for inhaled influenza vaccination.     

Impact of the GP contract on inequalities associated with influenza immunisation: a retrospective population-database analysis

Background

Influenza immunisation is recommended for all people aged ≥65 years and younger people with particular chronic diseases. The Quality and Outcomes Framework (QOF) has provided new financial incentives for influenza immunisation since 2004.

Aim

To determine the impact of the 2004 UK General Medical Services contract on the overall uptake of, and socioeconomic inequalities associated with, influenza immunisation.

Design and setting

Retrospective general-practice population database analysis in 15 general practices in Scotland, UK.

Method

Changes in influenza-immunisation uptake for those in at-risk groups between 2003–2004 and 2006–2007 were measured, and variation in uptake examined using multilevel modelling.

Results

Uptake rose from 67.9% in 2003–2004 to 71.4% in 2006–2007. The largest increases were seen in those aged <65 years with chronic disease, with uptake rising from 49.6% to 58.4%, but rates remained considerably lower than in those aged ≥65 years. Differences between practices narrowed (median odds ratio [OR] for two patients randomly selected from different practices: 2.13 (95% confidence interval [CI] = 2.00 to 2.26) in 2003–2004 versus 1.44 (95% CI = 1.40 to 1.49) in 2006–2007. However, inequalities in uptake by patient socioeconomic status did not change: adjusted OR for most deprived versus most affluent was 0.75 (95% CI = 0.70 to 0.80) in 2003–2004 versus 0.72 (95% CI = 0.68 to 0.76) in 2006–2007.

Conclusion

Overall uptake rose significantly and differences between practices narrowed considerably. However, socioeconomic and age inequalities in influenza immunisation persisted in the first 3 years of the QOF. This contrasts with other ecological analyses, which have concluded that the QOF has reduced inequalities. The impact of financial incentives on inequalities is likely to vary, and some kinds of care may require more targeted improvement activity and support.     

Humoral and cellular response to influenza vaccine in HIV-infected children with full viroimmunologic response to antiretroviral therapy

OBJECTIVE: It is unclear whether the ability to respond to vaccines is restored by antiretroviral therapy. We evaluated the influenza-specific immune responses elicited by a virosomal vaccine in HIV-infected children on long-term successful highly active antiretroviral therapy (HAART). METHODS: This was an observational, prospective, open-label study enrolling 24 HIV-infected, HAART-treated (85 months' mean exposure), vaccine-naive children (median age=11.9 years) and 14 age- and gender-matched healthy controls. Mean CD4 T-cell counts (>900 cells/microL) and percentages (>37%) were comparable. The HIV RNA level was <50 copies/mL in all patients. Children received a single dose of trivalent virosome-adjuvanted influenza vaccine. A/H3N2-, A/H1N1-, and B-antigen-specific antibody (Ab) titers and subclasses and vaccine-specific interferon-gamma (IFNgamma)- and interleukin (IL)-2-producing T lymphocytes were analyzed at baseline and 1 and 6 months after immunization. RESULTS: Seroconversion (>or=4-fold Ab titer raise in >40% of patients) and seroprotection (Ab titer>or=1:40 in >70% of patients) was achieved at 1 month in both groups; however, fewer HIV-infected children fulfilled these criteria. The A/H3N2- and A/H1N1-specific Ab geometric mean titers were lower in HIV-infected children compared with healthy controls at 1 and 6 months; interestingly, a boost in vaccine-specific IgG3 T helper 1 type Ab was seen in healthy controls alone. Finally, vaccine specific-IFNgamma- and IL-2-producing T lymphocytes were reduced at both time points in HIV-infected children compared with healthy controls. CONCLUSIONS: One injection of virosomal-adjuvanted influenza vaccine stimulates good immune responses, although the humoral and cellular immune responses are reduced in HIV-infected children compared to healthy children. This indicates that immunologic function impairments may persist upon HIV infection even if HIV-positive viremia is suppressed and immune recovery seems to be achieved.     

Antibody response to a two-dose influenza vaccine regimen in adult lymphoma patients on chemotherapy

A study was conducted to determine if a two-dose regimen of influenza vaccine would enhance the immunologic response of 41 patients with lymphoma receiving chemotherapy. Hemagglutinin-inhibiting antibody responses to influenza A/H1N1, A/H3N2 and B virus occurred in 32 %, 24 % and 20 % of patients following one dose, and in 49 %, 41 % and 46 % of patients following two doses, respectively. Responses to one or more vaccine components occurred in 42 % of patients after one dose and in 71 % after two doses. Fifty percent of the patients who did not respond after one dose responded after two doses. A two-dose regimen of influenza immunization may significantly enhance the response rate of cancer patients receiving chemotherapy.     

高致病性人禽流感H5N1疫苗滴鼻免疫应答效果的初步研究

目的 通过高致病性人禽流感H5N1全病毒-MF59佐剂疫苗滴鼻免疫Balb/c小鼠,评价该疫苗所诱导的系统免疫与黏膜免疫应答效果.方法 以不同剂量抗原按比例与MF59佐剂配伍制成粘膜疫苗,滴鼻免疫Balb/c小鼠,二免2周采血检测血清IgG、IgM效价及血清中HAI(HA inhibitor)的中和抗体效价,同时收集鼻、肺灌洗液,检测其lgG和slgA抗体效价.结果 H5NI+MF59组血清抗体效价较H5NI组有显著升高(P＜0.01);在各剂量组中,随着剂量的增加抗体效价呈上升趋势.12μg腭后抗体效价呈下降趋势,以HSNI+MF59(12μg)组效价最高;肺鼻灌洗液中,均可检测到特异性分泌型IrA、IsG,其中特异性分泌型IgA效价略高于IgG;抗体亚型的分布以IgG1、IgG2b为主.结论 灭活高致病性禽流感全病毒H5N1在佐剂MF59作用下可诱导机体产生体液免疫应答,同时还可以在黏膜局部产生特异性分泌型IgA、IsG,为高致病人禽流感病毒I-15N1黏膜疫苗的研制奠定了基础.     

Whole influenza virus vaccine is more immunogenic than split influenza virus vaccine and induces primarily an IgG2a response in BALB/c mice

The aim of this study was to compare the kinetics and the magnitude of the humoral immune response to two different influenza vaccine formulations, whole and split virus vaccines. BALB/c mice were immunized intramuscularly with one or two doses (3 weeks apart) of 7.5, 15 or 30 µg of haemagglutinin of monovalent A/Panama/2007/99 (H3N2) split or whole virus vaccine. The two vaccine formulations induced similar kinetics of the antibody-secreting cells response; however, differences in the magnitude were observed in the spleen and bone marrow. Vaccination with whole virus vaccine generally elicited a quicker and higher neutralizing antibody response, particularly after the first dose of vaccine. The two vaccine formulations gave different immunoglobulin G (IgG) subclass profiles. Split virus vaccine stimulated both IgG1 and IgG2a antibodies suggestive of mixed T-helper 1 (Th1) and Th2 response, whereas whole virus vaccine induced mainly an IgG2a antibody response, which is indicative of a dominant Th1 response. The increased immunogenicity of whole virus vaccine in a naïve population could reduce the vaccine concentration needed to provide protective immunity.