Benefits of increasing the dose of influenza vaccine in residents of long‐term care facilities: A randomized placebo‐controlled trial

Increased vaccine doses and mid‐season boosting may increase the proportion of residents with protective immunity from influenza in long‐term care facilities. In a multi‐center study (1997–1998), 815 residents from 14 long‐term care facilities were assigned at random to receive 15 or 30 µg of inactivated influenza vaccine, followed by a 15 µg booster vaccine or a placebo vaccine at Day 84. Seroresponses were re‐analyzed by hemagglutination‐inhibition (≥4‐fold titer increases, protective titer ≥40, geometric mean titers. Forty percent of the participants had pre‐vaccination titers ≥40. At Day 25 after vaccination, this increased to 66.3% after a 15 µg dose versus 73.3% after a dose of 30 µg (P = 0.049). Participants receiving a 30 µg dose followed by a 15 µg booster showed more ≥4‐fold titer increases at Day 109 (43.6% vs. 35.4%, P = 0.003) and protective titers ≥40 (74.2% vs. 64.6%, P = 0.041), compared to those receiving only a 15 µg dose. Differences were most apparent in participants with low pre‐vaccination titers. Booster vaccination after an initial 15 µg dose of the vaccine did not increase the protective rate (61.9% vs. 63.9% after placebo). The number of participants needed to vaccinate to protect one additional resident by a dose of 15 µg was 4, by a dose of 30 µg 3, and 15 when using a 30 µg dose instead of 15 µg. Doubling the dose of influenza vaccine increased protection‐related responses among residents of long‐term care facilities, especially in those with low pre‐vaccination titers. J. Med. Virol. 81:908–914, 2009. © 2009 Wiley‐Liss, Inc.     

Long‐term immunogenicity of preservative‐free hepatitis B vaccine formulations in adults

Vaccination with recombinant hepatitis B vaccines is highly effective in preventing hepatitis B infection. Recently, a preservative‐free (PF) formulation of hepatitis B vaccine [GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium] has been licensed. The immunogenicity of the PF hepatitis B vaccine and antibody persistence 6 years later was assessed in this study. This formulation was compared with the preservative‐ containing (PC) formulation of the vaccine and a low‐preservative (LP) content formulation. Five hundred forty‐one healthy adult subjects were evaluated in the primary study. Over 94% of the subjects in the three study groups had seroprotective anti‐HBs antibody concentrations (≥10 mIU/ml) 1 month after completing primary vaccination. Antibody measurements in 242 healthy adults who returned for the follow‐up study and who had received primary vaccination 6 years earlier showed that over 81% of subjects in the three study groups still had anti‐HBs antibody concentrations ≥10 mIU/ml. No apparent differences in antibody decline or distribution between the study groups were observed. These results indicate that the removal of preservatives from the hepatitis B vaccine does not affect adversely its immunogenicity both in the short and in the longer term. J. Med. Virol. 81:1710–1715, 2009. © 2009 Wiley‐Liss, Inc.     

国产流行性感冒病毒疫苗免疫原性研究的meta分析

目的 评价国产流行性感冒(简称流感)病毒疫苗的免疫原性.方法 通过文献检索搜集2012年9月前发表的有关国产与进口流感病毒疫苗免疫原性比较研究的文献,利用Stata10.0软件进行meta分析.结果 共有20篇符合标准的文献纳入本研究.结果显示:国产流感病毒疫苗B型抗体阳转率显著高于进口流感病毒疫苗(P=0.036,RR=1.036,95％ CI:1.002～1.070),未发现国产流感病毒疫苗3个亚型的保护率及H1N1和H3N2抗体阳转率与进口流感病毒疫苗存在显著差异(P＞0.05).进一步的亚组分析发现:国产流感全病毒灭活疫苗B型抗体阳转率(P=0.024,RR=1.040,95％CI:1.005～ 1.077)及保护率(P=0.031,RR =1.059,95％CI:1.005～1.116)、H3N2抗体(P=0.019,RR=1.053,95％ CI:1.009 ～1.098)保护率均显著高于进口流感病毒疫苗.结论 国产流感病毒疫苗具有较好的免疫原性.     

Immunologic uniqueness of the genital tract: challenge for vaccine development

Although the genital tract is considered to be a component of the mucosal immune system, it displays several distinct features not shared by other typical mucosal tissues and external secretions. Both male and female genital tract tissues lack inductive mucosal sites analogous to intestinal Peyer's patches. Consequently, local humoral and cellular immune responses stimulated by infections [with e.g. Neisseria gonorrhoeae, Chlamydia trachomatis, papilloma virus, and human immunodeficiency virus (HIV-1)] are weak or absent, and repeated local intravaginal immunizations result in minimal humoral responses. In contrast to typical external secretions such as intestinal fluid that contain secretory immunoglobulin A (S-IgA) as the dominant isotype, semen and cervico-vaginal fluid contain more IgG than IgA. Furthermore, irrespective of the route of infection, humoral immune responses to HIV-1 are dominated by specific IgG and low or absent IgA antibodies in all external secretions. Because a significant proportion of IgG in genital tract secretions is derived from the circulation, systemic immunization may provide protective IgG antibody-mediated immunity in the genital tract. Furthermore, combined systemic and mucosal (oral, rectal, and especially intranasal) immunization may induce protective humoral responses in both the systemic and mucosal compartments of the immune system.     

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.     

Intranasal administration of adjuvant‐combined vaccine protects monkeys from challenge with the highly pathogenic influenza A H5N1 virus

The effectiveness in cynomolgus macaques of intranasal administration of an influenza A H5N1 pre‐pandemic vaccine combined with synthetic double‐stranded RNA (polyI/polyC12U) as an adjuvant was examined. The monkeys were immunized with the adjuvant‐combined vaccine on weeks 0, 3, and 5, and challenged with the homologous virus 2 weeks after the third immunization. After the second immunization, the immunization induced vaccine‐specific salivary IgA and serum IgG antibodies, as detected by ELISA. The serum IgG antibodies present 2 weeks after the third immunization not only had high neutralizing activity against the homologous virus, they also neutralized significantly heterologous influenza A H5N1 viruses. The vaccinated animals were protected completely from the challenge infection with the homologous virus. These results suggest that intranasal immunization with the Double stranded RNA‐combined influenza A H5N1 vaccine induce mucosal IgA and serum IgG antibodies which could protect humans from homologous influenza A H5N1 viruses which have a pandemic potential. J. Med. Virol. 82:1754–1761, 2010. © 2010 Wiley‐Liss, Inc.     

Experimental hookworm infection: a randomized placebo‐controlled trial in asthma

Background Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma. Objectives To determine the effects of experimental hookworm infection in asthma. Methods Thirty‐two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD₂₀AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects. Results Mean PD₂₀AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: ?1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated. Conclusions Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non‐significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken. Cite this as: J. R. Feary, A. J. Venn, K. Mortimer, A. P Brown, D. Hooi, F. H. Falcone, D. I. Pritchard and J. R. Britton, Clinical & Experimental Allergy, 2010 (40) 299– 306.     

Safety and immunogenicity of an alum-adjuvanted whole-virion H7N9 influenza vaccine: a randomized,blinded, clinical trial

ObjectivesA case of H7N9 influenza virus infection was first identified in China in 2013. This virus is considered to have high pandemic potential. Here we developed an H7N9 influenza vaccine containing an aluminium adjuvant and evaluated the safety and immunogenicity of the vaccine.MethodsFrom October 2017 through August 2018 we conducted a randomized, double-blinded, single-centre phase I clinical trial in China among 360 participants aged ≥12 years. All participants received two doses of the vaccine (7.5, 15 or 30 μg haemagglutinin antigen) or placebo at an interval of 21 days. Adverse event data were collected for 30 days after vaccination. Serum samples were collected on days 0, 21 and 42 for the haemagglutinin inhibition (HI) antibody assay.ResultsA total of 347 participants (347/360, 96.4%) completed the study. The proportions of vaccine-related adverse events after one injection were 56.7% (34/60) in the 7.5-μg group, 86.7% (52/60) in the 15-μg group and 86.7% (52/60) in the 30-μg group. The proportions of adverse events after two injections were less than those reported after the first dose. None of the serious adverse events were related to the vaccine. After receiving two doses of the 7.5-μg vaccine, the proportion of participants achieving an HI titre of ≥40 was 98.2% (55/56, 95%CI 72.3~100.0%), with a geometric mean titre (GMT) of 192.6 (95%CI 162.9~227.8).ConclusionsThe alum-adjuvanted H7N9 whole-virion inactivated vaccine was safe and strongly immunogenic in a population aged ≥12 years.     

Improved adjuvanting of seasonal influenza vaccines: Preclinical studies of MVA‐NP+M1 coadministration with inactivated influenza vaccine

Licensed seasonal influenza vaccines induce antibody (Ab) responses against influenza hemagglutinin (HA) that are limited in their ability to protect against different strains of influenza. Cytotoxic T lymphocytes recognizing the conserved internal nucleoprotein (NP) and matrix protein (M1) are capable of mediating a cross‐subtype immune response against influenza. Modified vaccinia Ankara (MVA) virus encoding NP and M1 (MVA‐NP+M1) is designed to boost preexisting T‐cell responses in adults in order to elicit a cross‐protective immune response. We examined the coadministration of HA protein formulations and candidate MVA‐NP+M1 influenza vaccines in murine, avian, and swine models. Ab responses postimmunization were measured by ELISA and pseudotype neutralization assays. Here, we demonstrate that MVA‐NP+M1 can act as an adjuvant enhancing Ab responses to HA while simultaneously inducing potent T‐cell responses to conserved internal Ags. We show that this regimen leads to the induction of cytophilic Ab isotypes that are capable of inhibiting hemagglutination and in the context of H5 exhibit cross‐clade neutralization. The simultaneous induction of T cells and Ab responses has the potential to improve seasonal vaccine performance and could be employed in pandemic situations.     

Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time

Reports of human infections with highly pathogenic H5N1 avian influenza viruses in many countries in Asia and Africa with varying case fatality rates highlight the pandemic potential of these viruses. In order to contain a rapidly spreading influenza virus in a pandemic scenario, a vaccine which can induce rapid and robust immune responses, preferably in a single dose, is necessary. Murine beta-defensin 2 (Mbd2), a small molecular weight protein expressed by epithelial cells, has been shown to enhance antigen-specific immune responses by recruiting and activating professional antigen presenting cells to the site of vaccination. This study assessed the potential of Mbd2 to enhance the immunogenicity and protective efficacy of a human adenovirus (HAd)-based vaccine expressing the hemagglutinin (HA) and nucleoprotein (NP) [HAd-HA–NP] of an H5N1 influenza virus. A single inoculation of mice with both HAd-HA–NP and a HAd vector expressing Murine β-defensin 2 (HAd-Mbd2) resulted in significantly higher levels of both humoral and cell-mediated immune responses compared to the groups vaccinated only with HAd-HA–NP. These responses were evident even at day 7 post-immunization. Furthermore, the HAd-HA–NP + HAd-Mbd2-immunized group receiving the lowest vector dose (2 × 10⁷ + 1 × 10⁷) was completely protected against an rgH5N1 virus challenge on day 7 post-vaccination. These results highlight the potential of Mbd2 as a genetic adjuvant in inducing rapid and robust immune responses to a HAd-based vaccine.     

Evaluation of influenza prevention in the workplace using a personally controlled health record: randomized controlled trial

Background

Personally controlled health records (PCHRs) are accessible over the Internet and allow individuals to maintain and manage a secure copy of their medical data. These records provide a new opportunity to provide customized health recommendations to individuals based on their record content. Health promotion programs using PCHRs can potentially be used in a variety of settings and target a large range of health issues.

Objectives

The aim was to assess the value of a PCHR in an employee health promotion program for improving knowledge, beliefs, and behavior around influenza prevention.

Methods

We evaluated a PCHR-based employee health promotion program using a randomized controlled trial design. Employees at Hewlett Packard work sites who reported reliable Internet access and email use at least once every 2 days were recruited for participation. PCHRs were provided to all participants for survey administration, and tailored, targeted health messages on influenza illness and prevention were delivered to participants in the intervention group. Participants in the control group received messages addressing cardiovascular health and sun protection. The main outcome measure was improvement in knowledge, beliefs, and behavior around influenza prevention. Secondary outcomes were influenza vaccine rates among household members, the impact of cardiovascular health and sun protection messages on the control group, and the usability and utility of the PCHR-based program for employees.

Results

The intervention did not have a statistically significant effect on the influenza knowledge elements we assessed but did impact certain beliefs surrounding influenza. Participants in the intervention group were more likely to believe that the influenza vaccine was effective (OR = 5.6; 95% CI = 1.7-18.5), that there were actions they could take to prevent the flu (OR = 3.2; 95% CI = 1.1-9.2), and that the influenza vaccine was unlikely to cause a severe reaction (OR = 4.4; 95% CI = 1.3-15.3). Immunization rates did not differ between the intervention and control groups. However, participants in the intervention group were more likely to stay home during an infectious respiratory illness compared with participants in the control group (39% [16/41] vs 14% [5/35], respectively; P = .02). The program also succeeded in improving recognition of the signs of heart attack and stroke among participants in the control group. Overall, 78% of participants rated the PCHR as “extremely/very” easy to use, and 73% responded that they would be “extremely/very” likely to participate again in a PCHR-based health promotion system such as this one.

Conclusions

With a small sample size, this study identified a modest impact of a PCHR-based employee health program on influenza prevention and control. Employees found the PCHR acceptable and easy to use, suggesting that it should be explored as a common medium for health promotion in the workplace.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00142077","term_id":"NCT00142077"}}NCT00142077     

Efficacy of oseltamivir compared with zanamivir in COPD patients with seasonal influenza virus infection: a randomized controlled trial

Influenza viruses exacerbate chronic obstructive pulmonary disease (COPD) with considerable morbidity and mortality. Zanamivir and oseltamivir are effective in treating influenza. However, their efficacy in relieving influenza symptoms in COPD patients remains unknown, with the lack of controlled trials in this subject. Therefore, we conducted this randomized controlled trial to investigate the clinical efficacy of both interventions in this population. Patients were allocated to two groups (80 patients each): oseltamivir (OSELTA) and zanamivir (ZANA) groups. Oseltamivir (75 mg) was orally administered twice daily for 5 days, while zanamivir (10 mg) was inhaled twice daily for 5 days. Clinical parameters including body temperature, influenza symptoms (i.e., sore throat, cough, etc.), and serial blood tests were recorded on days 1, 3, and 7. We analyzed primary (changes in body temperature) and secondary outcomes (changes in non-specific symptoms) using the pre-protocol and intention-to-treat analyses. Differences between groups were assessed using t-test. Oseltamivir and zanamivir significantly reduced body temperature on the 3rd day after treatment; however, the number of patients who reported clinical improvement in influenza-like symptoms was significantly higher in the OSELTA group compared to the ZANA group on days 3 (85 vs 68.8%, P=0.015) and 7 (97.5 vs 83.8%, P=0.003). However, no significant changes in hematological (white blood cells and its subtypes) and inflammatory (C-reactive protein) parameters were noted (P>0.05). Our results suggested that oseltamivir and zanamivir are effective in reducing body temperature, while oseltamivir led to better clinical improvement regarding influenza-like symptoms in patients with COPD.     

A randomized,double‐blind,placebo‐controlled,dose‐finding trial with Lolium perenne peptide immunotherapy

Background

A novel subcutaneous allergen immunotherapy formulation (gpASIT+?) containing Lolium perenne peptides (LPP) and having a short up‐dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety.

Methods

This prospective, double‐blind, placebo‐controlled, phase IIb, parallel, four‐arm, dose‐finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment.

Results

Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per‐protocol set). Also, 39% of patients in the 170‐μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen‐binding assays revealed a highly significant (P < .001) dose‐dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG₄ levels increased to 1.6‐fold (70 μg), 3.1‐fold (170 μg) and 3.9‐fold (370 μg) (mPP).

Conclusion

Three‐week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.

     

Effects of short‐term sitagliptin treatment on immune parameters in healthy individuals,a randomized placebo‐controlled study

Sitagliptin, a dipeptidyl‐peptidase 4 (DPP‐4) inhibitor, improves blood glucose control in patients with type 2 diabetes by blocking cleavage of glucagon‐like peptide 1 (GLP‐1). In type 2 diabetes patients sitagliptin use is associated with an increase in minor infections, and in new‐onset type 1 diabetes patients the ability of sitagliptin to dampen autoimmunity is currently being tested. DPP‐4, also known as CD26, is expressed on leucocytes and can inactivate many chemokines important for leucocyte migration, as well as act as a co‐stimulatory molecule on T cells. Therefore, this study was conducted to test whether sitagliptin is immunomodulatory. In this randomized, placebo‐controlled trial, healthy volunteers were given sitagliptin or placebo daily for 28 days, and blood was drawn for immune assays. No significant differences were observed in the percentage of leucocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide (LPS) or anti‐CD3. Individuals taking sitagliptin displayed increases in the percentage of cells expressing higher levels of CD26 at early time‐points compared to placebo controls, but these differences resolved by day 28 of treatment. Therefore, in healthy volunteers, treatment with sitagliptin daily for 28 days does not overtly alter systemic immune function.     

Abundance and specificity of influenza reactive circulating memory follicular helper and non‐follicular helper CD4 T cells in healthy adults

CD4 T‐cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B‐cell production of isotype‐switched, high‐affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5, a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein (NP) or haemagglutinin (HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history.