Influenza

The `weekly returns' system for the reporting of infectious and communicable diseases to the Birmingham Research Unit of the Royal College of General Practitioners is described. A detailed analysis of the influenza returns for the winter epidemic of 1975/76 is presented and compared with similar data from the previous ten-year period.

This analysis allows the following generalizations to be made which can, to a limited extent, be used as broad guidelines for predictions.

In any week in which a rate of 20 or more reports per 100,000 population is followed by a week in which there is a trebling of the rate, a major epidemic is imminent in which a peak rate of 500 cases per 100,000 population can be expected within three to four weeks.

In any week other than a week referred to previously in which a rate of 30 cases or more per 100,000 population is followed by a doubling of the rate, a moderate epidemic is imminent and peak rates in the range 150 to 500 per 100,000 population will be reached within three to four weeks.

The earlier in the critical period just before and just after Christmas that either of these changes are noted, the earlier and larger the peak is likely to be. Where neither of these thresholds is crossed, the peak rate for reported influenza is unlikely to exceed 150 cases per 100,000 people.

     

Adjuvanted Influenza Vaccine

black triangle Adjuvanted influenza vaccine is composed of 2 type A and 1 type B inactivated influenza subunits combined with an oil-and-water emulsion (MF59). Each dose contains 15microg haemagglutinin per strain. black triangle Adjuvanted influenza vaccine was immunogenic in elderly vaccinees and in younger adults after 1 to 3 consecutive annual injections. black triangle According to studies available to date, the adjuvanted vaccine was more immunogenic than the nonadjuvanted subunit or split virus vaccines and the virosomal vaccine for 1 to 3 of the 3 strains tested per injection. black triangle The immunogenic effect generally persisted for longer after the adjuvanted vaccine than the nonadjuvanted subunit vaccine in elderly recipients. black triangle The adjuvanted vaccine also appeared to be more effective than the nonadjuvanted subunit vaccine against antigenically different heterovariant strains in elderly vaccinees. black triangle The 28-day seroprotection rate in 4 studies was significantly greater after the adjuvanted vaccine for 1 or 2 of the 3 strains tested compared with the nonadjuvanted subunit vaccine and the virosomal vaccine and for 1 of 3 strains compared with the split virus vaccine. black triangle The incidence of systemic adverse events was generally low. Local reactions such as pain, erythema and induration occurred more frequently with the adjuvanted than the 2 nonadjuvanted or the virosomal vaccines; however, these were mild and transient.     

Liposomal Influenza Vaccine

black triangle This trivalent liposomal influenza vaccine consists of purified influenza haemagglutinin inserted into a membrane of phosphatidylcholine and phosphatidylethanolamine. It contains 15microg of haemagglutinin per viral strain per dose. black triangle The vaccine is immunogenic in the elderly, in younger adults and in children and adolescents with or without cystic fibrosis. black triangle Seroconversion rates were significantly higher with the liposomal vaccine than with a subunit vaccine for 3 of 3 and 2 of 3 strains in 2 published studies. Seroconversion occurred in a significantly greater number of participants receiving the liposomal vaccine than in those receiving a whole virus vaccine for all 3 strains in 1 study. black triangle Seroprotection rates were significantly better with the liposomal vaccine than with a subunit vaccine for 2 of 3 and 1 of 3 strains in 2 trials, and greater than with a whole virus vaccine for 2 of 3 strains in 1 trial. black triangle In a study in children with cystic fibrosis, a single dose of the liposomal vaccine was reported to have greater immunogenicity than 2 half doses (statistical analysis not performed). black triangle Local adverse reactions such as pain at the injection site, local induration, redness and swelling are transient and usually mild. black triangle Liposomal influenza vaccine did not induce a mean antiphospholipid antibody response in elderly volunteers.     

Influenza vaccine immunology

Studying the spread of influenza in human populations and protection by influenza vaccines provides important insights into immunity against influenza. The 2009 H1N1 pandemic has taught the most recent lessons. Neutralizing and receptor-blocking antibodies against hemagglutinin are the primary means of protection from the spread of pandemic and seasonal strains. Anti-neuraminidase antibodies seem to play a secondary role. More broadly cross-reactive forms of immunity may lessen disease severity but are insufficient to prevent epidemic spread. Priming by prior exposure to related influenza strains through infection or immunization permits rapid, potent antibody responses to immunization. Priming is of greater importance to the design of immunization strategies than the immunologically fascinating phenomenon of dominant recall responses to previously encountered strains (original antigenic sin). Comparisons between non-adjuvanted inactivated vaccines and live attenuated vaccines demonstrate that both can protect, with some advantage of live attenuated vaccines in children and some advantage of inactivated vaccines in those with multiple prior exposures to influenza antigens. The addition of oil-in-water emulsion adjuvants to inactivated vaccines provides enhanced functional antibody titers, greater breadth of antibody cross-reactivity, and antigen dose sparing. The MF59 adjuvant broadens the distribution of B-cell epitopes recognized on HA and NA following immunization.     

流感大流行期间疫苗免疫方案的传染病模型

目的模拟流感大流行期间疫苗免疫方案控制疫情的效果,对比两种疫苗免疫方案的效果差异,为制订应急方案提供数据参考。方法基于传染病的自然规律,在传统SEIR模型的基础上建立对人群免疫的传染病模型,采用感染率（AR）作为判断指标,对全人群免疫和部分人群免疫（排除康复人群）两种免疫方案进行效果对比。结果对于R0在2左右的流感大流行,感染者均表现临床症状的情况下,随着疫苗延迟时间（TL）和完成时间（DV）的缩短,感染率下降。当控制目标设定为将感染率控制在50%以下时,采用全人群免疫方案的最大TL和DV组合为40和30 d;采用部分人群免疫方案的最大TL和DV组合为两者均为40 d,或两种方案的TL和DV最大组合均为30和80 d。如果不能在短期内开展和完成疫苗计划（TL在30 d内,DV为20 d内）,则部分人群免疫方案可以更快地降低感染率。结论为最大程度地减少大流行期间的生命损失,将感染率控制在50%以下,防病重点应为尽早开展和完成疫苗计划,如果TL在30 d以上,则部分人群的免疫方案更有利于疫情的控制。     

Influenza Vaccination and Asthma

Influenza is an important epidemic and pandemic illness associated with serious morbidity and mortality in unprotected communities. Patients at increased risk of infection are those with pre-existing cardiopulmonary disease including asthma. The influenza virus has the ability to produce antigenic changes posing problems for vaccine development. Influenza vaccines have been available for over 50 years. Despite the continuing global threat posed by infection and recommendations in many countries that immunisation should be widely given, uptake rates are variable and often poor. It has been demonstrated that infection with influenza and other respiratory viral pathogens can produce exacerbations of asthma throughout the age groups. Despite this, vaccine uptake rates in asthmatic populations are quite low. Poor uptake rates are attributed to a number of factors and we review the evidence for the widely held view that influenza vaccination produces exacerbations of chronic airflow obstruction including asthma. Observational studies have found conflicting results: some post immunisation changes in bronchial hyperreactivity and increased requirements of bronchodilator therapy have been in some, but not all, studies. Placebo-controlled trials have not demonstrated any clinical deterioration although one study showed a small reduction in peak expiratory flow rate. Intranasal administration of cold-adapted live vaccines and new nucleic acid vaccines are briefly considered. Live adapted vaccines have been shown to be effective in influenza immunoprophylaxis and limited data on their use in patients with asthma suggest that they can be administered safely. In conclusion, based up on current studies and evidence, it seems likely that influenza infection produces morbidity in patients with asthma but that any potential adverse effects of influenza immunisation are outweighed by the benefits in this population. However, placebo-controlled trials are few and only small numbers of asthmatic patients have been investigated.     

Influenza vaccination in the elderly

Influenza vaccination of elderly people has been shown to be useful. All vaccine types are well tolerated by higher age group vaccinees. Actually, whole virus vaccine, split virus vaccine and subunit vaccine are used in the vaccination of the elderly. Some studies have suggested that the induction of serum influenza antibody production was reduced in elderly persons when compared with that elicited in younger persons. However, investigations on the protective efficacy of influenza vaccination in the elderly have demonstrated a clinical protection of 50% for preventing hospitalization.

Live attenuated influenza vaccine conferred protection similar to that obtained with a conventional subunit vaccine. A virosomal unilamellar trivalent hemagglutinin vaccine showed promising serological results compared with those obtained with a whole cell vaccine and with a subunit vaccine, respectively. The actual policy is to vaccinate persons 65 years of age and the groups that can transmit influenza to them. Each year's vaccine should contain three virus strains representing the influenza viruses that are likely to circulate in the upcoming winter.     

Influenza and HIV: Lessons from the 2009 H1N1 Influenza Pandemic

Influenza is a common respiratory disease in adults, including those infected with HIV. In the spring of 2009, a pandemic influenza A (H1N1) virus (pH1N1) emerged. In this article, we review the existing literature regarding pH1N1 virus infection in HIV-infected adults, which suggests that susceptibility to pH1N1 virus infection and severity of influenza illness are likely not increased in HIV-infected adults without advanced immunosuppression or comorbid conditions. The risk of influenza-related complications, however, may be increased in those with advanced immunosuppression or high-risk comorbid conditions. Prevention and treatment of high-risk comorbid conditions and annual influenza vaccination should continue to be part of HIV clinical care to help prevent influenza illness and complications. Additional information about pH1N1 vaccine immunogenicity and efficacy in HIV-infected patients would be useful to guide strategies to prevent influenza virus infection in this population.     

Influenza vaccination for older adults

Influenza vaccines were developed in the 1930s and were shown in randomized clinical trials to prevent influenza in young healthy adults. The significant morbidity and mortality associated with influenza in adults, age 65 y and older, prompted the early recommendation for influenza vaccination in that age group, based on efficacy data in younger adults. Subsequently a number of studies have demonstrated vaccine effectiveness in older adults, but it appears to be lower than in younger adults. New vaccines are being developed with enhanced immunogenicity to improve the protection of older adults. In the meantime, the currently licensed influenza vaccines need to be administered annually to prevent the estimated 90,000 hospitalizations and 5,000 deaths attributed to influenza in adults ≥65 y of age each year.     

Isolation of Influenza C Virus during an Outbreak of Influenza A and B Viruses

During the winter of 1996 to 1997 two cases of influenza C were confirmed, one by isolation and the second by serology (fourfold increase in hemagglutination inhibition antibodies). The cases of influenza C occurred during an outbreak of influenza A (H₃N₂) and B viruses. The positive isolation was from one of three throat washings sent to the laboratory, and the other case was from a group of 51 students participating in a study of influenza virus vaccination. It seems, therefore, that influenza C virus should also be considered when examining patients with respiratory infections during the influenza season.     

Influenza, autoimmunity and atherogenesis

It has been observed during influenza epidemics and in a number of population and clinical trials that this prevalent viral infection was associated with increased death rates from cardiovascular diseases. The clinical and experimental data that may explain accelerated coronary atherosclerosis in influenza infection with implications involving autoimmune mechanisms are reviewed in this article. Both cellular and humoral autoimmune mode could be proposed to participate in the onset or progression of atheromatous lesions due to influenza infection.     

The Association between Influenza Treatment and Hospitalization-Associated Outcomes among Korean Children with Laboratory-Confirmed Influenza

There are limited data evaluating the relationship between influenza treatment and hospitalization duration. Our purpose assessed the association between different treatments and hospital stay among Korean pediatric influenza patients. Total 770 children ≤ 15 yr-of-age hospitalized with community-acquired laboratory-confirmed influenza at three large urban tertiary care hospitals were identified through a retrospective medical chart review. Demographic, clinical, and cost data were extracted and a multivariable linear regression model was used to assess the associations between influenza treatment types and hospital stay. Overall, there were 81% of the patients hospitalized with laboratory-confirmed influenza who received antibiotic monotherapy whereas only 4% of the patients received oseltamivir monotherapy. The mean treatment-related charges for hospitalizations treated with antibiotics, alone or with oseltamivir, were significantly higher than those treated with oseltamivir-only (P < 0.001). Influenza patients treated with antibiotics-only and antibiotics/oseltamivir combination therapy showed 44.9% and 28.2%, respectively, longer duration of hospitalization compared to those treated with oseltamivir-only. Patients treated with antibiotics, alone or combined with oseltamivir, were associated with longer hospitalization and significantly higher medical charges, compared to patients treated with oseltamivir alone. In Korea, there is a need for more judicious use of antibiotics, appropriate use of influenza rapid testing.

Graphical Abstract

相似文献   

Perimyokarditis bei Influenza A Virus-Infektion

Summary A 48-year old man was admitted with suspected acute myocardial infarction because of severe precordial pain and monophasic ST-elevations in the ECG. The patient's history of an ongoing infection, the localization, extent, and course of the ECG changes as well as the development of a pericardial effusion suggested viral perimyocarditis. The diagnosis was supported by a significant rise of antibodies (seroconversion) against influenza A virus.

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Abkürzungsverzeichnis BSG Blutsenkunsgeschwindigkeit - CK Creatin-Kinase - EKG Elektrokardiogramm - ASAT Asparagin-Amino-Transferase - GOT Glutamat-Oxalacetat-Transaminase - ALAT Alanin-Amino-Transferase - GPT Glutamat-Pyruvat-Transaminase     

Influenza viral messenger RNA

Influenza viral messenger RNA (mRNA) free from both ribosomal RNA and newly synthesized host mRNA was isolated from the polyribosomes of infected canine kidney cells. Cordycepin was added to infected cells to inhibit ribosomal RNA and host mRNA synthesis. To separate viral mRNA from the small amount of ribosomal RNA which continued to be synthesized in the presence of cordycepin, polyribosomes were dissociated with puromycin and high salt: the viral mRNA was released to sediment 8–22 S, thus separable from the ribosomal RNA which was quantitatively retained in the 60 S and 40 S ribosomal subunits.Viral mRNA was rendered 100% ribonuclease-resistant after annealing to virion RNA (vRNA) and is, therefore, totally complementary to vRNA. This complementary RNA (cRNA) contains polyadenylate (polyA) segments which are heterogeneous in length, ranging from 50 to 200 nucleotides. In contrast to cRNA, vRNA does not contain polyA.     

High Titer and Avidity of Nonneutralizing Antibodies against Influenza Vaccine Antigen Are Associated with Severe Influenza

The importance of neutralizing antibody in protection against influenza virus is well established, but the role of the early antibody response during the initial stage of infection in affecting the severity of disease is unknown. The 2009 influenza pandemic provided a unique opportunity for study because most patients lacked preexisting neutralizing antibody. In this study, we compared the antibody responses of 52 patients with severe or mild disease, using sera collected at admission. A microneutralization (MN) assay was used to detect neutralizing antibody. We also developed an enzyme-linked immunosorbent assay (ELISA) which detects both neutralizing and nonneutralizing antibodies against viral antigens from a split-virion inactivated monovalent influenza virus vaccine. While the MN titers were not significantly different between the two groups (P = 0.764), the ELISA titer and ELISA/MN titer ratio were significantly higher for patients with severe disease than for those with mild disease (P = 0.004 and P = 0.011, respectively). This finding suggested that in patients with severe disease, a larger proportion of serum antibodies were antibodies with no detectable neutralizing activity. The antibody avidity was also significantly higher in patients with severe disease than in those with mild disease (P < 0.05). Among patients with severe disease, those who required positive pressure ventilation (PPV) had significantly higher ELISA titers than those who did not require PPV (P < 0.05). Multivariate analysis showed that the ELISA titer and antibody avidity were independently associated with severe disease. Higher titers of nonneutralizing antibody with higher avidity at the early stage of influenza virus infection may be associated with worse clinical severity and poorer outcomes.     

Intranasal Administration of Influenza Vaccines

AbstractThis review article focuses on intranasal immunisation against influenza,although it also encompasses antigen uptake and processing in the nasopharyngealpassages, host defence from influenza and current influenza vaccination practices.Improvement of current vaccination strategies is clearly required; current proceduresinvolve repeated annual injections that sometimes fail to protect the recipient. It isenvisaged that nonpercutaneous immunisation would be more attractive to potentialvaccinees, thus improving uptake and coverage. As well as satisfying noninvasivecriteria, intranasal influenza immunisation has a number of perceived immunologicaladvantages over current procedures. Perhaps one of the greatest attributes of thisapproach is its potential to evoke the secretion of haemagglutinin-specific IgAantibodies in the upper respiratory tract, the main site of viral infection. Inactivated influenza vaccines have the advantage that they have a long historyof good tolerability as injected immunogens, and in this respect are possibly morelikely to be licensed than attenuated viruses. Inert influenza vaccines are poormucosal immunogens, requiring several administrations, or prior immunologicalpriming, in order to engender significant antibody responses. The use of vaccinedelivery systems or mucosal adjuvants serves to appreciably improve theimmunogenicity of mucosally applied inactivated influenza vaccines. As is the casewhen they are introduced parenterally, inactivated influenza vaccines are relativelypoor stimulators of virus-specific cytotoxic T lymphocyte activity following nasalinoculation. Live attenuated intranasal influenza vaccines are at a far moreadvanced stage of clinical readiness (phase III versus phase I). With the use of liveattenuated vaccines, it is possible to stimulate mucosal and cell-mediatedimmunological responses of a similar kind to those elicited by natural influenzainfection. In children, recombinant live attenuated cold-adapted influenza viruses arewell tolerated. Moreover, cold-adapted influenza viruses usually stimulate protectiveimmunity following only a single nasal inoculation. Safety of recombinant liveattenuated cold-adapted influenza viruses has also been demonstrated in high riskindividuals with cystic fibrosis, asthma, cardiovascular disease and diabetes mellitus.They are not suitable for immunising immunocompromised patients, however, andare poorly efficacious in individuals with pre-existing immunity to strains closelyantigenically matched with the recombinant virus. According to the reviewedliterature, it is apparent that intranasal administration of vaccine as an aerosol issuperior to administration as nose drops. The information reviewed in this papersuggests that nasally administered influenza vaccines could make a substantialimpact on the human and economic cost of influenza.     

IgA Deficiency and Influenza Infection

A prospective study of influenza infection was carried out on 90 blood donors deficient for serum IgA as tested with double immunodiffusion. Half of them lacked IgA even by radioimmunoassay (RIA). A correlation existed between serum haemagglutination-inhibiting (HI) antibody and resistance to infection, suggesting that the serum HI antibody was an important determinant of protection. The rate of infection as evidenced by a fourfold or greater rise in HI titre, was about the same in the RIA-negative and RIA-positive donors and only slightly higher than the corresponding rate in pregnant women and in a ship's crew.     

Influenza virus and CNS manifestations.

Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. An increasing incidence of influenza-associated encephalitis/encephalopathy has been reported in Japan, mainly in children. A variety of other clinical CNS manifestations, such as Reye's syndrome, acute necrotising encephalopathy (ANE), and myelitis as well as autoimmune conditions, such as Guillain-Barre's syndrome, may occur during the course of influenza infection. Virological diagnosis is essential and based on virus isolation, antigen detection, RNA detection by PCR, and serological analyses. Neuroimaging with CT and MRI of the brain are of prognostic value. The pathogenic mechanisms behind the influenza CNS complications are unknown. The treatment is symptomatic, with control of vital functions in the intensive care unit, antiepileptic medication and treatment against brain oedema.     

Traditional and New Influenza Vaccines

SUMMARY

The challenges in successful vaccination against influenza using conventional approaches lie in their variable efficacy in different age populations, the antigenic variability of the circulating virus, and the production and manufacturing limitations to ensure safe, timely, and adequate supply of vaccine. The conventional influenza vaccine platform is based on stimulating immunity against the major neutralizing antibody target, hemagglutinin (HA), by virus attenuation or inactivation. Improvements to this conventional system have focused primarily on improving production and immunogenicity. Cell culture, reverse genetics, and baculovirus expression technology allow for safe and scalable production, while adjuvants, dose variation, and alternate routes of delivery aim to improve vaccine immunogenicity. Fundamentally different approaches that are currently under development hope to signal new generations of influenza vaccines. Such approaches target nonvariable regions of antigenic proteins, with the idea of stimulating cross-protective antibodies and thus creating a “universal” influenza vaccine. While such approaches have obvious benefits, there are many hurdles yet to clear. Here, we discuss the process and challenges of the current influenza vaccine platform as well as new approaches that are being investigated based on the same antigenic target and newer technologies based on different antigenic targets.     

Response of Influenza Vaccines Against Heterovariant Influenza Virus Strains in Adults with Chronic Diseases

The ability of influenza vaccination to provide cross-protection against heterovariant influenza strains was evaluated in a double-blind, randomized, trial in north-east Italy during the winter of 2005-2006. Of 238 adult subjects with underlying chronic diseases, 120 received MF59-adjuvanted subunit vaccine (Sub/MF59) and 118 received a conventional subunit vaccine (Subunit). Immunogenicity was measured for A/H3N2 and B influenza strains against both the homologous vaccine strains (A/New York/55/2004 and B/Jiangsu/10/2003), and the heterovariant strains recommended for the 2006-2007 season (A/Wisconsin/67/2005 and B/Malaysia/2506/2004). Although both vaccines conferred serological protection against the homologous vaccine strains and the 2006-2007 heterovariant A/H3N2 strain for a majority of subjects, the antibody response was highest in the Sub/MF59 vaccine group. For example, MF59-adjuvanted vaccination conferred significantly greater (P = 0.002) protection against the heterovariant A/H3N2 strain than the conventional subunit vaccine (79.2% vs. 61.0% of subjects, respectively). In conclusion, these results demonstrate that protection provided by influenza vaccination in adults affected by chronic diseases is lower against heterovariant strains than for homologous strains. However, addition of MF59 adjuvant to a subunit vaccine enhances immunogenicity against the A/H3N2 heterovariant strain, conferring broader protection than a conventional subunit vaccine in this population, who are at higher risk of influenza-related complications.