RNA viruses with a segmented genome, hence prone to mutation. The WHO's system of nomenclature for flu viruses was updated in 2011. Seasonal 'flu occurs owing to minor mutations, pandemic 'flu (ie affecting more than one continent) occurs as a result of more major mutations and tends to cause more burden upon the population as it affects the young and middle aged more. Spanish 'flu in 1918 caused 20-50 million deaths worldwide.
The most significant surface molecules are the haemagglutinin and neuraminidase proteins. The former latch on to host cells in the process of infection, the latter cleave bonds after exocytosis of daughter virus particles, releasing them from the parent.
Immunisation and drugs against influenza are directed against these two molecules, and the classification of different strains depends on them.
While there are just 2 types of neuraminidase, the appearance of a new haemagglutinin strain is usually associated with a pandemic eg Spanish 'flu (1918, H1N1), Asian 'flu (1957, H2N2), Hong Kong 'flu (1968, H3N2). Hence the appearance and continued spread of avian H5N1 will almost certainly result in another pandemic in due course even if Swine flu (2009, A(H1N1)pmd09) is first in the 21st century.
Seasonal influenza has direct and indirect mortality impacts across the world. There is very good evidence that at a population level influenza vaccination has been very effective at mitigating these effects.
AetiologyInfluenza virus is a negative-strand RNA virus transmitted by droplets and fomites.
The incubation period is relatively short, just 1-3 days, but does vary. Onset of illness is sudden, with fever and prostration. Every muscle aches. Initial infection, and signs, are respiratory. Headache and gastrointestinal upset are common. Benign myositis (with raised muscle enzymes eg creatine kinase) especially affecting the calves is seen in type B infection.
Children under 2 have the highest risk for complications and/or hospitalization, although morbidity and mortality is also very high in the institutionalised elderly.
Complications of influenza
Severe complications are primary influenza pneumonia, staphylococcal or pneumococcal pneumonia pneumonia, invasive bacterial sepsis, encephalopathy, myocarditis. There is also a consistent association with myocardial infarction in those over 65 and stroke in those over 75. This risk is confined to the week after the infection and is also found with other viral respiratory tract viruses, although most if not all have lower risk. Influenza B seems to have the highest risk of cardiovascular complications. There is evidence that immunity to bacterial pathogens eg haemophilus, staphylococcus, pneumococcus is reduced.
Meningoencephalitis can occur, as can necrotizing encephalopathy (characterized by normal CSF and negative PCR). The latter is rare over 10 yrs of age - MRI shows bilateral high intensity T2 signals in thalamus, brainstem and cerebellum.
There is evidence that some complications such as Guillain-Barre syndrome or narcolepsy are caused by shared epitopes in strains of the virus (including those used in immunisation) activating autoimmunity such as expression of CD4+ T cell clones.
Death from influenza
Death occurs rapidly in 50% of fatal cases (underlying disease common, but not essential). Death may be owing to influenza per se, or (often) to complications such as bacterial superinfections.
In a pandemic deaths are likely to occur in young people, whereas in other years old age or lowered resistance is more usually associated with death. With improved management of bacterial co-infection, historical mortality rates may not be valid. The death rate does vary depending on the viruses individual characteristics and other issues such as hygiene practices. The total population death burden can be modelled for influenza.
See also immunology and Influenza
EpidemiologyThe burden of influenza has been shown to be underestimated due to the large number of asymptomatic infections and imperfect case ascertainment. Further influenza burden also is reflected in morbidity due to myocardial infarction, stroke and other complications not just symptomatic infection. During the 2015 southern hemisphere flu season a study in Auckland New Zealand attempted to qualify this in a large city. At the peak the virus type distribution was approximately half type B and half type A with one of subtyped strains of A, A(H3N2) predominating and there had been a fair vaccine match. For every death, 4.6 were admitted to ITU, 120 were hospitalised, 2000 visited their GP, 16,000 became sick with symptoms and 45,000 were infected with no noticeable symptoms (ie they seroconverted) .
Early 2015 Northern Hemisphere influenza activity peaked in North America the last week of December, Eastern Asia by mid January and Europe by mid February. This was associated with the largest excess mortality in those over 65 for 4 years. A similar picture is expected in 2018 with peaks in the whole USA, UK and France early January but with other countries likely to have a lag. Active strains can include relatively vaccine resistant claides but this issue tends to be overplayed. Similar issues arise with the drugs available to treat early infection and neuraminidase inhibitor sensitive influenza A(H3N2), A(H1N1)pdm09 and B is still the rule, allowing effective mitigation in subgroups of presentations. In Southern Hemisphere winter 2017 the active strains there and in Asia were again influenza A(H3N2) and some B and A(H1N1)pdm09. The later in India was reported to have killed thousands. The Northern Hemisphere winter 2018 outbreak was probably dominated in terms of morbidity by the B strains of the earlier Southern Hemisphere outbreak. While in 2017 Avian influenza outbreaks have not caused significant human disease, with most deaths being due to avian influenza A(H7N9) virus in China, such outbreaks can be locally very virulent as with the Egyptian outbreak of avian influenza A(H5N1) in December 2014 which had the most human cases ever reported in one month.
Morbidity also reflects secondary infection and individual characteristics. For example the elderly are most susceptible to secondary consequences such as myocardial infarction and stroke.
|Detection probability||95% CI|
|Proportion infections asymptomatic||65%||55-74%|
Surveillance of influenza
The WHO and ECDC relate to national organs such as the Health Protection Agency's Centre for Infections which collaborates with others including the Royal College of General Practitioners' Birmingham-based research unit to monitor laboratory reports of influenza, and clinical reports of influenza-like-illness (ILI), and thus identify when influenza is circulating in the community. (This is a form of public health surveillance.)
Decisions about when influenza levels exceed the level at which antiviral treatments may be used in the NHS for the prevention or treatment of influenza are made by government ministers, based - at least in part - on advice from the HPA.
An indirect but suggestive measure of significant influenza is weekly death rate data. In the case of European weekly mortality initial data from a few countries can be suggestive of the seasonal outbreak that follows. Such data also suggests the variation, due to vaccination rates and other factors in herd immunity. Seasonal influenza epidemiology in the Southern Hemisphere can be relevant to the epidemiology 6 months later in the Northern Hemisphere. International comparisons can also be very suggestive as to the most effective public health strategies for vaccination and where the design of the social/health care system might be impairing effective vaccine delivery.
Links to surveillance reports
- WHO influenza reports
- EU weekly influenza reports
- UK weekly influenza reports
- USA weekly influenza reports
- Canada weekly influenza reports
- Hong Kong weekly influenza reports
- Singapore weekly infectious disease reports
- Australia weekly influenza reports
- New Zealand weekly influenza reports
Mutation of the influenza virus
The influenza virus changes and evolves through two main mechanisms: "drift", and "shift". (New research has recently challenged previous understanding of this.) Influenza B has neuraminidase but not haemagglutinin, therefore fewer antigen changes occur than with 'Flu A and most adults are fully or partially immune each year.
As a consequence of this antigenic "drift", different vaccines are recommended by the World Health Organisation each year.
Influenza viruses can infect a wide range of animal hosts. For the most part, viruses only infect a single species (or group of closely related species). Occasionally, however, viruses can cross from one species to another.
In some cases viruses will cause disease in one species, but can infect another without causing any symptoms.
Poultry, pigs, and horses have all been associated with strains of influenza virus that have infected humans.
If an animal is infected with two different strains of influenza virus simultaneously, it is possible for the viral nucleic acids to produce proteins for both strains in the same cell, and for the proteins to reassemble, creating a novel influenza virus with features of both the parent strains. This may be quite dramatically different from previous viruses, with different antigenicity, virulence, and pathogenicity in humans.
Sometimes a third host is thought the most likely context for reassortment - for example, it is thought that strains of influenza virus that usually infect poultry and humans might undergo reassortment in pigs.
Reassortment of this kind is thought to be most likely to happen when different species live in very close contact with each other.
When a pandemic emerges, the pattern of disease in the population is quite different from that of seasonal 'flu. Because of the lack of immunity, it will tend to attack all population groups equally. It may not begin in winter time. A pandemic typically occurs in waves, with a 15 week interval , achieving a cumulative attack rate of 25%. There are, however, great variations in age affected, and in severity. Clinically there can be variation eg Asian 'flu was characterized by a high incidence of diarrhoea, beginning up to a week before respiratory symptoms appeared. It also had a longer than average incubation period. 1 in 200 hospitalized is a reasonable estimate. See also pandemic references and pandemic influenza articles.
This can be very accurately modelled in terms of epidemiological ascertainment and resulting disease burden. Most of the rest of this article refers to seasonal 'flu as selective vaccination has proved to be a very effective public health measure in reducing the impact on population mortality and health services.
- Virus can be found by culture or PCR in the upper airway.
- Retrospective serological diagnosis is possible.
Not routinely applicable. Appropriate on occasion if clinically indicated (for example if viral pneumonia suspected).
The use of neuraminidase inhibitors is strictly regulated in the UK, under Schedule 2 of the National Health Service (General Medical Services Contracts) (Prescription of Drugs etc.) (Amendment) Regulations 2004, which came into force on 3rd January 2005. In England, prescribing of these drugs in primary care is now formally restricted to those circumstances and those at-risk patient groups specified by NICE (chronic lung/cardiac/renal disease, immunodeficiency). Treatment should be initiated within 48 hours of onset. It has been shown in pregnant women during the 2009 pandemic that treatment upon symptoms without awaiting serology reduced mortality. Schedule 2 also enables GPs in England to write private prescriptions for prophylactic oseltamivir for their patients who have been in close contact with an influenza sufferer when influenza is circulating at sufficiently high levels, even though they are not in the ‘at-risk’ groups specified by NICE, in accordance with the product licence. Post-exposure prophylaxis is for 10 days. Amantadine is not recommended for this purpose.
- Flu treatment - zanamivir (review), amantadine and oseltamivir (No. 58)
- Full Guidance on the the use of zanamivir, oseltamivir and amantadine for the treatment of influenza
- Flu prevention - amantadine and oseltamivir (No. 67)
HPA page on the use of anvirals in the treatment of seasonal influenza, which has links to detailed guidance and flowcharts.
Not routinely applicable.
The NICE recommendations referred to in the Treatment section also cover the use of antiviral chemoprophylaxis in certain settings.
NB - while treatment of people who have influenza with antivirals is useful, but of relatively limited value, chemoprophylaxis not only reduces infection rates and complication rates in people who receive it, but also dramatically reduces the quantity and duration of viral shedding in people who may be incubating the disease - which makes them far less infectious (if at all) to others, and can have a dramatic effect of the spread of the infection in a community such as a nursing home.
Advance recommendations for vaccination
These are made about 8 months in advance so can not be perfect due to the time lag in vaccine production. The last time there was a significant miss was 2015, and this resulted in morbidity and mortality that emphasised how important vaccination is as a public health measure most of the time. WHO recommended that influenza vaccines for use in the 2017-2018 northern hemisphere influenza season contain the following viruses :
- an A/Michigan/45/2015 (H1N1)pdm09-like virus
- an A/Hong Kong/4801/2014 (H3N2)-like virus
- a B/Brisbane/60/2008-like virus.
There may be national level recommendations to fine tune this and with the increasing range of vaccines with differential population effectiveness in terms of say age (eg children as opposed to the elderly), these are common.
Preventing influenza is worth-while if it prevents hospitalisation, deaths, and illness - especially complications of pneumonia, which may be responsible for much of the seasonal mortality. Vaccination against influenza can be effective in preventing illness and complications, and is offered to people at higher risk, including old people - although there is some evidence that the vaccine may be less effective in older people, and that alternative strategies such as immunising their contacts and carers might be more effective.
Simple measures such as hand washing and avoiding unnecessary social contact are very effective.
Vaccination against influenza
About influenza vaccines
Flu strains covered by the vaccine
Because there is constant change to the circulating influenza strains, the flu vaccine has to be changed each year, to ensure the best possible "match" between the vaccine and circulating strains.
Flu vaccines generally contain antigens from three ("trivalent") or (four "tetra-" or "quadrivalent") strains of the flu virus: each has two influenza A strains; with one or two B strains in the tri- and quadrivalent vaccines. Adjuvants may be added and different production methods are possible.
The WHO makes recommendations for the composition if the vaccines each year, based on surveillance of strains circulating (and remember that influenza is seasonal, with most cases happening in winter; and that the Southern Hemisphere winter happens in the May to September, in contrast to the Northern Hemisphere winter). For example the WHO states: It is recommended that trivalent vaccines for use in the 2017-2018 northern hemisphere influenza season contain the following:
- "an A/Michigan/45/2015 (H1N1)pdm09-like virus;
- "an A/Hong Kong/4801/2014 (H3N2)-like virus; and a B/Brisbane/60/2008-like virus.
"It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Phuket/3073/2013-like virus."
Note that live attenuated influenza vaccine (LAIV) routinely offered to children is a quadrivalent vaccine.
During the 2017-18 there were a higher than usual number of flu B cases; and a high proportion of these were B(Yamagata) lineage strains. There is some cross-protection against these strains from the trivalent vaccines used this year; but the quadrivalent vaccine provides much better protection - suggesting that the burden of influenza related disease this season may have been lower if a higher proportion of patients had received the (slightly more expensive, but still cost-effective) quadrivalent vaccine.
Types of influenza vaccine
Apart from the strains covered, there are several ways that influenza vaccines can be subcategorised, including:
- Route/method of administration
- Live or inactivated
- Adjuvanted or unadjuvanted
- Presence or absence of other substances of interest (such as gelatin, which some religious groups may object to; or egg protein, which can cause allergic or anaphylactic reactions).
There are tri- and quadrivalent versions of each.
If a vaccine is to be effective, it needs to generate immunity to antigens present on flu in a way which prevents illness (and, ideally, infection and infectiousness). Immunity to these antigens can be generated by presenting the antibodies to the immune system with more or less other parts of the virus, or in other ways. Subpopulations may benefit most from a particular composition and as a public health measure cost effectiveness is always considered.
The vaccines are broadly categorised as comprising:
- Live attenuated influenza vaccine (LAIV) - offered to children, and administered as a nasal spray. From 2017 onwards (perhaps earlier) LAIV vaccines used in the UK are quadrivalent vaccines.
- Trivalent inactivated influenza vaccine (TIV) (not adjuvanted).
- Quadrivalent inactivated influenza vaccine (QIV) (not adjuvanted).
- Adjuvanted trivalent inactivated influenza vaccine (aTIV). The first such vaccine to be available in the UK was licensed in August 2017.
- Adjuvanted quadrivalent inactivated influenza vaccine (aTIV) - mentioned for hypothetical completeness, although in practice no such vaccine has been licensed in the UK.
Inactivated influenza vaccines
A virus can be simply killed - e.g. with formaldehyde - and injected. This often involves injecting many other proteins and other molecules, which can increase the stimulation of the immune system, enhancing the immune response; but which are also responsible for increased "reactogenicity" - including fever and other adverse events. Whole virus, subunit, or very pure "just the necessary antigens" vaccines can be created via genetic engineering, with the antigens being expressed by different organisms).
In the UK at present we use a range of inactivated vaccines.
In August 2017 an adjuvanted inactivated trivalent influenza vaccine (aTIV) was licensed in the UK and Europe. The manufacturers claim that this vaccine is more effective in older people (who are at increased risk of complications associated with influenza, and in whom influenza vaccines are generally less effective).
This claim was supported by the Joint Committee on Vaccination and Immunisation (JCVI) in their October 2017 minutes, in which they state that this vaccine is both effective and highly cost-effective in both the 65-74 and 75+ age groups. This resulted in revised [ http://psnc.org.uk/wp-content/uploads/2018/02/07648-Vaccine-ordering-for-2018-19-influenza-season-GPpharm-05022018.docx.pdf recommendations in vaccine use by age for the 2018/19 season].
This vaccine will be available for the 2018-19 Northern hemisphere influenza season (and presumably for the 2018 Southern hemisphere season); but the timing of the licensure and JCVI endorsement came after many UK GP practices and other vaccination providers had put in their orders for the 2018-19 season, so it is not clear how many older patients will benefit from it.
In the meantime, further evidence - some of it cited in the JCVI minutes - has emerged showing that non-adjuvanted inactivated flu vaccines are completely ineffective in over 75s, and of little or no benefit (depending partly on circulating strains) in the 65-74 age group.
It has, thus, become apparent that giving unadjuvanted vaccine to these older patients is a waste of resources, increasing the pressure to ensure that they receive aTIV instead.
Live organism influenza vaccines
Live organism vaccines ("Live attenuated influenza vaccines", LAIV) currently in use for influenza comprise influenza viruses that have been attenuated so that they do not cause illness.
Data from the USA appeared to show reduced efficacy for LAIV, compared to inactivated flu vaccines, so their use was curtailed. In the UK and Europe, however, LAIV has continued to be used. The reasons for these differences are still being explored.
Hybrid organisms - other live viruses or bacteria that have been genetically engineered to express antigens; and it may be that in future influenza vaccines may use such methods.
Genetically engineered vaccines may combine antigens with proteins which enhance the immune response, as adjvuants or like conjugated vaccines.
Route/method of administration
Live attenuated influenza vaccines currently available in the UK are administered as nasal drops. These vaccines are only licensed for use in under-18s in the UK and Europe, because of reduced efficacy at older ages. They may, however, be used "off-label" for people with needle phobia: better this than no vaccine. (See page 16 of the PHE guidance.)
Currently inactivated vaccines are all administered by injection - usually intramuscular - injection.
One novel route of administration was a vaccine (Intanza Ⓒ) used a special syringe to facilitate intradermal injection. This was also said - due to the increased immune cells in this layer of the dermis - to be more effective in older people, but it seems not to have gained market traction.
As with many other vaccines, the future of influenza vaccination may be administration via a microneedle patch.
Who should receive the influenza vaccination?
The Chief Medical Officer's recommendations for 2011 can be found at this DH page. There is also revised guidance from the JCVI here. The Green Book chapter on influenza vaccination was updated on 29 July 2011, and is available here. There is also this DH leaflet for 2011.
Each year, the WHO direct formulation of an influenza vaccine based on circulating strains. This is offered between September and mid-November to at risk groups e.g. elderly, or chronic disease eg asthma, cystic fibrosis, congenital heart disease. It is an inactivated vaccine, and some products are contraindicated in egg anaphylaxis - see the Green Book Influenza chapter (as above) for details.
Since a proportion of influenza vaccine doses are given opportunistically, when patients attend for whatever reason, following that recommendation absolutely would generate additional work and congestion in general medical practices, however it can be reflected in the operation of recall systems.
It is worth noting that the Cochrane Collaboration has published a number of reviews that are far less enthusiastic about influenza vaccination than are the JCVI and Department of Health. The minutes of the JCVI's meeting in February 2011 state:
- "The committee noted that there is some evidence that frontline healthcare workers may not consider influenza vaccination to be effective in preventing influenza and that this view may have may have stemmed in part from the findings of a Cochrane review of influenza vaccination of healthcare workers. The committee considered this review to be based on a highly flawed interpretation of the evidence and did not support the findings of the report."
Regrettably, If they have explained this opinion, they did not do so in the text of the minutes.
Vaccination of pregnant women
During the H1N1 flu pandemic it became clear that pregnant women infected with that strain of flu were at increased risk of complications. During a pandemic, and even during the flu season, a large proportion of the population gets flu. If even a small proportion of those infected experience severe complications, the number who do so can be large. As pregnant women are at increased risk of complications, it is worthwhile vaccinating them, to prevent complications.
Flu vaccination in pregnancy has the additional benefits including:
- Providing some protection to the baby in the first year of life, through passive immunity (maternal antibodies passed through the placenta) and possibly a reduced risk of catching flu from their mother.
- Reducing the risk of harm to the fetus caused by the mother’s influenza illness.
Concerns about vaccinating women in pregnancy
The harm caused by thalidomide last century has left a legacy of concern about giving pregnant women any medicine that can be avoided during pregnancy, including vaccines. Midwifes, rightly, tend to discourage women from taking any medicine that isn’t known to be safe and worthwhile.
Influenza vaccination has, however, been shown to be valuable in pregnancy (see above); and also to be safe, with no risk of teratogenicity. The benefits to the fetus far exceed any risks from the vaccine.
See also Vaccination of social and health care staff for more general discussion not specific to Influenza.
Healthcare workers with direct patient contact should be vaccinated against flu annually, as early as possible in the season - to reduce the chance of infecting their patients as well as to protect their only health. Mark Crislip has described those who refuse to be vaccinated as "dumb-asses" (or longer 2012 version).
The Chief Medical Officer letter recommends that social and health care staff should be vaccinated against flu, citing benefits in terms of improved patient outcomes (it stops the staff from infecting their patients) and reduction of staff illness and absenteeism. Uptake rates as part of the 2009 H1N1 (A) pandemic strategy in England were only 40%. Similar guidance applies in other countries, such as the USA.
A high level of immunisation in workers in care homes is associated with fewer deaths during winter in residents. Clearly the contribution of immunisation can be confounded by various other factors, such as greater care and organisation but it seems likely it is beneficial to patients to immunise their attendants. A recent review article, however, found that the evidence to support this is, as yet, poor..
Why is a different vaccine required each year?
Vaccination with influenza vaccine is thought to give long-term protection: revaccination is not because the vaccines given previously are unlikely to continue to work.
Rather, annual revaccination is necessary because of the rapid viral mutation, which means that the viruses circulating each year are sufficiently different from viruses circulating in previous years for antibodies induced by previous years' vaccines to have low activity against them.
New vaccines are in development that may not have this problem.
Misplaced concerns about "swine flu" vaccine in the 2010-11 seasonal vaccine
Some patients (and even some doctors who should know better) have expressed concerns about the fact that the seasonal vaccine for the 2010-11 (Northern hemisphere) season contains H1N1 strains.
Every year there is a new vaccine, containing vaccines to prevent the 'flu viruses which have been circulating most widely up until as recently as possible. Since H1N1 has largely displaced most other strains of flu, it would have been bizarre - and a cause for concern - not to include it in the seasonal vaccine.
Most of the concerns about the 2009 vaccine when it was released last year to try to prevent/curtail further spread of pandemic influenza:
- the speed of introduction;
- the adjuvant used or
- the tenuous historical links between H1N1 vaccine and Guillain-Barré Syndrome (GBS).
The first can be discussed and, one would hope, dismissed.
The second can be dismissed as the seasonal flu vaccine is unadjuvanted.
The third can be discussed and, one would hope, dismissed - the latest version of the Green Book (download it from the DH web site) contains information about research showing that while influenza does considerably increase the risk of GBS, vaccination doesn't appear to do so.
Supply of Influenza Vaccine
In the UK
Payment and Reimbursement
Vaccination is only about 60% effective. Efficacy varies from year to year as a result of prior immunity (from natural exposure and to vaccines), and the quality of the "match" between the vaccine strain and circulating strains of influenza. At a population level however repeated influenza vaccination is very effective. This is illustrated by the sustained reduction in the severity of seasonal influenza outbreaks.
This means that standard treatment must be offered in high risk groups such as pregnant women on first clinical suspicion, whatever their immunisation status.
General influenza references
- Influenza Gateway from BioMed Central
- Information on diagnosis of influenza from CDC here.
- Information on influenza from Health Protection Agency is available here.
- There's good information on the influenza virus at Wikipedia here.
- Medscape Influenza Resource Center (sponsored by GlaxoSmithKline).
- A good starting point for comprehensive references is the FLUwiki , (or the UK page at that site).
- Information on avian and pandemic influenza from World Health Organisation here.
- Information on pandemic influenza from UK Department of Health  is particularly good.
- Information on influenza from Health Protection Agency, including HPA pandemic plan, is available here.
- Financial Times "Ask the Expert" interview with Bruce Mann from the Cabinet Office on how organisations can prepare for Avian or pandemic Influenza
- Draft guidance on the operation of the coroner system in the event of pandemic influenza - for consultation
- ↑ ProMED-Mail. PRO/AH> Avian influenza (65): updated nomenclature (Archive No: 20111024.3168). 2011; Updated 25 October; Accessed: 2011 (25 October)
- ↑ Zimmer SM, Burke DS. Historical perspective--Emergence of influenza A (H1N1) viruses. The New England journal of medicine. 2009 Jul 16; 361(3):279-85.(Link to article – subscription may be required.)
- ↑ Morens DM, Taubenberger JK, Fauci AS. The persistent legacy of the 1918 influenza virus. The New England journal of medicine. 2009 Jul 16; 361(3):225-9.(Link to article – subscription may be required.)
- ↑ Blackburn RM, Zhao H, Pebody R, Hayward AC, Warren-Gash C. Laboratory-confirmed respiratory infections as predictors of hospital admission for myocardial infarction and stroke: time-series analysis of English data for 2004-2015. Clin Infect Dis. 2018 Jan 6. doi: 10.1093/cid/cix1144
- ↑ Kwong JC, Schwartz KL, Campitelli MA et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018;378:345-53 DOI:10.1056/NEJMoa1702090
- ↑ Nishiguchi S, Inada H, Kakutani T, Suganami Y, Kitagawa I, Kawada J. Case report; Co-infection with mycoplasma and influenza B resulting in a Guillain-Barré syndrome with anti-galactocerebroside antibody.. Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine. 2013 May 10; 102(5):1223-5.
- ↑ De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E. CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Science translational medicine. 2013 Dec 18; 5(216):216ra176.(Link to article – subscription may be required.)
- ↑ a b Foppa IM, Hossain MM. Revised estimates of influenza-associated excess mortality, United States, 1995 through 2005. Emerging themes in epidemiology. 2008; 5:26.(Epub) (Link to article – subscription may be required.)
- ↑ Presanis AM, Pebody RG, Paterson BJ, Tom BD, Birrell PJ, Charlett A, Lipsitch M, Angelis DD. Changes in severity of 2009 pandemic A/H1N1 influenza in England: a Bayesian evidence synthesis. BMJ (Clinical research ed.). 2011; 343:d5408.(Epub)
- ↑ Wolf Y, Viboud C, Holmes E, Koonin E, Lipman D. Long Intervals of Stasis Punctuated by Bursts of Positive Selection in the Seasonal Evolution of Influenza A Virus. Biology Direct 2006;1(34):1-62 - also at Biology Direct, and reported by Science Daily and US National Library of Medicine.
- ↑ Chowell G, Ammon CE, Hengartner NW, Hyman JM. Transmission dynamics of the great influenza pandemic of 1918 in Geneva, Switzerland: Assessing the effects of hypothetical interventions. Journal of theoretical biology. 2006 Jul 21; 241(2):193-204.(Link to article – subscription may be required.) free download at 
- ↑ Rasmussen SA, Jamieson DJ. 2009 H1N1 Influenza and Pregnancy - 5 Years Later. The New England journal of medicine. 2014 Oct 9; 371(15):1373-1375.(Link to article – subscription may be required.)
- ↑ WHO 2017 -2018 influenza vaccine recommendations
- ↑ Belongia EA, Shay DK. Influenza vaccine for community-acquired pneumonia. Lancet. 2008 Aug 2; 372(9636):352-4.(Link to article – subscription may be required.)
- ↑ Jackson ML, Nelson JC, Weiss NS, Neuzil KM, Barlow W, Jackson LA. Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a population-based, nested case-control study. Lancet. 2008 Aug 2; 372(9636):398-405.(Link to article – subscription may be required.)
- ↑ http://www.seqirus.com/newsroom/New-influenza-vaccine-offers-improved-protection-for-older-adults Seqirus. New influenza vaccine offers improved protection for older adults. Maidenhead, UK: Seqirus, 2017(22 August); 1-3.]
- ↑ New influenza vaccine offers improved protection for older adults. Maidenhead, UK: Seqirus, 2017 (22 August); 1-3.
- ↑ Pebody R, Warburton F, Ellis J, Andrews N, Potts A, Cottrell S, et al. End-of-season influenza vaccine effectiveness in adults and children, United Kingdom, 2016/17. Euro Surv 2017;22(44):17-00306, DOI: doi: 10.2807/1560-7917.ES.2017.22.44.17-00306.
- ↑ http://www.manchesterlmc.co.uk/news/flu-vaccine-consortium-2018/ Stevens PJ. Manchester Flu Vaccine Consortium 2018: Stockport Local Medical Committee 2017; 1-3.]
- ↑ Pebody R, McMenamin J, Nohynek H. Live attenuated influenza vaccine (LAIV): recent effectiveness results from the USA and implications for LAIV programmes elsewhere. Arch Dis Child 2017, DOI: 10.1136/archdischild-2016-312165
- ↑ Public Health England. The National Influenza Immunisation Programme 2017/18: Information for Health Care Practitioners about the use of the inactivated influenza vaccine: Public Health England, 2017 (July); 1-17.
- ↑ Davies SC, Beasley C, Ridge K. Seasonal flu immunisation programme 2011/12. London: Department of Health, 2011 (25 May); 1-16
- ↑ Joint Committee on Vaccination and Immunisation (JCVI). Minutes of the meeting held on Wednesday 2 February 2011. London: Department of Health, 2011:1-23
- ↑ Salisbury D, Ramsay M, Noakes K. Chapter 19: Influenza. Immunisation against infectious disease. 29 July ed. London: HMSO, 2011:185-204
- ↑ Thomas RE, Jefferson T, Lasserson TJ. Influenza vaccination for healthcare workers who work with the elderly. Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD005187. DOI: 10.1002/14651858.CD005187
- ↑ Joint Committee on Vaccination and Immunisation (JCVI). Minutes of the meeting held on Wednesday 2 February 2011. London: Department of Health, 2011:1-23 (see p6, S22).
- ↑ Jit M, Cromer D, Baguelin M, Stowe J, Andrews N, Miller E. The cost-effectiveness of vaccinating pregnant women against seasonal influenza in England and Wales. Vaccine. 2010 Dec 10; 29(1):115-22.(Link to article – subscription may be required.)
- ↑ Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, Omer SB, Shahid NS, Breiman RF, Breiman RE, Steinhoff MC. Effectiveness of maternal influenza immunization in mothers and infants. The New England journal of medicine. 2008 Oct 9; 359(15):1555-64.(Link to article – subscription may be required.)
- ↑ Poehling KA, Szilagyi PG, Staat MA, Snively BM, Payne DC, Bridges CB, Chu SY, Light LS, Prill MM, Finelli L, Griffin MR, Edwards KM. Impact of maternal immunization on influenza hospitalizations in infants. American journal of obstetrics and gynecology. 2011 Jun; 204(6 Suppl 1):S141-8.(Link to article – subscription may be required.)
- ↑ Eick AA, Uyeki TM, Klimov A, Hall H, Reid R, Santosham M, O'Brien KL. Maternal influenza vaccination and effect on influenza virus infection in young infants. Archives of pediatrics & adolescent medicine. 2011 Feb; 165(2):104-11.(Link to article – subscription may be required.)
- ↑ Omer SB, Goodman D, Steinhoff MC, Rochat R, Klugman KP, Stoll BJ, Ramakrishnan U. Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS medicine. 2011 May; 8(5):e1000441.(Link to article – subscription may be required.)
- ↑ Tamma PD, Steinhoff MC, Omer SB. Influenza infection and vaccination in pregnant women. Expert review of respiratory medicine. 2010 Jun; 4(3):321-8.(Link to article – subscription may be required.)
- ↑ Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, Glezen WP. Safety of influenza vaccination during pregnancy. American journal of obstetrics and gynecology. 2005 Apr; 192(4):1098-106.(Link to article – subscription may be required.)
- ↑ NHS Employers. Flu vaccination letters to staff released. 2013, Updated 16 September 2013; Accessed: 2013 (23 September)
- ↑ Davies S, Keogh B, Cosford P, Salisbury D. Flu vaccination for doctors. London: Department of Health, Public Health England, NHS England, 2013 (Undated - ??16 September 2013 ); 1-6
- ↑ Cummings J, Bennett V, Salisbury D. Flu vaccination for nurses and midwives. London: Department of Health, Public Health England, NHS England, 2013 (Undated - ??16 September 2013 ); 1-5
- ↑ Middleton K, Salisbury D. Flu vaccination for allied health professionals. London: Department of Health, Public Health England, NHS England, 2013 (Undated - ??16 September 2013 ); 1-5
- ↑ Chief Medical Officer, Chief Nursing Officer, Officer CP. The influenza immunisation programme 2007/2008. PL/CMO/2007/3, PL/CNO/2007/1, PL/CPHO/2007/1. London: Department of Health, 2007:1-12
- ↑ Pandemic H1N1 vaccine uptake figures for England by SHA for healthcare workers
- ↑ Centers for Disease Control and Prevention. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR (RR) 2006;55(Early Release) (or as a pdf)
- ↑ Hayward AC, Harling R, Wetten S, Johnson AM, Munro S, Smedley J, et al. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial. BMJ 2006;333(7581):1241- (may require subscription)
- ↑ Thomas RE, Jefferson TO, Demicheli V, Rivetti D. Influenza vaccination for health-care workers who work with elderly people in institutions: a systematic review. The Lancet Infectious Diseases 2006;6(5):273-279 (subscription may be required)
- ↑ Positive Phase I and Pre-Clinical Data Suggest Acambis' M2e-Based Universal Influenza Vaccine, ACAM-FLU-A(TM), Could Tackle Infl. Last updated 03 January 2008 @ 09:11. Last viewed 03 January 2008.
- ↑ Salisbury D, Ramsay M, Noakes K. Chapter 19: Influenza. Immunisation against infectious disease. 20 September ed. London: HMSO, 2010:185-208
- ↑ Chief Medical Officer. The influenza immunisation programme 2006/2007 (PL/CMO/2006/3, PL/CNO/2006/3, PL/CPHO/2006/2). Department of Health 29 June 2006 with advice on influenza vaccination for the 2006-2007 season (or direct to PDF version)
- ↑ Influenza Subgroup. Minutes of the Influenza Subgroup meeting, 9 March 2006.
- ↑ Joint Committee on Vaccination and Immunisation. Draft minutes of the meeting held on Wednesday 21 June 2006.
- ↑ Rasmussen SA, Jamieson DJ. 2009 H1N1 Influenza and Pregnancy - 5 Years Later. The New England journal of medicine. 2014 Oct 9; 371(15):1373-1375.(Link to article – subscription may be required.)