Human immunity to influenza

Human influenza viruses are well adapted to their hosts. That is they infect humans easily and transmit easily from one human to another, usually without killing their hosts. Immunity comes either from experiencing infection or from vaccination. Immunity following infection by one strain or vaccination with a specific type or subtype often does not protect completely against subsequent variants of the same type or subtype. The extent to which influenza A(H3N2), A(H1N1), and B viruses circulate may vary by season. In addition, as the antigenic properties of these viruses might change due to continuous evolution of these viruses under immune pressure (antigenic drift), the virus strains of A(H3N2), A(H1N1) and B included in the vaccine have to be reviewed by the WHO annually and possibly changed. Also new vaccines may have to be made when variants of the virus emerge through antigenic shift.(Gerdil 2003)

Most of the acquired protection against influenza comes from antibodies in the blood. Some additional protection comes from cell-based immunity and IgA antibodies produced on mucous membranes, like those of the respiratory tract.

After the first (primary) infection, or vaccination, virus neutralizing antibodies to the haemagglutinin and neuraminidase appear in the blood in about one to two weeks and rise to a peak in about four weeks. Antibodies inhibit haemagglutination, agglutination of red blood cells due to multiple red blood cells bound by one virus, and so this is referred as haemagglutination inhibition (HAI). HAI correlates fairly well with virus neutralisation (Ada, 1986). Hence often the levels of these specific antibodies are used as a proxy for the presumed level of protection with higher titres more than 1: 40 or 1:80 (in the older person) taken to indicate immunity.* After a second or further infection or repeat vaccination the antibodies appear and rise more quickly. The antibodies usually persist for months or years, although in people with weaker immune systems like the elderly and those with chronic illness they decline more quickly. However, the problem with influenza is that antibodies to one type or subtype of influenza do not give protection to other influenza virus types or subtypes (so called cross-protection). Equally they do not give full protection against subsequent drift variants of the same type or subtype. That is why seasonal influenza vaccines contain a mix of influenza virus types and subtypes and the composition has to be reviewed each year by the WHO (Gerdil 2003).

Treatment and public health management of influenza

Most simple influenza cases, are just treated symptomatically, that is the patient is sent home to bed and isolated so that they cannot infect other persons and given medicines that will reduce their temperatures and relieve the general feeling of illness and sore muscles. Doctors may or may not attempt to confirm the diagnosis by taking specimens for laboratory analysis. It is important that patients are monitored to detect if patients are deteriorating and perhaps develop a secondary infection for which intensive medical interventions are needed. Many doctors will take a risk based approach considering whether the patient is at greater risk of developing complications and secondary infections.

Recently, antiviral drugs, first the M2 inhibitors like amantadine and rimantidine (acting only against type A viruses) and then the neuraminidase inhibitors like oseltamivir and zanamivir (acting against both A & B viruses), have been found to be effective for treatment and for prophylaxis (Moscona 2005a). However, they have to be used early in the infection (best within 24 hours after the symptoms start and certainly within 48 hours). Licensing of amantadine, rimantadine and zanamivir varies by country and by its expected use, treatment or prophylaxis. For oseltamivir there is a European license for treatment and prophylactic use. The use of these drugs is very variable
between countries. Although vaccination is the preferred option for preventing influenza, antivirals can be particularly useful when the vaccine fails (due to antigenic mismatch with circulating virus, waning immunity in elderly, patient being immunocompromised, etc), when vaccine is not (yet) available, as well as during an outbreak of ‘avian’ influenza or an emerging pandemic. At least one EU country (the UK) makes specific recommendations on when to use anti-virals according to the levels of circulating influenza viruses as determined by surveillance.

In addition to the above measures the public health management includes the strong promotion and adoption of the ECDC recommended personal protective measures:

• Regular hand washing
• Good Respiratory Hygiene – covering mouth and nose when coughing
  or sneezing, using tissues and disposing of them correctly
• Mask-wearing in health care settings by those with symptoms of acute
  febrile respiratory infections
• Early isolation, usually at hope of those feeling unwell and feverish and
  having other symptoms of influenza

which are considered to reduce the risk of people acquiring or transmitting
infections.

Resistance to antivirals

Resistant mutants to the M2 inhibitors have been detected in a number of countries to the extent that these are not always recommended. To date there has been few instances of resistance to the neuraminidase inhibitors and resistant viruses that transmit on are very rare. (Moscona 2005b) Antiviral resistance in Europe is monitored by the VIRGIL project in collaboration with the European Influenza Surveillance Scheme (EISS) and by a number of individual National Influenza Centres (Meijer 2006).

The contribution of virological surveillance

For selection of vaccine candidate viruses matching the virus strain expected to circulate in the coming season and for keeping a close watch on the evolution of influenza viruses there is a Global Influenza Surveillance Network, managed by WHO and comprised of National Influenza Centres including those that are part of the European Influenza Surveillance Scheme (EISS) and the Community Network of Reference Laboratories for Human Influenza in Europe. These continuously report and share influenza viruses with a series of four highly specialist WHO Collaborating Centres. In Europe, a WHO Collaborating Centre is located in the UK (Mill Hill), where there is also the National Institute of Biological Standards and Controls (NIBSC) which further refines and prepares suitable viruses for passing onto industrial vaccine producers (ECDC 2007). Based on data arising from this surveillance each year WHO convenes specialist meetings at which it agrees on recommendations on the composition of the influenza vaccine for the next season. Separate meetings and recommendations are made for the northern hemisphere (which includes Europe) and the southern hemisphere. Current influenza vaccines are recommended to contain antigens protecting against two influenza A subtypes, H3N2 and H1N1, and one of the two lineages of type B virus.

The influenza vaccines

Currently there are 3 types of vaccines used in Europe, all of them
inactivated, some formulations are also adjuvanted:

• split virus vaccines consisting of virus particles disrupted by detergent
  treatment;
• subunit vaccines consisting essentially of haemagglutinin and
  neuraminidase from which other virus components have been
  removed;
• whole virus vaccines consisting of inactivated viruses.

Live attenuated influenza vaccine given by nasal sprays are starting to
become available, though they have been mostly been developed for use in
children for whom vaccination is not generally recommended in Europe
(Fukuda 2006).

Vaccine strategy

The approach with influenza is to reduce the risk of people at greater risk of complications from becoming infected. Hence, the approach is one of selective vaccination.

People to whom influenza vaccine is recommended

A survey by ECDC in 2006 of EU and EEA counties found that all the reporting countries were recommending annual vaccination to the two largest groups which are highlighted by WHO (WHO 2002) (See Table 1)

1. Older people above a nationally-defined age
2. All people over 6 months of age with chronic medical conditions:
   notably chronic heart or lung diseases, metabolic or renal disease, or
   immunodeficiencies.

Many countries especially emphasise the importance of annual vaccination of people living in residential care for the elderly and disabled. These findings are very similar to the results of an earlier survey by the European Scientific Working Group on Influenza (ESWI 2000) See Table 1. Few EU countries recommend vaccination of children or offering vaccines to pregnant women. This is different from policy in the United States (CDC 2007). An expert panel convened by ECDC considered there was as yet insufficient evidence on the burden of infection in children to take any view for or against vaccination. (ECDC Panel report 2007).

Health Care Staff

Health care staff are expected to protect themselves and their patients from influenza by use of protective measures. The majority of countries in Europe recommend that all health care staff should be immunised against influenza. This is partially to protect the staff who are more likely to be exposed through their work than other people. However it is more to protect their patients, especially those at higher risk of infection and disease. However all reports are that only a minority of health care workers take up this offer.

Estimates of vaccine efficacy and effectiveness, the extent to which vaccine protects in optimal circumstances (efficacy) and in practice (effectiveness), vary according to the match between vaccine and the circulating viral strain and by age group and clinical category. Generally, the vaccines work somewhat less well in the elderly and those with chronic ill-health. In trials, inactivated influenza vaccines have consistently been shown to prevent laboratory-confirmed illness in between 70% and 90% of healthy adults though the results are less in field effectiveness studies.(Turner 2003, Treanor J et al 1999, Nichol 2007, Skronowski 2007, Wilde 1999) The reduction in hospitalisations and deaths is less dramatic but still significant.(Mangtani 2004) Trial data cannot help here as hospitalisations, pneumonia and deaths are too uncommon to be revealed by trial data which also usually exclude those most at risk. Instead, observational data have to be used. These data are more subject to bias (Simonsen 2007). However modern epidemiological studies can compensate for these biases and when this is done positive effects are consistently observed (see table 2), though there are minority opinions that disagree (Jefferson 2005, 2006).

Contraindications to Vaccination

On empirical grounds, as most viruses used for influenza vaccines are grown in eggs, egg-based vaccines should not be used for individuals with a definite history of serious allergic reactions to egg products.

Giving Vaccines

Most inactivated influenza vaccines are injected into the muscle in the outer upper arm. A single injection annually is sufficient except for previously unvaccinated preschool children with medical conditions for whom WHO recommends 2 doses at least one month apart.

Reactions to vaccines

The three groups of inactivated influenza vaccine show minor differences in the mild reactions that sometimes follow vaccination. In trials, when whole virus vaccines are used, between one in five and one in six of those vaccinated experience local reactions in the arm, lasting for one or two days. Short term reactions such as mild fever, malaise and muscle pains are reported in a much smaller proportion in the first few hours following vaccination. In contrast, trials of the split and subunit vaccines show even fewer reduced systemic reactions. There have been no strong temporal associations of the current vaccines with more severe reactions.

Reactions to vaccines

The three groups of inactivated influenza vaccine show minor differences in the mild reactions that sometimes follow vaccination. In trials, when whole virus vaccines are used, between one in five and one in six of those vaccinated experience local reactions in the arm, lasting for one or two days. Short term reactions such as mild fever, malaise and muscle pains are reported in a much smaller proportion in the first few hours following vaccination. In contrast, trials of the split and subunit vaccines show even fewer reduced systemic reactions. There have been no strong temporal associations of the current vaccines with more severe reactions.

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 Estimated Elderly Population Immunized (Percentage) n = 18 EU / EEA countries

References

1. Ada G L, Jones P D. The immune response to influenza virus infection. Curr Top Microbiol Immunol. 1986;128:1–54.

2. Centers for Disease Control and Prevention 2006; Prevention and control of influenza. Recommendations of the Advisory Committee on Immunisation Practices (ACIP) 2007. MMWR 56 RR-6   

3. European Centre for Disease Prevention and Control.(2007a) Interim ECDC Scientific and Public Health Briefing: Sharing influenza Virus Samples – Version November 2007.

4. ECDC Scientific Panel Childhood immunisation against influenza (2007b)

10. M. Kroneman, W. J. Paget, G.A. van Essen. Influenza vaccination in Europe: an inventory of strategies to reach target populations and optimise vaccination uptake.Euro Surveill 2003;8(6):130-138. Available online:

13. Moscona A (2005a). Neuraminidase inhibitors for influenza. N Engl J Med. 2005;353:1363-1373. http://content.nejm.org/cgi/reprint/353/13/1363.pdf

14. Moscona A (2005b) Oseltamivir resistance – disabling our influenza defences. NEJM, 2005; 353:2633-2636

16. Nichol K, Nordin JD, Nelson DB, Mullooly JP, Hak E (2007). Effectiveness of Influenza Vaccine in the Community-Dwelling Elderly. NEJM 2007; 357: 1373-81.

17. Paget WJ, Marquet R, Meijer A, van der Velden J. Influenza activity in Europe during eight seasons (1999-2007): an evaluation of the indicators used to measure activity and an assessment of the timing, length and spread across Europe. BMC Infectious Diseases. 2007;7(1):141.

24. World Health Assembly (2003) Resolution Prevention and control of influenza pandemics and annual epidemics WHA 2003. 56:19

25. WHO (2002) Influenza vaccines: WHO Position paper Wkly Epi Rec 2002; 77:230-9