Attending:

Professor Karl Nicholson
Professor Lewis Ritchie
Dr John Wood
Dr Douglas Fleming

Scottish Executive
Dr Elizabeth Stewart

Welsh Assembly Government
Dr Richard Roberts
Neil Robins

Health Protection Agency
Dr John Watson
Prof Maria Zambon
Dr John Edmunds
Dr Richard Pitman

Health Protection Scotland
Dr Jim McMenamin

MHRA
Dr Phillip Bryan

Department of Health
Dr Jane Leese (Chair)
Dr Karen Noakes
Rachael Horner
Daniel Eghan (minutes)

Executive Summary

Influenza vaccination for children under 2 years: Estimating the burden of influenza is difficult. Although uncertainties remain, the burden is however considerable, mainly in the elderly. However, the burden in children is significant with large numbers of GP consultations, hospitalisations, and even some deaths, occurring annually in children in England and Wales.

Modelling presented to the Subgroup suggested that a vaccination strategy for pre-school children could reduce the burden, provided high levels of coverage were achieved. Such a policy was only cost-effective, however, if pre-school vaccination resulted in significant reductions in influenza in adults. More work is required, particularly on efficacy of the vaccine in young children and benefits to the children themselves, before the Subgroup can make a recommendation.

Influenza vaccination in pregnancy: The Department will collate all the evidence the Subgroup has considered, for a decision at the next meeting.

Influenza vaccination should be recommended for people with multiple sclerosis, particularly relapsing MS

No safety issues requiring regulatory action had arisen in 2004/05.

The Subgroup was updated on the influenza pandemic preparedness work being undertaken by the Department. Members were invited to the next meeting of the full JCVI on 19 October, when this would be covered in more detail.

1. Introduction: Purpose of meeting

The Subgroup was formerly chaired by the Chairman of the main JCVI. He had retired and a new chair had yet to be appointed.

The main policy areas to be considered were:

• Influenza immunisation in children under 2
• Influenza immunisation for pregnant women
• Pandemic Influenza

Members were informed that the UK's preparations for an influenza pandemic were to be a major item on the agenda of the next meeting of the main JCVI (19 October). Members of this committee were welcome to attend for that item, and should inform the secretariat.

There were no declarations of interest from members.

2. Apologies

Apologies were received from Dr Alan Hay, Dr Mair Powell, Professor Simon Kroll and Dorian Kennedy.

3. Minutes of last meeting

The minutes were agreed as a true record. Under 'Matters arising' it was noted that this meeting had originally been scheduled for June, but had been delayed by the pressure of other business.

4. Influenza vaccine for children under 2

Assessing the burden of influenza

The first paper estimated the current burden of influenza in England and Wales. The health burden is measured in terms of GP consultations, hospitalisations, respiratory, circulatory and neoplasm deaths attributable to influenza.

The details of the estimates were broadly similar to those previously derived, i.e. approximately:

• 800,000 GP consultations/year (derived from 2 years GPRD data)
• 19,000 hospitalisations (derived from 7 years HES data)
• 10,000 respiratory deaths (derived from 11 years mortality data)
• 18,000 all cause deaths ( " " )

The limited period of GPRD data was commented on.

Estimating the impact of childhood influenza vaccination programmes in England and Wales

The paper used a model to assess the possible impact of routine pre-school influenza vaccination (annual vaccination of children 6-11 months; 6-23 months; 6-35 months and 6-59 months of age) on the burden of influenza in the children themselves and in the wider population.

For the model 50% vaccine efficacy and 60% coverage was assumed for the elderly and 65% efficacy and 92% coverage in children, giving effective coverage of 30% and 60% respectively. Pre-school influenza vaccination was estimated to have a significant impact on influenza infections, particularly in the targeted age groups (1-4 year olds). The greater the age range included in the policy, the greater the effect. There was a proportionately greater impact on influenza B infections (more concentrated in the target group) than influenza A.

A reduction in overall hospitalisations and deaths was largely the result of prevention of cases in the elderly. Nevertheless, pre-school vaccination is expected to reduce a significant number of hospitalisations for influenza A in those under 5 years old.

Various sensitivity analyses had been performed.

Clarification was sought on some points in the paper:

• (The proportion of infections experiencing clinical illness and seeking GP consultation is age dependent. The figure of 50% comes from the Tecumseh study which was under intense surveillance and probably not representative in this regard of the general UK population)
• the number of susceptibles was poorly known, but mixing seemed more important than susceptibility
• there appeared to be a linear relation between coverage and cases prevented; effective coverage may have been overestimated
  
• the assumptions for mixing across age groups were challenged
• weaknesses were the age of the data, infection was based on serology, and the burden was only an estimate.

The conclusion was that most benefit was in the elderly.

Other possibly relevant work was discussed. Previous studies had also suggested that influenza in children drives flu in all age groups. Strathclyde University was looking at social mixing in relation to MMR, as are the modelling unit in the HPA. There were a few other population based studies: one family based study showed an impact on the family. Very few looked at community effect: one had in the 1968/69 pandemic. A Japanese study in the NEJM was based on unreliable epidemiology. A recent US study claimed an impact, but there was no measure of reduction of illness in children. The US recommendation for vaccinating children was based on work on live attenuated vaccines, with good diagnostic tests and measurement of benefits for children themselves.

The 65+ age group was not a homogeneous group: some, for instance in residential homes, had very little social mixing.

Economic impact of paediatric influenza vaccination

The model again used GPRD data. A 2 dose schedule was assumed for everyone in the first year and previously unvaccinated children thereafter, otherwise a single dose was administered. The perspective taken was that of the health care provider (NHS), therefore costs to the patient and wider society (from, for instance, absenteeism) are ignored.

There was estimated to be a net cost to the health service from the vaccination programme. If pre-school immunisation results in significant reductions in influenza in adults, however, it is estimated to be cost effective, resulting in a cost per life year gained of <£1,000. The most cost-effective policy was immunising 6-23 months (cost per life gained £515). If there is no effect on adult influenza, the policy was not cost-effective (using a threshold of £30,000 per life year gained).

The model assumes the vaccine is effective in very young children, and there are few data on this. There are also assumptions on the cost of hospitalisations for acute respiratory illness which will be influenced by RSV.

It was acknowledged that there were difficulties with the parameterisation. What had been used were the best available data. It was anticipated that more data should become available following the introduction of childhood policies in other countries.

The impact of adult vaccination had also not been fully evaluated.

It was agreed that further information was required, ideally from an RCT:

• on the efficacy of the vaccine (does it protect in the first 2 winters of life, would it reduce hospitalisations)
• how did conventional inactivated vaccine compare with live attenuated vaccine in the under 2s
• studies would need to show real benefits for young children rather than for anyone else: immunogenicity data alone would be insufficient.

A Cochrane review had found negligible information. We should try to ascertain what work is being undertaken in the US: if other studies are published it will be difficult to do a randomised study.

5. Influenza vaccine in pregnancy

At its last meeting, the Subgroup had agreed that pregnant women and their very young babies were at increased risk from influenza. The group was concerned about safety, particularly in the first trimester.

The MHRA advised that currently licensed influenza vaccines are not contra-indicated in pregnancy. The SPC states they may be given in the second and third trimesters, and in the first trimester 'if there are risk factors'. The Subgroup had previously reviewed a paper demonstrating safety in the first trimester.

The Subgroup was minded to recommend the vaccine for women expecting to deliver during the influenza season, i.e. those in the second and third trimesters during the influenza immunisation programme. A vaccine without thiomersal would be preferable. The Department agreed to summarise all the evidence before the Subgroup came to its final recommendation.

6. Immunisation of people with MS

The National Institute for Health and Clinical Excellence (NICE) guidelines on the management of patients with multiple sclerosis had included annual influenza immunisation among its recommendations. The Multiple Sclerosis Society had become aware of people denied the vaccination. This group was not currently covered by the DH immunisation policy.

The Subgroup's attention was drawn to the literature on which the NICE recommendation was based. The evidence was limited, and no cost-effectiveness analysis had been performed. What evidence there was pointed to possible exacerbations in patients with relapsing multiple sclerosis following influenza infection, and no harm from influenza vaccination. The Subgroup thought that there were additional risks should such patients need to be admitted to hospital.

The Subgroup agreed that these patients should be offered influenza vaccine. It would cause little additional work for GPs (adding possibly 1-2 patients per GP to their influenza immunisation register).

The subgroup agreed that if MS is to be added to the list of risk groups recommended to receive flu vaccination for next year's flu camapign then they should first look again at neurological disease in general. A study of mortality in the1989-90 epidemic had shown a higher mortality in people with neurological disease, although most would now be covered by the 'age 65 years and over' policy.

7. Immunisation of household contacts of a severely immunocompromised person

It was agreed that, as for carers, this would fall in the category of 'at the doctor's discretion'.

8. Influenza vaccine adverse reactions (ADRs) MHRA

The report provided data on suspected ADR's reported in association with influenza vaccine from 1 August 2004 to 31 August 2005. The data were extracted from MHRA's adverse drug reaction on-line information tracking (ADROIT) database of Yellow Card data.

A total of 143 reactions were reported of which 71% were serious. Most of these reports were received in October and November. There were 7 suspected ADR's with fatal outcome but not necessarily due to the vaccine. Currently around 12 million doses of influenza vaccine are administered each year.

No significant safety issues were identified during this period and no regulatory action taken for safety reasons.

A US study had suggested a slightly greater incidence of Bell's palsy than with other vaccines. MHRA is looking at this with Dr Elizabeth Miller of HPA.

Correspondence had been received with anecdotal evidence of patients with disturbed diabetic control following influenza vaccination. On average 1-2 reports a year mentioned diabetic control over the last 15 years. There was no suggestion from the cards that this was a significant problem. The correspondent had been asked to ensure Yellow Cards were completed for any future possible reactions, and that more systematic data were collected.

9. Avian flu

The Department of Health has put out a tender for around 2.6 million doses of an H5N1 vaccine. This has been done on a precautionary basis, on the grounds that should an H5N1 pandemic virus emerge from the avian strains currently circulating in SE Asia, the vaccine might at least offer some limited protection for people at highest risk, for example health care workers. There is currently no licensed H5N1 vaccine.

Although DEFRA currently assess the risk of H5N1 influenza in poultry in the UK as low, the vaccine could potentially be used to protect poultry workers likely to be exposed.

Our contingency stock of seasonal influenza vaccine would be suitable for immunising exposed poultry workers against human influenza in the event of an 'out of season' outbreak of avian influenza in poultry, a policy previously agreed to prevent potential co-infection and subsequent reassortment between human and avian viruses in a person.

10. Pandemic influenza update

The Government continues to give pandemic preparedness planning high priority. The March version of the UK Influenza Pandemic Contingency Plan is being revised to take account of comments received and further work, plus the revised WHO Phases. It is hoped to republish it in the autumn. Planning Guidance has been issued to the NHS, and guidance for the NHS on the strategy for stockpiling, storage, delivery and supply of antivirals will follow shortly. Clinical Management and Infection Control Guidelines are in preparation. A whole series of public information materials are also being launched this autumn, to help set the scene for a potential pandemic.

An inconsistency in the current draft of the plan was pointed out, which had caused some confusion as to whether health care workers could expect antiviral prophylaxis. Except for very few special cases (mainly early in a pandemic), the antiviral stockpile is for treatment only. The draft will be amended accordingly.

The Subgroup was asked to confirm its advice on priority groups for vaccination. The list was a provisional list, to be finalised as information about the characteristics of the pandemic becomes available to inform policy decisions. It was not possible to number the priorities, and decisions about whether essential workers should take precedence over clinical risk groups was a political, not a medical, decision. There had been difficulties in identifying 'key workers'.

The Department continues discussions with European vaccine manufacturers. All are now working to develop a vaccine and generate the data required for submission of a pandemic influenza vaccine core dossier to the EMEA. All but one is now based on an H5N1 vaccine. None is expected to be in a position to submit such a dossier before 2007.

Members asked about the detail required for the core dossier. A guideline has been issued, but it does not specify the numbers required for studies. The first application will be a 'test case'. There is a section on efficacy in animals. There will be a requirement for pharmaceutical companies to submit a safety plan with their licence application. The secretariat will circulate a copy of the dossier for members (it is on the EMEA website with the guidance note).

Preliminary work in the USA suggests unadjuvanted H5N1 vaccine is poorly immunogenic and requires very high doses to produce an immune response.

The UK has produced some of the best work on immunogenicity of different formulations of a novel influenza vaccine, including on H1, and on cross protection studies. The Subgroup asked that the UK continue to support pandemic vaccine research over and above that now being undertaken by manufacturers. Particular areas of concern are:

• priming strategies
• data across all age groups, including children
• strategies for optimal use of limited antigen
• head to head studies of putative vaccines

The need for post-marketing surveillance studies to be set up in advance so that they can be operational quickly was re-iterated, and for protocols for other studies to be performed in a pandemic to be established in advance. The paperwork involved in setting up and getting ethical approval for clinical trials now takes at least 6 months.

The MRC is holding a meeting to discuss pandemic influenza research later this year.

11. Any other business

Delays in deliveries of seasonal influenza vaccine
The Department confirmed that several companies had announced delays of up to 3-4 weeks in deliveries of their influenza vaccines. The Industry's claim that this was due to delays in receiving materials from NIBSC was not true. The overall total supply would not be affected.

Influenza vaccination for Hajj pilgrims
A request had been received to make influenza vaccination free to pilgrims attending Hajj and Umra. The Hajj comes forward by 10 days each year so there will be 2 Hajj in 2006 - in January and December. An estimated 2 million people attend the Hajj, where they live in close quarters in a 'tent city'. The risk of acute respiratory infection in such circumstances is documented and was acknowledged, but it was outside the Subgroup's remit to advise on payments for vaccines for travel purposes.

The Department would check that the information leaflet produced each year on health issues covers the risk of acute respiratory illnesses. Many pilgrims are in fact older people who already fall within the Department's policy.

12. Date of next meeting

The next meeting would be scheduled for March 2006, exact dates to be circulated.

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