Attending:

Professor Jonathan Friedland (CHAIR)
Professor Andrew Hall
Dr Robert George
Dr Nick Andrews
Dr Paul Heath
Dr Derrick Crook
Dr David Dance
Dr Punam Mangtani
Dr Caroline Trotter
Dr Mair Powell
Dr Syed Ahmed
Dr Ray Borrow

Health Protection Agency
Professor Elizabeth Miller
Dr John Edmunds

Health Protection Scotland
Dr Jim McMenimin

Scottish Executive
Dr Elizabeth Stewart

DHSS Northern Ireland
Dr Lorraine Doherty

DH
Dr Dorian Kennedy
Dr Karen Noakes
Bela Vatsa (minutes)
Daniel Eghan

Executive summary

1. Overall, the incidence of invasive pneumococcal disease (IPD) is increasing in those aged 65 years and over in England and Wales, although the 23 valent pneumococcal polysaccharide vaccine (PPV) immunisation programme for those 65 years and over is thought to have reduced the expected IPD annual increase of 6% .

In Scotland there appears to be a fall in the incidence of IPD that corresponds to the introduction of PPV routinely to all those aged 65 years and over. It remained to be determined whether this observation was influenced by the introduction of the vaccination programme to all those 65 years and over in Scotland in one year (compared to England and Wales where the programme was staggered over 3 years). The views of the group were that this was a relatively inexpensive immunisation programme that had probably reduced the incidence of pneumococcal disease in a relatively small number of individuals by its protective benefits against IPD. However, it had probably made little impact on pneumococcal disease overall as the majority of pneumococcal disease was non bacteraemic pneumonia. In addition, the expected herd immunity benefits of the Pneumococcal Conjugate Vaccine (PCV) childhood vaccination programme may significantly outweigh the possibly limited benefits of the PPV programme. The sub-group decided further information is required before formulating advice to main JCVI.

2. There has been a very clear population level impact of the PCV infant programme in reducing IPD. Herd immunity is expected to have an effect in older unimmunised ages which may first become apparent by next winter, but UK data on this will not be available for at least 6 months. It was suggested that PCV (or similar vaccines with increased valency) should be considered for use in adults.

3. PPV vaccination after PCV vaccination may give reduced protection against pneumococcal disease and may indeed interfere with the effectiveness of the initial PCV vaccination. The committee agreed further evidence was required so requested a literature search.

Three groups were identified for consideration:

• At-risk children who have received PCV and are then offered PPV
• Older at-risk age groups who are immunocompetent
• Older at-risk age groups who are immunocompromised

4. The Group discussed the association between influenza and pneumococcus, with particular reference to an influenza pandemic. It was noted that while vaccines offer one area to be explored, the use of antibiotics would also be expected to reduce the impact of pneumococcal infections. Data on co-infection are expected but are not available yet. The question of vaccination during a flu pandemic should be considered once we know the expected benefits of herd immunity following the routine PCV programme.

MINUTES

1. Announcements and apologies

Members were welcomed to the first meeting of the JCVI subgroup on Pneumococcal vaccine.

Apologies were received from: Professor David Goldblatt, Dr Richard Roberts, Professor David Salisbury, and Dr Lorraine Doherty.

The chair reminded members that declaration of Interests had already been taken when setting up this meeting. However details would be required if there have been any changes since filling in these forms.

The following members declared interests in Wyeth or Merck (Sanofi Pasteur in the UK):
Jonathan Friedland: Non-personal, non-specific
Raymond Borrow: Non-personal, specific
Paul Heath: Non-personal specific
Syed Ahmed: Non-personal specific
Derick Crook: Non-personal specific
Jim McMeninmin: Non-personal specific
David Dance: Personal specific, non-personal none
Elizabeth Miller: Non-personal specific
Robert George: Personal specific, non-personal specific

It was noted that all members present were exceptionally permitted to take part in the discussions. The chairman pointed out that members who had declared personal specific interest were allowed to take part in the discussions as they were pertinent to them, but were not allowed to vote or make recommendations from the sub-group. This exception will not apply to deliberations of main JCVI, which is responsible for advising Ministers and is governed by the usual rules as detailed in the Members' Code of Practice.

The main aim of this meeting was to get together an independent expert group composed of existing JCVI members and experts in the field of pneumococcal epidemiology, public health policy, cost-effectiveness modelling, and vaccine efficacy and safety to address the specific issues below.

The terms of reference of the group are to provide advice to JCVI on:

• The effectiveness of the pneumococcal polysaccharide vaccine (PPV) immunisation programme for older people and whether the current recommendations should be changed.
• How this affects our current recommendations for risk groups under 65 years who are also recommended PPV vaccination
• The effectiveness of the PPV immunisation for older people in light of the recent pneumococcal conjugate vaccine (PCV) recommendations for infants and the expected herd immunity benefits.
• Whether additional clinical risk groups should be offered pneumococcal immunisation.
• The expected benefits of introducing a conjugate vaccine with increased valency (9, 11, 13 valent conjugate vaccine) into the routine childhood immunisation programme.
• Use of Pneumococcal vaccines during an influenza pandemic.
  

2. Impact of the 23 valent pneumococcal polysaccharide vaccine (PPV) immunisation programme for those 65 years and over.

The Committee were updated by the HPA on the impact of the PPV immunisation programme for those aged 65 years and over. The incidence of invasive pneumococcal disease (IPD) has been increasing but it is difficult to be certain as to the cause - a true increase or better reporting. The programme may have prevented an expected 6% annual increase in IPD in those 65 years and over. The Broome and screening methods give similar overall effectiveness results, but estimates differ by age cohort. Overall vaccine effectiveness by the screening method is estimated as 28% (22-36) and as 22% (5-36) by the Broome method for individuals vaccinated at anytime. Although there appear to be some cohort differences between the age at vaccination, these are not statistically significant. There is a statistically significant decline in effectiveness over time. Vaccine effectiveness in the first year of vaccination is 49%. This drops to 15% after the first year.

Scottish data (table 1 of HPS paper) shows an overall increase in IPD since 1999/2000 with a slight decline from early 2000s to 2005/06 in the over-65s after which a slight upturn was seen. There are no data for duration of protection, but work has been done on vaccine effectiveness over time since vaccination. The committee raised points on: the observed higher effectiveness possibly being due to use of the screening method and end of season coverage data; the need to stratify IPD data on over-65s to identify cases attributable to vaccine type versus non-vaccine type; the need to look at population impact based on effectiveness and population vaccinated in year of change. It was commented that data on hospitalisation and pneumonia would be useful.

A paper was presented looking at hospital admission trends for pneumonia in England using Hospital Episode Statistics (HES). Only a small percentage of hospital admissions for pneumococcal pneumonia are recorded as such (around 1200 admissions per year). There was a 34% increase in the age-standardised incidence of hospital admissions for all pneumonia in England between 1997/98 and 2004/05. Data for 2005/06 indicate that this trend is continuing. Increases in hospital admissions for pneumonia have also been noted in the US, Denmark and the Netherlands. An ageing population and rising prevalence of co-morbidities does not fully explain the increase. Other explanations may include changes to health care organisation in England (e.g., changes in GP provisions of out-of hours care) or changes in HES coding were discussed. There was no correlation with PPV vaccine coverage (at population level only).

The observation that there was no apparent reduction in cases of non- bacteraemic pneumonia was not unexpected as previous studies had shown PPV to provide no apparent protection against non IPD endpoints. The recommendation in 2002 to introduce routine PPV vaccination was based on the protection this would offer against IPD.

The group considered a relatively small number of papers that have been published since the meta analysis examining the impact and expected cost-effectiveness of introducing PPV vaccination in the UK that was presented to JCVI in 2002. The results were generally more positive in terms of protective benefits against IPD and non bacteraemic pneumonia, in line with the results from Scotland.

The group raised some limitations to the papers considered:

• In some of the studies, flu vaccination was also given to those individuals receiving PPV and if not taken into account would add to the prevention of pneumococcal disease;
• there is a potential publication bias resulting in higher efficacy results;
• One member of the group found the paper by Vila-Corcoles et al, 2006, showing reduction in hospitalisations and pneumococcal pneumonia, convincing but it was also pointed out that retrospective case control studies compare two groups who are often dissimilar and tend to produce higher efficacy results than randomised controlled trials (RCTs);
• One member of the group found the 2006 paper by Musher et al strongest in terms of methodology and consistent with other studies in finding 54% effectiveness against bacteraemic pneumonia but no affect on non bacteremic pneumonia.

The views of the group were that this was a relatively inexpensive immunisation programme that had reduced the incidence of pneumococcal disease in a relatively small number of individuals by its protective benefits against IPD but had made little impact on pneumococcal disease overall as the majority of pneumococcal disease was non bacteraemic pneumonia. In addition, the expected herd immunity benefits of the Pneumococcal Conjugate Vaccine (PCV) childhood vaccination programme may significantly outweigh the possibly limited benefits of the PPV programme.

Actions:
The group decided that the following further information was required in order to make a decision on whether to continue with the PPV vaccination programme for those aged 65 years and over:

• Health Protection Scotland (HPS) would provide data on non bacteraemic pneumonia and hospital admissions for pneumonia if available and compare methodologies with HPA counterparts who have calculated PPV vaccine effectiveness using the data for England; data on duration of vaccine protection against IPD.
• The Secretariat would contact Northern Ireland to see whether they have any data on the impact of the PPV programme.
• The Secretariat would follow up a Lancet paper by Ortqvist which was published around 5 years ago on the impact of PPV vaccination in Sweden.
• A pre-publication Cochrane review will be circulated to members in confidence prior to the next meeting for their views. The Secretariat would also circulate any additional information obtained from other countries, e.g. Sweden, following their earlier Lancet publication.

This information will be necessary for the subgroup to advise JCVI whether the programme should continue, be stopped immediately or be stopped when the herd immunity benefits of the PCV programme take effect.

3. Impact of the pneumococcal conjugate vaccine (PCV) infant programme so far.

The HPA presented data on the impact of the PCV programme for children. There has been a clear population level impact, with a flattening of the curve for IPD reports since the programme started in 2006 - even for 6B serotype, where there was evidence that PCV confers less protection than the other 6 serotypes. From an epidemiological perspective, the lower immunity to the 6B serotype will likely have no impact as together with herd immunity and the booster dose at 13 months, there will be good population protection.

Herd immunity is expected to start to have an effect in older unimmunised ages by next winter. An age-stratified transmission dynamic model has been developed by the HPA and has been fitted to US data (although coverage data is poor). It will be fitted to UK data when this becomes available. The model will be used to look at the expected impact of the PCV programme over 5 and 10 years. Another carriage study by the HPA is also planned this winter to identify the direct and indirect effects of the vaccination programme.

The group discussed the recent paper by Barricarte et al (2007) whose study indicates that there is a higher risk of IPD caused by non-PCV7 serogroups among vaccinated children. The group considered that this paper did not look at the population effect of PCV vaccination but at a select number of children where vaccine coverage was low. The increase in non-PCV7 disease may be a result of replacement carriage where coverage is not high enough to achieve herd immunity. It was difficult to understand the results as this observation has not been reported elsewhere. This has not been observed in the UK data.

It was suggested that PCV should be considered for use in adults. A study included with the papers shows that PCV and PPV induce similar antibody responses in the 65 and over age group, although the elderly might benefit from a double dose of PCV. The 7-valent vaccine covers the serotypes causing 50-60% of all IPD in those over 65 years of age. In order to consider the added benefit of vaccinating the elderly with PCV, the group would need to know the expected herd immunity effect from the PCV programme for children in older people.

Data from the UK on herd immunity effects will not be available for at least 6 months but data is available from other countries, e.g. USA, where 4 years into the PCV programme a 55% decline was seen in IPD caused by the PCV7 serotypes in adults over 50 years of age (with a 28% decline in IPD overall). Initial effects may be most marked in younger adults who are in more contact with children.

4. PPV Vaccination for clinical risk groups

The group discussed Ray Borrow's paper on the subject of PPV vaccination following PCV vaccination. When a child in a clinical risk group reaches two years, they are given PPV. Thus, children will receive three doses of PCV routinely, followed by PPV. The serotype responses to PCV and PPV for children with recurrent upper respiratory disease have shown that PPV is of no additional benefit as responses to the serotypes not covered by PCV did not induce protective levels of antibody. There are ongoing discussions abroad about the use PPV in children and concerns have been raised about its benefits, although there have been no policy changes as yet.

A published paper outlining the potential for hyporesponsiveness was also included in the meeting papers. A hyporesponsiveness effect when polysaccharide vaccine follows conjugate vaccine is evident from the meningococcal vaccines where a depletion of the memory B cell pool is hypothesised when a meningococcal group C polysaccharide vaccine is given post MenC conjugate vaccine. There is no evidence of a clinically important effect with Meningococcal group C but for pneumococcal disease there may be clinical evidence of an effect, where PPV may give reduced protection from pneumococcal disease. It is difficult to be certain of whether this was the result of PPV vaccination or the result of an immune defect in specific individuals because of existing medical condition(s). Overall, there is a theoretical risk of hyporesponsiveness but clinical data are insufficient to determine whether this is a serious practical issue.

The Group also discussed repeat infection with the same serotype; immunocompromised people contracting uncommon serotypes and a Malawian study showing harmful effects of PPV in people with HIV; RCTs have shown PPV does not have much effect in people with chronic diseases.

The chair summarised the questions concerning children receiving PPV following PCV vaccination and whether it was effective or indeed interfered with the effectiveness of the initial PCV vaccination. Should older people in some or all of the clinical risk groups be given PCV instead of PPV. It was noted that 30-40% of IPD in those aged 5 to 64 years was caused by the PCV7 serotypes but it was not known whether the distribution was the same for individuals with a pre-existing medical condition that predisposed them to pneumococcal disease.

The chair identified as recurring questions: the expected impact of herd immunity, and the efficacy of PPV.

Three groups were identified for consideration:

• At-risk children who have received PCV and are then offered PPV
• Older at-risk age groups not currently recommended PCV who are immunocompetent but who have a long term medical condition
• Older at-risk age groups not currently recommended PCV who are immunocompromised eg HIV

Actions:
1) The Secretariat agreed to undertake a literature review to establish the evidence for use of PCV in these age groups in place of PPV which is currently recommended.

2) The HPA and Oxford Vaccine Group will also look for evidence that the serotype distribution of pneumococcal disease in risk groups is the same as the normal population.

3) The HPA would consider whether it was feasible to follow up cases of IPD in children over 5 years of age to see whether any particular risk groups stood out as being at increased risk and a candidate for PCV recommendation.
The likely additional benefit of direct protection over indirect protection can be estimated once the serotype distribution of pneumococcal disease in these risk groups has been examined. Indirect protection in these age groups would be estimated using either early UK data or US data where the herd immunity effect has already been observed.

5. 5. Use of pneumococcal vaccines during an influenza pandemic

The chair asked the group to address the questions of whether pneumococcal vaccination should be offered more widely in the event of a pandemic to prevent the expected cases of secondary pneumococcal disease following flu. If this was considered an option which vaccine should be offered and which groups should be targeted for vaccination?

The Group discussed the association between flu and pneumococcus - studies in Africa suggest an interaction so there may be some benefit to pneumococcal vaccine use. Two mortality peaks can also be seen for the recent flu pandemics, in which one is likely to be a result of bacterial pneumonia and the other viral pneumonia.

In the UK, there is no way of linking flu and pneumococcal morbidity data. However, rapid flu and pneumococcus diagnostic testing (including serotyping) are being conducted in Leicester and Nottingham but there are no data available yet. The HPA would consider whether they are able to calculate the serotype distribution of pneumococcal disease following primary infection with flu.

There were several opinions on the viability of vaccinating everyone in the event of a pandemic. It was agreed that if a vaccine was to be used then the pneumococcal vaccine that works best should be used - i.e. PCV, although there is reluctance to use it outside of its recommended age group of <5 years. Widespread prophylactic vaccination ahead of a pandemic was not felt to be appropriate. This question should be considered alongside the matter of vaccinating older at-risk groups with PCV. It would be difficult to work out whether the vaccination of clinical risk groups with PCV is cost effective because the life expectancy of these groups is hard to measure. The clinical risk groups recommended pneumococcal vaccination are also medically diverse.

These questions would be re-visited once we know the expected benefits of herd immunity following the routine PCV programme and the additional individual burden of disease left in these individuals that can be attributable to the PCV7 serotypes .

Action:
The HPA would undertake an examination of their existing data to see whether there is information on serotype distribution of pneumococcal disease following influenza infection.

6. Scoping of issues to be addressed at next meeting

The actions to be undertaken by members of the group and the JCVI Secretariat, and to be addressed at the next meeting, have been noted in the relevant sections.

7. Date of next meeting

22 January 2008.

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