MenC and Hib meningitis: responding to JCVI recommended changes

UK’s infant immunisation schedule: our response to the Joint Committee on Vaccination and Immunisation (JCVI) recommendations on MenC and Hib meningitis

In the summer the JCVI published an interim statement on changes to the routine immunisation schedule for children in the UK. This was an important update for meningitis, as it addressed the withdrawal of Menitorix, the vaccine currently given to infants at 12 months to protect against Hib meningitis and Meningococcal Group C disease (commonly known as MenC). Stocks of Menitorix in the UK are anticipated to run out in 2025, meaning recommendations are made now by the JCVI, so they can be adopted and implemented by the UK’s Departments of Health, in England, Wales, Scotland and Northern Ireland.

In the summer we published our initial perspective on the JCVI’s recommended changes. Today we have submitted our formal response, addressing the JCVI proposed changes:

• To offer an additional dose of Hib-containing multivalent vaccine at 12 or 18 months of age

• To bring forward the second dose of measles, mumps and rubella (MMR) vaccine from 3 years 4 months to 18 months of age

• To end direct protection against MenC disease for infants (meaning babies will be reliant on the indirect protection generated from the teenage MenACWY vaccination programme).

Who are the JCVI?

The Joint Committee on Vaccination and Immunisation (JCVI) are an expert group who make recommendations to the UK government about who should receive routine vaccinations and when, with the aim of providing the best possible protection through the smallest number of vaccines, given at the most effective times.

Why is it being proposed that direct protection against MenC is ended?

Evidence from the teenage MenACWY vaccination programme suggest that it is protecting all age groups. How? By preventing transmission of the bacteria amongst the wider population, with the predictive modelling used by the JCVI to inform these recommendations indicating that ending MenC protection for infants would have minimal impact on case numbers.

What we are asking for: high teenage vaccine coverage, disease modelling clarification and maintaining infant MenC vaccination until 2025

As a patient group who represent many thousands of people affected by meningitis, we are using the opportunity to formally respond to these recommendations to:

• Highlight the importance of achieving high MenACWY vaccine coverage rates in teenagers, in order to ensure indirect protection for other age groups.

• Ask for clarification on some of the evidence underpinning the predictive model that these recommendations are based on, and for the model to be published so that the underlying assumptions can be scrutinised.

• Urge the JCVI not to drop direct MenC infant protection before 2025 (when stocks are expected to run out). We believe 2022 – 2025 will be essential to thoroughly test the underlying predictive model assumptions and to closely monitor disease levels as the effects of COVID restrictions diminish.

Read on for our full, formal response to the JCVI to understand more about why we are asking for these three requests.

Meningitis Research Foundation response to JCVI interim advice

We write in reply to the JCVI interim statement published on 5^th August[1] providing the following advice on changes in the UK childhood immunisation schedule as a result of the discontinuation of Menitorix (Hib/MenC) vaccine:

• To offer an additional dose of Haemophilus influenzae type b (Hib)-containing multivalent vaccine at 12 or 18 months of age

• To bring forward the second dose of measles, mumps and rubella (MMR) vaccine from 3 years 4 months to 18 months of age

• To discontinue direct protection against Meningococcal serogroup C (MenC) disease in infants

Meningitis Research Foundation (MRF) would like to thank the JCVI secretariat for making us aware of the proposed changes prior to publication of the interim statement, providing a forum for us to ask questions and for the invitation for us to provide a written response. This response to the JCVI interim statement has also been made publicly available on MRF’s website.

We are pleased to see that an additional dose of Hib containing vaccine has been proposed to replace the dose lost by the discontinuation of Menitorix. A booster dose of Hib containing vaccine is important for maintaining protection against Hib disease, now a very rare cause of meningitis thanks to the success of the UK immunisation programme. The resurgence of Hib disease in France following the removal of the booster Hib dose at 16-18 months of age serves as a reminder of the importance of maintaining a comprehensive schedule in infancy against these bacteria[2]. We are reassured that the JCVI have chosen a replacement vaccine which is appropriate for long term supply.

We are also pleased to see that administration of the MMR vaccine will be brought forward from 3 years 4 months to 18 months of age, to improve coverage of this vaccine. Viral meningitis is an important complication of measles and mumps.

The advice to remove the Hib/MenC vaccine Menitorix without offering replacement of direct protection to infants through an alternative MenC containing vaccine is a cause for concern. Our concerns span the following areas, which we discuss in more detail below:

• MenACWY vaccine coverage gaps and missed opportunities to vaccinate by GPs

• Unpredictability of meningococcal disease and the additional uncertainty caused by COVID-19

• Model reliability and strength of evidence of the underlying assumptions

• The burden of surplus cases which modelling cannot predict

• Undervaluation of the prevention of rare, severe disease in children

MenACWY vaccine coverage gaps and missed opportunities to vaccinate by GPs

As acknowledged in the minutes of the JCVI meeting in June 2022, if infants are to rely solely on indirect protection from MenC through herd immunity, uniformly high uptake rates of the MenACWY adolescent vaccine is critical[3]. Whilst uptake rates of this vaccine have improved since the height of COVID disruptions which involved school closures, there are still patches of low uptake and, as outlined in the June minutes, there is “substantial variation by local authority”. Equality of uptake will be vital to ensure we do not see localised resurgence in disease.

Our helpline has also been receiving calls from freshers’ students who are unable to access the MenACWY vaccine from their GP, despite being eligible by age after missing out on getting the vaccine at school. GPs are contracted to deliver MenACWY vaccine to eligible young people under the statement of financial entitlement as an essential service. However, there is speculation over whether confusion has arisen due to cessation of the enhanced service specification that reimbursed GPs specifically for delivering the freshers meningococcal vaccine programme. In addition, there is a lack of clarity over whether overseas students are eligible for this vaccine now that the enhanced service specification for freshers has ended.

With these concerns in mind, we would like to know what plans there are to address these urgent issues around MenACWY vaccine uptake.

Unpredictability of meningococcal disease and additional uncertainty caused by COVID-19

We have already seen an unexpectedly rapid resurgence of MenB disease in adolescents which has followed an unusual seasonal pattern and indicates that the effects of the easing of COVID-19 restrictions on meningococcal disease are far from predictable.

Additionally, we have seen surprising and unexplained spikes of disease in the past, such as the MenC spike in cases experienced in Yorkshire and the Humber in 2017/18 following removal of the infant dose at 3 months of age. This unexpected spike in cases was considered by the JCVI at the time to be “associated with vaccine coverage of adolescent MenACWY and herd immunity”, but local analysis did not identify any obvious gaps in the teenage programme[4]. The circulating strain was also not considered to be particularly virulent and the spike in cases occurred despite the MenC dose at 1 year still being in place. Case incidents like this illustrate how unpredictable meningococcal disease can be, even with the existing immunisation schedule in place.

We agree with the JCVI that enhanced monitoring from now until 2025 is crucial to establish whether or not the expected herd protection impact of the teenage MenACWY programme is maintained. It would also be prudent to use this additional time to continue to monitor any impacts of dropping to a 1+1 pneumococcal conjugate vaccine (PCV) programme, which also relies heavily on herd protection for its success, before additional vaccine doses are dropped from the schedule. Now that IPD levels in the under 5s have returned to pre-pandemic levels (meeting and sometimes exceeding 2018/19 levels) we would encourage the JCVI to undertake a sub-regional analysis of IPD in infants to assess whether gaps in vaccine coverage have impacted infant disease.

Given the unpredictable nature of meningococcal disease, we would be reassured to hear that the JCVI would be open to re-considering this interim advice and would react swiftly should this become necessary in the run up to 2025.

Model reliability and strength of evidence of the underlying assumptions

The minutes describe that modelling predicts a “small rise in cases” following the change[3]. It has not been possible to comment on all the assumptions underpinning the model because it is currently unpublished. However, we believe that the supporting evidence for some of the assumptions within the model needs further consideration and could contribute to a falsely reassuring picture when it comes to the predicted increase in cases following the removal of the MenC containing vaccine dose at 1 year of age. We outline our concerns about the model assumptions in more detail below.

Mixed evidence supporting carriage effects of MenACWY conjugate vaccines

Studies suggests that there are legitimate questions to ask about the confidence that can be placed in assuming that herd immunity generated from the teenage MenACWY programme will continue to protect infants who have no direct protection:

Mixed evidence supporting carriage effects of MenACWY conjugate vaccines

A recently published randomised controlled trial demonstrated a reduction in carriage of MenW and MenY, whilst not impacting carriage of MenB bacteria[5]. Within this study low carriage rates of MenC were maintained but also doubled (although this was not a statistically significant finding). In contrast, a recent systematic review found no evidence of reduced carriage of vaccine serogroups following immunisation with MenACWY using pooled data from 8 different studies but demonstrated reduced pharyngeal carriage of MenC following monovalent C conjugate vaccines[6]. Likewise, recent research from a study in South Australia found that carriage of MenACWY amongst school leavers immunised with MenACWY was similar to unvaccinated school leavers[7].

Response to adolescent MenACWY in primed versus unprimed children

It was noted that the majority of the current cohort of teenagers would have been primed for MenC in infancy. Previous studies have shown that efficacy was high even if teenagers had not been primed, however the JCVI acknowledged this may be due to carriage priming. Whilst the JCVI noted that this could be checked in a seroprevalence study as to whether a group who hasn’t been primed would have lower antibody levels than equivalent pre-vaccination children, they also note that by this point carriage prevalence would be low enough that a difference in immunogenicity due to priming or lack of would not have a big effect. However, this statement is only true if the model assumptions surrounding continued carriage decline were correct (and as previously stated, the evidence underpinning this is mixed). It is also difficult to draw solid conclusions from seroprevalence studies because whilst a correlate of protection is well established for IMD, it is not for carriage.

Lack of evidence supporting reduced meningococcal carriage in teenagers as a result of COVID-19 restrictions

The June 2022 minutes state that the model predicts fewer cases of meningococcal disease to prevent in 2025 due to the modelled decline in carriage prevalence of MenACWY cases both “due to the current teenage programme with effects from the COVID-19 pandemic accelerating the decline”.

We have already highlighted how evidence on the impact of the MenACWY programme on carriage prevalence is mixed. Now, evidence from South Australia also suggests that COVID-19lockdown measures may not reduce carriage prevalence[7]. The study found that although there was a decrease in disease incidence during and shortly after COVID-19 restrictions were put in place, carriage of meningococcal bacteria in school leavers increased post COVID-19 restrictions compared to before.

Additionally, the UK has recently been experiencing a rapid increase in MenB disease amongst UK adolescents aged 15-19[3] which are equalling levels experienced in this age group in the year 2017/18 (so pre-COVID). There has also been a higher incidence of disease in this age group in the summer months than would usually be expected, suggesting that COVID-19 restrictions have not had a lasting effect on MenB carriage and that effects of COVID-19 may just be adding to the unpredictability of this disease, rather than contributing to continued low levels. In addition, there have been a high level of cases associated with higher education settings in those aged up to 24 years, highlighting the importance of long-lasting protection from MenACWY order to maintain reduced population transmission.

Considering the lack of evidence on any lasting effect of COVID-19 restrictions on carriage prevalence, it will be important to consider models which do not assume any effects from this.

Cross protective effect of Bexsero

Modelling has anticipated a cross-protective effect of Bexsero but did not account for a scenario where Bexsero did not provide protection against MenW IMD. Including an assumption where no protection against MenW was afforded from Bexsero was something the JCVI previously considered to be important due to the possibility of circulating MenW strains downregulating NadA expression, and the emergence of MenW strains with reduced susceptibility to penicillin[8]. Additionally, there are MenC isolates such as those expanding in sub-saharan Africa (ST-10217 clonal complex) that do not possess the NadA gene. Bexsero may not provide cross protection if these strains reach Europe. We would like to see model iterations run with more conservative assumption on cross protectiveness of Bexsero to account for this.

We urge the JCVI to publish their model as soon as possible so that there is transparency around the assumptions included. We would also like to see a detailed sensitivity analysis which fully explores both best and worst-case scenarios in the areas mentioned above.

Surplus cases which modelling cannot account for

Meningococcal strains with increased transmissibility or virulence

Due to the difficulty in predicting the potential introduction of new meningococcal strains that have increased transmissibility or virulence these have not been included in the model. However, removal of direct protection to infants will leave them unprotected against such strains, so it is important to remember that this benefit is unaccounted for in the model.

Increase in cases contracted abroad

In 2019, there were over 3 million visits abroad from UK children aged 0-15. As of 2020 only 18 countries worldwide had an adolescent conjugate MenC containing vaccination programme, which might provide herd protection to visitors to that country. This is compared to 27 countries which deem the threat of endemic disease high enough to offer direct universal MenC protection to young children[9].

When direct MenC protection is dropped, children that leave the UK will not be protected abroad and will have had very little natural exposure to the bacteria. This cohort of susceptible children will increase over time. Cases contracted abroad could still require expensive treatment in the UK and arguably an estimation of numbers of these cases should be included when weighing up the benefits of vaccination.

Undervaluation of the prevention of rare, severe disease in children

Whilst we appreciate that the JCVI have a commitment to spend NHS funds efficiently, we remain concerned that the extra-ordinary effects of this disease are not fully captured in a standard, current cost-effectiveness analysis and that the framework continues to undervalue prevention of this rare, severe disease in children.

The minutes indicate that no formal cost effectiveness analysis took place for the proposed changes, yet despite this, the June 2022 minutes stated that the incremental cost-effectiveness ratio would likely be >£100,000 per QALY. But questions about the fairness of the cost effectiveness framework as it relates to the assessment of vaccines that prevent rare yet severe illness in children have previously been raised and remain unresolved.[10] [11].

There is evidence to suggest the population at large prefers preventive interventions for severe illnesses that affect the youngest in society, and that these preferences are above the weighting given by the standard QALY approach. This is not currently accounted for in standard analyses. Nor is the potential peace of mind afforded by vaccination although CEMIPP recommended that research should be conducted into the potential inclusion of these effects[12]. For other public health interventions which have long lasting health effects, a discount rate of 1.5% has long been used so that the long-term benefits can be appropriately valued and there is a compelling case for applying a 1.5% discount rate for all health interventions. If some, or all, of these factors were considered in the evaluation of meningococcal vaccines their perceived value would substantially increase.

We know that the JCVI is aware of the terrible impact of infections that cause meningitis and septicaemia on children and families. However, some of the consequences of severe cases are difficult to predict and therefore impossible to capture in standard cost effectiveness analysis:

• The tragic death of two-year old Faye Burdett who was too old to receive the MenB vaccine on the NHS ignited the largest public health petition in history, collecting over 800,000 signatures calling for wider access to the vaccine. The petition led to a debate in parliament and commitment from government to invest a considerable sum, suggested to be in the region of £1 million, in symptoms awareness amongst the public and clinicians.

• The case of Kia Gott, who has been left severely disabled as a result of developing MenC disease at 5 months of age following removal of the infant MenC dose, has already generated huge amounts of press attention and has sparked a petition calling for the reintroduction of the vaccine for infants.

• Fatal cases of MenB disease in several teenagers across the country in 2017 led to the Prime Minister calling for a meeting between bereaved families and the Secretary of State for Health and Social Care. As a result of this, a multi-agency working group was set up to address challenges in the recognition, treatment and follow-up for those affected.

The public outcry that we see again and again following cases of meningitis, including multiple petitions calling for wider vaccine access, serve to highlight the strong aversion and horror the public have towards this extraordinary and unpredictable disease, and the fear associated with it. They also make a strong case for incorporating a public preference weighting and the peace of mind benefits of vaccination into the cost effectiveness framework.

Summary

Meningococcal disease is the most feared by parents because it strikes healthy children without warning, is difficult to distinguish from milder self-limiting illnesses in the early stages, causes mutilating injuries and can be fatal within 24 hours.

Thanks to our world class childhood immunisation programme, we are seeing fewer and fewer cases of meningococcal disease in young infants in the UK. This is incredible progress against a disease which once affected in excess of 1,000 children under 5 annually across England. However, it also means that clinicians are becoming increasingly unfamiliar with treating cases of disease which could lead to poorer outcomes. A recent audit of adult treatment guidelines for meningitis in the UK found that none of the cases analysed were treated according to best practice guidelines.[13]

Removing direct protection from MenC in infants is predicted to lead to a small increase in cases. It is reassuring that Menitorix stocks will not run out until 2025, but the interim statement and minutes are unclear about when these changes will come into effect. Given the uncertainties, both in the evidence underpinning the model assumptions and the post COVID landscape, we would strongly urge the JCVI not to drop direct infant protection with MenC prior to 2025 (when stocks are expected to run out). This time is essential to thoroughly test the underlying model assumptions and closely monitor disease levels as the effects of COVID-19 restrictions diminish. Given the unpredictable nature of this disease, we would be reassured to hear that the JCVI are open to re-considering their interim advice and would react swiftly should this become necessary in the run up to 2025.

Whilst there continue to be cases of MenC, MenW and MenY disease amongst UK infants we advocate for the broadest possible protection. Removal of the MenC vaccination in infancy is a missed opportunity to provide even broader protection to infants. Replacing protection with MenACWY in the infant schedule or even MenABCWY (if and when that vaccine becomes available) would maintain resilience against the future introduction of virulent strains and protect UK infants at home and abroad. It would also ensure continued protection against MenW at a time when strains are starting to exhibit signs of antibiotic resistance. Whilst we appreciate that adapting the infant MenB schedule could marginally improve protection in infants through cross protective effects of the vaccine, direct protection via these means is by no means complete. With reduced protection in the most vulnerable age groups the importance of robust surveillance to detect and respond to threats becomes more important than ever.

If infants must rely on indirect protection from the teenage MenACWY programme, it is essential that vaccination uptake in this age group remains high across all locations and educational settings. We are committed to continuing to work with UKHSA on raising awareness of the teenage MenACWY vaccination programme amongst school aged children and the under 25’s, especially university students, to ensure the best protection possible for those vulnerable to this deadly disease.

Vinny Smith, Chief Executive, Meningitis Research Foundation

Further resources

What vaccines are there for meningitis?

Meningococcal Groups ACWY vaccine in the UK and Ireland

Meningococcal Group C vaccine

Meningitis symptoms checker

Our initial perspective on the JCVI’s recommended changes (August 2022)

References

1. JCVI. Joint Committee on Vaccination and Immunisation (JCVI) interim statement on the immunisation schedule for children. 5th August 2022. [cited 2022 August]; Available from: https://www.gov.uk/government/publications/jcvi-interim-statement-on-changes-to-the-childhood-immunisation-schedule/joint-committee-on-vaccination-and-immunisation-jcvi-interim-statement-on-the-immunisation-schedule-for-children.

2. Hong, E., et al., Haemophilus influenzae type b (Hib) seroprevalence in France: impact of vaccination schedules. BMC Infect Dis, 2021. 21(1): p. 715.

3. JCVI. Joint Committee on Vaccination and Immunisation. Minutes from meeting 17th June 2022. [cited 2022 August 2022]; Available from: https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation.

4. JCVI. Joint Committee on Vaccination and Immunisation. Minute of the meeting on 3rd October 2018. [cited 2022 August]; Available from: https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation.

5. Carr, J.P., et al., Impact of meningococcal ACWY conjugate vaccines on pharyngeal carriage in adolescents: evidence for herd protection from the UK MenACWY programme. Clin Microbiol Infect, 2022.

6. McMillan, M., et al., Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis. Clin Infect Dis, 2021. 73(3): p. e609-e619.

7. McMillan, M., et al., Impact of COVID-19 Containment Strategies and Meningococcal Conjugate ACWY Vaccination on Meningococcal Carriage in Adolescents. Pediatr Infect Dis J, 2022.

8. JCVI. Joint Committee on Vaccination and Immunisation. Miunte of the meetign held on 4th and 5th February 2020. [cited 2022 August]; Available from: https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation.

9. Meningitis Research Foundation. Meningitis Progress Tracker. [cited 2019 October]; Available from: https://www.meningitis.org/mpt

10. Cost-Effectiveness Methodology for Immunisation Programmes & Procurements Working Group. Review of Cost-Effectiveness Methodology for Immunisation Programmes & Procurements (CEMIPP). Report presented to the Department of Health 20 July 2016. 2016 [cited 2022 August]; Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/683872/CEMIPP_report_2016__2_.pdf.

11. Department of Health and Social Care. Cost-effectiveness methodology for Immunisation Programmes and Procurements (CEMIPP). The government’s decision and summary of consultation responses. 2019 [cited 2022 August]; Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/807856/CEMIPP_Consultation_Response_1.pdf.

12. Department of Health and Social Care, Cost-effectiveness methodology for vaccination programmes. Consultation on the Cost-Effectiveness Methodology for Vaccination Programmes and Procurement (CEMIPP) Report. 2018.

13. Ellis, J., et al., Clinical management of community-acquired meningitis in adults in the UK and Ireland in 2017: a retrospective cohort study on behalf of the National Infection Trainees Collaborative for Audit and Research (NITCAR). BMJ Open, 2022. 12(7): p. e062698.